Total synthesis of the pentacyclic diterpenoid tropone hainanolidol

Article abstract of DOI:10.1071/CH00124

The total synthesis of the unusual diterpenoid tropone, hainanolidol (1), discovered in the bark of the yew species, Cephalotaxus hainanensis, has been completed in 26 steps from 3,5-dimethylanisole. The intramolecular cyclopropanation reaction of the ary

Full text of DOI:10.1071/CH00124

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 53, 2000
© CSIRO 2000
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Aust. J. Chem., 2000, 53, 819–830
Total Synthesis of the Pentacyclic Diterpenoid
Tropone Hainanolidol
A
A
A
A
Barbara Frey, Adam P. Wells, Frances Roden, Ty Duong Au,
A
A
A,B
David C. Hockless, Anthony C. Willis and Lewis N. Mander
A
Research School of Chemistry, Institute of Advanced Studies, Australian National University, Canberra,
A.C.T. 0200, Australia.
B
Author to whom correspondence should be addressed (e-mail: mander@rsc.anu.edu.au).
The total synthesis of the unusual diterpenoid tropone, hainanolidol (1), discovered in the bark of the yew species,
Cephalotaxus hainanensis, has been completed in 26 steps from 3,5-dimethylanisole. The intramolecular
cyclopropanation reaction of the aryl ring in (30) by means of the rhodium mandelate-catalysed reaction of the
diazoacetyl function was used to assemble the 5/7 ring system of (31), at the same time elaborating a
cycloheptatriene moiety that could be transformed subsequently to the tropone functionality in the target molecule.
While removing the acetal protecting group from (31) an unexpected Mukaiyama–type aldol process was induced
by ZnBr , affording (32), the structure of which was determined by X-ray analysis. With greater care, the aldehyde
2
(33) could be obtained and the desired carbocyclic ring system completed by means of a base-catalysed aldol
reaction with the newly formed hydroxyl being employed subsequently in the formation of the δ-lactone function
in (35). Desilylation, reduction of the C-10 carbonyl function and brief exposure to acid finally afforded (1). This
last step took advantage of the stability of the tropylium ion (40) to provide a ‘thermodynamic sink’ for the reaction
outcome. The synthesis of (1) also constitutes a formal synthesis of the troponoid ether, harringtonolide (2), since
this compound had been obtained previously from (1) by means of a transannular oxidation process. Methodology
for the assembly of the tropone moiety in (1) and (2) was modelled on the simpler bi- and tricyclic systems, (13)
and (22), respectively.
Keywords: Hainanolidol; diterpenoids; Yew bark; tropones; harringtonolide.
LeT.Mlotaan.lSderyntheisofHai anol idol
C
0
1
4
BarbaraFrey, AdamP.Wel ls, FrancesRoden, yT
DuongAu, DavidC. Hockless,AnthonyC.Wil isandLewisN. Mander
Introduction
The diterpenoid tropone, harringtonolide (2), was first
isolated in North America from seeds of Cephalotaxus
harringtonia (Taxaceae) and its structure established by X-
1
ray crystallography. At about the same time, (2) was
independently discovered in the bark of the related Chinese
species Cephalotaxus hainanensis, given the name
2
hainanolide, and found to have anti-neoplastic and anti-
3
viral properties. In C. hainanensis, (2) was accompanied by
the closely related, but biologically inactive carbinol,
hainanolidol (1), the structure of which was established by
conversion into (2) by transannular oxidation with lead tetra-
4
acetate (Scheme 1). More recently, two further tropones of
5
this type (3) and (4) have been discovered in C. fortunei.
In order to explore the chemistry and therapeutic potential
of these unusual compounds, we have pursued a program of
total synthesis that led initially to the preparation of carbinol
6
(10) (R = H) as outlined in Scheme 2. When attempts to
nucleophilic displacement of a suitably activated substituent
attached to C-12. We now report the details of this study
which has culminated in the synthesis of rac.-hainanolidol
(1) and the formal synthesis of harringtonolide by virtue of
convert (10) into (2) by means of an oxidative transannular
process failed, we decided to modify our approach to
incorporate an additional hydroxyl into the side chain with a
view to forming the ether ring in harringtonolide (2) through
Manuscript received 27 September 2000
© CSIRO 2000
10.1071/CH00124
0004-9425/00/100819

820
L. Mander et al.
the conversion (1) → (2). Model studies concerned with the
elaboration of the tropone moiety found in this type of
molecule are also described.
obtain much better yields of (13) when copper(II)
acetoacetate was employed as the cyclopropanation catalyst
(ca 70%), but with all other substrates, rhodium acetate or
11
mandelate gave very acceptable results.
Our initial attempt at tropone formation was effected by
bromination, then base-induced elimination of HBr
following a procedure developed by Scott and Chamberlin.
Results and Discussion
Model Studies on Tropone Formation
12
While developing the main synthetic approaches to (1) and
(2), we also prepared a number of simpler analogues that
were designed to assist in refining the methodology that
would be required to prepare the tropone moiety in the target
molecules. The first of these studies is summarized in
Tropone (18) was obtained satisfactorily in this way,
although we were alarmed to find that a clean sample
displaying all the expected signals in an H n.m.r. spectrum
1
had completely decomposed 10 minutes later, affording a
dark brown solution. Of even greater concern was the
discovery that transformation of alcohol (16) to the
corresponding tropone (19) by this procedure failed
completely. We were relieved to find, however, that simple
treatment of both (13) and (16) with mercury(II) nitrate
furnished the tropones in acceptable yields. Curiously, (18)
prepared in this way was reasonably stable.
7
Schemes 2 and 3. Diazoketone (11), a known compound,
was readily prepared, but its conversion into (12), by
8
rhodium-catalysed
intramolecular
cyclopropanation,
occurred in disappointing yield. Two other major products,
9
10
(14) and (15) , were formed in similar amounts.
Competing CH insertion to give (15) was not unexpected,
while the formation of alkene (14) with concomitant loss of
Before proceeding further it was deemed advisable to
examine these processes on a substrate that incorporated a
methyl group at the cyclopropanation site, given the
potential for a significant perturbation of the various
conversions. Accordingly, diazoketone (20) was prepared
11
ketene also has precedent. Ketone (12) was very prone to
undergo oxidation, especially during chromatography, so
isomerisation to (13) was usually carried out with this and
subsequent examples before attempting resolution of the
product mixture. For this particular series, we were able to
13
from the parent dihydrocinnamic acid and treated with

Total Synthesis of Hainanolidol
821
HCl that are likely to accompany the isolation of acyl
chlorides, has proven to be generally effective for acid-
17
18
sensitive substrates.
Cyclopropanation
rhodium mandelate then furnished an unstable adduct that
was immediately treated with DBU (1,8-
catalysed by
19
Diazabicyclo[5.4.0]undec-7-ene (1,5-5)) to give the slightly
less labile cycloheptatriene (31a) (84% overall yield).
In the expectation that chelation between the silyl ether
and acetal functions would assist in the liberation of the
aldehyde function from the dimethyl acetal group, (31a) was
treated with ZnBr . Initial experiments with this reagent
2
afforded (32a), presumably as
Mukaiyama-like aldol process,
a
consequence of
the structure being
a
20
determined by single-crystal X-ray analysis (Fig. 1). With
more carefully controlled conditions, however, aldehyde
(33a) could be obtained as the major product (61% nett
yield) and subsequent exposure to basic alumina gave the
desired aldol product (34a) (76% yield). Only the equatorial
rhodium acetate. Transformation to (22) proceeded
satisfactorily, as did subsequent treatment with mercury(II)
nitrate to afford tropones (23) and (26) (Scheme 4). Thus
14
encouraged, we returned to the main project.
3α-epimer (δ
3.14 Hz, J 8.7 Hz, J
10.2 Hz, J
3βH
3,2
3,3a 3,OH
Synthesis of Hainanolidol (1)
2.1 Hz) was detected, suggesting that the aldol process was
21
6
under thermodynamic control. Treatment of (34a) with
Intermediate (7) was oxidised with m-chloroperoxybenzoic
K CO in aqueous MeOH furnished lactone (35a) in a very
modest 33% yield, but this could be elevated to 65% by
recycling recovered (34a).
acid in MeOH with a view to forming an α-hydroxy acetal
array from the enol ether function (Scheme 6). A 3:1 mixture
of a hydroxy dimethyl acetal with a γ-lactone-containing
product was obtained, the latter presumably arising from
reaction between the newly introduced hydroxyl and the 3°
ester group. A nOe experiment on this latter compound
indicated that the methyl and acetal groups attached to the
lactone ring were in a trans relationship, and therefore that
the lactone possessed structure (28). The presumed hydroxy
acetal precursor was accordingly assigned structure (27), and
the major epimer structure (29). In the latter case,
lactonization was presumably inhibited by the requirement
for the methyl and acetal groups to adopt an eclipsed
2
3
Unfortunately, as a consequence of the lactonization
step, the TBDMS function was folded into a very hindered
environment, and desilylation proved not to be possible.
The alternative approach, involving removal of the TB-
DMS protecting group from (34a) prior to lactonization,
was examined; however, while the parent diol was readily
obtained, it could not be induced to lactonize, possibly be-
cause of additional hydrogen bonding with the adjacent
hydroxyl. We therefore tried replacing the TBDMS group
22
with the more labile isopropyldimethylsilyl function. The
15
sequence from acetal (29) to (31b) proceeded smoothly,
but aldehyde (33b) was obtained in only 20% yield, and
conformation. Following protection of (29) as its tert-
16
butyldimethylsilyl (TBDMS) ether, the primary methyl
23
so we turned to the diethylisopropylsilyl (DEIPS) pro-
ester was hydrolysed, and then diazoketone (30a) prepared
by treating the sodium carboxylate with Vilsmeier reagent
and adding the reaction mixture directly to an excess of
diazomethane, affording (30a) in 80% overall yield from
(29). This procedure, designed to avoid traces of adventitious
tecting group. Yields previously obtained with the TB-
DMS group could be reproduced for the sequence
(29) → (35c), and then desilylation was effected smoothly
with tetrabutylammonium fluoride (TBAF). There was the

822
L. Mander et al.

Total Synthesis of Hainanolidol
823
(1). Unfortunately, it has not been possible to obtain a sample
of natural hainanolidol for direct comparison. In view of the
2
conversion outlined in Scheme 1, the preparation of (1) also
constitutes a formal synthesis of harringtonolide (2).
Experimental
General
Microanalyses were conducted by the Australian National University
Analytical Services Unit, Canberra. Low resolution EI mass spectra
(70 eV) and high resolution accurate mass measurements were
recorded on a VG Autospec double focussing mass spectrometer.
Infrared spectra were recorded on Perkin-Elmer 683 or 1800 Fourier
1
13
Transform Infrared spectrophotometers. H n.m.r. and C n.m.r.
spectra were recorded on a Varian Gemini 300 spectrometer at 300
MHz and 75.5 MHz respectively. Analytical thin layer chromatography
was carried out on Merck aluminium t.l.c. plates precoated with silica
KG60 F . Flash chromatography was conducted on Merck Kieselgel
254
60 silica gel.
3-(6'-Methoxy-1',2',3',4'-tetrahydro-1’-naphthyl)-1-diazo-propan-2-
one (11)
prospect that the resulting hydroxy ketone (36) might cyclize
A solution of 6'-methoxy-1',2',3',4'-tetrahydro-1’-naphthylacetic acid
to the corresponding hemi-acetal (37), which could then be
(1.6 g, 7.2 mmol) in CH Cl (10 ml) was carefully added to a mixture
2
2
24
deoxygenated
to afford an immediate precursor to
of oxalyl chloride (10 ml) and dimethyl formamide (1 drop). After
stirring at room temperature for 10 min, the mixture was evaporated to
dryness under high vacuum. Benzene (5 ml) was added, and the mixture
again evaporated under high vacuum. The residue was dissolved in
ether and added slowly to a freshly prepared solution of diazomethane
in ether (excess). After 10 min, the yellow solution was passed down a
column of silica to decompose the excess diazomethane. The pale
yellow solution was evaporated to dryness to give 1.75 g of the crude
diazoketone (11). Chromatography on silica gel (hexane/EtOAc, 8:1)
harringtonolide (2), but there was no indication of hemi-
acetal formation.
Steric shielding of the upper face of the cyclopentanone
ring was expected to steer the approach of reagents to the
lower face, and so we were not surprised when reduction of
(36) with sodium borohydride gave diol (38). Clearly, the syn
relationship between the hydroxyls in this diastereomer does
gave pure diazoketone (1.6g, 90% yield), m.p. 84–86°C [Found: C,
not readily allow ether formation by the usual S 2 type of
N
+.
69.0; H, 6.8; N, 11.2%; M , 216.1145. C
H, 6.6; N, 11.5%; C
H N O requires C, 68.8;
14 16 2 2
displacement; however, attempts to reverse the
+
+.
H NO (M -N ) requires M , 216.1150]. υ
14 16 2 2 max
stereochemical outcome by means of a directed reduction
-1 1
2105, 1640, 1610, 1500 cm . H n.m.r. (300 MHz) δ 7.05, d, J 8.4 Hz,
25
using tetramethylammonium triacetoxyborohydride
to
H8'; 6.71, dd, J 2.7, 8.4 Hz, H7'; 6.61, d, J 2.7 Hz, H5'; 5.75, s, CH=N ;
2
3.76, s, OMe; 3.30-3.40, m, H1'; 2.50-2.80, 4H, m; 1.60-1.95, 4H, m.
obtain the preferred 10α-epimer were unproductive. We had
anticipated that this dilemma would probably arise when
deciding to utilize (29) as an intermediate, knowing from
earlier work that we were likely to obtain the 10β-epimer
(38) from reduction of the cyclopentanone moiety. Alcohol
(27) had been our preferred starting material, since it was
expected to lead to 12-epi-(38), but apart from the question
of yield, our attempts to open the lactone ring in (28) and
prepare a silylated derivative of (27) proved to be
impractical.
13
C n.m.r. (75MHz) δ 194.1, C2; 157.5, C6'; 138.2, C4'a; 131.4, C8'a;
129.2, C8'; 113.54, 112.04, C5, C7; 55.1, OMe; 55.0, CH=N ; 48.41,
2
C1'; 33.80, C3; 29.74, 28.22, C2', C4'; 19.47, C3'.
7-Methoxy-1,2,2a,3,4,5,-hexahydro-(8H)-benz[cd]-azulen-1-one (13)
(a) A solution of diazoketone (11) (100 mg) in CH Cl (25 ml) was
2
2
added slowly over 3.5 hr (syringe pump) to a solution of Rh (OAc) (3
2
4
1
mg) in CH Cl (10 ml) at reflux. Analysis of the H n.m.r. spectrum of
2
2
the crude product indicated the formation of a 1 : 1.4:1.5 mixture of the
desired triene (12) with alkene (14) and ketone (15), respectively. When
the red solution was evaporated to dryness, and chromatographed on
silica gel (hexane/EtOAc, 4:1), only (14) and (15) were recovered. In a
repeat experiment, DBU (2 drops) was added to a solution of the crude
In order to bring the synthesis to a conclusion, we
reluctantly decided to postpone the direct synthesis of
harringtonolide (2) and, instead, delete the 10β-hydroxyl in
(38) with a view to preparing hainanolidol (1). We were
reasonably confident that this step could be combined with
formation of the tropone moiety by ionisation of the
protonated alcohol, leading ultimately to hainanolidol (1) via
the tetraene (39) and tropylium ion (40). This expectation
was reinforced by model experiments with (16) and (25) that
furnished (17) and (24), respectively (Schemes 4, 5), the
conversions depending on the intermediate tropylium
moieties to provide a ‘thermodynamic sink’ for the reaction
outcome. When briefly exposed to acid followed by base,
product in CH Cl (10 ml) and after 5 min, the solution washed with
2
2
1M HCl, brine and dried (MgSO ). Chromatography on silica gel
4
(hexane/EtOAc, 4:1) afforded:
10
1
Alkene (14) (9.0 mg), H n.m.r. (300 MHz) δ 7.59, d, J 8.7Hz, H8;
6.72, dd, J 2.7, 8.7 Hz H7; 6.61, d, J 2.7 Hz, H5; 5.33, 4.82, 2×d, J 1.3
Hz, =CH2; 3.79, s, OMe; 2.81, m, 2H, H4; 2.50, m, 2H, H2; 1.85, m,
2H, H3.
+.
Triene (13) (11 mg) (Found: M , 216.1150. C
H O requires
14 16 2
+.
1
M , 216.1150). H n.m.r. (300 MHz) δ 5.95, dd, J 6.1, 8.5 Hz, H9; 5.27,
br s, H6; 3.59, s, OMe; 3.19, ddd, J 2.3, 8.5, 13.5 Hz, H8; 2.80-2.95, m,
H2a; 2.73, dd, J 7.9, 17.8 Hz, H2; 2.45-2.55, 2H, m, H5, H'5; 2.20, dd,
J 6.1, 13.5 Hz, H8'; 2.10, dd, J 8.7, 17.8 Hz, H’2; 1.95-2.05, 2H, m;
13
1.60-1.80, 1H, m; 1.15-1.30, 1H, m. C n.m.r. (75MHz) δ 205.9, C1;
1
(38) afforded in ca. 50% yield, a product with H n.m.r. and
146.7, C7; 135.9, 134.4, 127.4, C5a, 9a, 9b;115.2, C9; 101.1, C6; 56.1,
OMe; 45.9, C2a; 35.8, 32.6, C2, C8; 30.9, 29.6, C3, C5; 22.5, C4. Mass
2
mass spectral data matching those reported for hainanolidol

824
L. Mander et al.
spectrum m/z 216 (M, 100%), 201 (17), 188 (58), 174 (40), 160 (30),
1-Hydroxy-1,2,2a,3,4,5-hexahydro-(7H)-benz[cd]azulen-7-one (19)
145 (30), 128 (36), 115 (58), 91 (43).
A solution of hydroxytriene (16) (9.3 mg, 0.0887 mmol) in acetonitrile
(5 ml) and water (1 ml) was treated with Hg(NO3)2 (20 mg) and stirred
under nitrogen at room temperature for 5 min. The solution was
quenched in water (1 ml) and extracted with CH Cl (2 × 2 ml). The
9
+.
Ketone (15) (19 mg), m.p. 64-66°C (lit. 67-69°C) (Found: M ,
+.
1
216.1150. C
H O requires M , 216.1150). H n.m.r. (300 MHz) δ
14 16 2
7.01, d, J 8.5 Hz, H8; 6.73, dd, J 2.7, 8.5 Hz, H7; 6.64, d, J 2.7 Hz, H5;
2
2
13
3.79, s, OMe; 3.48, m, 1H, H8b. C n.m.r. (75MHz) δ 218.7, 157.8,
organic phase was dried over MgSO4 and evaporated to dryness to give
11 mg of a pale yellow solid. This crude material was purified by
preparative t.l.c. on silica gel (EtOAc/chloroform, 1:1, plus 5% MeOH)
136.9, 130.3, 130.1, 113.5, 112.6, 55.2, 45.6, 45.1, 37.9, 34.9, 29.0,
24.4. Mass spectrum m/z 216 (M, 65%), 173 (100), 159 (40), 144 (13),
128 (18), 115 (34), 13 (103), 91 (22).
(b) A solution of diazoketone (11) (30 mg) in 1,2-dichloroethane
(1 ml) was added slowly to a solution of Cu(acac) (3 mg) in 1,2-
dichloroethane (1 ml) at reflux. The red solution was evaporated to
dryness, and chromatographed on silica gel (hexane/EtOAc, 4:1) to
give 20 mg of the unstable triene (13) (75% yield).
+.
to give 3.3 mg (31% yield) of tropone (19). (Found: M , 202.0992.
+
1
C
H O requires M , 202.0994). H n.m.r. (300 MHz) δ 7.28, 1H, d,
13 14 2
2
J 11.6 Hz; 6.90, 1H, d, J 11.6 Hz; 6.87, 1H, s; 4.92, 1H, m; 3.35–3.75,
1H, br s; 2.50–2.75, 4H, m; 2.05–2.15, 1H, m; 1.70–1.90, 2H, m; 1.40–
13
1.60, 1H, m; 1.15–1.35, 1H, m. C n.m.r. (75MHz) 186.9, 149.3,
147.7, 147.6, 139.9 (2×C), 133.7, 76.1, 42.6, 41.3, 32.7, 28.5, 21.9.
7-Methoxy-1,2,2a,3,4,5,-hexahydro-(8H)-benz[cd]-azulen-1-ol (16)
4-(2',6'-Dimethyl-4'-methoxyphenyl)-1-diazobutan-2-one (20)
A solution of the crude trienone (13) (600 mg) in MeOH (50 ml) was
Dimethylformamide (1 drop) was added to oxalyl chloride (6.25 ml,
0.072 mol) and stirred under nitrogen. The mixture was treated with a
solution of 3-(2',6'-dimethyl-4-methoxyphenyl)-propanoic acid
treated with NaBH (100 mg) at 0 °C for 30 min. The solution was
4
diluted with 0.1 M HCl in brine, and extracted thoroughly with EtOAc.
The organic phase was dried over MgSO4 and evaporated to give a pale
yellow oil (635 mg, 88%). Chromatography on silica gel (hexane/
EtOAc, 4:1) gave 410 mg (60% over two steps) of the unstable alcohol
13
(1.00 g) in CH Cl . The reaction mixture was allowed to evaporate
2
2
under a flow of nitrogen with the aid of a warm water bath then placed
under a high vacuum. Benzene (2 ml) and ether (100 ml) were added to
the reaction mixture, the resulting solution then added slowly to a
solution of diazomethane and stirred for 15 h. The mixture was then
filtered through a silica gel column, eluting with ether, and evaporated
to dryness. Diazoketone (20) was obtained as a yellow solid, m.p. 55–
+.
+.
1
(16) (Found: M , 218.1310. C
H O requires M , 218.1307). H
14 18 2
n.m.r. (300 MHz) 5.30, m, H9; 5.02, s, H6; 4.58, dd, J 6.7, 8.5 Hz, H1;
3.51, s, OMe; 2.88, ddd, J 2.2, 8.4, 14.0 Hz, H8; 2.30-2.50, 6H, m; 1.97-
13
2.08, 1H, m; 1.40-1.60, 1H, m; 1.00-1.25, 2H, m. C n.m.r. (75MHz)
148.5, C7; 145.8, C9a, 134.7, 131.6, C5a, C9b; 110.3, C9; 99.4, C6;
72.6, C1; 55.4, OMe; 44.2, C2a; 38.2, 32.1, 31.3, 29.5, 22.5, C4.
+.
56°C (812 mg, 75% yield) (Found: C, 67.6; H, 7.2; N, 11.9%; M ,
+.
232.1212. C
H
N O requires C, 67.2; H, 6.9; N, 12.1%; M ,
13 16
2 2
–1
1
232.1212). υ
2105, 1640, 1610, 1585 cm . H n.m.r. (300 MHz) δ
6.58, 2H, s, H3’, H5’; 5.25, br s, H1; 3.75, s, OMe; 2.93–2.87, 2H, m,
H4; 2.44–2.42, 2H, m, H3; 2.30, 6H, s, CH3. C n.m.r. (75 MHz) δ
max
1,2,2a,3,4,5-Hexahydro-(7H)-benz[cd]azulen-7-one (17)
13
A solution of the hydroxy triene (16) (55 mg, 200 µmol) in
tetrahydrofuran (THF, 1 ml) was treated with 100 µl of concentrated
HCl. After 10 min at room temperature, the mixture was quenched with
saturated bicarbonate solution, and extracted thoroughly with EtOAc.
The organic layer was dried over MgSO4 and evaporated to dryness to
give 45 mg (95%) of the crude material. Preparative t.l.c. on silica gel
(EtOAc/chloroform, 1:1, plus 4% MeOH) gave the unstable tropone
194.2, 157.4, 137.3, 129.3, 113.5, 54.9, 54.2, 40.2, 24.2, 19.9.
6-Methoxy-4,8-dimethyl-2,3-dihydro-1(8aH)-azulenone (21)
A solution of diazoketone (20) (800 mg, 3.448 mmol) in dry CH Cl
2
2
(100 ml) was added slowly to a flask containing rhodium(II) acetate in
dry CH Cl (20 ml) under nitrogen. The reaction mixture was heated
1
2
2
(17) in 50% yield (23 mg). H n.m.r. (300 MHz) δ 7.10, 1H, d, J 11.9
gently under reflux for 15 min, then the solvent was removed under
reduced pressure to afford an unstable green oil which was used directly
Hz; 6.90, 1H, d, J 11.9 Hz; 6.89, 1H, s; 1.50–3.00, 10H, m; 1.20–1.35,
13
1H, m. C n.m.r. (75MHz) δ 186.9, 149.7, 147.7, 146.6, 139.5, 139.1,
–1
1
in the following experiments. υ
1740, 1630 cm
.
H n.m.r.
max
135.1, 46.4, 36.4, 33.1, 31.9, 28.2, 22.6.
(300 MHz) δ 5.81, s, H7; 5.67, s, H5; 3.61, s, OMe; 2.84–2.52, 5H, m;
13
1.86, s, Me; 1.83, s, Me. C n.m.r. (75 MHz) δ 218.7, C1; 157.8, C6;
1-Oxo-1,2,2a,3,4,5-hexahydro-(7H)-benz[cd]azulen-7-one (18)
131.9, 126.4, 125.3, C3a, C4, C8; 120.3, C7; 107.6, C5; 54.6, OMe;
54.3, C8; 38.9, C2; 25.7, C2; 19.8, 18.2, 4-Me, 8-Me.
(a) A solution of triene (13) (23 mg, 0.106 mmol) in THF (1.0 ml) at
–78°C under an atmosphere of nitrogen was treated with a solution of
N-bromosuccinimide (20.3 mg) in MeOH (5 ml) also cooled to –78°C
and stirred for one h. Hunig’s base (0.2 ml) was added and stirring
continued at –78°C for 20 min. After evaporation of solvent the res-
6-Methoxy-4,8-dimethyl-2,3-dihydro-1(7H)-azulenone (22)
A solution of crude ketone (21) in CH Cl (50 ml) under nitrogen was
2
2
treated with 200 µl of DBU. The reaction was quenched with pH 7
phosphate buffer (10 ml) and the organic layer washed with brine, then
dried over MgSO4 and evaporated to dryness to give 700 mg of an
orange–brown oil. Chromatography on silica gel (pentane/EtOAc, 2:1),
idue was extracted with carbon tetrachloride, again reduced to dryness
+
and the residue dissolved in CH Cl (3 ml). Dowex 50 (H ) resin (ca
2
2
3.0 g) was added and the mixture stirred for 2 h, filtered and reduced
1
to dryness, affording a yellow solid (20.3 mg). A H n.m.r. spectrum
+.
afforded ketone (22) (287 mg, 41% yield) as a yellow solid (Found: M ,
indicated that this material was ca 90% tropone (18). Chromatography
on silica gel (hexane/EtOAc, 1:2) led to extensive loss of material.
(b) A solution of methoxytriene (13) (150 mg, 0.69 mmol) in
acetonitrile (7 ml) and water (1.5 ml) was treated with Hg(NO3)2 (225
mg, 0.69 mmol) and stirred under nitrogen at room temperature for
5 min. The solution was quenched in water (1 ml) and extracted with
CH Cl (2 × 2 ml). The organic phase was dried over MgSO4 and
+.
204.1150. C
H
O requires M , 204.1150). υ
1700, 1630, 1605
13 16
2
max
–1
1
cm . H n.m.r. (300 MHz) δ 5.32, s, H5; 3.59, s, OMe; 2.75, 2H, dd,
6.7, 7.2 Hz, H2; 2.51, 2H, dd, 6.7, 7.2 Hz, H3; 2.46, 2H, s, H7; 2.42, s,
8-Me; 2.07, 4-Me. C n.m.r. (75 MHz) 208.0, C1; 145.0, C6; 135.9,
13
C8; 133.6, 132.3, 130.4, C3a, C4, C8a; 101.5, C5; 56.1, OMe; 41.8, C7;
37.8, C2; 24.6, C3; 20.7, 20.4, 4-Me, 8-Me. Mass spectrum m/z 204 (M,
98%), 189 (55), 161 (67), 147 (20), 131 (30), 119 (87), 105 (35), 91
(100).
2
2
evaporated to dryness to give 221 mg of a pale yellow solid. A portion
of this crude material (28 mg) was purified by preparative t.l.c. on silica
gel (EtOAc/chloroform, 1:1, plus 5% MeOH) to give 5.0 mg (18%
2,3-Dihydro-4,8-dimethyl-6-oxo-1(6H)-azulenone (23)
+.
+
yield) of tropone (18). (Found: M 200.0834. C
H O requires M ,
13 12 2
1
200.0837). H n.m.r. (300 MHz) δ 7.38, 1H, d, J 11.6 Hz, H8; 7.01, 1H,
m, H6; 6.98, ddd, J 1.1. 2.7, 11.6 Hz, H8; 3.08, 1H, m, H2a; 2.86, dd, J
7.0, 19.1 Hz, H2; 2.84, 1H, m, H5; 2.68, 1H, m, H’5; 2.30, 1H , m; 2.21,
dd, J 4.0, 19.1 Hz, H’2; 1.90–1.80, 1H, m; 1.42–1.30, 1H, m; 1.15–1.35,
1H, m. C n.m.r. (75MHz) δ 204.9, 187.3, 167.9, 146.2, 142.7, 140.0,
136.8, 128.9, 41.3, 37.4, 36.8, 27.1, 20.8.
A solution of the ketone (22) (20 mg, 0.098 mmol) in acetonitrile (5 ml)
and water (1 ml) was treated with Hg(NO3)2 (31.8 mg) and stirred under
nitrogen at room temperature for 5 min. The solution was quenched
with water (1 ml) and extracted with CH Cl (2 × 2 ml). The organic
2
2
13
phase was dried over MgSO4 and evaporated to dryness to give 32 mg
of a gum. This crude material was purified by preparative t.l.c. on silica

Total Synthesis of Hainanolidol
825
gel (EtOAc/chloroform, 1:1) with 5% MeOH) to give 5.0 mg (27%
The mixture was warmed to 10°C overnight and then treated with
+.
+.
yield) of tropone (23) (Found: M , 188.0837. C
H
O requires M ,
dimethyl sulfide (1 ml) and CH Cl . The solution was washed with sat.
12 12
2
2 2
–1
1
188.0837). υ
1710, 1620, 1600 cm . H n.m.r. (300 MHz) 7.06,
aq NaHCO , dried (MgSO ), filtered and concentrated under reduced
3 4
max
1H, d, J 2.3 Hz; 6.81, 1H, d, J 2.3 Hz; 2.97–2.94, 2H, m; 2.61–2.58, 2H,
pressure. Chromatography on silica gel (hexane/EtOAc, 1 : 1) afforded
the starting enol ether (7) (112 mg, 8% recovery) in addition to a more
polar component. This was rechromatographed (hexane/EtOAc, 2:1) to
give γ-lactone (28) (255 mg, 20% at 92% conversion) as an oil which
crystallised on standing. Recrystallisation (EtOAc/pentane) gave white
13
m; 2.55, 3H, s; 2.33, 3H, s. C n.m.r. (75 MHz) 207.1, C1; 186.2, C6;
166.6, C3a; 143.7, 140.5 C5, C7; 144.0, 143.6, 140.5, C4, C8, C8a;
34.4, C2; 28.8, C3; 24.0, 23.3, 4-Me, 8-Me. Mass spectrum m/z 188 (M,
16%), 160 (80), 145 (12), 132 (29), 117 (100), 103 (13), 91 (40).
needles, m.p. 143°C (Found: C, 64.65; H, 7.69%. C
H
O requires C,
22 30
7
1,2-Dihydro-4,8-dimethyl-6-methoxy-1(7H)-azulen-1-ol (25)
65.01; H, 7.44%). R 0.19 (hexane/EtOAc, 2:1). υ
(KBr) 2934s,
f
max
2914s, 2842s, 1768 (CO, s), 1728 (CO, s), 1613s, 1587s, 1280s, 1199s,
A solution of the ketone (22) (513 mg, 2.51 mmol) in MeOH (20 ml)
and THF (5 ml) under nitrogen was cooled to 0°C. CeCl3.H2O and
–1
1
1174s, 1111s, 1084s cm . H n.m.r. δ (300 MHz, CDCl ) 6.59, 6.43,
3
2×1H, 2×d, J
2.5 Hz, H5’, H7’; 4.40, 1H, d, J 5.0 Hz, H6; 3.96,
5’,7’
6,5
NaBH4 (95 mg) were added to the mixture, whereupon H gas evolved.
2
1H, dd, J 9.1 Hz, J 5.0 Hz, H5; 3.73, 3.70, 2×3H, 2×s, 6’-OMe, 9’-
5,4
5,6
The reaction was allowed to proceed for 10 min before being quenched
in 0.1 M HCl (10 ml), extracted with ether (×3) and washed with brine.
The extract was then dried over MgSO4 and evaporated to dryness,
giving the crude product (410 mg, 80%). Purification using a silica gel
column (hexane/EtOAc, 4:1) gave the bright yellow triene (25) (30 mg,
CO Me; 3.69, 1H, obscured m, H1’; 3.48, 3.47, 2×3H, 2×s, 2×6-OMe;
2
2.87–2.82, 2H, m, H4’; 2.74, 1H, dd, J
18.1 Hz, J
9.2 Hz, H9’;
gem
9’,11
2.65, 1H, m, H4; 2.28, 1H, partially obscured dd, J
18.1 Hz, J
9’,1’
gem
1.9 Hz, H’9’; 2.25, 3H, s, 8’-Me; 2.00, 1H, m, H3’; 1.79, 1H, m, H’3’;
13
1.13, 3H, d, J
6.8 Hz, 4-Me. C n.m.r. δ (75 MHz, CDCl ) 177.2,
+.
+.
4-Me, 4
3
25% yield) (Found: M , 206.1304. C
H O requires M , 206.1306).
13 18 2
C2; 172.7, CO Me; 157.0, C6’; 136.4, 135.5, C4a’, C8’; 130.0, C8a’;
–1
1
2
υ
3600, 1630, 1550 cm . H n.m.r. (300 MHz) δ 5.13, s, H5; 4.81,
max
115.1, 110.2, C5’, C7’; 105.4, C6; 80.9, C5; 56.2, 55.8, 54.8, 2×6-OMe,
t, J 3 Hz, H1; 3.53, s, OMe; 2.77–2.72, 1H, m, H3; 2.61, d, J 12.9, 1.7
Hz, H7; 2.46, dt, J 15.9, 5.4 Hz, H’3; 2.14, d, J 12.9 Hz, H’7; 2.00, s,
6’-OMe; 51.7, CO Me; 47.0, C3; 39.7, C1’; 38.4, C9’; 37.1, C4; 26.4,
2
+
20.4, C4’, C3’; 19.0, 8’-Me; 12.5, 4-Me. Mass spectrum m/z 406 (M ,
6%), 343 (6), 311 (5), 287 (7), 269 (6), 257 (12), 225 (6), 201 (17), 186
(6), 172 (8), 128 (9), 91 (5), 75 (100), 62 (8).
Further elution afforded hydroxy ester (29) (846 mg, 61% at 92%
conversion) as a yellow solid. recrystallisation (EtOAc/pentane) gave
off-white mixed crystals, m.p. 140–142°C (Found: C, 62.84; H, 8.08%.
13
Me; 1.94, s, Me; 1.89–1.82, 2H, m, H2, H'2. C n.m.r. (75 MHz) δ
147.4, C6; 139.3, 133.74, 129.25, 121.1, C3a, C4, C8, C8a; 100.6, C5;
73.7, C1; 55.5, OMe, 39.0, C7; 32.9, C2; 28.7 C3; 21.7, 21.2, 4-Me, 8-
Me. Mass spectrum m/z 206 (M, 100%), 191 (70), 173 (53), 162 (95),
147 (35), 128 (30), 119 (55), 105 (40), 91 (83).
C
H O requires C, 63.00; H, 7.81%). R 0.11 (hexane/EtOAc, 2:1).
22 34 8 f
2,3-Dihydro-3-hydroxy-4,8-dimethyl-6(1H)-azulen-1-ol (26)
υ
(KBr) 3517 (OH, s), 2999s, 2953s, 2934s, 2853s, 1742 (CO, s),
max
A solution of hydroxytriene (25) (18.3 mg, 0.0887 mmol) in acetonitrile
(5 ml) and water (1 ml) was treated with Hg(NO3)2 (34 mg) and stirred
under nitrogen at room temperature for 5 min. The solution was
1729 (CO, s), 1606s, 1591s, 1470s, 1454s, 1430s, 1225s, 1147s, 988s
–1
1
cm
. H n.m.r. δ (300 MHz, CDCl ) 6.44, 6.38, 2×1H, 2×d, J
3 5,7
2.5 Hz, H5, H7; 4.33, 1H, br dd, J 6.8 Hz, J 2.5 Hz, H2'; 4.24, 1H,
d, J
9-CO Me; 3.48, 3.41, 2×3H, 2×s, 1'-OMe, 2-CO Me; 3.31, 3H, s, 1'-
OMe; 3.01, 1H, d, J
1',2'
2',3'
quenched in water (1 ml) and extracted with CH Cl (2 × 2 ml). The
2
2
6.8 Hz, H1'; 4.10, 1H, m, H1; 3.68, 3H, s, 6-OMe; 3.53, 3H, s,
1',2'
organic phase was dried over MgSO4 and evaporated to dryness to give
32 mg of a pale yellow solid. This crude material was purified by
preparative t.l.c. on silica gel (EtOAc/chloroform, 1:1, plus 5% MeOH)
2
2
2.7 Hz, OH; 2.86, 2H, m, H4; 2.78, 1H, dd,
OH,2'
J
14.3 Hz, J 3.8 Hz, H9; 2.57, 1H, m, H3α; 2.24, 3H, s, 8-Me;
gem
9,1
+.
to give 5.3 mg (31% yield) of tropone (26). (Found: M , 190.0993.
2.18, 1H, dd, J
dt, J
14.3 Hz, J 9.5 Hz, H’9; 2.01, 1H, m, H3'; 1.56, 1H,
9,1
gem
+.
–1 1
C
H
O requires M , 190.0994). υ
2950, 1620 cm . H n.m.r.
14.2 Hz, J
7.3 Hz, J
7.3 Hz, H3β; 0.95, 3H, d, J
12 14
2
max
3β,3α
3β,4α
3β,4β 3',4'
13
(300 MHz) δ 6.87, 6.85, 2×s, H5, H7; 5.16, d, J 6.2 Hz, H1; 3.10, ddd,
J 19.0, 8.2, 8.2 Hz, H3; 2.81, 1H, ddd, J 19.0, 9.0, 2.4 Hz, H’3; 2.40, s,
Me; 2.19, s, Me; 2.16, m, H2; 1.94, m, H’2. C n.m.r. (75 MHz) δ
7.1 Hz, 3'-Me. C n.m.r. δ (75 MHz, CDCl ) 176.5, 172.6, 9-CO Me,
2-CO Me; 157.5, C6; 137.1, 136.9, C4a, C8; 129.8, C8a; 113.5, 110.8,
C5, C7; 105.5, C1'; 68.6, C2'; 55.6, 54.1, 2×1'-OMe; 54.7, 6-OMe; 53.1,
C2; 51.6, 51.5, 9-CO Me, 2-CO Me; 39.2, C3'; 35.6, C1; 35.3, C9;
25.9, 25.4, C4, C3; 19.2, 8-Me; 8.6, 3'-Me. Mass spectrum m/z 438
(M , 16%), 406 (M MeOH, 26), 362 (15), 333 (21), 304 (27), 273
(13), 259 (7), 232 (14), 201 (36), 173 (18), 129 (7), 101 (14), 75 (100).
3
2
2
13
186.2, C6;149.0, 146.5, 145.7, 145.4, C3a, C4, C8, C8a; 140.8, 140.3,
C5, C7; 79.2, C3; 34.9, C2; 31.5, C-3; 21.7, 21.1, 4-Me, 8-Me. Mass
spectrum m/z 190 (M,15%), 161 (29), 147 (100), 129 (27), 115 (15),
105 (23), 91 (28).
2
2
+
+ -
2,3-Dihydro-4,8-dimethyl-6(1H)-azulenone (24)
A solution of hydroxytriene (25) (20 mg, 0.097 mmol) in THF (1 ml)
was treated with conc. HCl (100 µl) and stirred at room temperature for
10 min. The solution was quenched with saturated bicarbonate solution
and extracted thoroughly with EtOAc. The organic phase was dried over
MgSO4 and evaporated to dryness to give 33 mg of an orange gum. This
crude material was purified by preparative t.l.c. on silica gel (EtOAc/
chloroform, 1:1 plus 5% MeOH) to give 8.6 mg (50% yield) of tropone
Methyl (1SR, 2SR, 1'SR, 2'RS)-6-methoxy-2-(1,1-dimethoxy-2'-t-
butyldimethylsilyloxy-but-3'-yl)-1-methoxycarbonylmethyl-8-methyl-
1,2,3,4-tetrahydro-2-naphthoate
A solution of hydroxy acetal (29) (846 mg, 1.93 mmol) in CH Cl (85
2
2
ml) was treated with TBDMS-triflate (1.00 ml, 4.35 mmol) and 2,6-di-
t-butyl-4-methylpyridine (2.00 g, 9.74 mmol). The mixture was stirred
+.
+.
(24) (Found: M , 174.1044. C
H O requires M , 174.1044). υ
12 14 max
at room temp. for 24 h and then diluted with sat. NaHCO and extracted
3
1 1
1620 cm- . H n.m.r. (300 MHz) δ 6.90, 2H, s, H5, H7; 2.90 4H, t, J 7.8
with Et O. The combined organic layers were washed with brine, dried
2
13
Hz, H1, H3; 2.20, 6H, s, 2×Me; 1.94–1.89, 2H, m, H2. C n.m.r. (75
(MgSO ), filtered and concentrated under reduced pressure.
4
MHz) δ 186.0, C6; 147.4, 145.3, C3a, C4, C8, C8a; 139.5, C5, C7; 37.7,
C1, C3; 25.7, C2; 21.1, 2×Me.
Chromatography on silica gel (hexane/EtOAc, 4:1) gave the silyl ether
(874 mg, 82%) as an oil. (Found: C, 63.22; H, 9.04%. C
H
O Si
29 48
8
requires C, 63.01; H, 8.75%). R 0.57 (hexane/EtOAc, 2:1). υ
(film)
f
max
Methyl (4SR, 5SR, 1'SR, 2'SR)-3',4,4',5-Tetrahydro-6'-methoxy-5-
(dimethoxymethyl)-4,8'-dimethyl-2-oxospiro[furan-3(2H),2'(1'H)-
naphthalene]-1'-acetate (28) and Methyl (1SR, 2SR, 2'RS, 3'SR)-2-(1,1-
dimethoxy-2'-hydroxy-but-3'-yl)-6-methoxy-8-methyl-1-
2951s, 2930s, 2855s, 1737 (CO, br, s), 1613s, 1587s, 1463s, 1433s,
–1 1
1255s, 1192s, 1162s, 1115s, 1090s, 1069s cm . H n.m.r. δ (300 MHz,
CDCl ) 6.45, 6.39, 2×1H, 2×d, J 2.5 Hz, H5, H7; 4.37, 1H, br d, J
3
5,7
1',2'
3.6 Hz, H2'; 4.22, 1H, d, J
3.6 Hz, H1'; 3.96, 1H, br dd, J 10.1 Hz,
1',2'
1,9
methoxycarbonylmethyl-1,2,3,4-tetrahydro-2-naphthoate (29)
J
1.7 Hz, H1; 3.70, 3H, s, 6-OMe; 3.52, 3H, s, 9-CO Me; 3.46, 3.44,
1,3β
2
A solution of enol ether (7) (1.34 g, 3.44 mmol) in absolute MeOH
(200 ml) was cooled to –5°C (ice–salt bath) and treated with m-
chloroperoxybenzoic acid (mcpba) (50–55%, 1.90 g, ca. 5.77 mmol).
2×3H, 2×s, 2-CO Me, 1'-OMe; 3.24, 3H, s, 1'-OMe; 2.97, 1H, br dd,
J
2.20, 3H, s, 8-Me; 2.26–2.12, 2H, m, H'9, H3'; 1.56, 1H, m, H3β; 0.99,
2
14.3 Hz, J 3.5 Hz, H9; 2.89–2.84, 2H, m, H4; 2.44, 1H, m, H3α;
9,1
gem

826
L. Mander et al.
3H, d, J
7.1 Hz, 3'-Me; 0.88, 9H, s, OSiMe ; 0.13, 6H, s, OSiMe .
H3α; 2.30, 3H, s, 8-Me; 2.22–2.12, 2H, m, H'9, H3'; 1.65, 1H, m, H3β;
3',4'
3
2
13
C n.m.r. δ (75 MHz, CDCl ) 174.5, 173.4, 9-CO Me, 2-CO Me;
157.4, C6; 137.1, 137.0, C4a, C8; 131.0, C8a; 113.5, 111.0, C5, C7;
108.5, C1'; 70.4, C2'; 56.5, 55.7, 2×1'-OMe; 54.8, 6-OMe; 53.5, C2;
51.3, 51.2, 9-CO Me, 2-CO Me; 39.2, C3'; 36.3, C1; 35.0, C9; 26.1,
1.00, 3H, d, J
7.0 Hz, 3'-Me; 0.87, 9H, s, OSiCMe ; 0.14, 0.12,
3
2
2
3',4' 3
13
2×3H, 2×s, OSiMe . C n.m.r. δ (75 MHz, CDCl ) 179.3, CO H;
2 3 2
174.5, CO Me; 157.4, C6; 137.1, one peak overlapping, C4a, C8;
2
130.8, C8a; 113.6, 111.0, C5, C7; 108.6, C1'; 70.4, C2'; 56.8, 55.7,
2
2
OSiCMe ; 25.9, 25.3, C4, C3; 19.3, 8-Me; 18.5, OSiCMe ; 11.1, 3'-
2×1'-OMe; 54.8, 6-OMe; 53.5, C2; 51.3, CO Me; 39.2, C3'; 36.0, C1;
3
3
2
+
+-
Me; –3.1, –4.8, OSiMe . Mass spectrum m/z 552 (M , 4%), 551 (M H,
35.1, C9; 26.1, OSiCMe ; 25.9, 25.3, C4, C3; 19.3, 8-Me; 18.5,
2
3
+–
13), 495 (4), 389 (6), 368 (16), 313 (13), 285 (8), 257 (9), 215 (23), 185
(9), 129 (31), 111 (22), 83 (47), 57 (100).
OSiCMe ; 11.2, 3'-Me; –3.1, –4.9, OSiMe . m/z 521 (M OH, 6%),
3 2
495 (17), 477 (32), 431 (22), 389 (29), 357 (26), 311 (22), 273 (22), 255
(17), 232 (29), 215 (84), 143 (34), 115 (31), 75 (100).
Methyl (1SR, 2SR, 1'SR, 2'RS)-6-methoxy-2-(1,1-dimethoxy-2'-
dimethylisopropylsilyloxy-but-3'-yl)-1-methoxycarbonylmethyl-8-
methyl-1,2,3,4-tetrahydro-2-naphthoate
Methyl (1SR, 2SR, 1'SR, 2'RS)-1-carboxymethyl-6-methoxy-2-(1,1-
dimethoxy-2'-dimethylisopropylsilyloxy-but-3'-yl)-8-methyl-1,2,3,4-
tetrahydro-2-naphthoate
This compound was prepared by the procedure described above for the
1
TBDMS ether. H n.m.r. δ (300 MHz, CDC1 ) 6.46, 6.38, 2×1H, 2×d,
This compound was prepared by the procedure described above for the
3
1
J
, J 2.5 Hz, H5, H7; 4.30, 1H, d, J 6.1 Hz, H2'; 4.13, 1H, d, J
TBDMS ether. H n.m.r. δ (300 MHz, CDCI ) 6.48, 6.39, 2×1H, 2×d,
5,7 7,5
1',2'
1',2'
3
6.1 Hz, H1'; 4.06, 1H, br dd, J 9.5 Hz, J 2.8 Hz, H1; 3.70, s, 3H, 6-
J
J
J
2.5 Hz, H5, H7; 4.30, 1H, br d, J + 5.5 Hz, H2'; 4.13, 1H, d,
1,9
1,9
5,7 7,5 1',2'
OMe; 3.53, 3H, s, 9-CO Me; 3.44, 3.42, 2×3H, 2×s, 2-CO Me; 3.44,
5.5 Hz, H1'; 4.06, 1H, br dd, J 9.4 Hz, J 2.5 Hz, H1; 3.71, 3H,
2
2
1',2'
1,9 1,9
3.42, 2×3H, 2×s, 2-CO Me, 1'-OMe; 3.29, 3H, s, 1'-OMe; 2.87–2.80,
s, 6-OMe) 3.44, 3.39, 2×3H, 2×s, 2-CO Me, 1'-OMe; 3.30, 3H, s, 1'-
2
2
3H, m, H'9, H4; 2.57, 1H, m, H3α; 2.30, 3H, s, 8-Me; 2.18, 1H, dd J
OMe; 2.90–2.83, 3H, m, H9, H4; 2.60, 1H, m, H3α; 2.31, 3H, s, 8-Me;
gem
14.3 Hz, J 9.7 Hz, H9; 2.11, 1H, br q, J
7.1 Hz, H3'; 1.58, 1H, m,
2.18, 1H, dd, J
14.7 Hz, J 9.4 Hz, H'9; 2.10, 1H, br q, J
7.0 Hz,
1,9
3',4'
gem
9,1
3',4'
H3β; 0.98, 3H, d, J 7.1 Hz, 3'-Me; 0.90, 7H, brs, i-propyl; 0.10, 0.09,
H3'; 1.56, 1H, m, H3β; 0.99, 3H, d, J
7.0, 3'-Me; 0.90, 7H, br s, I-
3',4'
3',4'
13
13
2×3H, 2×s, SiMe . C n.m.r. δ (75.5 MHz, CDC1 ) 174.3, 173.2,
propyl; 0.10, 0.09, 2×3H, 2×s, OSiMe . C n.m.r. δ (75.5 MHz,
2
3
2
2×CO Me; 157.3, C6; 137.0, 136.6, C4a, C8; 131.0, C8a; 113.6, 110.9,
CDC1 ) 178.9, CO H; 174.3, CO Me; 157.4, C6; 137.1, 136.7, C4a,
2
3
2
2
C5, C7; 107.4, C1'; 70.4, C2'; 56.0, 6-OMe; 54.8, 2×1'-OMe; 52.7, C2;
C8; 131.0, C8a; 113, 8, 111.0, C5, C7; 107.6, C1'; 70.5, C2'; 56.4, 6-
OMe; 54.9, 54.8, 2×1'-OMe; 52.9, C2; 51.2, CO Me; 39.6, C3'; 35.9,
C1; 35.4, C9; 25.9, 25.4, C4, C3; 19.4, 8-Me; 17.0, SiCHMe ; 15.0,
51.4, 51.1, 2×CO Me; 39.5, C3'; 35.8, C1; 35.3, C9; 25.9, 25.3, C4, C3;
2
2
19.5, 8-Me; 17.0, SiCHMe ; 15.0, SiCHMe ; 9.9, 3'-Me; –3.8, –4.2,
2
2
2
SiMe .
SiCHMe ; 10.1, 3'-Me; -3.7, -4.2, SiMe .
2 2
2
Methyl (1SR, 2SR, 1'SR, 2'RS)-1-carboxymethyl-6-methoxy-2-(1,1-
dimethoxy-2'-diethylisopropylsilyloxy-but-3'-yl)-8-methyl-1,2,3,4-
tetrahydro-2-naphthoate
Methyl (1SR, 2SR, 1'SR, 2'RS)-6-methoxy-2-(1,1-dimethoxy-2'-
diethylisopropylsilyloxy-but-3'-yl)-1-methoxycarbonylmethyl-8-
methyl-1,2,3,4-tetrahydro-2-naphthoate
This compound was prepared by the procedure described above for the
This compound was prepared by the procedure described above for the
1
TBDMS ether. H n.m.r. δ (300 MHz, CDCl ) 10.5–11.2, 1H, br s,
1
3
TBDMS ether. H n.m.r. δ (300 MHz, CDC1 ) 6.45, 6.35, 2×1H, 2×d,
3
CO H; 6.45, 6.38, 2×1H, 2×d, J 2.5 Hz, H5, H7; 4.37, 1H, br d, J
2
5,7
1',2'
J
2.5 Hz, H5, H7; 4.38, 1H, d, J
5.1 Hz, H2'; 4.15, 1H, d, J
5.1
5,7
1',2'
1',2'
4.9 Hz, H2'; 4.15, 1H, d, J
4.9 Hz, H1'; 4.05, 1H, br d, J 8.8 Hz,
1',2'
1,9
Hz, H1'; 4.00, 1H, br dd, J 10.1 Hz, J
1.7 Hz, H1; 3.66, 3H, s, 6-
1,9
1,3β
H1; 3.68, 3H, s, 6-OMe; 3.44, 3.42, 2×3H, 2×s, 2-CO Me, 1'-OMe;
2
OMe; 3.48, 3H, s, 9-CO Me; 3.42, 3.415, 2×3H, 2×s, 2-CO Me, 1'-
2
2
3.26, 3H, s, 1'-OMe; 2.91, 1H, dd, J
14.6 Hz, J 2.7 Hz, H9; 2.83,
gem
9,1
OMe; 3.24, 3H, s, 1'-OMe; 2.86, 3H, m; 2.58, 1H, m; 2.20, 3H, s, 8-Me;
2H, m; 2.60, 1H, m; 2.31, 3H, s, 8-Me; 2.25–2.10, 2H, m; 1.53, 1H, m;
2.20–2.07, 2H, m; 1.56, 1H, m; 0.99–0.95, 16H, m, 3'-Me, DEIPS;
13
0.98–0.90, 16H, m, 3'-Me, DEIPS; 0.68–0.60, 4H, DEIPS. C n.m.r. δ
13
0.68–0.61, 4H, DEIPS. C n.m.r. δ (75 MHz, CDCl ) 174.3, 173.1, 9-
3
(75 MHz, CDCl ) 179.2, CO H; 174.3, CO Me; 157.4, C6; 137.1,
3
2
2
CO Me, 2-CO Me; 157.3, C6; 137.0, 136.7, C4a, C8; 130.8, C8a;
2
2
136.7, C4a, C8; 130.9, C8a; 113.7, 111.0, C5, C7; 108.2, C1'; 70.4, C2';
113.5, 110.8, C5, C7; 108.0, C1'; 70.2, C2'; 56.0, 55.4, 2×1'-OMe; 54.7,
6-OMe; 52.9, C2; 51.2, 51.0, 9-CO Me, 2-CO Me; 39.6, C3'; 35.8, C1;
56.4, 55.7, 2×1'-OMe; 54.8, 6-OMe; 53.0, C2; 51.1, CO Me; 39.7, C3';
2
2
2
35.7, C1; 35.2, C9; 25.8, 25.5, C4, C3; 19.2, 8-Me; 17.6, 2×C,
35.0, C9; 25.8, 25.4,, C4, C3; 19.1, 8-Me; 17.6, 2×C, SiCHMe ; 13.8,
2
SiCHMe ; 14.1, SiCHMe ; 10.2, 3'-Me; 7.33, 7.28, SiCH Me; 4.5, 4.4,
2
2
2
SiCHMe ; 10.1, 3'-Me; 7.3, 7.2, SiCH Me; 4.4, 4.3, SiCH Me.
2
2
2
SiCH Me.
2
Methyl (1SR, 2SR, 1'SR, 2'RS)-1-carboxymethyl-6-methoxy-2-(1,1-
dimethoxy-2'-t-butyldimethylsilyloxy-but-3'-yl)-8-methyl-1,2,3,4-
tetrahydro-2-naphthoate
Methyl (1SR, 2SR, 1'SR, 2'RS)-1-(3"-diazo-2"-oxopropyl)-6-methoxy-
2-(1,1-dimethoxy-2'-t-butyldimethylsilyloxy-but-3'-yl)-8-methyl-
1,2,3,4-tetrahydro-2-naphthoate (30a)
To a solution of the diester prepared above (874 mg, 1.58 mmol) in
MeOH (65 ml) were added 5.2 N methanolic KOH (50 ml) and 5.2 N
aq KOH (15 ml) and the mixture stirred overnight at room temp. The
MeOH was then removed under reduced pressure and the residue
A solution of the acid prepared above (99 mg, 0.184 mmol) in THF (5
ml) was treated with NaH (60% dispersion in oil, 8.9 mg, 0.223 mmol)
and the mixture stirred at room temp. until gas evolution had ceased (ca.
20 min). Vilsmeier’s reagent [prepared from oxalyl chloride (80 µl,
1.02 mmol) and dmf (79 µl, 1.02 mmol) in benzene (3 ml)] was then
added and stirring continued for a further 30 min. The mixture,
containing the intermediate acid chloride, was then poured into an ice-
cold ethereal solution of diazomethane and allowed to stir for 5 min.
Excess diazomethane was evaporated under a stream of nitrogen and
then the mixture concentrated to dryness. Chromatography on silica gel
(hexane/EtOAc, 2:1) afforded diazoketone (30a) (89 mg, 86%) as a
diluted with Et O, cooled to 0°C and carefully acidified with 20% aq
2
HCl. The mixture was extracted with Et O and the combined organic
2
layers washed with sat. NaHCO and brine, dried (MgSO ) and
3
4
concentrated to afford the title acid (744 mg, 87%) as a colourless foam.
Trituration of this material with Et O gave a crystalline solid, m.p. 80°C
2
(Found: C, 62.29; H, 8.93%. C
H
O Si requires C, 62.42; H, 8.61%).
28 46
8
R 0.18 (hexane/EtOAc, 2:1). υ
(KBr) 2998m, 2945s, 2853m, 1743
(CO, s), 1699 (CO, s), 1613m, 1586m, 1461m, 1273s, 1169s, 1103s,
f
max
+
yellow oil. (Found: C, 61.87; H, 8.01; N, 4.82%; M , 562.3077.
–1
1
+
1059s, 1048s, 832s, 774s cm . H n.m.r. δ (300 MHz, CDCl ) 6.46,
C
H
N O Si requires C, 61.89; H, 8.24; N, 4.98%; M , 562.3074).
3
29 46
2
7
6.40, 2×1H, 2×d, J 2.5 Hz, H5, H7; 4.37, 1H, br d, J
3.4 Hz, H2';
R 0.41 (hexane/EtOAc, 2:1). υ
(film) 3094w, 2951s, 2856m, 2101
5,7
1',2'
f
max
4.22, 1H, d, J
3.4 Hz, H1'; 3.96, 1H, br d, J 8.8 Hz, H1; 3.71, 3H,
(CN , s), 1727 (CO, s), 1640 (CO, s), 1606s, 1321s, 1301s, 1250s,
1',2'
1,9
2
–1
1
s, 6-OMe; 3.46, 3.42, 3.24, 3×3H, 3×s, 2×1'-OMe, 2-CO Me; 3.03, 1H,
1235s, 1200s, 1147s, 1117s, 1062s, 836s cm . H n.m.r. δ (300 MHz,
CDCl ) 6.45, 6.40, 2×1H, 2×d, J 2.3 Hz, H5, H7; 4.84, 1H, br s,
2
dd, J
14.6 Hz, J 2.7 Hz, H9; 2.89–2.85, 2H, m, H4; 2.61, 1H, m,
gem
9,1
3
5,7

Total Synthesis of Hainanolidol
827
CH=N ; 4.41, 1H, br d, J
3.5 Hz, H2'; 4.25, 1H, d, J 3.5 Hz, H1';
1',2'
m, H2, H5; 2.42, 3H, s, 9-Me; 2.39–2.31, 2H, m, H4α, H3'; 2.14, 1H,
2
1',2'
3.97, 1H, br d, J 9.9 Hz, H1; 3.71, 3H, s, 6-OMe; 3.48, 3.23, 6H, 3H,
br d, J
12.4 Hz, H'8; 2.04, 1H, m, H4β; 0.94, 3H, partially obscured
1,9
gem
13
2×s, 2×1'-OMe, CO Me; 2.93–2.85, 3H, m, H9, H4; 2.60, 1H, m, H3α;
d, 3'-Me; 0.92, 9H, s, OSiCMe ; 0.14, 0.11, 2×3H, 2×s, OSiMe .
C
2
3
2
2.26, 3H, s, 8-Me; 2.22–2.10, 2H, m, H'9, H3'; 1.54, 1H, m, H3β; 1.00,
3H, d, J 7.2 Hz, 3'-Me; 0.86, 9H, s, OSiCMe ; 0.14, 0.13, 2×3H, 2×s,
n.m.r. δ (75 MHz, CDCl ) 206.4, C1; 177.7, CO Me; 146.3, C7; 135.8,
3
2
135.1, 131.1, 131.1, C9, C9a, C9b, C5a; 107.1, C1'; 99.5, C6; 73.4, C2';
3',4'
13
3
OSiMe . C n.m.r. δ (75 MHz, CDCl ) 194.5, COCH=N ; 174.4,
56.0, 7-OMe; 55.3, 54.9, 2×1'-OMe; 51.6, CO Me; 48.6, C3; 42.0,
2
3
2
2
CO Me; 157.4, C6; 137.5, 136.8, C4a, C8; 131.0, C8a; 113.3, 111.1,
41.6, C2, C8; 41.4, 36.8, C2a, C3'; 29.9, 27.0, C5, C4; 26.3, OSiCMe ;
2
3
C5, C7; 108.6, C1'; 70.3, C2'; 56.8, CH=N ; 55.9, 54.8, 54.8, 6-OMe,
20.5, 9-Me; 18.7, OSiCMe ; 9.9, 10-Me; –3.2, –4.1, OSiMe . Mass
3 2
2
+
2×1'-OMe; 53.5, C2; 51.3, CO Me; 39.2, C3'; 36.8, C1; 26.1,
spectrum m/z 534 (M , 7%), 502 (16), 445 (22), 339 (21), 327 (13), 286
(51), 271 (16), 255 (30), 243 (25), 227 (20), 202 (20), 159 (26), 89 (60),
75 (100), 59 (45).
2
OSiCMe ; 25.9, 25.5, C4, C3; 19.5, 8-Me; 18.5, OSiCMe ; 11.2, 3'-
3
3
+
Me; –3.0, –4.8, OSiMe ; C9 not observed. Mass spectrum m/z 562 (M ,
2
20%), 531 (39), 502 (61), 445 (36), 285 (58), 227 (37), 201 (51), 185
(27), 173 (39), 159 (22), 89 (71), 75 (100), 59 (24).
Methyl (2aSR, 3SR, 2'RS, 3'SR)-2,2a,3,4,5,8-Hexahydro-7-methoxy-3-
(1,1-dimethoxy-2'-dimethylisopropylsilyloxy-but-3'-yl)-9-methyl-1-
oxo-1H-benz[cd]azulene-3-carboxylate (31b)
Methyl (1SR, 2SR, 1'SR, 2'RS)-1-(3"-diazo-2"-oxopropyl)-6-methoxy-
2-(1,1-dimethoxy-2'-dimethylisopropylsilyloxy-but-3'-yl)-8-methyl-
1,2,3,4-tetrahydro-2-naphthoate (30b)
This compound was prepared by the procedure described above for the
1
TBDMS ether. H n.m.r. δ (300 MHz, CDC1 ) 5.14, 1H, br s, H6; 4.08,
3
1H, d, J 6.7 Hz, H1'; 3.69, 1H, br d, J 6.7 Hz H2'; 3.66, 3H, s, 7-
1',2'
1',2'
This compound was prepared by the procedure described above for the
OMe; 3.57, 3H, s, 3-CO Me; 3.32, 3.29, 2×3H, 2×s, 2×1'-OMe; 3.24,
2
1
TBDMS ether. H n.m.r. δ (300 MHz, CDC1 ) 6,46, 6.39, 2×1H, 2×d,
3
1H, m, H2α; 2.89, 1H, dd, J
12.4 Hz, J 1.9 Hz, H8; 2.77, 2.56, 3H,
m, H2, H5, H'5; 2.46, 1H, m, H2'; 2.40, 3H, s, 9-Me; 2.34–2.24, 2H, m,
gem
8,6
J
2.5 Hz, H5, H7; 4.91, 1H, br s, CH=N ; 4.33, 1H, d, J
5.6 Hz,
5,7
2
1',2'
H2'; 4.15, 1H, d, J 5.6 Hz, H1'; 4.02, 1H, br d, J 9.7 Hz, H1; 3.70,
1',2'
1,9
H42, H10; 2.11, 1H, br d, J 12.4 Hz, H'8; 2.65, 1H, m, H4β; 0.95–
gem
13
3H, s, 6-OMe; 3.48, 3.45, 2×3H, 2×s, 2-CO Me, 1'-OMe; 3.29, 3H, s,
2
0.92, 10H, m, 3'-Me, i-propyl; 0.08, 6H, br s, SiMe . C n.m.r. δ (75.5
MHz, CDC1 ) 206.3, C1; 177.4, 3-CO Me; 146.5, C7; 135.9, 135.1,
2
1'-OMe; 2.88–2.83, 2H, m, H4; 2.76, 1H, dd, J
12.9 Hz, J 3.1 Hz,
gem
9,1
3
2
H9; 2.58, 1H, m, H3α; 2.26, 3H, s, 8-Me; 2.15–2.08, 2H, m, H3', H9;
1.55, 1H, m, H3β; 0.98, 3H, d, J 7.1 Hz, 3'-Me; 0.89, 7H, br s, i-
132.0, 132.0, C9, C9a, C9b, C5a; 105.7, C1'; 99.7, C6; 73.6, C2'; 56.1,
3',4'
7-OMe; 54.9, 53.6, 2×1'-OMe; 51.6, CO Me; 48.7, C2; 42.1, 41.8, C2,
2
13
propyl 1; 0.10, 0.09, 2×3H, 2×s, SiMe . C n.m.r. δ (75.5 MHz,
CDC1 ) 194.4, COCH=N ; 174.3, CO Me; 157.4, C6; 137.4, 136.4,
2
C8; 41.7, 37.2, C2, C10; 29.8, 27.6, C5, C4; 20.5, 9-Me; 17.2, 17.1,
3
2
2
SiCHMe 15.0, SiCHMe ; 9.3, 3'-Me; –3.8, –3.9, SiMe .
2;
2
2
C4a, C8; 131.0, C8a; 113.5, 111.1, C5, C7; 107.6, C14; 70.3, C2'; 55.0,
54.9, 6-OMe, 2×1'-OMe; 52.8, C2; 51.2, CO Me; 42.0, CH=N ; 39.5,
2
2
C3'; 36.6, C1; 25.9, 25.5, C4, C3; 19.5, 8-Me; 17.0, SiCHMe ; 15.0,
2
Methyl (2aSR, 3SR, 2'RS, 3'SR)-2,2a,3,4,5,8-Hexahydro-7-methoxy-3-
(1,1-dimethoxy-2'-diethylisopropylsilyloxy-but-3'-yl)-9-methyl-1-oxo-
1H-benz[cd]azulene-3-carboxylate (31c)
SiCHMe ; 10.0, 3'-Me; –3.7, –4.1, SiMe .
2
2
Methyl (1SR, 2SR, 1'SR, 2'RS)-1-(3"-diazo-2"-oxopropyl)-6-methoxy-
2-(1,1-dimethoxy-2'-diethylisopropylsilyloxy-but-3'-yl)-8-methyl-
1,2,3,4-tetrahydro-2-naphthoate (30c)
This compound was prepared by the procedure described above for the
1
TBDMS ether. H n.m.r. δ (300 MHz, CDCl ) 5.15, 1H, br s, H6; 4.11,
3
1H, d, J
6.5 Hz, H1'; 3.75, 1H, br d, J
6.5 Hz, H2'; 3.66, 3H, s, 7-
1',2'
1',2'
This compound was prepared by the procedure described above for the
OMe; 3.59, 3H, s, CO Me; 3.34, 3.31, 2×3H, 2×s, 2×1'-OMe; 3.2, 1H,
2
1
TBDMS ether. H n.m.r. δ (300 MHz, CDCl ) 6.45, 6.38, 2×1H, 2×d,
m; 2.90, 1H, dd, J
12.3 Hz, J 1.8 Hz, H8; 2.75–2.60, 4H, m; 2.42,
3
gem
8,6
J
2.4 Hz, H5, H7; 4.86, 1H, br s, CH=N ; 4.40, 1H, br d, J
5.3 Hz,
3H, s, 9-Me; 2.52, 1H, m; 2.35, 1H, m; 2.13, 1H, d, J
12.3 Hz, H'8;
5,7
2
1',2'
gem
H2'; 4.19, 1H, d, J
3H, s, 6-OMe; 3.48, 3.47, 3.27, 3×3H, 3×s, 2×1'-OMe, CO Me; 2.90–
2.75, 3H, m; 2.60, 1H, m; 2.24, 3H, s, 8-Me; 2.20–2.10, 2H, m; 1.52,
1H, m; 1.05–0.95, 16H, m, 3'-Me, DEIPS; 0.70–0.60, 4H, DEIPS.
n.m.r. δ (75 MHz, CDCl ) 194.3, COCH=N ; 174.0, CO Me; 157.1,
C6; 137.2, 136.3, C4a, C8; 130.6, C8a; 113.2, 110.8, C5, C7; 107.8,
5.3 Hz, H1'; 4.10, 1H, br d, J 8.1 Hz, H1; 3.70,
2.04, 1H, m) 1.04–0.94, 16H, m, 3'-Me, DEIPS; 0.71–0.63, 4H, DEIPS.
1',2'
1,9
13
C n.m.r. δ (75 MHz, CDCl ) 206.0, C1; 177.3, CO Me; 146.3, C7;
2
3
2
135.7, 134.8, 131.9, 131.7, C9, C9a, C9b, C5a; 105.7, C1'; 99.5, C6;
13
C
73.6, C2'; 55.9, 7-OMe; 54.7, 53.6, 2×1'-OMe; 51.4, CO Me; 48.6, C3;
2
41.8, 41.6, C2, C8; 41.5, 37.2, C2a, C3'; 29.7, 27.4, C5, C4; 20.3, 8-Me;
3
2
2
17.65, 17.6, SiCHMe ; 13.7, SiCHMe ; 9.2, 3'-Me; 7.3, 7.2, SiCH Me;
2
2
2
C1'; 70.4, C2'; 56.2, CH=N ; 55.4, 54.5, 54.5, 6-OMe, 2×1'-OMe; 52.7,
4.4, 4.3, SiCH Me.
2
2
C2; 50.8, CO Me; 39.4, C3'; 36.3, C1; 36.1, C9; 25.6, 25.3, C4, C3;
2
19.1, 8-Me; 17.4, 2×C, SiCHMe ; 13.7, SiCHMe ; 9.9, 3'-Me; 7.2, 7.1,
2
2
SiCH Me; 4.3, 4.2, SiCH Me.
2
2
Methyl (2aSR, 3SR, 9bSR, 10SR, 11RS, 12SR)-3-(2'-
t-Butyldimethylsilyloxy-1'-oxo-but-3'-yl)-2,2a,3,4,5,8-hexahydro-7-
methoxy-9-methyl-1-oxo-1H-benz[cd]azulene-3-carboxylate (33a) and
Methyl (2aSR, 3SR, 2'RS, 3'SR)-11-t-Butyldimethyl silyloxy-
1,2,2a,3,4,5-hexahydro-10-hydroxy-7-methoxy-9,12-dimethyl-1-oxo-
3,9a-propano-9aH-benz[cd]azulene-3-carboxylate (32a)
Methyl (2aSR, 3SR, 2'RS, 3'SR)-2,2a,3,4,5,8-Hexahydro-7-methoxy-3-
(1,1-dimethoxy-2'-t-butyldimethylsilyloxy-but-3'-yl)-9-methyl-1-oxo-
1H-benz[cd]azulene-3-carboxylate (31a)
A solution of diazoketone (13a) (180 mg, 0.32 mmol) in CH Cl (5 ml)
2
2
A mixture of acetal (31a) (100 mg, 0.19 mmol) and ZnBr (47 mg, 0.21
was treated with Rh (mandelate) (10 mg, 0.012 mmol) and the mixture
2
2
4
mmol) in CH Cl (7.5 ml) was stirred at room temp., under an
heated at reflux for 10 min under an atmosphere of nitrogen. DBU (2
drops) was added and the solution stirred for ca. 2 min, then diluted
2
2
atmosphere of nitrogen, for 18 h. The solution was then diluted with
CH Cl , washed with 2 N NaOH and water, dried (MgSO ) and
with CH Cl and washed with 0.5 N HCl and 2 N NaOH. The organic
2
2
4
2
2
concentrated under reduced pressure. Chromatography on silica gel
(hexane/EtOAc, 2:1) gave the starting acetal (31a) (9 mg, 9% recovery)
and aldehyde (33a) (51 mg, 56% at 91% conversion) as a pale yellow
phase was dried, filtered and concentrated under reduced pressure.
Chromatography on silica gel (hexane/EtOAc, 2:1) gave
cycloheptatriene (31a) (112 mg, 65%) as an oil. (Found: C, 64.71; H,
+
+
solid. Recrystallisation (EtOAc/pentane) gave a white solid, m.p.
8.63%; M , 534.3020. C
H O Si requires C, 65.14; H, 8.67%; M ,
29 46 7
+
110–112°C (Found: C, 65.92; H, 8.65%; M , 488.2591. C
H O Si
534.3013). R 0.49 (hexane/EtOAc, 2:1). υ
(film) 2953s, 2931s,
2856s, 1726 (CO, s), 1709 (CO, s), 1258s, 1220s, 1196s, 1151s, 1104s,
27 40 6
f
max
+
requires C, 66.36; H, 8.25%; M , 488.2594). R 0.52 (hexane/EtOAc,
f
–1
1
2:1). υ
(KBr) 3012m, 2968m, 2951m, 2926m, 2853m, 1726 (CO,
1060s, 835s cm . H n.m.r. δ (300 MHz, CDCl ) 5.15, 1H, br s, H6;
max
3
s), 1706 (CO, s), 1614s, 1259s, 1232s, 1221s, 1201s, 1176s, 1154s,
4.08, 1H, d, J
4.9 Hz, H1'; 3.72, 1H, br d, J 4.9 Hz, H2'; 3.66, 3H,
1',2'
1',2'
–1
1
1121s, 1103s, 1020s, 841s cm . H n.m.r. δ (300 MHz, CDCl ) 9.59,
1H, d, J
s, 7-OMe; 3.58, 3H, s, CO Me; 3.33, 3.32, 2×3H, 2×s, 2×1'-OMe; 3.18,
3
2
1.4 Hz, H1'; 5.15, 1H, br s, H6; 4.07, 1H, m, H2'; 3.72, 3H,
1H, m, H2a; 2.88, 1H, dd, J
12.4 Hz, J 1.8 Hz, H8; 2.76–2.53, 4H,
1',2'
gem
8,6

828
L. Mander et al.
s, 7-OMe; 3.59, 3H, s, CO Me; 3.37, 1H, m, H2a; 2.91, 1H, dd, J
Hz, J 8.7 Hz, J
2.1 Hz, H3; 2.94, 1H, dd, J
12.6 Hz, J 2.0
gem 6,8
2
gem
3,2
3,OH
12.3 Hz, J 1.8 Hz, H8; 2.68–2.52, 2H, m, H5; 2.67, 1H, dd, J
18.1
Hz, H6; 2.92, 1H, dd, J
10.2 Hz, J
7.2 Hz, H3a; 2.54, 1H, d,
8,6
gem
3a,3
3a,10b
Hz, J
9.5 Hz, H2; 2.41, 3H, s, 9-Me; 2.45–2.35, 2.26–2.09, 1H, 3H,
J
2.1 Hz, OH; 2.42, 3H, s, 5-Me; 2.44–2.33, 2H, 1H, 2×m, H9α,
2,2a
OH,3
2×m, H4α, H4β, H8, H3'; 0.96, 9H, s, OSiCMe ; 0.95, 3H, d, J
7.5
H10; 2.21, 1H, br d, J
12.6 Hz, H6; 1.83–1.71, 2H, m, H1, H9β;
gem
3
3',4'
13
Hz, 3'-Me; 0.12, 0.05, 2×3H, 2×s, OSiMe . C n.m.r. δ (75 MHz,
1.02, 3H, d, J 7.0 Hz, 1-Me; 0.89, 9H, s, OSiCMe ; 0.12, 0.10, 2×3H,
2
3
13
CDCl ) 205.1, C1; 204.2, C1'; 176.7, CO Me; 146.7, C7; 135.6, 135.3,
2×s, OSiMe . C n.m.r. δ (75 MHz, CDCl ) 206.7, C4; 175.8, CO Me;
3
2
2
3
2
131.8, 131.6, C9, C9a, C9b, C5a; 99.7, C6; 79.0, C2'; 56.1, 7-OMe;
52.1, CO Me; 48.4, C3; 42.1, 41.6, C2, C8; 41.6, 39.4, C2a, C3'; 29.4,
146.7, C7; 138.9, C5; 132.7, 130.5, 129.9, C4a, C8a, C10c; 99.2, C8;
75.7, 73.3, C2, C3; 56.8, C3a; 56.1, 7-OMe; 51.6, CO Me; 47.2, C10a;
2
2
27.3, C4, C3; 25.9, OSiCMe ; 20.5, 9-Me; 18.3, OSiCMe ; 10.1, 3'-
42.1, C6; 42.0, C10b; 35.8, C1; 27.3, 26.6, C9, C10; 26.1, OSiCMe ;
3
3
3
+
Me; -4.0, -4.6, OSiMe . Mass spectrum m/z 488 (M , 95%), 431 (87),
20.9, 5-Me; 18.6, OSiCMe ; 12.4, 1-Me; –3.7, –4.4, OSiMe . Mass
3 2
2
+
339 (48), 271 (30), 255 (79), 227 (40), 202 (60), 169 (42), 143 (52), 73
(100), 59 (43).
spectrum m/z 488 (M , 44%), 431 (100), 401 (44), 371 (38), 356 (55),
339 (28), 75 (70).
Further elution afforded alcohol (32a) (15 mg, 16% at 91%
conversion) as a yellow solid. Recrystallisation (EtOAc/pentane)
gave small colourless prisms, m.p. 242–244°C (Found: C, 66.11; H,
Methyl (1SR, 2SR, 3RS,3aSR,10aRS,10bSR)-2-
diethylisopropylsilyloxy-1,2,3,3a,6,9,10,10b-octahydro-3-hydroxy-7-
methoxy-1,5-dimethyl-4-oxocyclohept[bc]acenaphthylene-10a(4H)-
carboxylate (34c)
8.53. C
H
O Si requires C, 66.36; H, 8.28%). R 0.35 (hexane/
27 40
6
f
EtOAc, 2:1). υ
(KBr) 3567 (OH, s), 2952m, 2931m, 2856m, 1732
max
(CO, s), 1686 (CO, s), 1644m, 1603w, 1535s, 1253m, 1230m, 1193s,
This compound was prepared by the procedure described above for the
–1
1
1163s, 1126s, 1096s, 1072s, 1042s, 837s cm . H n.m.r. δ (300 MHz,
CDCl ) 5.89, 1H, m, H6; 5.22, 1H, d, J 2.4 Hz, H8; 3.82–3.77, 2H,
1
TBDMS ether. H n.m.r. δ (300 MHz, CDCl ) 5.14, 1H, br s, H8; 3.82,
3
3
6,8
1H, dd, J 10.4 Hz, J 8.8 Hz, H2; 3.72, 3H, s, 7-OMe; 3.58, 3H, s,
2,1
2,3
m, H10, H11; 3.72, 3H, s, 7-OMe; 3.65, 3H, s, CO Me; 2.81–2.67,
2
CO Me; 3.18, 1H, br d, J
7.2 Hz, H10b; 3.11, 1H, ddd, J
10.2
2
10b,3a
3,3a
2.60–2.44, 1.94, 3H, 4H, 1H, 3×m, H2, H2a, H12, H4, H5; 2.43, 3H, s,
Hz, J 8.7 Hz, J
2.1 Hz, H3; 2.92, 1H, dd, J
12.6 Hz, J 2.0
3,2
3,OH
gem 6,8
9-Me; 2.33, 1H, dd, J
12.2 Hz, J
1.4 Hz, OH; 1.01, 3H, d, J
OH,10
OH,11
Hz, H6; 2.88, 1H, dd, J
10.2 Hz, J
7.2 Hz, H3a; 2.62, 1H, d,
3a,3
3a,10b
7.7 Hz, 12-Me; 0.91, 9H, s, OSiCMe ; 0.12, 0.08, 2×3H, 2×s, OSiMe .
3
2
J
2.1 Hz, OH; 2.48–2.33, 2H, 1H, 2×m, H9α, H10; 2.40, 3H, s, 5-
13
OH,3
C n.m.r. δ (75 MHz, CDCl ) 203.3, C1; 176.8, CO Me; 161.7, C7;
146.2, 144.5, C5a, C9; 124.7, C9b; 121.5, C6; 106.3, C8; 76.9, 75.0,
3
2
Me; 2.17, 1H, d, J
0.93, 16H, m, 3'-Me, DEIPS; 0.78–0.60, 4H, DEIPS. C n.m.r. δ (75
MHz, CDCl ) 206.9, C4; 175.8, CO Me; 146.8, C7; 139.0, C5; 132.7,
12.6 Hz, H'6; 1.78–1.65, 2H, m, H1, H9β; 1.01–
gem
13
C10, C11; 54.8, 7-OMe; 51.9, CO Me; 51.0, C2b; 44.2, C9b; 44.1,
2
3
2
42.0, C2a, C12; 40.6, C2; 33.8, 29.9, C4, C5; 25.7, OSiCMe ; 23.1, 6-
3
130.6, 129.8, C4a, C8a, C10c; 99.2, C8; 75.4, 73.4, C2, C3; 57.0, C3a;
Me; 18.4, OSiCMe ; 18.1, 12-Me; –4.7, –5.3, OSiMe . Mass spectrum
3
2
56.1, 7-OMe; 51.6, CO Me; 47.2, C10a; 42.1, C6; 42.0, C10b; 35.7,
+
2
m/z 488 (M , 74%), 470 (7), 431 (26), 399 (20), 371 (7), 339 (9), 285
(100), 255 (26), 227 (51), 202 (14), 167 (10), 149 (34), 115 (9), 99 (12),
73 (22).
C1; 27.2, 26.5, C9, C10; 20.9, 5-Me; 17.5, 2×C, SiCHMe ; 13.2,
2
SiCHMe ; 12.0, 3'-Me; 7.3, 7.2, SiCH Me; 4.3, 4.2, SiCH Me.
2
2
2
Methyl (1SR, 2SR, 3RS,3aSR,10aRS,10bSR)-1,2,3,3a,6,9,10,10b-
octahydro-2,3-Dihydroxy-7-methoxy-1,5-dimethyl-4-
oxocyclohept[bc]acenaphthylene-10a(4H)-carboxylate
Methyl (2aSR, 3SR, 2'RS, 3'SR)-3-(2'-Diethylisopropylsilyloxy-1'-oxo-
but-3'-yl)-2,2a,3,4,5,8-hexahydro-7-methoxy-9-methyl-1-oxo-1H-
benz[cd]azulene-3-carboxylate (33c)
Silyl ether (34a) (5.5 mg, 11.3 µmol) was dissolved in THF (1 ml) and
treated with TBAF (23 µl of a 1 M solution in THF, 23 µmol). The
solution was stirred at room temp. under an atmosphere of nitrogen for
1 h, after which time t.l.c. indicated that reaction was incomplete. A
further aliquot of TBAF was added (10 µl, 10 µmol) and stirring
continued for another 30 min. The mixture was then diluted with water
This compound was prepared by the procedure described above for the
1
TBDMS ether. H n.m.r. δ (300 MHz, CDCl ) 9.6, 1H, s, H1'; 5.15, 1H,
3
br s, H6; 4.15, 1H, m, H2'; 3.71, 3H, s, 7-OMe; 3.59, 3H, s, CO Me;
2
3.40–3.30, 1H, m; 2.90, 1H, dd, J
12.4 Hz, J 2.0 Hz, H8; 2.75–
gem
8,6
2.50, 4H, m; 2.41, 3H, s, 9-Me; 2.26–2.12, 3H, m; 0.96, 9H, s,
and extracted with Et O. The combined organic layers were washed
2
OSiCMe ; 1.04–0.89, 16H, m, 3'-Me, DEIPS; 0.78–0.60, 4H, DEIPS.
3
with brine, dried (MgSO ), filtered and concentrated under reduced
4
13
C n.m.r. δ (75 MHz, CDCl ) 205.1, C1; 203.7, C1'; 176.7, CO Me;
3
2
pressure. Chromatography on silica gel (hexane/EtOAc, 1 :2) afforded
146.7, C7; 135.6, 135.2, 131.8, 131.7, C9, C9a, C9b, C5a; 99.7, C6;
1
the title diol (2.1 mg, 50%). H n.m.r. δ (300 MHz, CDCl ) 5.15, 1H,
3
79.8, C2'; 56.1, 7-OMe; 52.0, CO Me; 48.3, C3; 42.2, 41.6, C2, C8;
2
br s, H8; 3.74, 1H, dd, J 10.7 Hz, J 9.0 Hz, H2; 3.73, 3H, s, 7-OMe;
2,1
2,3
41.5, 39.4, C2a, C3'; 29.4, 27.2, C4, C3; 17.5, 2×C, SiCHMe ; 13.2,
2
3.58, 3H, s, CO Me; 3.22, 1H, br d, J
7.1 Hz, H10b; 3.15, 1H, dd,
2
10b,3a
SiCHMe ; 12.0, 3'-Me; 7.3, 7.2, SiCH Me; 4.3, 4.2, SiCH Me.
2
2
2
J
10.1 Hz, J 9.0 Hz, H3; 2.96, 1H, dd, J
=12.5 Hz, J 2.1 Hz,
gem 6,8
3,3a
3,2
H6; 2.93, 1H, dd, J
10.1 Hz, J
7.1 Hz, H3a; 2.49–2.41, 2.36,
3a,3
3a,10b
2H, 1H, 2×m, H9, H10α; 2.21, 1H, br d, J
12.5 Hz, H'6; 1.86–1.73,
gem
Methyl (1SR, 2SR, 3RS,3aSR,10aRS,10bSR)-2-
2H, m, H1, H10β; 1.58, 2H, br s, 2×OH; 1.07, 3H, d, J
6.8 Hz, 1-
1-Me,1
t-Butyldimethylsilyloxy-1,2,3,3a,6,9,10,10b-octahydro-3-hydroxy-7-
methoxy-1,5-dimethyl-4-oxocyclohept[bc]acenaphthylene-10a(4H)-
carboxylate (34a)
Me.
(1RS, 3aRS, 10aSR, 10bSR 11SR, 12SR)-12-t-Butyldimethylsilyloxy-
3a,5,8,10,10a,10b-hexahydro-7-methoxy-9,11-dimethyl-10-oxo-1,3a-
ethano-1H-cyclohept[3,4]indeno[1,7-cd]pyran-3(4H)-one (35a)
A solution of aldehyde (33a) (45 mg, 0.092 mmol) in CH Cl (5 ml)
2
2
was treated with basic, activated alumina (1 g) and the resultant
suspension stirred at room temp. for 16 h. The mixture was then filtered
and the retained solids washed with CH Cl . Concentration of the
A solution of (34a) (4.0 mg) was dissolved in MeOH (1 ml), and treated
with a saturated solution of K CO in MeOH/H O (1:1). The solution
2
2
2
3
2
filtrate and chromatography of the residue on silica gel (hexane/EtOAc,
4:1) afforded carbinol (34a) (28 mg, 62%) as a colourless solid.
was stirred vigorously for 1 h, then diluted with brine (10 ml) and
thoroughly extracted with CH Cl . The organic phase was washed with
2
2
Recrystallisation (EtOAc/pentane) gave white prisms, m.p. 135–
brine, and dried over MgSO before being evaporated to dryness. The
4
+
138°C (Found: C, 66.22; H, 8.45%; M , 488.2594. C
H O Si
residue was carefully chromatographed on silica gel (hexane/EtOAc,
27 40 6
+
requires C, 66.36; H, 8.25%; M , 488.2594). R 0.57 (hexane/EtOAc,
6:1) to provide lactone (35a) in 33% yield as a mixture with starting
f
6
1
2:1). υ
(KBr) 3515 (OH, m), 2952m, 2928m, 2855m, 1717 (CO, s),
material (34a) (47%) and the ∆ -isomer of (34a) (18%). H n.m.r. δ
max
1692 (CO, s), 1631m, 1600m, 1264m, 1219m, 1194s, 1103s, 1062s,
(300 MHz, CDC1 ) 5.27, 1H, s, H6; 4.83, 1H, t, J 4.4 Hz, H1; 3.68, 1H,
3
–1 1
836s cm . H n.m.r. δ (300 MHz, CDCl ) 5.16, 1H, br s, H8; 3.74, 1H,
dd, J 2.9, 4.4 Hz, H12; 3.59, 3H, s, OMe; 3.10–3.20, 2H, m, ABX,
H10a, H10b; 3.06, 1H, dd, J 2.0, 12.8 Hz, H8; 2.78, 1H, br dd, J 7.7,
18.1 Hz, H5; 2.42, 1H, m, H'5; 2.39, 3H, s, 9-Me; 2.20, 1H, dd, J 7.7,
3
dd, J 10.3 Hz, J 8.7 Hz, H2; 3.73, 3H, s, 7-OMe; 3.59, 3H, s,
2,1
2,3
CO Me; 3.18, 1H, br d, J
7.2 Hz, H10b; 3.14, 1H, ddd, J
10.2
2
10b,3a
3,3a

Total Synthesis of Hainanolidol
829
13
14.2 Hz, H4; 2.00, 1H, m, obscured, H11; 2.00, 1H, d, J 12.4 Hz, H'8;
1.92, 1H, ddd, J 7.7, 12.6, 14.2 Hz, H'4; 1.06, 3H, d, J 7.4 Hz, 11-Me;
0.89, 9H, s, OSiCMe ; 0.12, 0.09, 2×3H, 2×s, OSiMe .
during the overnight C n.m.r. δ acquisition. (Found: 344.1623.
1
C
H O requires 344.1623). H n.m.r. δ (300 MHz, CDC1 ) 5.58,
20 22 5 3
1H, d, J 5.2 Hz, H6; 5.12, 1H, br s, H10; 4.77, 1H, dd, J 3.3, 4.8 Hz, H1;
3.70, 1H, m, H12; 3.60, 3H, s, OMe; 3.10, 1H, d, J 12.8 Hz, H10b; 2.85,
1H, m, obscured, H10a; 2.82, 1H, dd, J 1.9, 12.8 Hz, H8; 2.65, 1H, dd,
J 7.7, 18.1 Hz, H5; 2.33, 1H, m, H'5; 2.08, 1H, d, J 12.8 Hz, H'8; 2.05,
1H, m, obscured, H4; 2.02, 3H, s, 9-Me; 1.87, 1H, q, J 6.8Hz, H11;
3
2
(1RS, 3aRS, 10aSR, 10bSR 11SR, 12SR)-12-Diethylisopropylsilyloxy-
3a,5,8,10,10a,10b-hexahydro-7-methoxy-9,11-Dimethyl-10-oxo-1,3a-
ethano-1H-cyclohept[3,4]indeno[1,7-cd]pyran-3(4H)-one (35c)
1.80, 1H, ddd, J 7.7, 12.6, 14.2 Hz, H'4; 1.06, 3H, d, J 7.0 Hz, 11-Me.
C n.m.r. δ (75 MHz, CDC1 ) 177.0, C3; 148.6, C7; 139.6, 131.2,
127.4, 119.0, C5a, C5b, C9a, C9b; 99.8, C6; 77.5, 76.4, 72.6, C1, C9,
C12; 55.8, OMe; 48.8, C3b; 43.7, C3a; 42.4, C8; 40.6, C10a; 33.2, C11;
28.1, C5; 23.1, C4; 20.1, 9-Me; 16.7, 11-Me. Mass spectrum m/z 344
13
A solution of (34c) (190 mg, 0.48 mmol) was dissolved in MeOH
(1 ml), and treated with a saturated solution of K CO in MeOH/H O
3
2
3
2
(1:1). The solution was stirred vigorously for 30 min, then diluted with
brine (10 ml) and thoroughly extracted with CH Cl . The organic phase
2
2
+
was washed with brine, and dried over MgSO before being evaporated
(M , 91%), 329 (28), 327 (32), 326 (100), 325 (46), 311 (34), 267 (12),
4
to dryness. The residue was carefully chromatographed on silica gel
(hexane/EtOAc, 6:1) to provide the title compound in 30% yield, with
a recovery of 30% of the starting material. (Found: C, 68.68; H, 8.40%;
239 (14), 217 (22), 214 (22).
( )-Hainanolidol (1)
+
+
M , 470.2483. C
470.2488). H n.m.r. δ (300 MHz, CDC1 ) 5.26, 1H, s, H6; 4.88, 1H, t,
H O Si requires C, 68.90; H, 8.14%; M ,
27 38 5
A sample of (38) (4 mg) was dissolved in THF (2 ml) and treated with
0.1 ml of conc. HCl. After standing for 10 min at room temp, the
mixture was quenched with sat. aqu. NaHCO solution (5 ml) and
1
3
J 4.4 Hz, H1; 3.70, 1H, dd, J 2.9, 4.4 Hz, H12; 3.58, 3H, s, OMe; 3.10–
3.20, 2H, m, ABX, H10a, H10b; 3.06, 1H, dd, J 2.0, 12.8 Hz, H8; 2.78,
1H, br dd, J 7.7, 18.1 Hz, H5; 2.42, 1H, m, H'5; 2.39, 3H, s, 9-Me; 2.18,
1H, dd, J 7.7, 14.2 Hz, H4; 2.02, 1H, m, obscured, H11; 2.00, 1H, d, J
3
extracted with EtOAc. The organic phase was dried over MgSO , and
4
evaporated to dryness. The crude material was purified by preparative
t.l.c. (silica, EtOAc/chloroform, 1:1, with 5% MeOH) to give ~2 mg of
the title compound. (Found: 312.1354. C
12.4 Hz, H'8; 1.92, 1H, ddd, J 7.7, 12.6, 14.2 Hz, H'4; 1.04, 3H, d, J 7.4
H
O requires 312.1361).
19 20
4
13
Hz, 11-Me; 0.75–0.9, 13H, m, DEIPS; 0.4–0.6, 4H, m, DEIPS.
C
λ
(EtOH) 240 (log ε 4.50), 321 (4.05). υ
(neat) 3100 (s, br),
max
max
n.m.r. δ (75 MHz, CDC1 ) 200.6, C10; 176.2, C3; 145.3, C7; 134.0,
–1
1
3
1760s, 1620s, 1590m, 1530m cm . H n.m.r. δ (500 MHz, CDC1 )
3
133.5, 131.7, 131.3, C5a, C5b, C9a, C9b; 100.1, C6; 78.8, C1; 73.7,
C12; 56.2, OMe; 47.7, C3b; 42.6, C3a; 42.3, C10a; 41.0, C8; 35.2, C11;
27.8, C5; 23.5, C4; 20.1, 9-Me; 16.9, 11-Me; 47.7, 3b; 42.6, C3a; 42.3,
C8; 41.0, C10a; 35.2, C11; 27.8, C5; 23.5, C4; 19.8, 9-Me; 16.9, 16.8,
SiCHMe ; 16.75, 11-Me; 12.4, SiCHMe ; 6.7, 2×C, SiCH Me; 3.4,
6.92, 1H, br s, H8; 6.84, 1H, br s, H6; 4.57, 1H, t, J 4.2 Hz, H1; 3.80,
1H, dd, J 1.6, 4.5, 5.7 Hz, H12; 3.70, 1H, d, J 18.5 Hz, H10β; 3.49, 1H,
d, J 10.9, H10b; 3.24, 1H, dd, J 18.5, 11.1, H10α; 3.16, 1H, m, H10a;
2.89, 1H, m, H5; 2.80, 1H, m, H'5; 2.42, 1H, m, H4; 2.33, 3H, s, 9-Me;
2
2
2
1.85, 1H, dt, J 14.6, 7.6 Hz, H'4; 1.45, 1H, m, H11; 0.99, 3H, d, J 7.1Hz,
+
3.2, SiCH Me. Mass spectrum m/z 470 (M , 37%), 442 (14), 441 (39),
13
2
11-Me. C n.m.r. δ (75 MHz, CDC1 ) 184.2, C7; 177.0, C3; 141.5, C8;
3
428 (40), 427 (100).
138.0, 6; 145.4, 144.7, 142.1, 139.0, C5a, C5b, C9a, C9b; 77.6, C1;
75.6 C12; 51.5, C3b; 44.3, C3a; 37.2, C10a; 37.4, C11; 30.4, C5; 25.0,
+.
C4; 21.6, 9-Me; 16.9, 11-Me. Mass spectrum m/z 312 (M , 47%), 285
(6), 284 (44), 238 (21), 221 (34), 207 (81), 197 (33). 196 (80), 181 (34),
169 (33), 167 (55), 165 (47), 155 (42), 153 (48), 143 (100, 128 (40), 115
(1RS, 3aRS, 10aSR, 10bSR 11SR, 12SR)-3a,5,8,10,10a,10b-
Hexahydro-12-hydroxy-7-methoxy-9,11-dimethyl-10-oxo-1,3a-ethano-
1H-cyclohept[3,4]indeno[1,7-cd]pyran-3(4H)-one (36)
(25).
Silyl ether (35c) (52 mg, 0.11 mmol) was dissolved in THF (3 ml) and
the solution was cooled to 0°C. The solution was treated with TBAF
(0.1 ml of a 1M solution in THF), and allowed to stir for 5 min. The
orange mixture was quenched with ice water (10 ml) and extracted with
EtOAc. The organic phase was washed with brine, dried over
magnesium sulphate, and evaporated to dryness. Chromatography on
2
Hainanolidol (lit.) . λ
240 (log ε 4.50), 321 (4.05). υ
3100 (s,
max
max
–1 1
br), 1760s, 1620s, 1590m, 1530m cm . H n.m.r. δ (60 MHz, CDC1 )
3
6.90, 2H, m, H6, H8; 4.62, 1H, t, H1; 3.78, 1H, t, H12; 3.65–3.0, 5H,
m; 2.9–2.3, 3H, m; 2.24, 3H, s, 9-Me; 1.94, 1H, m; 1.54, 1H, m; 1.02,
+.
3H, d, 11-Me. Mass spectrum m/z 312 (M , 78%), 285 (11), 284 (51),
238 (13), 221 (23), 207 (63), 197 (26). 196 (73), 181 (23), 169 (23), 167
(39), 165 (32), 155 (34), 153 (33), 143 (100, 128 (28), 115 (13).
silica gel (hexane/EtOAc, 1:2) provided the deprotected alcohol (36) in
1
85% yield. (Found: 342.1458. C
H
O requires 342.1467). H n.m.r.
20 22
5
δ (300 MHz, CDC1 ) 5.29, 1H, br s, H6; 4.94, 1H, t, J 4.9 Hz, H1; 3.76,
3
X-ray Structure Determination of Alcohol (16a)
1H, q, J 4.15 Hz, H12; 3.64, 3H, s, OMe; 3.24, 1H, dd, J 4.9, 12.5 Hz,
H10a; 3.16, 1H, br d, J 12.5 Hz, H10b; 3.07, 1H, dd, J 2.0, 12.8 Hz, H8;
2.80, 1H, dd, J 7.7, 18.1 Hz, H5; 2.45, 1H, m, H'5; 2.39, 3H, s, 9-Me;
2.18, 1H, dd, J 7.7, 14.2 Hz, H4; 2.03, 1H, d, J 12.4 Hz, H'8; 1.90–2.08,
Crystal Data. C
H O Si, M 488.69, monoclinic, C2/c, a 25.170(4),
27 40 6 r
3
b 10.904(2), c 21.132(2) Å, β 114.208(9)°, V 5290(1) Å , Z 8, D
x
–3
-1
1.227 g cm , λ (Cu Kα) 1.5418 Å, µ 10.74 cm , F(000) 2112, T 213
K, R 0.085 for 2787 observed reflections.
13
2H, m, H'4, H11; 1.09, 3H, d, J 7.3 Hz, 11-Me. C n.m.r. δ (75 MHz,
Data Collection And Processing: A yellow prismatic crystal of size
0.3 × 0.2 × 0.1 mm was mounted on a quartz fibre. All measurements
were made on a Rigaku AFC6R four-circle diffractometer with graphite
monochromated Cu Kα radiation and a rotating anode generator. Lat-
tice parameters were obtained from least-squares analysis of the setting
angles of 25 reflections with 43.5 < θ < 47.3°. Intensity data were col-
lected at a temperature of 213 K using the ω-2θ scan technique to a
maximum 2θ value of 120°. The total number of reflections measured
was 4310. Equivalent reflections were merged to yield 3938 unique data
CDC1 ) 203.7, C10; 176.2, C3; 145.9, C7; 134.6, 134.1, 132.5, 130.4,
3
C5a, C5b, C9a, C9b; 100.6, C6; 78.3, C1; 74.1, C2; 56.1, OMe; 47.4,
C3b; 42.6, C3a; 42.5, C8; 41.1, C10a; 33.5, C11; 27.8, C5; 23.2, C4;
+
20.1, 9-Me; 16.9, 11-Me. Mass spectrum m/z 342 (M , 100%), 327
(66), 296 (5), 281 (7), 267 (16), 265 (16), 251 (10).
(1RS, 3aRS, 10aSR, 10bSR 11SR, 12SR)-3a,5,8,10,10a,10b-
Hexahydro-10,12-dihydroxy-7-methoxy-9,11-dimethyl-1,3a-ethano-
1H-cyclohept[3,4]indeno[1,7-cd]pyran-3(4H)-one (38)
(R 0.062), of which 2787 with I > 3σ(I) were used in structure solu-
int
26
To ketone (36) (31 mg, 0.091 mmol) dissolved in MeOH (2 ml), was
tion and refinement. Structure solution was by direct methods.
27
added NaBH (10 mg, excess). The reaction mixture was stirred at
Refinement with anisotropic displacement factors for all non-hydro-
4
room temp until complete by t.l.c. (40 minutes). The mixture was
diluted with brine (5 ml) and acidified to pH 3 with 0.5M HCl. The
aqueous phase was extracted with EtOAc, and the organic extracts were
washed with brine, dried over Mg SO and evaporated to dryness. The
crude material (30 mg) appeared to be ~80% pure by n.m.r. analysis.
The sample was purified by preparative t.l.c. (silica, hexane/EtOAc,
1:3) to give pure diol (38) (10 mg). This sample degraded significantly
gen atoms gave rise to unacceptably large ratios between maximum and
minimum displacements of atoms C(115), C(116), C(117) and C(118),
all within the OSi(CH ) (C H ) group, suggesting that these atoms
3 2
4 12
were disordered. Consequently these atoms were each split over two
sites and the relative populations were refined. Restraints were imposed
on bond distances involving the disordered atoms. Hydrogen atoms at-
tached to carbon atoms were included at calculated positions (those cor-
2
4

830
L. Mander et al.
11
12
13
14
responding to the minor orientation of the disordered OSi(CH ) (C H )
group were omitted); the alcohol hydrogen atom on O(101) was not lo-
Morris, J. C., Mander, L. N., and Hockless, D. C. R., Synthesis,
1998, 455.
Chamberlin, R. E., Ph.D. Dissertation, University of Nevada-
Reno, 1983.
Kende, A. S., Koch, K., and Smith, C. A., J. Am. Chem. Soc., 1988,
110, 2210.
A preliminary account of this work has been published: Frey, B.,
Wells, A. P., Rogers, D. R., and Mander, L. N., J. Am. Chem. Soc.,
1998, 120, 1914.
Emde, H., Domsch, D., Feger, H., Frick, U., Götz, A., Hergott,
H. H., Hofmann, K., Kober, W., Krägeloh, K., Oesterle, T.,
Steppan, W., West, W., and Simchen, G., Synthesis, 1982, 1.
Corey, E. J., Cho, H., Rücker, C., and Hua, D. H., Tetrahedron
Lett., 1985, 22, 3455–3458.
King, G. R., Mander, L. N., Monck, N. J. T., Morris, J. C., and
Zhang H., J. Am. Chem. Soc., 1997, 119, 3828.
Kennedy, M., and McKervey, M. A., J. Chem. Soc., Chem.
Commun., 1988, 1028.
Agaskar, P. A., Cotton, F. A., Falvello, L. R., and Hahn, S., J. Am.
Chem. Soc., 1986, 108, 1214.
Mukaiyama, T., Org. React., 1982, 28, 203.
Cf. White J. M., Rogers D. H., and Mander L. N., Acta Cryst.,
1991, C47, 2254.
Corey, E. J., and Varma, R. K., J. Am. Chem. Soc., 1971, 93, 7319.
Toshima, K., Mukaiyama, S., Kinoshita, M., and Tatsuta, K.,
Tetrahedron Lett., 1989, 30, 6413.
Barton, D. H. R., Hartwig, W., Motherwell, R. S. H., Motherwell,
W. B., and Stang, A., Tetrahedron Lett., 1982, 23, 2019
(a) Evans, D. A., Chapman, K. T., and Carreira, E. M., J. Am.
Chem. Soc., 1988, 110, 3560–3578. (b) Bhaskar, K. V., and
Mander, L. N., Tetrahedron Lett., 1996, 37, 719
Altomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A.,
Burla, M. C., Polidori, G., and Camalli, M., J. Appl. Crystallogr.,
1994, 27, 435.
teXsan. Single Crystal Structure Analysis Software. Version 1.8;
Molecular Structure Corp., 3200 Research Forest Drive, The
Woodlands, TX 77381, USA, 1997.
'International Tables for X-ray Crystallography', Vol. 4, pp 99–101,
149–150 (Kynoch Press: Birmingham, England, 1974).
3 2
4 9
cated. Full matrix least-squares refinement on F using 299 parameters
2
gave final R 0.085. The weighting scheme used was w = [σ (F) +
2 –1
0.0001F ] and the maximum shift/error ratio in the final cycle was
0.04. The maximum and minimum heights in the final difference map
–3
were 0.64 and –0.53 e Å with the major features being located in the
disordered region of the structure. Neutral-atom scattering factors with
28
anomalous dispersion corrections were used throughout.
15
Acknowledgments
16
17
18
19
The authors are most grateful to Dr George Buta, U.S.
Department of Agriculture, Beltsville, Maryland for the
provision of an authentic sample of harringtonolide, to
Professor Huang Liang, Materia Medica, Beijing for helpful
correspondence, and to Bruce Twitchin for technical
assistance in the preparation of early intermediates.
20
21
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http://www.publish.csiro.au/journals/ajc