Exploratory studies on the synthesis of the unusual diterpenoid tropone harringtoriolide

C S I R O P U B L I S H I N G

Australian Journal

of Chemistry

Volume 52, 1999

A journal for the publication of original research

in all branches of chemistry and chemical technology

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Published by CSIRO PUBLISHING

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the Australian Academy of Science

Aust. J. Chem., 1999, 52, 1093–1108

Exploratory Studies on the Synthesis of the

Unusual Diterpenoid Tropone Harringtonolide*

Daniel H. Rogers,^ABarbara Frey,^AFrancis S. Roden,^A

Friedrich-Wilhelm Russkamp,^AAnthony C. Willis^Aand Lewis N. Mander^A,B

^AResearch School of Chemistry, Institute of Advanced Studies,

Australian National University, Canberra, A.C.T. 0200.

^BAuthor to whom correspondence should be addressed.

Various approaches to the total synthesis of the unusual diterpenoid tropone (2), discovered in the yew species

Cephalotaxus harringtonia and C. hainanensis, are described. The rhodium-catalysed intramolecular cyclopropa-

nation reaction of an aryl ring by means of the transition metal catalysed reaction of a diazoacetyl function was used

to assemble the 5/7 ring system and to provide a cycloheptatrienyl precursor to the tropone moiety, e.g. (28) Q (29)

and (38) Q (39). In the most promising approach, the carbocyclic system was assembled by means of the aldol reac-

tion (42) Q (43) with the newly formed ␣-hydroxyl being employed subsequently in the formation of the ␦-lactone

function of (44). The tropone ring may be formed from the methoxycycloheptatriene moiety simply by treatment

with mercuric nitrate. Tropone (45) was formed from (44) in this way, but attempts to convert it into harringtono-

lide by means of transannular oxidation based on the 4-hypoiodite failed. The crystal structure of an intermediate is

reported.

Introduction

The diterpenoid tropone harringtonolide (2) was first iso-

lated in North America from seeds of Cephalotaxus harring-

tonia (Taxaceae) and its structure established by X-ray

crystallography.¹It was shown to be an inhibitor of plant

growth in tobacco and beans, also causing necrosis under

some conditions. Harringtonolide was independently dis-

covered in the bark of the related Chinese species

Cephalotaxus hainanensis, given the name hainanolide,²and

was found to have anti-cancer and anti-viral properties,

being active against Lewis lung carcinoma, Walker carci-

noma, Sarcoma-180, and L-1210, L-615 and P-388

leukaemias, as well as showing in vitro activity against

influenza type A, Newcastle disease, Japanese B encephali-

tis and vaccinia viruses.³In C. hainanensis, (2) was accom-

panied by the closely related, but biologically inactive

carbinol, hainanolidol (1), the structure of which was estab-

lished by conversion into (2) by transannular oxidation with

lead tetraacetate (Scheme 1).⁴In order to explore the chem-

istry and therapeutic potential of these unusual compounds,

we embarked upon a program of total synthesis some years

ago, recently culminating in the total synthesis of (±)-(1) and

the formal synthesis of (2).⁵In this paper we describe the

underpinning methodology that was developed for this syn-

thesis and a number of other approaches to (2) that were

explored.⁶

Results and Discussion

Retrosynthetic analysis led logically to the initial proposi-

tion that we should base our approach to (2) on the sequence

outlined in Scheme 2. The substituent OR²was intended to

serve ultimately as a leaving group in the formation of the

ether ring of (2), while the pivotal arene cyclopropanation

reaction (5) Q (6) Q (7) was based on the precedents pro-

vided by the studies of McKervey and coworkers in simpler

systems.⁷Thus, the proposed synthesis is broadly simplified

to one of preparing a suitably substituted phenanthrene

derivative (3). The synthesis of molecules like (3) appeared

to be readily achievable through the adaptation of our well

established methodology encompassing the Birch reductive

alkylation of aromatic acids⁸and the controlled C-acylation

of preformed enolates with alkyl cyanoformates.⁹

As outlined in Scheme 3, the preparation of the phenan-

threne-derived intermediate (13) that we expected to serve as

* Dedicated to Professors Roy Jackson, John Pinhey, Rod Rickards, Sever Sternhell and Wal Taylor in recognition of their very considerable con-

tributions to science, and the inspiration and friendship that they have provided to the senior author and other Australian chemists.

Manuscript received 29 July 1999

10.1071/CH99093

0004-9425/99/111093

1094

D. H. Rogers et al.

Table 1. Atomic coordinates and isotropic displacement

parameters for the non-hydrogen atoms in C₁₈H₂₀O₄

a suitable precursor to (3) and thence (4), proceeded

smoothly and efficiently (for the preparation of iodide (9) see

the Experimental section). Cyclization of (11) with Lewis

acids afforded the undesired 2-methyl 4-methoxy isomer

(12), but mainly (13) was obtained on treatment with

polyphosphoric acid. From an inspection of molecular

models, the cis stereochemistry was expected to be favoured

and this was confirmed by single-crystal X-ray analysis (Fig.

1 and Tables 1 and 2).*

C-Acylation of enone (13) was expected to be problemat-

ical, given the sterically crowded environment of C 5, but

when methyl cyanoformate was used as the acylating

reagent,⁹the ␤-keto ester (14) was obtained in good yield,

with only a minor amount of O-acylated product being

formed. The crystal structure of (13) had shown that the con-

former in which the ester group adopts an equatorial dispo-

1

3

* *

Σ Σ U a a a .a

j ij i

U

=

eq

i

j

i

j

Atom

X/a

Y/b

Z/c

U_eq

C(1)

0.3692(3)

0.2878(3)

0.2419(2)

0.1845(2)

0.2704(3)

0.4030(2)

0.4346(2)

0.4672(2)

0.4796(4)

0.4934(2)

0.4896(2)

0.5136(2)

0.5705(4)

0.4593(2)

0.4316(2)

0.4056(3)

0.3575(2)

0.4223(2)

0.5619(2)

0.6384(2)

0.5892(2)

0.7195(3)

0.0752(3)

0.1219(3)

0.2740(3)

0.3249(3)

0.3621(3)

0.3339(3)

0.4299(3)

0.5782(3)

0.6445(4)

0.6673(3)

0.6102(3)

0.6897(2)

0.8295(4)

0.4641(3)

0.3735(3)

0.2124(3)

0.1245(3)

0.1679(3)

0.1382(3)

0.2120(3)

0.0188(2)

–0.0169(5)

0.0719(2)

0.0068(2)

0.0021(2)

–0.0635(1)

0.0840(2)

0.1280(2)

0.2080(1)

0.1990(2)

0.1113(2)

0.2720(2)

0.3538(2)

0.4295(1)

0.4265(2)

0.3636(2)

0.2916(2)

0.3075(2)

0.2269(2)

0.1485(2)

0.1644(2)

0.1364(2)

0.2116(1)

0.2343(3)

0.042(1)

0.048(2)

0.045(2)

0.065(1)

0.042(2)

0.031(1)

0.029(1)

0.033(1)

0.052(2)

0.034(1)

0.048(1)

0.054(2)

0.035(1)

0.030(1)

0.039(1)

0.035(1)

0.031(1)

0.036(1)

0.069(1)

0.050(1)

0.062(2)

C(2)

C(3)

O(31)

C(4)

C(5)

C(6)

C(7)

C(71)

C(8)

C(9)

O(91)

C(92)

C(10)

C(11)

C(12)

C(13)

C(14)

C(141)

O(142)

O(143)

C(144)

sition relative to the enone ring was preferred, thus rendering

the ␣-face of the molecule convex. We were therefore con-

fident that nucleophiles would add to the enone function to

furnish 8␣-adducts. This was indeed the case with the addi-

tion of lithium methyl cuprate to (14), which proceeded in

good yield to give a mixture of the ␤-keto ester (16) with its

enol form (15). Given the ease with which ␤-keto esters nor-

mally enolize, we were surprised to find that the tautomers

were separable on chromatography. Although such a sepa-

ration would normally be impractical, interconversion in this

Fig. 1. ORTEP diagram of enone (13) (C₁₈H₂₀O₄) showing the labelling

of the non-H atoms. Thermal ellipsoids are shown at 50% probability

levels except for H atoms which are drawn as small circles.

* An Accessory Publication consisting of hydrogen atom coordinates, anisotropic displacement parameters, torsion angles, additional interatomic

distances and angles, least-squares planes, and structure factor amplitudes is available (until 31 December 2004) from the Australian Journal of

Chemistry, P.O. Box 1139, Collingwood, Vic. 3066.

Studies on the Synthesis of Harringtonolide

1095

Table 2. Selected bond distances (Å) and angles (deg) for

C₁₈H₂₀O₄

induced by an appropriate electrophile (Scheme 4). When

the feasibility of such a process was successfully achieved in

the model system (22) Q (23) (Scheme 5),¹¹we were encour-

aged to test such an approach on an actual intermediate and

accordingly initiated the sequence outlined in Scheme 6.

The starting point for the new approach was enone (13)

which was this time C-acylated with benzyl cyanoformate in

anticipation of the need to liberate a free 5-carboxy function

under mild conditions. A 13 : 3 : 1 mixture of ester (24), its

5␤-epimer and the enol carbonate (25) was obtained, and,

given our experience with the preparation of the methyl ester

analogue (16), we were not surprised to find that the C 5

epimers were separable by chromatography, although a pure

sample of the 5␤-epimer could not be obtained. The crude

product from this step was subjected to cyclopropanation

with the methylene ylide derived from dimethyl sulfoxide,¹²

and a separable mixture of epimeric esters was again formed,

although this time the enol tautomer was also observed

(5␤/5␣/enol 31 : 53 : 16 as measured by ¹H n.m.r. spec-

troscopy). Preliminary experiments (not reported) with the

preferred 5␤-epimer, aimed at elaborating an analogue of

diazoketone (5) (cf. Scheme 2), indicated that a successful

outcome was unlikely, so we continued with the major ester

(26). This intermediate has the incorrect stereochemistry at

C 5, but there appeared to be a reasonable prospect of inver-

sion at C 5 by means of a trans Q cis isomerization of the

C,D-ring fusion once the indanone moiety had been formed,

as in (30).

Reduction of the 6-carbonyl group, followed by protection

of the resulting 6␣-carbinol and then liberation of the 5-car-

boxyl by hydrogenolysis, smoothly afforded (27), but con-

version into the corresponding acyl chloride could not be

achieved by standard procedures. Dimethyl formamide is

often used as a catalyst in the preparation of acid chlorides,

the chloro iminium derivative being the actual agent, but was

ineffectual in the present situation. When the sodium salt of

(27) was treated with an excess of the preformed iminium

chloride derived by treatment of dimethylformamide with

oxalyl chloride, however, the acyl chloride was obtained in

good yield and subsequently converted by diazomethane into

diazoketone (28). Arene cyclopropanation,¹³catalysed by

rhodium mandelate,¹⁴then gave (29) in gratifyingly high

yield (93%). This type of adduct, in which H4a is flanked by

two double bonds and the C 4 carbonyl group, is especially

vulnerable to attack by adventitious O₂, but conjugation of the

⌬⁵-alkene bond by brief treatment with 1,8-diazabicy-

clo[5.4.0]undec-7-ene to give (30) improved stability to a

certain extent.All attempts to invert the stereochemistry at the

indanone ring junction (via enolate formation) led to decom-

position products—␤-elimination of the OSiMe₂Bu^tgroup

was indicated from the ¹H n.m.r. spectra. Attempts to form the

free carbinol by treatment with tetrabutylammonium fluoride,

with a view to effecting isomerization by means of a retroal-

dol/aldol process, were similarly unsuccessful.

C(1)–C(2)

1.324(4)

1.465(4)

1.500(4)

1.520(3)

1.402(3)

1.512(4)

1.378(4)

1.389(4)

1.519(4)

1.533(4)

1.320(3)

C(1)–C(14)

C(3)–O(31)

C(4)–C(5)

C(5)–C(14)

C(6)–C(11)

C(7)–C(8)

C(9)–O(91)

O(91)–C(92)

C(11)–C(12)

C(13)–C(14)

C(141)–O(142)

O(143)–C(144)

1.509(4)

1.215(3)

1.537(4)

1.546(3)

1.401(3)

1.392(3)

1.375(3)

1.415(4)

1.514(4)

1.538(4)

1.194(4)

1.453(4)

C(2)–C(3)

C(3)–C(4)

C(5)–C(6)

C(6)–C(7)

C(7)–C(71)

C(8)–C(9)

C(9)–C(10)

C(10)–C(11)

C(12)–C(13)

C(14)–C(141)

C(141)–O(143)

C(2)–C(1)–C(14)

C(2)–C(3)–O(31)

O(31)–C(3)–C(4)

C(4)–C(5)–C(6)

125.0(3)

C(1)–C(2)–C(3)

122.0(3)

122.3(3)

122.4(3)

111.6(2)

112.3(2)

121.3(2)

121.7(2)

118.2(2)

124.5(2)

115.5(2)

120.6(2)

122.0(2)

115.1(2)

110.6(2)

107.4(2)

108.0(2)

124.7(2)

123.0(2)

C(2)–C(3)–C(4)

115.3(2)

111.5(2)

110.4(2)

120.0(2)

118.6(2)

120.1(2)

120.5(2)

120.0(2)

118.4(2)

120.2(2)

117.7(2)

112.0(2)

108.4(2)

110.3(2)

112.1(2)

112.4(2)

117.4(2)

C(3)–C(4)–C(5)

C(4)–C(5)–C(14)

C(5)–C(6)–C(7)

C(7)–C(6)–C(11)

C(6)–C(7)–C(8)

C(7)–C(8)–C(9)

C(8)–C(9)–C(10)

C(9)–O(91)–C(92)

C(6)–C(11)–C(10)

C(10)–C(11)–C(12)

C(12)–C(13)–C(14)

C(1)–C(14)–C(13)

C(5)–C(14)–C(13)

C(13)–C(14)–C(141)

C(14)–C(141)–O(143)

C(141)–O(143)–C(144)

C(6)–C(5)–C(14)

C(5)–C(6)–C(11)

C(6)–C(7)–C(71)

C(71)–C(7)–C(8)

C(8)–C(9)–O(91)

O(91)–C(9)–C(10)

C(9)–C(10)–C(11)

C(6)–C(11)–C(12)

C(11)–C(12)–C(13)

C(1)–C(14)–C(5)

C(1)–C(14)–C(141)

C(5)–C(14)–C(141)

C(14)–C(141)–O(142)

C(142)–C(141)–O(143)

case is presumably impeded by the extreme steric crowding

in this region of the molecule. Although (16) lacks a func-

tional group at C 7, it was of interest to investigate the elab-

oration of the lactone function as a preliminary to the

preparation of a suitable analogue of (4), especially as lac-

tonization requires the formation of an all-boat conformation

[2.2.2] ring system which then places the 5-carboxy function

into an even more crowded environment. In the event, reduc-

tion of either (15) or (16) with zinc borohydride and subse-

quent treatment with acid afforded lactone (17) in moderate

yield. This intermediate was shown to have the undesired ␣-

configuration at C 5, however, as indicated by a doublet for

H5 (J_5,4b6.7 Hz). Unfortunately, all attempts to achieve

epimerization at C 5 by kinetically controlled protonation

were unproductive.

With a view to preparing (3; R¹= CO₂Me, R²= H), the

cuprate adduct from (14) was trapped with t-

butyldimethylsilyl chloride, but all attempts to introduce an

oxygen function at C 7 in the resulting adduct (18) proved to

be futile, with no discrete products being obtained. We there-

fore reordered the sequence for introducing R¹and OR²by

adding lithium methyl cuprate to (13), trapping the adduct

with Bu^tMe₂SiCl, and oxidizing the product (19) with

osmium tetraoxide.¹⁰Oxygenation now proceeded smoothly,

affording a mixture of the 7␤-axial isomer (20) with its 7␣-

epimer. This mixture was therefore converted into a mixture

of methoxymethyl ethers and equilibrated with base to afford

the more stable 7␣-epimer (21). This time, however, appli-

cation of the cyanoformate-based acylation procedure failed

completely, with starting material being returned.

Given the difficulties in preparing an intact phenanthrene

derivative with the correct configuration at the sterically

crowded C 5 location, an alternative approach was devised

whereby the desired stereochemistry might be established by

In contemplating the formation of the cyclic ether func-

tion and the trans vicinal methyl group in harringtonolide,

we had considered the possibility of intramolecular attack by

a hydroxy group on a suitably disposed cyclopropane ring

1096

D. H. Rogers et al.

Studies on the Synthesis of Harringtonolide

1097

ing an acid chloride)—arene cyclopropanation was carried

out efficiently (81% yield); the very labile adduct (39) was

again [cf. (29) Q (30)] stabilized by base-catalysed isomer-

ization to (40). Deprotection of the aldehyde function with

Me₂BBr¹⁵resulted in concomitant hydrolysis of the enol

function and the formation of an aldol-like product. We were

hopeful that the aldol reaction had occurred in the desired

manner [cf. (33) Q (34)], but a ¹³C n.m.r. spectrum clearly

showed that the product lacked a methine carbon relative to

the starting material and that a new quaternary carbon had

been formed in the process. After close examination of n.m.r.

spectra, it seemed likely that the product possessed structure

(41). Following the selective hydrolysis of the acetal function

through the use of a platinum catalyst¹⁶to give (42), however,

means of an intramolecular aldol reaction, e.g. (33) Q (34),

following arene cyclopropanation, as outlined in Scheme 7.

In order to test the feasibility of this new approach, we

set about to prepare the simpler aldehyde (42) and study its

conversion into lactone (45) (Scheme 8). We were also

hopeful that it might be possible for (45) to serve as an

actual intermediate.

The mixture of ketol (20) with its 7-epimer was oxida-

tively cleaved by Pb(OAc)₄–MeOH to aldehyde (35), which

was transformed into the enol ether (36) by means of a Wittig

reaction. Methanolysis gave acetal (37) and, after further

elaboration to diazoketone (38)—this time, by utilizing a

mixed carbonate anhydride in order to avoid exposure of the

acetal function to acid (an inevitable consequence of prepar-

1098

D. H. Rogers et al.

a base-catalysed aldol reaction proceeded smoothly to afford

(43), as confirmed by n.m.r. spectra and single-crystal X-ray

analysis.¹⁷Ketone (43) was reduced under Luche condi-

tions¹⁸to the desired ␤-epimer, which was then partially con-

verted into lactone (44) by K₂CO₃in aqueous methanol,

recycling of recovered hydroxy ester raising the yield to 68%.

The tropone functionality was then established by treatment

with mercuric nitrate to afford secoharringtonolide (45), the

structure of which was evident from the downfield shift in the

¹H n.m.r. spectra of the 5-methyl resonance from ␦ 2.02 in

(44) to ␦ 2.40 in (45), and signals at ␦ 6.91 and 6.95 for H 6

and H 8. This method for preparing tropones from methoxy-

cyclohexatrienes is general and further examples will be

described in due course.

tionality that should allow (ultimately) for the completion of

the ether ring. Although the present sequence was regarded

essentially as a model system, there appeared to be a reason-

able prospect of converting (45) into (2) through transannu-

lar oxidation. However, under most standard conditions, e.g.

Pb(OAc)₄, I₂¹⁹and PhI(OAc)₂, I₂,²⁰there was no sign of the

desired (2). An authentic sample of harringtonolide was

available, but t.l.c. comparisons with the various reaction

mixtures showed no trace of the desired product. Treatment

of (42) with N-iodosuccinimide²¹did afford a small amount

of a very unstable product, the ¹H n.m.r. spectrum of which

was consistent with iodide structure (46) (the stereochem-

istry at C 2 was determined from the lack of coupling

between H 2 and H 1), but this intermediate is clearly not

suitable for direct ether formation by nucleophilic displace-

ment. Accordingly, as reported elsewhere,⁵the sequence out-

lined in Scheme 8 was modified to include a substituent

adjacent to the aldehyde function as in (33) (Scheme 7), and

The preparation of (42) by this approach had clearly

established the general feasibility of preparing the har-

ringtonolide system by this new strategy. Moreover, enol

ether (36) affords the opportunity to introduce further func-

Studies on the Synthesis of Harringtonolide

1099

2-(3´-Methoxy-5´-methylphenyl)ethanol

culminated in the total synthesis of hainanolidol (1) and the

formal synthesis of harringtonolide (2).

Asolution of the carboxylic acid prepared above (30.0 g, 167 mmol)

in tetrahydrofuran (60 ml) was added dropwise, via a dropping funnel,

to a stirred suspension of LiAlH₄(6.8 g, 170 mmol) in dry tetrahydro-

furan (200 ml) maintained under a nitrogen atmosphere. The mixture

was kept at gentle reflux for a further 2 h and then the excess hydride

carefully destroyed by the slow addition of brine. HCl (2 ^M) was added

to completely dissolve the remaining precipitate and the aqueous phase

extracted with Et₂O. The combined organic phases were washed with

water, saturated aqueous NaHCO₃and brine, and then dried over

MgSO₄. Concentration under reduced pressure afforded the title

carbinol as a colourless oil (26.0 g, 94%), R_F0.35 (pentane/ethyl

acetate, 3: 1) (Found: C, 72.2; H, 8.6. C₁₀H₁₄O₂requires C, 72.3; H,

Experimental

General reaction conditions have been reported elsewhere.²²

1-Bromomethyl-3-methoxy-5-methylbenzene

A catalytic amount (0.5 g) of azobisisobutyronitrile was added to a

mixture of 1-methoxy-3,5-dimethylbenzene (27.2 g, 200 mmol) and

carefully dried N-bromosuccinimide (44.0 g, 247 mmol) in dry CCl₄

(350 ml). The mixture was irradiated with two 250-W tungsten lamps

and heated at reflux until all of the N-bromosuccinimide had been con-

sumed (c. 1 h). The cooled solution was washed sequentially with 2 ^M

NaHSO₃solution, water and brine, and the aqueous washings were then

extracted with dichloromethane. The combined organic phases were fil-

tered (phase-separation paper), dried (MgSO₄) and concentrated under

reduced pressure to afford a pale yellow oil. Distillation of this material

under reduced pressure gave three major fractions. The first fraction

comprised mostly starting material and the benzyl bromide (3.8 g total,

ratio 7 : 3), while the second fraction contained only the benzyl bromide

(28.8 g, 67%) (b.p. 85–90°/0.05 mmHg). This material was further puri-

fied by chromatography on silica gel (pentane/ethyl acetate, 4: 1) and

recrystallization (ethyl acetate/pentane) to give white needles of the

target bromide, m.p. 42–43°, R_F0.72 (pentane/ethyl acetate, 4 : 1)

(Found: C, 50.1; H, 5.2; Br, 37.1. C₉H₁₁BrO requires C, 50.3; H, 5.2; Br,

37.2%). ␯_max(film) 2960, 2840, 1598s, 1465, 1300s, 1155s, 1065s, 840,

8.5%). ␯

(film) 3700–2800, 2940s, 2840, 1598s, 1460s, 1290s,

max

1150s, 1070, 835, 700 cm^–1. ¹H n.m.r. (300 MHz) ␦ 2.32, br s, 5´-Me;

2.80, br t, J_1,26.6 Hz, H2; 3.20–3.00, br s, 8´-OH; 3.38, t, 2H, J_2,1

6.6 Hz, H 1; 3.78, s, OMe; 6.51, 6.61, 6.65, 3×br s, ArH. ¹³C n.m.r. (75

MHz) ␦ 21.4, 5´-Me; 39.2, C 2; 55.0, 3´-OMe; 63.4, C 1; 111.7, 112.5,

C 2´, C 4´; 122.3, C 6´; 139.7, 140.0, C 1´, C 5´; 159.7, C 3´. Mass spec-

trum m/z 166 (M, 61%), 148 (6), 136 (50), 135 (100), 123 (24), 121

(19), 105 (33), 91 (33), 79 (16), 77 (16).

2-(3´-Methoxy-5´-methylphenyl)ethyl Methanesulfonate

A solution of the carbinol prepared above (28.1 g, 169 mmol) in dry

pyridine (200 ml) was cooled to –10°, under a nitrogen atmosphere, and

treated with a solution of methanesulfonyl chloride (21.3 g, 186 mmol)

in dichloromethane (20 ml) over c. 5 min. The resulting mixture was

stirred for 2 h at –10° before the addition of water (5 ml). Stirring was

continued at 0° for 15 min and then the reaction mixture diluted with

Et₂O and washed with sufficient 2 M HCl to remove the pyridine, fol-

lowed by saturated aqueous NaHCO₃and brine. The organic phase was

dried (MgSO₄) and concentrated under reduced pressure to give the title

mesylate (37.6 g, 91%) which was used directly without further purifi-

cation, R_F0.38 (pentane/ethyl acetate, 3: 1) (Found: C, 54.0; H, 6.6; S,

13.3. C₁₁H₁₆O₄S requires C, 54.1; H, 6.6; S, 13.1%). ␯_max(film) 2960,

2840, 1600s, 1460s, 1360s, 1295, 1170s, 1075, 955, 840s cm^{–1. 1}H

n.m.r. (300 MHz) ␦ 2.31, br s, 5´-Me, 2.86, s, OSO₂Me; 2.98, br t, J_2,1

6.4 Hz, H2; 3.77, s, OMe; 4.39, t, J_1,26.4 Hz, H1; 6.58, 6.62, 6.64,

3×br s, ArH. ¹³C n.m.r. (75 MHz) ␦ 21.4, 5´-Me; 35.4, C 2; 37.0,

SO₂Me; 55.0, 3´-OMe; 70.3, C 1; 111.6, C 2´; 113.1, C 4´; 122.1, C 6´;

137.5, 139.9, C 1´, C 5´; 159.8, C 3´. Mass spectrum m/z 244 (M, 15%),

149 (20), 148 (100), 136 (5), 135 (35), 119 (5), 117 (7), 105 (10), 91

(17), 77 (10).

1

695s cm^–1. H n.m.r. (300 MHz) ␦ 2.30, br s, 5-Me, 3.78, s, 3-OMe,

4.39, s, H1´; 6.64, 6.69, 6.77, 3×br s, ArH. ¹³C n.m.r. (75 MHz) ␦ 21.4,

Me; 41.0; C 1´; 55.1, OMe; 112.0, C 4; 113.7, C 2; 122.6, C 6; 134.3,

C 5; 139.8, C 1; 159.7, C 3. Mass spectrum m/z 216, 214 (M, 27, 29%),

136 (13), 135 (100), 91 (10). The third fraction and distillation residue

comprised mostly of 2-bromo-5-methoxy-1,3-dimethylbenzene (c.

20% of total).

3´-Methoxy-5´-methylbenzeneacetonitrile

Dried NaCN (6.86 g, 140 mmol) was added in one portion to a solu-

tion of the benzyl bromide prepared above (15.1 g, 70.2 mmol) in dry

1-methylpyrrolidin-2-one (100 ml) at room temperature under a nitro-

gen atmosphere. The solution was left to stir overnight and then diluted

with Et₂O, washed sequentially with 2 M HCl, water and brine and dried

over MgSO₄. Evaporation of the solvent and distillation of the residual

pale yellow oil gave pure nitrile (10.3 g, 91%) as a colourless oil, b.p.

136–141°/17 mmHg, R_F0.50 (pentane/ethyl acetate, 83: 17) (Found: C,

74.4; H, 6.8. C₁₀H₁₁NO requires C, 74.5; H, 6.9%). ␯ (film) 2940,

max

2-(3´-Methoxy-5´-methylphenyl)ethyl Iodide (9)

1

2840, 2250, 1600s, 1465s, 1330s, 1290s, 1070s, 830, 705 cm^–1. H

NaI (100 g, 670 mmol) was added to a stirred solution of the mesy-

late prepared above (32.0 g, 131 mmol) in acetone (280 ml) at room

temperature over a period of c. 5 min. The resultant mixture was then

heated at reflux, under a nitrogen atmosphere, for 2 days. The cooled

solution was treated with Et₂O and the resulting slurry washed sequen-

tially with water, 1 ^MNaHSO₃, water and brine, and then dried over

MgSO₄. Evaporation of the solvent gave iodide (9) as a pale yellow oil

(33.3 g, 92%) which was used directly without further purification, R_F

0.90 (pentane/ethyl acetate, 3: 1) (Found: C, 43.4; H, 4.7; I, 46.0.

n.m.r. (300 MHz) ␦ 2.32, br s, 5´-Me; 3.66, s, H 2; 3.78, s, OMe; 6.66,

13

br s, H 2´, H 4´; 6.72, br s, H 6´. C n.m.r. (75 MHz) ␦ 21.0, 5´-Me; 23.0,

C 2; 54.9, OMe; 110.3, C 4´; 113.9, C 2´; 117.7, CN; 120.7, C 6´; 130.9,

140.0, C 1´, C 5´; 159.8, C 3´. Mass spectrum m/z 162 (M+1, 11%), 161

(M, 100), 160 (13), 146 (33), 135 (12), 121 (16), 116 (15), 91 (34).

3´-Methoxy-5´-methylbenzeneacetic Acid

An aqueous solution of 3 m KOH (50 ml, 150 mmol) was added

slowly to a stirred solution of the nitrile prepared above (10.8 g, 67.0

mmol) in EtOH (100 ml) at room temperature and the resulting mixture

heated under reflux for 11 h. The solution was then concentrated under

reduced pressure and the residue diluted with water and extracted with

Et₂O. The acidified aqueous phase (pH 2) was extracted thoroughly

with Et₂O and the combined organic layers were washed with water and

brine and then dried over MgSO₄. Evaporation of the solvent afforded

the title acid as a pale yellow solid which was recrystallized (ethyl

acetate/pentane) to give white needles (12.0 g, 99%), m.p. 86°. R_F0.1

(pentane/ethyl acetate, 83: 17) (Found: M^+•, 180.0786. C₁₀H₁₂O₃

C₁₀H₁₃IO requires C, 43.5; H, 4.8; I, 46.0%). ␯ (film) 2960, 2840,

max

1595s, 1460s, 1290s, 1260s, 1170s, 1150s, 1065s, 840 cm^–1. ¹H n.m.r.

(300 MHz) ␦ 2.36, br s, 5´-Me; 3.14, m, H1; 3.36, m, H 2; 3.81, s, OMe;

6.58, 6.64, 6.66, 3×br s, ArH. ¹³C n.m.r. (75 MHz) ␦ 5.3, C 1; 21.4, 5´-

Me; 40.3, C 2; 55.0, OMe; 110.9, C 2´; 112.9, C 4´; 121.4, C 6´; 139.6,

C 5´; 141.8, C 1´; 159.7, C 3´. Mass spectrum m/z 277 (M+1, 3%), 276

(M, 27), 150 (11), 149 (100), 134 (16), 119 (28), 117 (17), 115 (10), 91

(48), 77 (23).

requires M^+•, 180.0802). ␯

(CHCl₃) 3700–2500, 1710s, 1600s,

1-[2´-(3´´-Methoxy-5´´-methylphenyl)ethyl]-1,4-dihydrobenzoic Acid

(10)

Benzoic acid (10.9 g, 89.5 mmol) was added to a solution of freshly

distilled, dry NH₃(400 ml) and dry tetrahydrofuran (100 ml) in a three-

necked flask fitted with a dry-ice condenser and a nitrogen inlet, at

–78°. Lithium metal (1.31 g, 0.19 mol) was added in small portions

until the reaction mixture sustained a persistent blue colour. The solu-

max

1460s, 1295s, 1155, 1065s cm^–1. ¹H n.m.r. (300 MHz) ␦ 2.29, br s, 5´-

Me; 3.56, s, H 2; 3.76, s, OMe; 6.64, br s, H2´, H 4´; 6.68, br s, H6´. ¹³

C

n.m.r. (75 MHz) ␦ 21.2, 5´-Me; 40.9, C 2; 54.9, OMe; 111.9, 113.6, C 2´,

C 4´; 122.5, C 6´; 134.3, 139.5, C 1´, C 5´; 159.5, C 3´; 177.7, CO. Mass

spectrum m/z 180 (M, 49%), 136 (17), 135 (100), 121 (14), 105 (18), 91

(37), 77 (22).

1100

D. H. Rogers et al.

tion was maintained at reflux temperature (–30°) for 20 min, then

cooled to –78° and treated dropwise with a solution of iodide (9)

(26.0 g, 94.2 mmol) in dry tetrahydrofuran (50 ml) over c. 10 min. Once

addition was complete, the mixture was kept at reflux (–30°) for 30 min

and then the NH₃allowed to boil off over 3 h. The volatile components

were removed under reduced pressure and the residue was partitioned

between water and pentane. The layers were separated and the aqueous

phase, after acidification to pH 2 with 2 ^MHCl, was extracted with

Et₂O. The combined organic phases were washed with water and brine,

and then dried over MgSO₄. Removal of the solvent under reduced

pressure afforded acid (10) as a white solid (28.9 g, 98%) (Found: C,

3500–2420, 2950, 1700s, 1595s, 1460, 1295, 1150s, 1065, 84^m0^ac^xm^–1. ¹H

n.m.r. (300 MHz) ␦ 2.08–2.00, m, 2H; 2.31 br s, 5´´-Me; 2.54–2.48, br

m, 2H; 2.75–2.68, m, W_h/28.5 Hz, H4; 3.79, s, OMe; 5.85, m, H2, H6;

6.00, m, H 3, H5; 6.54, 6.57, 6.61, 3×br s, ArH. ¹³C n.m.r. (75 MHz) ␦

21.3, 5´´-Me; 30.6, 26.0, C 1´, C 2´; 41.1, C 4; 47.7, C 1; 52.0, 54.9,

OMe; 110.9, 111.9, C 2´´, C 4´´; 121.5, C 6´´; 126.0, C 3, C 5; 126.8,

C 2, C 6; 139.2, 143.3, C 1´´, C 5´´; 159.6, C 3´´; 175.0, CO. Mass spec-

trum m/z 272 (M, 4%), 227 (11), 150 (100), 149 (57), 135 (40), 119

(13), 105 (87), 91 (50), 79 (28), 77 (30).

Methyl (4b␣,8a␣)-4-Methoxy-2-methyl-6-oxo-4b,5,9,10-tetra-

hydrophenanthrene-8a(6H)-carboxylate (12)

To a solution of the dienone (11) (100 mg, 0.33 mmol) in dry

dichloromethane (3 ml) under nitrogen, was added TiCl₄(50 ␮l) drop-

wise at –20°. The resulting dark red solution was allowed to warm to

room temperature over 20 min and was then quenched by the dropwise

addition of water (1 ml). The mixture was extracted with ether and the

combined organic phases were washed sequentially with water and

brine, and dried over MgSO₄. Removal of solvent under vacuum

1

afforded a pale yellow oil (92 mg), which was determined by the H

n.m.r. spectrum to contain a 4: 1 mixture of enones (12) and (13) which

were separated by repeated chromatography (pentane/ethyl acetate,

3: 1) on silica gel. Enone (12) was recrystallized from ethyl

acetate/pentane to give colourless plates, m.p. 121–123°. R_F0.26

(pentane/ethyl acetate, 3: 1) (Found: C, 72.3; H, 7.0. C₁₈H₂₀O₄requires

C, 72.0; H, 6.7%). ␯ (film) 2960, 1735s (CO), 1680s (CO), 1615,

1585, 1460, 1245, 11^m8^a0^x, 1060, 830 cm^–1. ¹H n.m.r. (300 MHz) ␦ 1.97,

m, H 9␤; 2.24, dd, J_5␤,5␣17.0 Hz, J_5␤,4b13.8 Hz, H5␤; 2.35, m, H 9␣;

2.28, s, 2-Me; 2.92–2.74, m, H 10; 2.95, br dd, J_5␣,5␤17.0 J_5␣,4b4.6 Hz,

H5␣; 3.67, 3.81, 2×s, OMe; 4.14, br dd, J_4b,5␤13.8, J_4b,5␣4.6 Hz, H4b;

6.52, br s, H 1, H 3; 6.08, br d, J_7,810.1 Hz, H 7; 6.95, d, J_8,710.1 Hz,

H8. ¹³C n.m.r. (75 MHz) ␦ 21.1, 2-Me; 26.1, 26.6, C 9, C 10; 32.8, C 4b;

40.4, C 5; 49.2, C 8a; 52.3, 54.9, OMe; 108.7, C 1; 121.3, C 3; 123.2,

C 4a; 128.4, C 7; 134.2, C 2; 136.4, C 10a; 151.2, C 8; 156.4, C 4; 173.1,

CO; 198.2, C 6. Mass spectrum m/z 301 (M+1, 19%), 300 (M, 100), 242

(12), 241 (67), 240 (21), 212 (9), 148 (25).

75.0; H, 7.2. C₁₇H₂₀O₃requires C, 75.0; H, 7.4%). ␯

(film)

Methyl 1-[2´-(3´´-Methoxy-5´´-methylphenyl)ethyl]-1,4-

dihydrobenzoate

An ether solution of acid (10) (23.7 g, 87.1 mmol) was cooled to 0°

and treated dropwise with freshly prepared diazomethane in Et₂O until

the solution maintained a constant yellow colour. The remaining dia-

zomethane was then destroyed by the addition of glacial acetic acid and

the solvent removed under reduced pressure to afford the methyl ester

as a pale yellow oil (24.9 g, 100%), R_F0.63 (pentane/ethyl acetate, 3 : 1)

Methyl (4b␣,8a␣)-2-Methoxy-4-methyl-6-oxo-4b,5,9,10-tetra-

hydrophenanthrene-8a(6H)-carboxylate (13)

Dienone (11) (3.50 g, 11.7 mmol) was treated with warm polyphos-

phoric acid (100 ml) and the mixture mechanically stirred at 35° under

an atmosphere of nitrogen for 2 h. The resulting viscous, dark brown

mixture was poured onto ice (250 g) with vigorous agitation using a

stirring rod. The solution was extracted once with Et₂O and twice with

ethyl acetate and the combined organic phases were washed with satu-

rated aqueous NaHCO₃and brine, then dried over MgSO₄. Evaporation

of the solvent and repeated chromatography (pentane/ethyl acetate,

3: 1) afforded an 8: 1 mixture of ketone (13) (2.8 g, 80%) and the iso-

meric (12) (350 mg, 10%). The desired isomer (13) was recrystallized

from ethyl acetate/pentane to give colourless cubes, m.p. 133–134°, R_F

0.19 (pentane/ethyl acetate, 3: 1) (Found: C, 72.1; H, 7.0. C₁₈H₂₀O₄

requires C, 72.0; H, 6.7%). ␯_max(film) 2950, 2840, 1735s, 1685s, 1605s,

1485, 1255, 1145s, 1060, 855, 805, 780, 755 cm^–1. ¹H n.m.r. (300 MHz)

2.02, m, H9␤; 2.32, dd, J_5␤,5␣17.1, J_5␤,4b14.1 Hz, H5␤; 2.33, br s, 4-

Me; 2.41, m, H 9␣; 2.67, ddd, J_5␣,5␤17.1, J_5␣,4b4.4, J_5␣,70.9 Hz, H5␣;

2.98–2.78, m, H10; 3.65, 3.73, 2×s, OMe; 3.96, br dd, J_4b,5␤14.1, J_4b,5␣

4.4 Hz, H4b; 6.07, dd, J_7,810.3, J_7,5␣0.9 Hz, H7; 6.46, 6.50, 2×br d, J_1,3

2.0 Hz, H 1, H3; 6.97, d, J_8,710.3 Hz, H 8. ¹³C n.m.r. (75 MHz) ␦ 18.9,

4-Me; 26.1, 27.4, C 9, C 10; 35.7, C 4b; 49.2, C 8a; 41.7, C 5; 52.7, 55.0,

OMe; 111.4, 115.0, C 1, C 3; 128.2, C 4a; 128.8, C 7; 134.7, C 4; 137.1,

C 10a; 152.0, C 8; 157.7, C 2; 173.5, CO; 198.1, C 6. Mass spectrum m/z

301 (M+1, 20%), 300 (M, 98), 242 (12), 241 (64), 240 (25), 148 (100),

212 (11), 149 (15), 135 (13).

(Found: C, 75.6; H, 7.8. C₁₈H₂₂O₃requires C, 75.5; H, 7.7%). ␯

max

1

(CHCl₃) 2950, 1730s, 1598s, 1460s, 1230s, 1070s, 840, 695 cm^–1. H

n.m.r. (300 MHz) ␦ 2.03–1.96, m, H 2´; 2.31, br s, 5´´-Me; 2.51–2.44,

m, H 1´; 2.73–2.68, br m, W_h/26.5 Hz, H 4; 3.71, 3.78, s, OMe; 5.85, m,

H2, H 6; 5.97, m, H 3, H 5; 6.54, 6.56, 6.60, 3×br s, ArH. ¹³C n.m.r. (75

MHz) ␦ 21.3, 5´´-Me; 26.0, 30.6, C 1´, C 2´; 41.1, C 4; 47.7, C 1; 52.0,

54.9, OMe; 110.9, 111.9, C 2´´, C 4´´; 121.5, C 6´´; 126.0, C 3, C 5;

126.8, C 2, C 6; 139.2, 143.3, C 1´´, C 5´´; 159.6, C 3´´; 175.0, CO. Mass

spectrum m/z 286 (M, 24%), 227 (40), 150 (100), 105 (79), 137 (11),

135 (39), 91 (30).

Methyl 1-[2´-(3´´-Methoxy-5´´-methylphenyl)ethyl]-4-oxo-1,4-

dihydrobenzoate (11)

A suspension of dry CrO₃(19.5 g, 195 mmol) in dichloromethane

(150 ml) was cooled to –20° and treated in one portion with 3,5-

dimethylpyrazole (19.6 g, 200 mmol) and the resulting dark brown

mixture stirred for 20 min at –10°. A solution of the ester prepared

above (7.00 g, 24.5 mmol) in dichloromethane (10 ml) was then added

dropwise over c. 2 min and the mixture warmed to –5° over 3 h. A solu-

tion of 5 ^MNaOH (100 ml, 500 mmol) was slowly added and the reac-

tion temperature allowed to rise to 0° over 30 min. Florisil (c. 30 g) was

then added and the resulting green slurry stirred at 0° for 15 min, before

being filtered through a plug of silica gel. The filtrate was concentrated

and the residue diluted with Et₂O and washed sequentially with 2 M

HCl, 2 M NaHSO₃, water, saturated NaHCO₃and brine. The organic

phase was dried (MgSO₄) and concentrated under reduced pressure.

Chromatography on silica gel (pentane/ethyl acetate, 3: 1) afforded

dienone (11) as a pale yellow oil (4.8 g, 65%) (Found: M^+•, 300.1363.

C₁₈H₂₀O₄requires M^+•, 300.1362), R_F0.21 (pentane/ethyl acetate, 3: 1).

Dimethyl (4b␣,5␣,8a␣)-2-Methoxy-4-methyl-6-oxo-4b,5,9,10-

tetrahydrophenanthrene-5,8a(6H)-dicarboxylate (14)

A freshly prepared solution of Prⁱ₂NLi, from the addition of diiso-

propylamine (71.4 mg, 0.71 mmol) to n-BuLi in hexane (0.40 ml, 1.6 ^M,

0.64 mmol), was added to a stirred solution of enone (13) (169 mg, 0.56

mmol) in tetrahydrofuran (2 ml) at –78° for 1 h. Following the addition

of methyl cyanoformate (85 mg, 1.0 mmol), the mixture was stirred for

27 h at –78°. The solution was then quenched with water (5 ml) and

extracted three times with Et₂O. The combined organic layers were

washed with brine and dried over MgSO₄. After removal of the solvent,

␯

(CHCl₃) 2950, 1735s, 1655s, 1630s, 1598s, 1460, 1230s, 1060s,

8^m60^axs, 690 cm^–1. ¹H n.m.r. (300 MHz) ␦ 2.20, s, 5´´-Me; 2.30–2.20, m,

2H; 2.48–2.43, m, 2H; 3.76, 3.75, 2×s, OMe; 6.40, d, J_3,2= J_5,69.8 Hz,

H3, H5; 6.56, 6.46, 6.53, 3×br s, ArH; 7.09, d, J_2,3= J_6,59.8 Hz, H2,

H6. ¹³C n.m.r. (75 MHz) ␦ 21.2, 5´´-Me; 30.4, C 2´; 39.6, C 1´; 52.1,

C 1; 53.0, 55.0, OMe; 111.0, 112.6, C 2´´, C 4´´; 121.3, C 6´´; 130.2, C 3,

C 5; 139.3, C 1´´, C 5´´; 147.6, C 2, C 6; 159.6, C 3´´; 170.4, CO; 184.4,

C 4. Mass spectrum m/z 300 (M, 24%), 152 (17), 150 (11), 149 (100),

148 (42), 135 (50), 121 (20), 119 (12), 91 (27), 79 (10), 77 (13).

1

the residue was checked by H n.m.r. analysis which indicated an

83: 10: 7 mixture of ester (14) with starting enone (13) and enol car-

bonate. The mixture was chromatographed on silica gel (hexane/ethyl

acetate, 2 : 1) to give enol carbonate (12 mg, 6%) and then ester (14)

(175 mg, 86%).

Studies on the Synthesis of Harringtonolide

1101

Enol carbonate (Found: M^+•, 358.1413. C₂₀H₂₂O₆requires M^+•,

358.1416). ␯_max2955, 2840, 1762, 1736, 1608, 1589, 1441, 1266, 1198,

1168, 1146, 1066 cm^–1. ¹H n.m.r. (300 MHz) ␦ 2.04, ddd J_gem13.5,

J_9␣,10␣5.7, J_9␣,10␤1.7 Hz, H 9␣; 2.21–2.29, m, H 9␤; 2.33, s, 4-Me;

2.60–2.80, m, H 10; 3.68, 3.75, 3.81, 3×s, OMe; 4.53, br s, H4b; 5.28,

of an equimolar mixture of (15) and (16) (20 mg) in tetrahydrofuran (1

ml) was added and stirring continued overnight. Ether (50 ml) was

added and the mixture washed with brine and dried (MgSO₄). After

concentration, the residue was dissolved in EtOH (5 ml), oxalic acid

solution (10% aqueous, 2.0 ml) added, and the mixture heated under

reflux for 17 h. After dilution with water, the product was extracted into

ethyl acetate (2×20 ml), dried (MgSO₄) and chromatographed on silica

gel. Lactone (17) (11 mg, 64%) was eluted with hexane/ethyl acetate

(3: 2). ␯_max(film) 2920, 2870, 1760, 1605, 1485, 1145 cm^–1. ¹H n.m.r.

(300 MHz) ␦ 1.01, d, J 7.0 Hz, 8-Me; 1.8–2.4, m, 3H; 2.14, s, 4-Me;

2.7–3.1, m, 2H; 2.87, d, J_4b,56.7 Hz, H5; 2.88, m, 2H; 3.74, 3.83, 2×s,

OMe; 3.84, m (partly obscured), H4b; 4.85, m, H 6; 6.52, 6.56, 2×d, J

2.4 Hz, H 1, H 3. ¹³C n.m.r. (75 MHz) ␦ 19.5, 8-Me; 22.1, 4-Me; 23.5,

26.1, C 9, C 10; 24.2, C 8; 34.9, C 7; 39.5, C 4b; 44.3, C 8a; 50.0, C 5;

52.9, 55.1, OMe; 76.5, C 6; 111.5, 116.5, C 1, C 3; 126.9, C 4a; 138.3,

138.4, C 4, C 10a; 157.4, C 2; 173.7, CO; 177.4, CO. Mass spectrum m/z

344 (M, 22%), 316 (100), 298 (26), 214 (46).

m, H 5; 5.88–5.98, m, H 7, H 8; 6.41, 6.63, 2×d, J_1,32.5 Hz, H1, H3. ¹³

C

n.m.r. (75 MHz) ␦ 19.5, 4-Me; 24.0, 26.5, C 9, C 10; 35.9, C 4b; 48.0,

C 8a; 52.5, 55.0, 55.2, OMe; 111.0, 115.0, C 1, C 3; 117.2, C 5; 121.9,

C 8; 126.8, C 4a; 133.1, C 7; 135.8, 137.5, C 4, C 10a; 143.5, C 6; 153.2,

O–CO–O; 157.6, C 2; 174.8, CO.

Ester (14) crystallized from Et₂O to afford a white solid, m.p. 145°,

R_F0.46 (hexane/ethyl acetate, 1: 1) (Found: C, 66.9; H, 6.1. C₂₀H₂₂O₆

requires C, 67.0; H, 6.2%). ␯_max(film) 3015, 2958, 2840, 1741, 1675,

1601, 1586, 1431, 1250, 1148 cm^–1. ¹H n.m.r. (300 MHz) ␦ 2.03, dddd,

J

_gem14.3, J_{9␤, 10␣}8.2, J_9␤,10␤5.4 Hz, H 9␤; 2.51, m, H 9␣; 2.21, s, 4-Me;

2.85, ddd, J_gem17.1, J_10␤,9␣7.8, J_10␤,9␤5.4 Hz, H10␤; 3.00, m, H 10␣;

3.59, d, J_5,4b11.2 Hz, H 5; 3.60, 3.61, 3.76, 3×s, OMe; 4.51, d, J_4b,511.2

Hz, H 4b; 6.14, d, J_7,810.2 Hz, H7; 6.50, br s, H1, H 3; 7.06, d, J_8,710.2

Hz, H 8. ¹³C n.m.r. (75 MHz) ␦ 19.2, 4-Me; 27.2, 29.6, C 9, C 10; 39.6,

C 4b; 48.8, C 8a; 52.2, 52.8, 54.9, OMe; 57.3, C 5; 111.4, 114.6, C 1,

C 3; 125.9, C 4a; 127.2, C 7; 137.1, 137.7, C 4, C 10a; 152.8, C 8; 158.0,

C 2; 169.7, CO; 173.6, CO; 193.7, C 6. Mass spectrum m/z 358 (M,

93%), 327 (25), 299 (73), 267 (100), 239 (53), 225.0 (38), 211 (36), 196

(25), 181 (22), 165 (32), 148 (55), 128 (33), 115 (21).

Dimethyl (4b␣,5␣,8␣,8a␣)-6-t-Butyldimethylsilyloxy-2-methoxy-4-

methyl-4b,5,9,10-tetrahydrophenanthrene-5,8a(8H)-dicarboxylate

(18)

Asolution of CuI (190.4 mg, 0.34 mmol) in tetrahydrofuran (0.8 ml)

was cooled to –20° and a 1.6 ^Msolution of MeLi (470 ␮l, 0.74 mmol)

in Et₂O was added dropwise and stirred for 15 min. A mixture of enone

(14) (40 mg, 0.112 mmol), Bu^tMe₂SiCl (100 mg, 0.663 mmol) and hex-

amethylphosphoramide (82 mg, 0.46 mmol) in tetrahydrofuran was

then added over 20 min and the mixture stirred for a further 15 min

between –20 and –10°. The solution was neutralized with NH₃(10%)

and extracted three times with Et₂O. The combined organic layers were

washed with NH₃(10%) and water and dried over MgSO₄.

Concentration under reduced pressure gave the crude product (55 mg,

100%) which, after chromatography on Al₂O₃(hexane/ethyl acetate,

6: 1), yielded silyl ether (18) (34 mg, 62%) as a colourless oil, R_F0.62

(hexane/ethyl acetate, 2: 1) (Found: C, 66.1; H, 8.5. C₂₇H₄₀O₆Si

requires C, 66.4; H, 8.3%). ␯_max(film) 2952, 1730, 1607, 1591, 1433,

1299, 1256, 1216, 1146, 882, 841 cm^–1. ¹H n.m.r. (300 MHz, acetone)

␦ 0.26, s, SiMe₂; 0.94, s, Bu^t; 1.11, d, J_8-Me,86.8 Hz, 8-Me; 2.27, s, 4-

Me; 2.18–2.32, m, H9; 2.38–2.46, m, H 8; 2.84, ddd, J_gem18.0, J_10␤,9

9.2, J_10␤,98.9 Hz, H 10␤; 2.95, ddd, J_5,4b10.3, J_5,71.7, J_5,81.6 Hz, H5;

3.06, ddd, J_gem18.0, J_10␣,9␤9.1, J_10␣,9␣3.1 Hz, H 10␣; 3.52, 3.68, 3.77,

3×s, OMe; 4.01, dd, J_4b,510.3, J_4b,9␣1.4 Hz, H4b; 5.12, dd, J_7,85.9, J_7,5

1.7 Hz, H7; 6.52, 6.57, d, J 2.4 Hz, ArH. ¹³C n.m.r. (75 MHz, acetone)

␦ –4.4, –4.5, SiMe₂; 18.6, SiCMe₃; 19.3, 19.5, Me; 26.0, SiCMe₃; 27.1,

27.2, C 9, C 10; 35.2, 39.0, C 4b, C 8; 50.4, C 8a; 51.7, 52.2, OMe; 54.1,

C 5; 55.2, OMe; 109.2, 112.3, 114.6, C 1, C 3, C 7; 131.3, C 4a; 136.6,

138.0, C 4, C 10a; 146.7, C 6; 158.6, C 2; 173.8, CO; 175.7, CO. Mass

spectrum m/z 472.4 (M –CH₄, 10%), 457.3 (45), 441.1 (74), 415 (100),

381.3 (39), 355.3 (17), 185.2 (12), 148.2 (5), 81 (9), 73.1 (18).

Dimethyl (4b␣,8␣,8a␣)-6-Hydroxy-2-methoxy-4,8-dimethyl-7,8,9,10-

tetrahydrophenanthrene-5,8a(4bH)-dicarboxylate (15) and Dimethyl

(4b␣,5␣,8␣,8a␣)-2-Methoxy-4,8-dimethyl-6-oxo-4b,5,7,8,9,10-

hexahydrophenanthrene-5,8a(6H)-dicarboxylate (16)

Methyllithium (6.5 ml of a 1.55 ^Msolution in Et₂O, 10 mmol) was

added dropwise to a stirred suspension of dry CuI (955 mg, 5.1 mmol)

in dry tetrahydrofuran (20 ml) maintained at –20° under an argon atmo-

sphere. The resulting pale yellow solution was allowed to warm to –10°

over 15 min and then recooled to –20°. A solution of ketone (14) (300

mg, 0.84 mmol) in tetrahydrofuran (3 ml) was added dropwise over c. 5

min and the solution stirred for 1 h at –20°, at –10° for a further 1 h, and

then overnight at 4°. The reaction mixture was poured into saturated

NH₄Cl solution (150 ml) and extracted with Et₂O (4×50ml) and ethyl

acetate (2×50 ml). After drying (MgSO₄) and concentration, the residue

was filtered through silica gel (20 g; hexane/ethyl acetate, 1 : 1), and then

resolved by m.p.l.c. (hexane/ethyl acetate, 1: 1). The enol tautomer (15)

was eluted first as a pale yellow oil (89 mg, 30%) (Found: M^+•,

374.1716. C₂₁H₂₆O₆requires M^+•, 374.1729). ␯

(film) 2950, 1730,

1650, 1605, 1440, 1235, 1065 cm^–1. ¹H n.m.r. (30^m0^aM^xHz) ␦ 1.00, d, J 7.0

Hz, 8-Me; 2.16–2.51, m, 2H; 2.51, s, 4-Me; 2.6–3.0, m, 5H; 3.54, 3.57,

3.74, 3×s, OMe; 4.49, s, H4b; 6.39, 6.56, 2×d, J 2.4 Hz, H 1, H3; 12.65,

br s, enol. ¹³C n.m.r. (75 MHz) ␦ 17.1, 8-Me; 19.6, 4-Me; 29.5, 33.1, C 9,

C 10; 35.4, C 8; 36.4, C4b; 50.4, C 8a; 50.8, 51.8, 54.9, OMe; 99.6, C5;

109.7, 113.8, C 1, C 3; 129.8, C4a; 139.5, 140.9, C 4, C10a; 157.2, C2;

170.7, CO; 172.5, C 6; 176.9 CO. Mass spectrum m/z 374 (M, 20%), 357

(2), 342 (16), 327 (100), 314 (25), 267 (51), 231 (59), 148 (47).

Methyl (4b␣,8␣,8a␣)-6-t-Butyldimethylsilyloxy-2-methoxy-4,8-

dimethyl-4b,5,9,10-tetrahydrophenanthrene-8a(8H)-carboxylate (19)

A mixture of tautomers (15) and (16) was obtained next (72 mg,

19%), then pure ␤-keto ester (16) was obtained as a pale yellow oil

Methyllithium (100 ml of a 1.6 ^Msolution in Et₂O, 160 mmol) was

added dropwise to a stirred suspension of dry CuI (15.3 g, 80.3 mmol)

in dry tetrahydrofuran (100 ml) maintained at –20° under a nitrogen

atmosphere. The resulting pale yellow solution was allowed to warm to

–10° over 15 min and then recooled to –20°. A mixture of ketone (13)

(8.00 g, 24.0 mmol), t-butyldimethylsilyl chloride (14.5 g, 96.3 mmol)

and hexamethylphosphoramide (8.4 ml, 48.3 mmol) in tetrahydrofuran

(30 ml) was added dropwise over c. 5 min and the solution allowed to

warm to 0° over 2 h. The reaction mixture was poured into ice-cold 2 ^M

NH₃and the resulting blue mixture extracted with Et₂O. The combined

organic layers were washed with sufficient 2 ^MNH₃to remove all

remaining traces of copper, followed by water and brine. After drying

(MgSO₄) and concentration, the residual silicon impurities were

removed under high vacuum at 70° to give a clear oil which solidified

on standing. Recrystallization from ethyl acetate/pentane afforded

silylenol ether (19) as colourless cubes. Subjection of the mother

liquors to chromatography on silica gel (pentane/ethyl acetate, 83 : 17)

gave additional quantities of the title compound (combined yield 10.4 g,

(76 mg, 20%) (Found: M^+•, 374.1716. C₂₁H₂₆O₆requires M^+•,

1

374.1729). ␯

(film) 2950, 1730, 1605, 1435 cm^–1. H n.m.r. (300

MHz) ␦ 1.05,^md^ax, J 7.0 Hz, 8-Me; 2.2–2.5, m, 3H; 2.33, s, 4-Me; 2.7–3.1,

m, 4H; 3.40, d, J 12.0 Hz, H 5; 3.55, 3.60, 3.76, 3×s, OMe; 4.39, d, J

12 Hz, H 4b; 6.48, 6.52, 2×d, J 2.4 Hz, H 1, H 3. ¹³C n.m.r. (75 MHz) ␦

17.4, 8-Me; 19.2, 4-Me; 27.5, 28.9, C 9, C 10; 36.8, C 8; 38.2, C 4b;

43.5, C 7; 50.3, C 8a; 50.9, 52.1, 55.0, OMe; 60.3, C 5; 111.5, 114.3,

C 1, C 3; 128.4, C 4a; 137.1, 137.8, C 4, C 10a; 157.8, C 2; 169.6, CO;

175.3, CO; 204.9 CO. Mass spectrum m/z 374 (M, 52%), 358 (10), 342

(12), 327 (94), 315 (53), 314 (56), 267 (56), 231 (85), 199 (100).

(4b␣,5␣,6␣,8␣,8a␣)-6-Hydroxy-2-methoxy-4,8-dimethyl-

4b,5,7,8,9,10-hexahydrophenanthrene-5,8a(6H)-dicarboxylic Acid 5-

Methyl Ester 8a,6-Lactone (17)

NaBH₄(76 mg) was added to a stirred suspension of ZnBr₂(225 mg)

in tetrahydrofuran (10 ml) and the mixture stirred for 30 min. Asolution

1102

D. H. Rogers et al.

91%), m.p. 102–104°. R_F0.85 (pentane/ethyl acetate, 83: 17) (Found:

nitrogen to a solution of the carbinol (20) plus its 7-epimer (150 mg,

0.451 mmol) in dichloromethane (3 ml) and stirred for 4 days at room

temperature. The solution was washed with saturated NaHCO₃and

water, then the aqueous layer was extracted three times with

dichloromethane. The combined organic layers were washed sequen-

tially with water and brine, then dried over MgSO₄. Chromatography

on silica gel (hexane/ethyl acetate, 6: 1) afforded the title compound (90

mg, 53%) as a solid, m.p. 107°, R_F0.32 (hexane/ethyl acetate, 2 : 1)

C, 70.0; H, 9.0%; M^+•, 430.2539. C₂₅H₃₈O₄Si requires C, 69.7; H, 8.9%;

M^+•, 430.2539). ␯ (film) 2950s, 2860s, 1725s (CO), 1680, 1610s,

max

1460s, 1260s(br), 1170s, 1050s, 840s(br) cm^–1. ¹H n.m.r. (300 MHz) ␦

–0.36, –0.50, 2×s, OSiMe₂; 0.89 s, OSiCMe₃, 0.93, d, J_8-Me,86.8 Hz, 8-

Me; 1.74, dddd, J_gem18.0, J_5␤,4b11.2, J_5␤,71.5, J_5␤,81.5 Hz, H5␤;

1.97–2.13, m, H 9; 2.31, m, H8; 2.32, dd, J_gem18.0, J_5␣,4b6.8 Hz, H5␣;

2.35, br s, 4-Me; 2.92–2.71, m, H 10; 3.38, br dd, J_4b,5␤11.2, J_4b,5␣6.8

Hz, H 4b; 3.52, 3.71 2×s, OMe; 4.57, dd, J_7,85.3, J_7,5␤1.5 Hz, H 7; 6.40,

6.54, 2×br d, J_1,32.2 Hz, H 1, H 3. ¹³C n.m.r. (75 MHz) ␦ –4.4, –4.7,

(Found: C, 66.9; H, 7.7. C₂₁H₂₈O₆requires C, 67.0; H, 7.5%). ␯

max

(KBr) 2954, 2910, 2838, 1727, 1606, 1587, 1482, 1465, 1339, 1302,

1258, 1197, 1172, 1148, 1100, 1064, 1037 cm^–1. ¹H n.m.r. (300 MHz) ␦

0.98, d, J_8-Me,87.4 Hz, 8-Me; 2.32, s, 4-Me; 2.48, ddd, J_9␣,9␤11.0, J_9␣,10␣

4.5, J_9␣,10␤1.1 Hz, H9␣; 2.22–2.40, m, 2H; 2.58–2.72, m, 2H;

2.76–2.90, m, 2H; 3.38, 3.61, 3.73, 3×s, OMe; 3.85, ddd, J_4b,5␤13.0,

J_4b,5␣3.7, J_{4b, 9␣}0.3 Hz, H4b; 3.94, d, J_7,85.0 Hz, H7; 4.66, 4.72, 2×d,

J 6.8 Hz, OCH₂O; 6.43, 6.57, 2×d, J 2.5 Hz, ArH. ¹³C n.m.r. (75 MHz)

␦ 14.1, 8-Me; 19.0, 4-Me; 27.2, 27.6, C 9, C 10; 35.3, C 4b; 41.6, C 5;

43.3, C 8; 49.8, C 8a; 51.8, 54.9, 56.1, OMe; 82.6, C 7; 96.4, OCH₂O;

111.3, 114.7, C 1, C 3; 128.6, C 4a; 135.4, 136.9, C 4, C 10a; 157.4, C 2;

174.5, CO; 208.9, C 6. Mass spectrum m/z 376 (M, 98%), 331 (44), 313

(16), 299 (11), 285 (22), 271 (16), 255 (34), 243 (24), 232 (100), 213

(16), 201 (71), 187 (59), 173 (64), 161 (24), 141 (21), 129 (24), 115

(19), 91 (11), 69 (19).

;

OSiMe₂17.9, OSiCMe₃; 18.8, 8-Me; 19.6, 4-Me; 25.5, OSiCMe₃;

26.0, 27.0, C 9, C 10; 30.7, C 8; 34.8, C 5; 38.0, C 4b; 48.6, C 8a; 51.2,

54.8, OMe; 107.9, C 7; 111.4, 113.9, C 1, C 3; 132.5, C 4a; 134.6, 136.2,

C 10a, C 4; 147.0, C 6; 157.0, C 2; 176.0, CO. Mass spectrum m/z 430

(M, 4%), 373 (7), 233 (15), 232 (100), 201 (6), 173 (13), 141 (9), 75

(59).

Methyl (4b␣,7 ␤,8␣,8a␣)-7-Hydroxy-2-methoxy-4,8-dimethyl-6-oxo-

4b,5,7,8,9,10-hexahydrophenanthrene-8a(6H)-carboxylate (20) and

the 7␣-Epimer

The enol ether prepared above (3.56 g, 8.28 mmol) was added to a

stirred solution of N-methylmorpholine N-oxide (1.55 g, 13.2 mmol) in

a mixture of acetone, water and t-butyl alcohol (150 ml, 30: 20: 1) at

room temperature under nitrogen. The solution was cooled to –5° and

treated dropwise with a catalytic amount of OsO₄(3 large crystals) in t-

butyl alcohol (2 ml). The cooling bath was then removed and the solu-

tion stirred at ambient temperature for 24 h. The reaction mixture was

diluted with Et₂O and washed with 2 M HCl, water, saturated aqueous

NaHCO₃and brine, then dried (MgSO₄) and concentrated under

reduced pressure. The resulting black oil was chromatographed on

silica gel (pentane/ethyl acetate, 2: 1) to give a mixture of 7-hydroxy

ketones (2.17 g, 79%) as a 4: 3 mixture of ␤- and ␣-epimers.

Methyl (4b␣,7␣,8␣,8a␣)-2-Methoxy-7-methoxymethoxy-4,8-dimethyl-

6-oxo-4b,5,7,8,9,10-hexahydrophenanthrene-8a(6H)-carboxylate (21)

A solution of NaOMe (0.16 ^M, 1.35 ␮l, 0.216 mmol) in MeOH was

added to a solution of the ketone prepared above (80 mg, 0.213 mmol)

in absolute MeOH (5 ml) and stirred at room temperature under nitro-

gen for 21 h. The solution was washed with NH₄Cl and extracted six

times with Et₂O. The combined organic layers were washed with water

and dried over MgSO₄. The resulting precipitate was collected by fil-

tration to afford the methoxymethyl ether (21) as a colourless solid (80

mg, 100%), m.p. 170° (R_F0.22 (hexane/ethyl acetate, 2: 1) (Found: C,

66.7; H, 7.7. C₂₁H₂₈O₆requires C, 67.0; H, 7.5%). ␯ (KBr) 2945,

2838, 2823, 1738, 1690, 1604, 1587, 1479, 1455, 14^m3^a4^x, 1300, 1277,

The ␤-epimer (20) was recrystallized from ethyl acetate/pentane as

white needles, m.p. 173–176°, R_F0.31 (pentane/ethyl acetate, 2: 1)

(Found: C, 68.7; H, 7.6. C₁₉H₂₄O₅requires C, 68.7; H, 7.3%). ␯

max

(film) 3470, 2950, 2840, 1725s, 1605s, 1160 cm^–1. ¹H n.m.r. (300 MHz)

␦ 1.14, d, J_8-Me,87.0 Hz, 8-Me; 1.59, dq, J_8,712.3, J_8,8-Me7.0 Hz, H 8;

1.72, ddd, J_gem13.8, J_9␤,1012.1, J_9␤,106.8 Hz, H 9␤; 2.28, br s, 4-Me;

2.38, dddd, J_gem13.8, J_9␣,106.6, J_9␣,101.0, J_9␣,4b0.9 Hz, H 9␣; 2.44, dd,

1

1251, 1218, 1187, 1157, 1146, 1125, 1057, 1031 cm^–1. H n.m.r. (300

MHz) ␦ 0.91, d, J_8-Me,87.1 Hz, 8-Me; 2.32, s, 4-Me; 2.23–2.32, m, 3H;

2.51–2.71, m, 2H; 2.78, br dd, J_9␣,9␤12.1, J_9␣,10␣6.5 Hz, H 9␣; 2.94, br

dd, J_gem17.1, J_10␤,9␤5.6 Hz, H10␤; 3.40, 3.61, 3.72, 3×s, OMe; 3.78,

dd, J_4b,5␤13.3, J_4b,5␣5.3 Hz, H 4b; 4.67, d, J_7,85.9 Hz, H 7; 4.69–4.74,

m, OCH₂O; 6.42, 6.57, d, J 2.3 Hz, ArH. ¹³C n.m.r. (75 MHz) ␦ 11.3, 8-

Me; 19.4, 4-Me; 26.8, 28.3, C 9, C 10; 35.9, C 4b; 44.7, C 5; 45.4, C 8;

51.9, C 8a; 52.7, 55.5, 56.4, OMe; 78.1, C 7; 96.0, OCH₂O; 112.0,

115.3, C 1, C 3; 129.6, C 4a; 134.0, 137.4, C 4, C 10a; 158.0, C 2; 174.7,

CO; 207.1, C 6. Mass spectrum m/z 376 (M, 100%), 331 (55), 314 (87),

299 (25), 271 (25), 255 (71), 243 (38), 232 (80), 201 (75), 187 (42), 173

(54), 161 (17), 141 (152), 129 (21), 115 (13), 91 (7), 69 (16).

J

_gem19.6, J_5␤,4b13.6 Hz, H 5␤; 2.75, dd, J_gem19.6, J_5␣,4b4.2 Hz, H5␣;

3.00, br ddd, J_gem17.9, J_10,9␤12.1, J_10,9␣6.6 Hz, H 10; 2.79, br dd, J_gem

17.9, J_10,9␤6.8 Hz, H10; 3.43, br s, 7-OH; 3.63, 3.74, 2×s, OMe; 4.12,

ddd, J_4b,5␤13.6, J_4b,5␣4.2, J_4b,9␣0.9 Hz, H 4b; 4.46, br d, J_7,812.3 Hz,

H7; 6.44, 6.57, 2×br d, J_1,32.6 Hz, H 1, H 3. ¹³C n.m.r. (75 MHz) ␦ 13.1,

8-Me; 19.1, 4-Me; 26.8, 27.8, C 9, C 10; 32.3, C 4b; 40.5, C 5; 44.1, C 8,

49.4, C 8a; 51.6, 54.9, OMe; 74.8, C 7; 111.2, 114.9, C 1, C 3; 126.7,

C 4a; 136.2, 137.2, C 10a, C 4; 157.7, C 2; 173.9, CO; 211.4, C 6. Mass

spectrum m/z 332 (M, 100%), 314 (9), 273 (22), 255 (30), 246 (50), 232

(50), 201 (45), 173 (31).

The 7␣-epimer crystallized from ethyl acetate/pentane as white

needles, m.p. 161–166° (dec.). R_F0.22 (pentane/ethyl acetate, 2: 1)

5-Benzyl 8a-Methyl (4b␣,5␣,8a␣)-2-Methoxy-4-methyl-6-oxo-

4b,5,9,10-tetrahydrophenanthrene-5,8a(6H)-dicarboxylate (24)

A freshly prepared solution of Prⁱ₂NLi, from the addition of diiso-

propylamine (239 mg, 2.36 mmol) to n-BuLi (2.24 mmol) in hexane

(1.40 ml), was added to a solution of enone (13) (500 mg, 1.66 mmol)

in tetrahydrofuran (6.5 ml) and stirred at –78°. The solution was

warmed to –30° within 60 min and the solvent removed. The solution

was then cooled to –78°, then Et₂O (5 ml) and benzyl cyanoformate

(563 mg, 3.49 mmol) were added (producing a precipitate) and the

mixture was stirred for 70 h at –78°. The solution was quenched with

water and extracted three times with Et₂O. The combined organic layers

were washed with brine and dried over MgSO₄. After removal of the

solvent, the residue was chromatographed on silica gel (hexane/ethyl

acetate, 2: 1) to afford enol carbonate (25) (48 mg, 7%), followed by

ester (24) (300 mg, 41%), both as oils.

(Found: C, 68.6; H, 7.3. C₁₉H₂₄O₅requires C, 68.7; H, 7.3%). I.r.

1

(CHCl₃) ␯

3470, 2950, 2840, 1720s, 1605s, 1145 cm^–1. H n.m.r.

max

(300 MHz) ␦ 0.82, d, J_8-Me,87.3 Hz, 8-Me; 2.32, m, H 9␣; 2.33, dd, J_gem

14.9, J_5␤,4b13.2 Hz, H 5␤; 2.33, br s, 4-Me; 2.56, m, H 9␤; 2.73, dd,

J

_gem14.9, J_5␣,4b5.3 Hz, H5␣; 2.75, dq, J_8,8-Me7.3, J_8,76.2 Hz, H8; 2.95,

m, H 10; 2.78, m, H10; 3.52–3.42, br s, OH; 3.62, 3.73, 2×s, OMe;

3.80, ddd, J_4b,5␤13.2, J_4b,5␣5.3, J_4b,9␣0.9 Hz, H 4b; 4.65, br d, J_7,86.2

Hz, H7; 6.44, 6.58, 2×br d, J_1,32.6 Hz, H 1, H 3. ¹³C n.m.r. (75 MHz) ␦

9.8, 8-Me; 18.8, 4-Me; 25.9, 27.9, C 9, C 10; 35.5, C 4b; 42.5, C 5; 45.5,

C 8; 51.1, C 8a; 52.0, 54.9, OMe; 73.9, C 7; 111.6, 114.8, C 1, C 3;

129.1, C 4a; 134.4, 136.7, C 10a, C 4; 157.5, C 2; 174.0, CO; 209.3, C 6.

Mass spectrum m/z 332 (M, 20%), 314 (10), 255 (33), 246 (20), 232

(26), 201 (27), 187 (20), 173 (23), 148 (17), 128 (18).

Enol carbonate (25): ¹H n.m.r. (300 MHz) ␦ 2.05, m, 1H; 2.20–2.41,

m, 2H; 2.33, s, 4-Me; 2.65–2.70, m, 1H; 3.69, 3.69, 3.77, 2×s, OMe;

4.54, s, H4b; 5.18, 5.30, 2×ABd, J_gem12.5 Hz, OCH₂Ph; 5.20, s, H5;

5.93, 5.95, 2×ABd, J_7,810.4 Hz, H 7, H 8; 6.43, 6.64, 2×br s, H1, H3;

7.35–7.40, m, ArH. ¹³C n.m.r. (75 MHz) ␦ 19.5, 4-Me; 24.0, 26.5, C 9,

Methyl (4b␣,7␤,8␣,8a␣)-2-Methoxy-7-methoxymethoxy-4,8-dimethyl-

6-oxo-4b,5,7,8,9,10-hexahydrophenanthrene-8a(6H)-carboxylate

4-(Dimethylamino)pyridine (22 mg, 0.066 mmol), Prⁱ₂NEt (594 mg,

4.59 mmol) and MeOCH₂Cl (360 mg, 4.47 mmol) were added under

Studies on the Synthesis of Harringtonolide

1103

C 10; 35.9, C 4b; 48.0, C 8a; 52.5, 55.0, OMe; 70.2, OCH₂Ar; 111.1,

115.1, C 1, C 3; 117.2, C 5; 121.9, 128.4, 128.6, 133.0, C 7, C 8, Ar CH;

126.8, C 4a; 135.8, 137.1, 137.5, 143.5, Ar C; 153.2, O–CO–O; 157.6,

C 2; 174.8, CO.

3.70, 2×s, OMe; 3.83, d, J_4b,511.6 Hz, H 4b; 4.39, br s, OH; 4.64, dd,

J

_6,78.5, J_6,52.8 Hz, H6; 4.49, 4.78, 2×d, J 12.2 Hz, OCH₂Ph; 6.39, 6.43,

2×d, J 2.5 Hz, H 1, H3; 6.82–6.85, m, ArH; 7.18–7.27, m, ArH. ¹³C

n.m.r. (75 MHz) ␦ 4.1, C 11; 16.1, 22.0, C 7, C 8; 19.3, 4-Me; 25.9, 28.0,

C 9, C 10; 29.1, C 4b; 47.1, C 5; 47.1, C 8a; 51.8, OMe; 54.7, OMe;

63.4, C 6; 66.7, OCH₂Ph; 110.6, 114.0, C 1, C 3; 126.8, C 4a; 128.0,

128.1, Ar CH; 134.6, 137.5, 137.9, Ar C; 157.7, C 2; 175.7, CO; 176.1,

CO. Mass spectrum m/z 450 (M, 100%), 341 (35), 313 (31), 297 (17),

281 (31), 253 (25), 237 (29), 148 (44), 91 (47).

Ester (24): R_F0.32 (hexane/ethyl acetate, 2: 1) (Found: C, 71.7; H,

6.0. C₂₆H₂₆O₆requires C, 71.9; H, 6.0%). ␯_max(film) 3033, 2953, 2839,

1738, 1680, 1606, 1588, 1484, 1456, 1248, 1200, 1148 cm^–1. ¹H n.m.r.

(300 MHz) ␦ 2.03, m, H 9; 2.26, s, 4-Me; 2.54, m, H 9; 2.86, ddd, J_gem

17.1, J_10␤,9␣8.0, J_10␤,9␤5.3 Hz, H 10␤; 3.01, m, H 10␣; 3.60, s, OMe;

3.66, d, J_5,4b11.7 Hz, H5; 3.76, s, OMe; 4.54, d, J_4b,511.7 Hz, H4b;

4.96, 5.14, 2×ABd, J 12.5 Hz, OCH₂; 6.15, d, J_7,810.3 Hz, H7; 6.50, br

s, H 1, H 3; 7.02–7.06, m, ArH; 7.06, d, J_8,710.3 Hz, H 8; 7.25–7.29, m,

ArH. ¹³C n.m.r. (75 MHz) ␦ 19.1, 4-Me; 27.1, 29.7, C 9, C 10; 39.5,

C 4b; 48.8, C 8a; 52.5, 54.7, OMe; 57.1, C 5; 66.5, OCH₂Ar; 111.2,

114.4, C 1, C 3; 125.7, C 4a; 126.9, 127.6, 127.8, 128.0, 128.1, Ar CH;

135.0, 137.1, 137.6, Ar C; 152.6, C 8; 157.9, C 2; 169.1, CO; 173.3, CO;

193.4, C 6. Mass spectrum m/z 434 (M, 55%), 375 (3), 343 (18), 325

(22), 299 (61), 267 (66), 267 (65), 240 (45), 225 (48), 211 (19), 197

(12), 181 (9), 165 (18), 148 (46), 128 (11), 115 (13), 91 (100).

5-Benzyl 8a-Methyl (4b␣,5␣,6␣,7␣,8␣,8a␣)-6-t-

Butyldimethylsilyloxy-2-methoxy-4-methyl-4b,5,7,8,9,10-

hexahydro-7,8-methanophenanthrene-5,8a(6H)-dicarboxylate

A solution of the hydroxy ester (360 mg, 0.799 mmol), prepared

above, in dichloromethane (50 ml) was added to a mixture of 2,6-di-t-

butyl-4-methylpyridine (1.0 g, 4.87 mmol) and Bu^tMe₂SiOTf (691 mg,

2.61 mmol), and then stirred at room temperature for 24 h. The solution

was treated with saturated NaHCO₃solution and extracted with Et₂O

(4×30 ml), washed four times with brine, and dried (MgSO₄). After

removal of the solvent, the residue was chromatographed on silica gel

(hexane/ethyl acetate, 10: 1) to give the title product (391 mg, 87%) as

a colourless oil, R_F0.59 (hexane/ethyl acetate, 2: 1) (Found: C, 69.9; H,

5-Benzyl 8a-Methyl (4b␣,5␣,7␣,8␣,8a␣)-2-Methoxy-4-methyl-6-oxo-

4b,5,7,8,9,10-hexahydro-7,8-methanophenanthrene-5,8a(6H)-

dicarboxylate (26)

8.0. C₃₃H₄₄O₆Si requires C, 70.2; H, 7.9%). ␯

(film) 2952, 2930,

A solution of trimethylsulfoxonium iodide (160 mg, 0.73 mmol) in

dimethyl sulfoxide (10 ml) was treated with NaH (27 mg, 0.73 mmol)

and the mixture stirred for 30 min at room temperature under a nitrogen

atmosphere. A portion of the resulting ylide solution (0.40 ml, 0.29

mmol) was added to a stirred solution of enone (24) (70 mg, 0.16 mmol)

in dimethyl sulfoxide (10 ml) under a nitrogen atmosphere. Stirring was

continued at 50° for 24 h, then water (10 ml) was added and the product

extracted into Et₂O (3×15 ml). After drying (MgSO₄) and removal of

solvent, the residue was chromatographed on silica gel (hexane/ether,

4 : 1) and recrystallized from Et₂O to afford cyclopropyl ketone (26)

(1.13 g, 52%) as colourless crystals, m.p. 122° (R_F0.31 (hexane/ethyl

acetate, 2 : 1) (Found: C, 72.5; H, 6.5. C₂₇H₂₈O₆requires C, 72.3; H,

2856, 1754, 1729, 1607, 1591, 1464, 1209, 11^m8^a9^x, 1149, 1122, 1094,

1063, 836, 738 cm^–1. ¹H n.m.r. (300 MHz) ␦ 0.03, 0.13, s, OSiMe₂; 0.58,

ddd, J_8,79.9, J_8,77.7, J_8,11␣4.4 Hz, H 8; 0.96, s, OSiCMe₃; 1.13–1.26, m,

H11; 1.45, m, H 7; 2.04, m, H 9␤; 2.38, s, 4-Me; 2.68–2.82, m, H10,

H9␣; 2.88, dd, J_5,4b11.9, J_5,63.7 Hz, H 5; 3.47, s, OMe; 3.69, d, J_4b,5

11.9 Hz, H 4b; 3.72, s, OMe; 4.72, dd, J_6,78.1, J_6,53.7 Hz, H6; 4.79,

4.87, 2×d, J 12.5 Hz, OCH₂Ph; 6.37, 6.46, H 1, H3; 7.01–7.04, m, ArH;

7.25–7.27, m, ArH. ¹³C n.m.r. (75 MHz) ␦ –5.5, –4.3, OSiMe₂; 6.0,

C 11; 18.1, OSiCMe₃; 18.1, 23.8, C 7, C 8; 19.7, 4-Me; 25.8, OSiCMe₃;

26.0, 28.5, C 9, C 10; 28.8, C 4b; 47.6, C 8a; 48.3, C 5; 51.7, 54.7, OMe;

65.81, C 6; 65.8, OCH₂; 110.3, 113.6, C 1, C 3; 128.2, C 4a; 127.8,

128.0, 128.3, Ar CH; 135.7, 137.2, 140.0, Ar C; 157.4, C 2; 170.5, CO;

176.2, CO. Mass spectrum m/z 564 (M, 13%), 507 (42), 447 (100), 429

(9), 356 (15), 329 (12), 237 (15), 212 (26), 185 (19), 91 (78), 73 (29).

6.3%). ␯ (KBr) 3097, 3061, 3013, 2954, 2924, 2877, 2843, 1726,

max

1

1688, 1602, 1588, 1478, 1295, 1254, 1205, 1161, 1058, 873 cm^–1. H

n.m.r. (300 MHz) ␦ 1.34, m, 1H; 1.79, dt, J_gem14.5, J_9␤,10␣9.0, J_9␤,10␤

9.0 Hz, H 9␤; 1.92–2.05, m, H 7, H 11␤;* 2.07, s, 4-Me; 2.29, m, 1H;

2.63, m, H9␣; 2.89–2.94, m, H 10; 3.11, d, J_5,4b11.1 Hz, H 5; 3.56, 3.73,

2×s, OMe; 4.09, br d, J_4b,511.0 Hz, H 4b; 5.05, 5.14, 2×d, J 12.5 Hz,

OCH₂Ph; 6.43, br s, H1, H3; 7.15–7.19, m, ArH; 7.27–7.32, m, ArH.

¹³C n.m.r. (75 MHz) ␦ 11.2, C 11; 19.0, 4-Me; 25.0, C 8; 25.8, 27.2, C 9,

C 10; 28.3, C 7; 34.4, C 4b; 44.7, C 8a; 52.3, 54.9, OMe; 58.8, C 5; 67.3,

OCH₂; 111.6, 114.3, C 1, C 3; 127.1, C 4a; 127.9, 128.1, 128.4, Ar CH;

135.0, 136.3, 137.2, Ar C; 157.9, C 2; 169.7, CO; 174.5, CO; 202.4, C 6.

Mass spectrum m/z 448 (M, 77%), 357 (23), 339 (28), 313 (60), 281

(20), 253 (48), 239 (30), 225 (24), 211 (20), 185 (20), 172 (15), 148

(42), 128 (12), 107 (16), 91 (100), 65 (22).

(4b␣,5␣,6␣,7␣,8␣,8a␣)-6-t-Butyldimethylsilyloxy-2-methoxy-4-

methyl-4b,5,7,8,9,10-hexahydro-7,8-methanophenanthrene-5,8a(6H)-

dicarboxylic Acid 8a-Methyl Ester (27)

Pd–C (5%, 50 mg, 0.047 mmol) was added to a solution of the ester

prepared above (380 mg, 0.673 mmol) in MeOH (50 ml) plus ethyl

acetate (5 ml) and HOAc (50 ␮l), and the mixture stirred for 14 h at room

temperature. The catalyst was removed by filtration and washed with

ethyl acetate. Removal of solvent afforded acid (27) (312 mg, 98%) as a

colourless solid, m.p. 153–155°, R_F0.43 (hexane/ethyl acetate, 2: 1)

(Found: C, 65.5; H, 8.2. C₂₆H₃₈O₆Si requires C, 65.8; H, 8.1%). ␯

(KBr) 3417, 3000, 2954, 2928, 2854, 1730, 1606, 1243, 1204, 1147, 8^m3^a6^x

cm^–1. ¹H n.m.r. (300 MHz) ␦ 0.07, 0.13, 2×s, OSiMe₂; 0.60, dt, J_8,79.1,

J_8,11␤9.1, J_8,11␣5.4 Hz, H8; 0.88, s, OSiCMe₃; 1.12, m, H11␣; 1.24, m,

H11␤; 1.44, m, H7; 2.02, m, H9␤; 2.32, s, 4-Me; 2.77, dd, J_5,4b11.8, J_5,6

3.8 Hz, H5; 2.65–2.94, m, H10, H9␣; 3.47, s, OMe; 3.61, d, J_4b,511.8

Hz, H4b; 3.70, s, OMe; 4.68, dd, J_6,78.0, J_6,53.8 Hz, H6; 6.37, 6.46,

2×d, J 2.5 Hz, ArH. ¹³C n.m.r. (75 MHz) ␦ –5.8, –4.3, OSiMe₂; 6.1, C 11;

17.7, 23.8, C7, C8; 17.9, OSiCMe₃; 19.5, 4-Me; 25.6, OSiCMe₃; 26.0,

28.5, C9, C10; 28.9, C4b; 47.3, C8a; 47.9, C5; 51.8, 54.7, OMe; 65.8,

C6; 110.2, 113.9, C1, C3; 127.8, C 4a; 137.3, 139.6, C4, C 10a; 157.4,

C2; 175.9, CO; 176.2, CO. Mass spectrum m/z 474 (M, 14%), 417 (48),

357 (100), 298 (24), 265 (12), 239 (47), 185 (18), 75 (25).

5-Benzyl 8a-Methyl (4b␣,5␣,6␣,7␣,8␣,8a␣)-6-Hydroxy-2-methoxy-4-

methyl-4b,5,7,8,9,10-hexahydro-7,8-methanophenanthrene-5,8a(6H)-

dicarboxylate

Lithium tri-sec-butylborohydride (2.50 ml, 1 ^M) was added to a solu-

tion of ketone (24) (460 mg, 1.03 mmol) in tetrahydrofuran (35 ml) at

–50°. The solution was allow to warm to –10° over 2 h, quenched with

NaOAc (3 ^M, 4 ml) and 30% H₂O₂(6 ml), and then stirred at room tem-

perature for 10 min. The solution was extracted with ethyl acetate (3×30

ml), washed with Na₂S₂O₃and brine, and then dried over MgSO₄. After

removal of the solvent, the residue was chromatographed over silica gel

(hexane/ethyl acetate, 4: 1) to give the title carbinol (372 mg, 80%) as

an oil, R_F0.32 (hexane/ethyl acetate, 2 : 1) (Found: C, 71.7; H, 6.5.

Methyl (4b␣,5␣,6␣,7␣,8␣,8a␣)-6-t-Butyldimethylsilyloxy-5-

diazoacetyl-2-methoxy-4-methyl-4b,5,7,8,9,10-hexahydro-7,8-

methanophenanthrene-8a(6H)-carboxylate (28)

A solution of acid (27) (18 mg, 0.0379 mmol) in tetrahydrofuran (2

ml) and NaH (1.8 mg, 0.045 mmol) were stirred for 3 h at room tem-

perature under nitrogen. In a separate flask, the Vilsmeier reagent was

prepared by adding dimethylformamide (24.5 mg, 0.336 mmol) to

C₂₇H₃₀O₆requires C, 72.0; H, 6.7%). ␯

(film) 3495, 3008, 2952,

max

2838, 1728, 1706, 1606, 1589, 1484, 1457, 1301, 1279, 1214, 1187,

1149, 737 cm^–1. ¹H n.m.r. (300 MHz) ␦ 0.65, m, H 8; 1.12, dt, J_11␤,88.5,

J

_11␤,78.5, J_gem6.3 Hz, H 11␤; 1.27, m, H 11␣; 1.51, m, H 7; 2.13, ddd,

_gem16.4, J_9␤,10␣9.4, J_9␤,10␤6.8 Hz, H9␤; 2.23, s, 4-Me; 2.59–2.69, m,

H9␣; 2.69, dd, J_5,4b11.6, J_5,62.8 Hz, H 5; 2.74–2.95, m, H10; 3.51,

* In compounds (26)–(30), position 11 refers to the methano group.

1104

D. H. Rogers et al.

(COCl)₂(44 mg, 0.344 mmol). The product was added to the sodium

salt of the acid and the mixture stirred until reaction was complete by

t.l.c. monitoring (2 h). The resulting solution of the acid chloride was

added to a solution of CH₂N₂in Et₂O (0.4 M, 20 ml), the reaction being

complete by t.l.c. monitoring after 5 min. After the residual CH₂N₂was

dispersed under a nitrogen flow, the solvent was removed by evapora-

tion. The residue was chromatographed over silica gel (hexane/ethyl

acetate, 2 : 1) to give diazoketone (28) (18 mg, 95%) as a solid, m.p.

141–143°, R_F0.42 (hexane/ethyl acetate, 2: 1) (Found: C, 65.0; H, 7.9;

N, 5.3%; M^+•, 498.2552. C₂₇H₃₈N₂O₅Si requires C, 65.0; H, 7.7; N,

5.6%; M^+•, 498.2550). ␯_max(KBr) 3105, 3010, 2956, 2928, 2888, 2856,

2098, 1727, 1660, 1604, 1331, 1073, 839 cm^–1. ¹H n.m.r. (300 MHz) ␦

0.07, 0.13, 2×s, OSiMe₂; 0.58, m, H 8; 0.95, s, OSiCMe₃; 1.13–1.22, m,

H11; 1.47, m, H 7; 2.01–2.14, m, H 9␤; 2.41, s, 4-Me; 2.65–2.89, m,

4H; 3.48, s, OMe; 3.71, d, J_4b,511.4 Hz, H 4b; 3.71, s, OMe; 4.61, dd,

19.3, 5-Me; 20.7, 22.1, C 1, C 2; 25.9, OSiCMe₃; 29.9, 30.4, C 9, C 10;

34.0, C 10b; 41.4, C 6; 45.3, C 10a; 52.1, 55.8, OMe; 60.3, 60.4, C 3,

C 3a; 100.5, C 8; 130.6, 131.2, 133.1, 136.4, C 4a, C 5, C 8a, C 10c;

147.3, C 7; 176.7, CO; 200.8, C 4. Mass spectrum m/z 470 (M, 25%),

413 (50), 353 (36), 338 (49), 311 (56), 279 (50), 251 (73), 223 (24), 209

(17), 179 (21), 165 (29), 149 (34), 129 (25), 105 (18), 91 (29), 75 (100).

Methyl [2S(?)-(1´␣,2´␣)]-2-[6´-Methoxy-2´-methoxycarbonyl-8´-

methyl-2´-(1´´-oxoprop-2´´-yl)-1´,2´,3´,4´-tetrahydronaphthalen-1´-

yl]acetate (35)

Lead tetraacetate (3.21 g, 7.22 mmol) was added in one portion to

a solution of the hydroxy ketones (20) and 7-epi-(20) (2.0 g, 6.02

mmol) in MeOH and benzene (60 ml, 35 : 65) at room temperature

under nitrogen. After 5 min the mixture was quenched with cold satu-

rated aqueous NaHCO₃and the resulting brown slurry extracted with

Et₂O. The combined organic phases were washed with water and brine,

dried (MgSO₄) and concentrated under reduced pressure.

Chromatography on silica gel (pentane/ethyl acetate, 3: 1) afforded

aldehyde (35) as a colourless oil (1.96 g, 90%), R_F0.39 (pentane/ethyl

acetate, 3: 1) (Found: M^+•, 362.1726. C₂₀H₂₆O₆requires M^+•,

362.1729). ␯_max(CHCl₃) 2945, 2840, 1725s, 1605s, 1480s, 1300, 1260,

J

_6,77.9, J_6,53.5 Hz, H6; 4.96, br s, CH=N₂; 6.38, 6.49, 2×d, J 2.5 Hz,

ArH. ¹³C n.m.r. (75 MHz) ␦ –5.4, –4.3, OSiMe₂; 6.0, C 11; 18.2,

OSiCMe₃; 18.9, 23.6, C 7, C 8; 19.9, 4-Me; 25.8, OSiCMe₃; 26.4, 28.9,

C 9, C 10; 29.4, C 4b; 47.9, C 8a; 51.8, OMe; 53.6, 54.4, C 5, CH=N₂;

54.8, OMe; 65.7, C 6; 110.7, 113.7, C 1, C 3; 128.1, C 4a; 137.2, 139.6,

C 4, C 10a; 157.5, C 2; 176.2, CO; 192.3, CO. Mass spectrum m/z 498

(M, 4%), 470 (M– N₂, 8), 413 (27), 353 (38), 311 (19), 279 (35), 251

(54), 237 (23), 185 (23), 129 (23), 115 (18), 89 (27), 73 (100).

1

1150s, 860 cm^–1. H n.m.r. (300 MHz) ␦ 1.06, d, J_3´´,2´´6.8 Hz, H3´´;

1.68, m, H3´␤; 2.25, br s, 8´-Me; 2.36, dd, J_gem14.7, J_2,1´7.6 Hz, H2;

2.48, dq, J_2´´,3´´6.8, J_2´´,1´´2.2 Hz, H 2´´; 2.60, m, H3´␣; 2.85, dd, J_gem

14.7, J_2,1´5.4 Hz, H 2; 3.02–2.84, m, H4´; 3.37, 3.60, 3.71, 3×s, OMe;

4.20, br dd, J_1´,27.6, J_1,25.4 Hz, H1´; 6.43, 6.49, 2×br s, H 5´, H 7´;

10.02, d, J_1´´,2´´2.2 Hz, H 1´´. ¹³C n.m.r. (75 MHz) ␦ 9.8, C 3´´; 18.9, 8´-

Me; 24.4, C 3´; 25.4, C 4´; 35.6, C 2; 35.9, C 1´; 49.8, C 2´´; 51.4, 51.5,

OMe; 53.4, C 2´; 54.7, OMe; 110.9, C 5´; 113.8, C 7´; 128.9, C 8a´;

136.6, 136.7, C 4a´, C 8´; 157.9, C 6´; 172.3, 173.1, CO; 202.7, C 1´´.

Mass spectrum m/z 362 (M, 19%), 233 (48), 201 (100), 199 (35), 189

(33), 173 (70), 128 (28), 115 (30), 83 (48), 59 (39).

Methyl (1␣,2␣,3␣,3a␤,10a␣,10b␣)-3-t-Butyldimethylsilyloxy-1,2-

methano-7-methoxy-5-methyl-4-oxo-1,2,3,3a,4a,9,10,10b-octahydro-

cyclohept[bc]acenaphthylene-10a(4H)-carboxylate (29)

A solution of diazoketone (28) (90 mg, 0.180 mmol) in

dichloromethane (2 ml) was added to Rh₂[(±)-mandelate]₄(9 mg, 0.011

mmol) and heated under reflux for 30 min until the reaction was com-

plete by t.l.c. monitoring. The solution was diluted with

dichloromethane, washed with NaHCO₃and dried over MgSO₄. The

solution was treated with pentane and the resulting precipitate collected

to afford the cycloheptatriene (29) (79 mg, 93%), m.p. 136–139°, R_F

0.61 (hexane/ethyl acetate, 2: 1) (Found: C, 68.9; H, 8.4%; M^+•,

Methyl [3´´R-(1´␣,2´␣)]-2-[6´-Methoxy-2´-(1´´-methoxybut-1´´-en-

3´´-yl)-2´-methoxycarbonyl-8´-methyl-1´,2´,3´,4´-tetrahydro-

naphthalen-1´-yl]acetate (36)

470.2481. C₂₇H₃₈O₅Si requires C, 68.9; H, 8.1%; M^+•, 470.2489). ␯

max

(film) 3002, 2953, 2929, 2855, 1749, 1732, 1626, 1546, 1256, 1196,

1162, 1151, 836 cm^–1. ¹H n.m.r. (300 MHz) ␦ 0.12, 0.17, 2×s, OSiMe₂;

0.62–0.70, m, H 11; 0.88, s, OSiCMe₃; 1.00, m, H1; 1.50, m, H 2; 1.68,

ddd, J_gem12.5, J_10␤,9␣9.8, J_10␤,9␤6.3 Hz, H 10␤; 1.92, s, 5-Me; 2.23, ddd,

NaN(SiMe₃)₂(15.5 ml of a 1.0 M solution in hexane, 15.5 mmol)

was added dropwise to a stirred suspension of exhaustively dried

[Ph₃PCH₂OCH₃]Cl (5.79 g, 16.9 mmol) in dry tetrahydrofuran (80 ml)

at room temperature under nitrogen. After 15 min, the deep red solution

was cooled to –78° and a solution of aldehyde (5.10 g, 14.1 mmol) in

dry tetrahydrofuran (15 ml) was added dropwise over c. 5 min. The

cooling bath was then removed and the solution left to stir for a further

2.5 h. The reaction mixture was quenched with water and extracted with

Et₂O. The combined organic phases were washed with water and brine,

then dried (MgSO₄) and concentrated under reduced pressure to afford

a pale yellow oil. Chromatography on silica gel (pentane/ethyl acetate,

4: 1) gave a c. 2: 1 mixture of (E)- and (Z)-methyl enol ethers as a

colourless oil, which was used directly without further purification. A

portion of the (E,Z)-isomer mixture was resolved by repeated flash

chromatography (pentane/ethyl acetate, 4 : 1) to provide sufficient

material for analysis.

J

_3a,10b14.8, J_3a,32.5, J 1.3 Hz, H 3a; 2.12–2.37, m, H 9, H 10␣; 2.52, br

s, H4a; 3.22, br d, J_10b,3a14.8 Hz, H 10b; 3.62, 3.72, 2×s, OMe; 4.63,

dd, J_3,27.7, J_3,3a2.5 Hz, H3; 5.58, br s, H 8; 5.77, br s, H6. ¹³C n.m.r. ␦

–4.6, –5.1, OSiMe₂; 6.7, C 11; 18.1, OSiCMe₃; 19.9, 5-Me; 20.6, 22.8,

C 1, C 2; 25.8, OSiCMe₃; 28.1, 32.4, C 9, C 10; 34.1, C 10b; 46.2,

C 10a; 52.1, OMe; 54.1, C 4a; 54.8, OMe; 58.0, 59.6, C 3, C 3a; 105.4,

C 8; 120.0, C 6; 122.4, 126.5, 134.3, C 5, C 8a, C 10c; 158.9, C 7; 176.1,

CO; 209.5, C 4. Mass spectrum m/z 470 (M, 25%), 413 (50), 353 (36),

338 (49), 311 (56), 279 (50), 251 (73), 223 (24), 209 (17), 179 (21), 165

(29), 149 (34), 129 (25), 105 (18), 91 (29), 75 (100).

Methyl (1␣,2␣,3␣,3a␤,10a␣,10b␣)-3-t-Butyldimethylsilyloxy-1,2-

methano-7-methoxy-5-methyl-4-oxo-1,2,3,3a,6,9,10,10b-octahydro-

cyclohept[bc]acenaphthylene-10a(4H)-carboxylate (30)

The more mobile (Z)-isomer crystallized from ethyl acetate/pentane

to give colourless prisms, m.p. 87–89°. R_F0.58 (pentane/ethyl acetate,

4: 1) (Found: C, 67.5; H, 8.0%; M^+•, 390.2041. C₂₂H₃₀O₆requires C,

67.7; H, 7.7%; M^+•, 390.2042). ¹H n.m.r. (300 MHz) ␦ 0.91, d, J_4´´,3´´7.0

Hz, H4´´; 1.58, m, H3␤; 2.17, dd, J_gem13.5, J_2,1´10.7 Hz, H2; 2.24, br

s, 8´-Me; 2.64, m, H3´␣; 2.80, dd, J_gem13.5, J_2,1´3.3 Hz, H2´; 2.86, m,

H3´´; 2.94–2.87, m, H4´; 3.35, 3.50, 3.60, 3.71, 4×s, OMe; 3.93, ddd,

1,8-Diazabicyclo[5.4.0]undec-7-ene (5 mg) was added to a solution

of ketone (29) (21 mg) in dichloromethane (2 ml) and the mixture

stirred for 1 min at room temperature. Ether (20 ml) was added and the

solution washed with 0.5 ^MHCl, saturated NaHCO₃and dried over

MgSO₄. Removal of solvent gave mainly one double-bond isomer,

cycloheptatriene (30) (16 mg, 76%), as a solid, m.p. 175–180°, R_F0.61

(hexane/ethyl acetate, 2: 1) (Found: M^+•, 470.2480. C₂₇H₃₈O₅Si

J

_1´,210.7, J_1´,23.3, J_1´,3␣1.5 Hz, H 1´; 4.63, dd, J_2´´,3´´10.6, J_2´´,1´´6.4 Hz,

H2´´; 6.01, d, J_1´´,2´´6.4 Hz, H1´´; 6.42, 6.44, 2×br s, ArH. ¹³C n.m.r.

(75 MHz) ␦ 17.0, C 4´´; 18.8, 8´-Me; 25.0, 25.8, C 3´, C 4´; 34.9, C 2;

35.0, C 1´; 36.6, C 3´´; 50.9, 51.2, OMe; 53.9, C 2´; 54.7, 59.4, OMe;

108.0, C 2´´; 111.0, 113.5, C 5´, C 7´; 130.3, C 8a´; 137.2, 137.6, C 4a´,

C 8´; 146.3, C 1´´; 157.7, C 6´; 174.7, 173.8, CO. Mass spectrum m/z

390 (M, 0.4%), 245 (0.3), 231 (0.7), 199 (0.3), 185 (0.8), 171 (0.4), 169

(0.4), 158 (0.4), 149 (0.4), 129 (0.6), 115 (0.7), 86 (5), 85 (100).

The less mobile (E)-isomer was obtained as a colourless oil, R_F0.57

(pentane/ethyl acetate, 4: 1) (Found: M^+•, 390.2041. C₂₂H₃₀O₆requires

requires M^+•, 470.2489). ␯

(film) 3003, 2953, 2928, 2855, 1731,

max

1718, 1622, 1557, 1258, 1223, 1192, 1164, 1139, 1097, 1068, 1045, 835

1

cm^–1. H n.m.r. (300 MHz) ␦ 0.12, 0.14, 2×s, OSiMe₂; 0.57–0.69, m,

H11; 0.88, s, OSiCMe₃; 0.99–1.07, m, H1; 1.49, 1.66–1.76, 2×m, H 2,

H10␤; 2.08, dd, J_gem12.5, J_6,82.7 Hz, H 6; 2.31, s, 5-Me; 2.15–2.31, m,

4H; 2.89, dd, J_gem12.5, J_6,82.0 Hz, H 6 ; 3.29, br d, J_10b,3a12.6 Hz,

H10b; 3.59, 3.75, 2×s, OMe; 4.66, dd, J_3,28.0, J_3,3a2.7 Hz, H 3; 5.08,

br s, H 8. ¹³C n.m.r. ␦ –4.6, –5.1, OSiMe₂; 5.8, C 11; 18.3, OSiCMe₃;

Studies on the Synthesis of Harringtonolide

1105

1

M^+•, 390.2042). H n.m.r. (300 MHz) ␦ 0.98, d, J_4´´,3´´6.9 Hz, H4´´;

Methyl [3´´R-(1´␣,2´␣)]-1-(1´-Diazo-2´-oxoprop-3´-yl)-2-(1´´,1´´-

dimethoxybut-3´´-yl)-6-methoxy-8-methyl-1,2,3,4-tetrahydronaphth-

alene-2-carboxylate (38)

1.58, m, H 3´␤; 2.16, dd, J_gem13.9, J_2,19.3 Hz, H 2; 2.24, br s, 8´-Me;

2.25, dq, J_3´´,2´´9.9, J_3´´,4´´6.9 Hz, H 3´´; 2.62, m, H 3´␣; 2.63, dd, J_gem

13.9, J_2,1´4.0 Hz, H2; 2.94–2.86, m, H 4´; 3.36, 3.54, 3.60, 3.71, 4×s,

OMe; 3.96, 1H, ddd, J_1´,29.3, J_1´,24.0, J_1´,3´␣1.6 Hz, H 1´; 4.99, dd, J_2´´,1´´

12.8, J_2´´,3´´9.9 Hz, H2´´; 6.35, d, J_1´´,2´´12.8 Hz, H 1´´; 6.41, 6.46, 2×d,

J 2.7 Hz, ArH. ¹³C n.m.r. (75 MHz) ␦ 18.4, C 4´´; 18.9, 8´-Me; 25.0,

25.9, C 3´, C 4´; 34.9, C 2; 35.9, C 1´; 39.4, C 3´´; 51.0, 51.5, OMe; 54.0,

C 2´; 54.8, 56.0, OMe; 104.6, C 2´´; 111.1, 113.7, C 5´, C 7´; 130.7,

C 8´a; 137.2, 137.4, C 4´a, C 8´; 147.9, C 1´´; 157.9, C 6´; 174.4, 173.6,

CO. Mass spectrum m/z (M, 0.2%), 231 (0.4), 185 (1), 173 (1), 149 (1),

141 (1), 129 (1), 115 (1), 86 (5), 85 (100).

Dry Et₃N (1.71 ml, 12.3 mmol) was added to a stirred solution of the

acid (37) (4.10 g, 10.0 mmol) in dry dichloromethane under N₂. The

solution was cooled to 0° (ice bath) and methyl chloroformate (0.88 ml,

11.3 mmol) was added dropwise.After 15 min, the reaction mixture was

diluted with dichloromethane, washed sequentially with 0.2 ^MHCl,

water and brine, and dried over MgSO₄. Evaporation of the solvent gave

essentially pure mixed anhydride as a pale yellow oil (4.7 g, 100%

recovery), R_F0.41 (25% ethyl acetate in pentane) (Found: M^+•,

466.2198. C₂₄H₃₄O₉requires M^+•, 466.2203), which was used directly

without further purification. ␯ 2950, 2840, 1825s, 1765, 1725s,

max

1

1605s, 1480s, 1300, 1150s, 1090s, 855 cm^–1. H n.m.r. (300 MHz) ␦

Methyl [3´´R-(1´␣,2´␣)]-2-[2´-(1´´,1´´-Dimethoxybut-3´´-yl)-6´-

methoxy-2´-methoxycarbonyl-8´-methyl-1´,2´,3´,4´-tetrahydronaph-

thalen-1´-yl]acetate

0.94, br d, 3H, J_4´´,3´´6.8 Hz, H4´´; 1.36, ddd, J_gem11.2, J_2´´,3´´11.0, J_2´´,1´´

3.1 Hz, H2´´; 1.51, m, H3´␤; 1.75, ddq, J_3´´,2´´11.0, J_3´´,4´´6.8, J_3´´,2´´2.2

Hz, H3´´; 2.26, ddd, J_gem11.2, J_2´´,1´´8.1, J_2´´,3´´2.2 Hz, H 2´´; 2.30, s,

8-Me; 2.34, dd, 1H, J_gem15.3, J_2,1´9.5 Hz, H2; 2.67, m, H 3´␣; 2.84, dd,

J_gem15.3, J_2,1´3.7 Hz, H2´; 2.92–2.83, m, 2H, H4´; 3.34, 3.35, 3.36,

3.70, 3.82, 5×s, OMe; 4.11, ddd, J_1´,29.5, J_1´,23.7, J_1´,3␣1.1 Hz, H1´;

4.43, dd, J_1´´,2´´8.1, J_1´´,2´´3.1 Hz, H 1´´; 6.41, 6.47, 2×d, J 2.7 Hz, H5,

H7. ¹³C n.m.r. (75 MHz) ␦ 15.4, C 4´´; 19.2, 8´-Me; 25.4, 25.9, C 4´,

C 3´; 34.0, C 2´´; 34.5, 35.1, C 1´, C 3´´; 35.2, C 2; 51.1, 52.6, 53.7,

OMe; 53.9, C 2´; 55.7, 54.8, OMe; 103.5, C 1´´; 111.0, 114.0, C 7´, C 5´;

129.1, C 8´a; 137.2, 137.3, C 4´a; C 8´; 149.4, O–CO–O; 157.8, C 6´;

166.8, C 1; 173.8, CO. Mass spectrum m/z 466 (M, 0.4%), 359 (0.5),

349 (0.6), 299 (0.6), 271 (0.6), 257 (1), 188 (4), 160 (3), 127 (3), 115

(8), 85 (100), 75 (51).

A catalytic amount of p-TsOH (150 mg) was added to a solution of

the mixture of methyl enol ethers (36) (c. 4.8 g) in methanol (70 ml).

(MeO)₃CH (1 ml) was added and the resulting solution stirred at reflux

for 2 h. The reaction mixture was then diluted with ether, washed with

dilute NaHCO₃solution, water and brine, and dried over MgSO₄.

Removal of solvent under vacuum and flash chromatography (20%

ethyl acetate in pentane) afforded the desired dimethyl acetal (R_F0.35)

which crystallized from pentane/ethyl acetate to give a white semicrys-

talline oil (4.50 g, 76% overall yield for two steps). ␯_max2950, 2840,

1725s, 1605s, 1480, 1300, 1260, 1150, 1120, 1050, 860 cm^–1. ¹H n.m.r.

(300 MHz) ␦ 0.93, br d, J_4´´,3´´6.8 Hz, H 4´´; 1.39, ddd, J_gem14.0, J_2´´,3´´

11.4, J_2´´,1´´3.3 Hz, H 2´´; 1.54, m, H 3´␤; 1.77, ddq, J_3´´,2´´11.4 J_3´´,4´´

6.8, J_3´´,2´´2.3 Hz, H 3´´; 2.20, dd, J_gem14.1, J_2,1´9.7 Hz, H 2; 2.24, br s,

8´-Me; 2.35, br ddd, J_gem14.0, J_2´´,1´´8.1, J_2´´,3´´2.3 Hz, H 2´´; 2.66, dd,

An unscratched, one-necked flask, charged with a freshly prepared,

ethanol-free solution of CH₂N₂in ether (c. 10-fold excess), was cooled

to 0° under nitrogen. A solution of the crude anhydride (4.7 g) in ether

(15 ml) was added dropwise and the reaction mixture was stirred at 5°

for 24 h. Excess solvent and CH₂N₂were removed on a rotary evapora-

tor in a well ventilated fume hood. Flash chromatography (25% ethyl

acetate in pentane) of the resulting yellow oil gave pure diazoketone (38)

(R_F0.20) as clear, pale yellow needles (3.3 g, 75% overall yield for two

steps), m.p. 80° (Found: C, 63.9; H, 7.8; N, 6.9. C₂₃H₃₂N₂O₆requires C,

63.9; H, 7.5; N, 6.5%). ␯_max2950, 2840, 2100s, 1720s, 1630s, 1605s,

1480, 1360s, 1300, 1160s, 1150s, 1050s, 905, 855 cm^–1. ¹H n.m.r. (300

MHz) ␦ 0.92, 3H, br d, J_4´´,3´´6.8 Hz, H4´´; 1.36, ddd, J_gem13.8, J_2´´,3´´

11.4, J_2´´,1´´3.0 Hz, H2´´; 1.50, m, H3␤; 1.77, ddq, J_3´´,2´´11.4 J_3´´,4´´6.8,

J

_gem14.1, J_2,1´4.0 Hz, H 2´; 2.68–2.59, m, H 3´␣; 2.84, m, H 4´; 3.33,

3.36, 3.37, 3.56, 3.71, 5×s, OMe; 4.06, ddd, J_1´,29.7, J_1´,24.0, J_1´,3´␣1.1

Hz, H 1´; 4.46, dd, J_1´´,2´´8.1, J_1´´,2´´3.3 Hz, H 1´´; 6.41, 6.45, 2×d, J 2.2

Hz, H 5´, H 7´. ¹³C n.m.r. (75 MHz) ␦ 15.2, H 4´´; 19.1, 8´-Me; 25.4,

26.0, C 3´, C 4´; 33.7, C 2´´; 35.0, 35.1, C 3´´, C 1´; 35.3, C 2; 51.1,

51.6, 52.8, 53.3, OMe; 53.9, C 2´; 54.8, OMe; 103.7, C 1´´; 110.9,

113.7, C 5´, C 7´; 130.0, C 8´a; 137.1, 137.2, C 4´a, C 8´; 157.7, C 6´;

173.1, 174.2, CO. Mass spectrum m/z 422 (M, 0.6%), 273 (0.6), 257

(0.8), 233 (0.9), 232 (0.8), 231 (1), 225 (0.9), 201 (2), 199 (2), 115 (5),

85 (100).

J_3´´,2´´2.2 Hz, H3´´; 2.12, br dd, J_gem13.0, J_3´,19.9 Hz, H3´; 2.20, s, 8-

Me; 2.41, br dd, J_gem13.8, J_2´´,1´´8.1 Hz, H2´´; 2.59, dd, J_gem13.0, J_3´,2´

3.1 Hz, H3´; 2.69–2.58, m, H3␣; 2.99–2.78, m, H4; 3.32, 3.37, 3.39,

3.71, 4×s, OMe; 4.03, br d, J_1,3´9.9 Hz, H1; 4.46, dd, J_1´´,2´´8.1, J_1´´,2´´3.0

Hz, H1´´; 4.99, br s, H1´; 6.44, 6.41, 2×d, J 2.4 Hz, H5, H7. ¹³C n.m.r.

(75 MHz) ␦ 15.4, C4´´; 19.3, 8-Me; 25.4, C3; 25.9, C4; 34.0, C2´´;

34.9, C3´´; 35.7, C1; 41.8, C3´; 51.1, 52.8, OMe; 53.6, C2; 53.9, 54.8,

OMe; 55.0, C1´; 103.8, C1´´; 111.0, 113.6, C7, C5; 130.0, C 8a; 137.0,

137.3, C4a, C 8; 157.6, C6; 174.1, CO; 194.1, C2´. Mass spectrum m/z

372 (2%), 349 (8), 285 (11), 115 (16), 85 (78), 75 (100).

[3´´ R-(1´␣,2´␣)]-2-[2´-(1´´,1´´-Dimethoxybut-3´´-yl)-6´-methoxy-2´-

methoxycarbonyl-8´-methyl-1´,2´,3´,4´-tetrahydronaphthalen-1´-

yl]acetic Acid (37)

Aqueous 2 ^MNaOH (30 ml) was added dropwise to a stirred solu-

tion of the ester prepared above (4.5 g, 10.7 mmol) in ethanol (100

ml) at room temperature. After 3 h, the reaction mixture was concen-

trated under vacuum and the residue diluted with ether, cooled to 5°

(ice bath), and carefully acidified to pH 2 with 1 ^MHCl. The phases

were separated and the aqueous phase was thoroughly extracted

twice more with ether; it was then washed with water and brine, and

dried over MgSO₄. Evaporation of the solvent gave acid (37) (4.25 g,

98% recovery) as a white solid, which was used without further

purification. ␯_max2940, 2840, 1720s, 1605, 1480, 1300, 1150s, 1125,

1055, 860 cm^–1. ¹H n.m.r. (300 MHz) ␦ 0.94, br d, J_4´´,3´´6.7 Hz, H 4´´;

1.37, ddd, J_gem11.5, J_2´´,3´´11.5 J_2´´,1´´3.8 Hz, H 2´´; 1.53, m, H 3´␤;

1.77, ddq, J_3´´,2´´11.5, J_3´´,4´´6.7, J_3´´,2´´1.9 Hz, H 3´´; 2.20, dd, J_gem

14.4, J_2,1´9.3 Hz, H 2; 2.26, br s, 8´-Me; 2.34, ddd, J_gem11.5, J_2´´,1´´

8.3, J_2´´,3´´1.9 Hz, H 2´´; 2.68, dd, J_gem14.4, J_2,1´3.8 Hz, H 2;

2.70–2.59, m, H 3´␣; 2.92–2.84, m, H 4´; 3.33, 3.34, 3.36, 3.72, 4×s,

OMe; 4.08, ddd, J_1´,29.3, J_1´,23.8, J_1´,3´␣1.4 Hz, H 1´; 4.45, dd, J_1´´,2´´

8.3, J_1´´,2´´3.1 Hz, H 1´´; 6.41, 6.47, 2×d, J 2.7 Hz, H 5´, H 7´. ¹³C

n.m.r. (75 MHz) ␦ 15.3, C 4´´; 19.2, 8´-Me; 25.4, 26.0, C 4´, C 3´;

34.0, C 2´´; 34.9, 35.1, C 3´´, C 1´; 35.3, C 2; 51.0, 52.6, 53.3, OMe;

53.9, C 2´; 54.8, OMe; 103.7, C 1´´; 110.9, 113.8, C 5´, C 7´; 130.0,

C 8´a; 137.1, C 4´a, C 8´; 157.6, C 6´; 174.0, 177.9, CO. Mass spec-

trum m/z 408 (M, 0.7%), 344 (1), 257 (0.8), 233 (2), 232 (7), 231 (2),

199 (2), 173 (4), 115 (4), 85 (100).

Methyl [3´R-(2a␣,3␣,9a␤)]-3-(1´,1´-Dimethoxybut-3´-yl)-7-methoxy-

9-methyl-1-oxo-2,2a,3,4,5,9a-hexahydro-1H-benz[ cd]azulene-3-

carboxylate (39)

A solution of the diazoketone (38) (2.25 g, 5.23 mmol) in

dichloromethane (15 ml) was added dropwise to a gently boiling sus-

pension of rhodium mandelate (c. 2 mol %) in dichloromethane (5 ml)

under argon. After 5 min, an aliquot from the reaction mixture was fil-

tered through a plug of cotton wool (to remove undissolved catalyst),

and the filtrate concentrated under vacuum to afford an 8: 1 mixture of

the unstable cycloheptatriene (39), R_F0.4 (20% ethyl acetate in

pentane) (Found: M^+•, 404.2195. C₂₃H₃₂O₆requires M^+•, 404.2199) and

a by-product of undetermined structure. Column chromatography led to

extensive decomposition, so the mixture was used directly without

further purification. ␯_max2950, 2840, 1740s, 1720s, 1160, 1050s, 930

cm^–1. ¹H n.m.r. (300 MHz) ␦ 1.11, 3H, br d, J_4´,3´6.8 Hz, H4´; 1.26, ddd,

J

_gem13.4, J_2´,3´10.5, J_2´,1´3.1 Hz, H 2´; 1.69, dddd, J_gem13.4, J_2´,1´7.9,

_2´,3´1.3, J_2´,4´≈ 1.0 Hz, H2´; 1.88, m, H4; 1.87, s, 9-Me; 2.06, ddq, J_3´,2´

1106

D. H. Rogers et al.

10.5, J_3´,4´6.8, J_3´,2´1.3 Hz, H 3´; 2.20–2.14, m, H 5, H 4; 2.69, ddd, J_gem

17.8, J_2␣,2a8.4, J_2␣,9a0.9 Hz, H 2α; 2.77, br s, H 9a; 2.82, ddd, J_gem17.8,

aldehyde (42) (R_F0.30; 332 mg, 75%) as very pale yellow needles, m.p.

147° (Found: C, 70.4; H, 7.6. C₂₁H₂₆O₅requires C, 70.4; H, 7.3%). ␯

2950, 2840, 1720s, 1705s, 1620, 1560, 1260, 1115, 1045, 845 cm^–1. ^m¹H^ax

n.m.r. (300 MHz) ␦ 1.02, br d, J_4´,3´6.6 Hz, H4´; 1.35–1.20, m, H2´;

1.86, ddd, J_4␤,4␣13.6, J_4␤,56.0 J_4␤,55.8 Hz, H4␤; 2.13, br d, J_gem12.3

Hz, H 8; 2.18–2.08, m, H4␣; 2.22, ddd, J_gem17.6, J_2´,3´10.8, J_2´,1´2.0

Hz, H2´; 2.39, dd, J_gem16.9, J_2,2a10.5 Hz, H 2; 2.39, br s, 9-Me;

2.48–2.39, m, H 5; 2.56, m, H3´; 2.60, dd, J_gem16.9, J_2,2a7.7 Hz, H2;

2.93, dd, J_gem12.3, J_8,62.0 Hz, H 8; 3.56, m, H2a; 3.59, 3.72, 2×s, OMe;

5.15, br s, H 6; 9.72, d, J_1´,2´2.0 Hz, H 1´. ¹³C n.m.r. (75 MHz) ␦ 16.1,

C 4´´; 20.0, 9-Me; 26.8, C 3´; 29.0, 29.9, C 4, C 5; 40.9, C 2a; 41.8, C 2;

42.9, C 8; 48.1, C 2´; 48.7, C 3; 51.8, 55.9, OMe; 99.8, C 6; 131.4,

131.8, 134.8, 135.8, C 5a, C 9, C 9a, C 9b; 147.1, C 7; 176.4, CO; 201.2,

C 1´; 204.9, C 1. Mass spectrum m/z 358 (M, 61%), 285 (36), 255 (27),

202 (93), 174 (36), 159 (32), 115 (35), 85 (35), 43 (100).

J

_2␤,2a12.5, J_2␤,9a1.8 Hz, H 2␤; 3.26, m (obscured), H2a; 3.26, 3.27,

3.60, 3.66, 4×s, OMe; 4.39, dd, J_1´,2´7.9, J_1´,2´3.1 Hz, H 1´; 5.56, br s,

H6; 5.77, br s, H 8. ¹³C n.m.r. (75 MHz) ␦ 15.8, C 4´; 20.4, 9-Me; 26.5,

C 4; 28.5, C 5; 30.1, C 3´; 37.0, C 2´; 42.6, 42.8, C 2a, C 2; 48.8, C 3;

51.6, 52.5, 53.0, OMe; 53.6, C 9a; 54.6, OMe; 103.6, C 1´; 104.8, C 6;

120.6, C 8; 126.1, 126.7, 133.1, C 9, C 9b, C 5a; 158.4, C 7; 176.7, CO;

216.0, C 1. Mass spectrum m/z 404 (M, <1%), 372 (11), 286 (10), 285

(53), 174 (13), 173 (14), 85 (100), 75 (65).

Methyl [3´R-(2a␣,3␣)]-3-(1´,1´-Dimethoxybut-3´-yl)-7-methoxy-9-

methyl-1-oxo-2,2a,3,4,5,8-hexahydro-1H-benz[ cd]azulene-3-

carboxylate (40)

To the crude reaction mixture obtained above in dichloromethane

(20 ml) at room temperature, was added 1,8-diazabicyclo[5.4.0]undec-

7-ene (3–4 drops). After 10 min, the resulting pale brown solution was

washed with 0.1 ^MHCl, water and brine, and dried over MgSO₄.

Removal of solvent afforded a pale green oil which was flash chro-

matographed to give the acetal (40) as a yellow oil (1.71 g, 81% overall

yield for two steps) (Found: M^+•, 404.2195. C₂₃H₃₂O₆requires M^+•,

404.2195). ␯_max2950, 2840, 1705s, 1620s, 1560, 1120, 1045s, 905

cm^–1. ¹H n.m.r. (300 MHz) ␦ 1.02, br d, J_4´,3´6.8 Hz, H 4´; 1.24, ddd, J_gem

14.1, J_2´,3´11.2, J_2´,1´3.3 Hz, H 2´; 1.77, ddd, J_gem14.1, J_2´,1´7.7, J_2´,3´

2.0 Hz, H 2´; 1.81, m, H 4␤; 2.03, ddq, J_3´,2´11.2, J_3´,4´6.8, J_3´,2´2.0 Hz,

H3´; 2.13, br d, J_gem12.5 Hz, H 8; 2.14–2.05, m, H 4␣; 2.36–2.43, m,

H5; 2.38, s, 9-Me; 2.49, dd, J_gem17.4, J_2,2a10.5 Hz, H 2; 2.70, dd, J_gem

17.4, J_2,2a7.7 Hz, H 2; 2.90, dd, J_gem12.5, J_8,62.0 Hz, H 8; 3.28, s,

2×OMe; 3.50, br dd, J_2a,210.5 J_2a,27.7 Hz, H 2a; 3.58, 3.68, 2×s, OMe;

4.41, dd, J_1´,2´7.7, J_1´,2´3.3 Hz, H 1´; 5.13, br s, H 6. ¹³C n.m.r. (75 MHz)

␦ 15.1, C 4´; 19.9, 9-Me; 26.8, C 4; 29.0, C 5; 32.3, C 3´; 35.8, C 2´;

40.8, C 2a; 41.7, C 8; 42.8, C 2; 49.3, C 3; 51.5, 52.6, 53.0, 55.7, OMe;

99.6, C 6; 103.2, C 1´; 133.7, 131.8, 131.0, C 9a, C 9b, C 5a; 136.3, C 9;

146.7, C 7; 176.2, CO; 205.0, C 1. Mass spectrum m/z 404 (M, 0.3%),

402 (0.3), 387 (0.3), 373 (2), 372 (4), 341 (2), 340 (1), 313 (2.5), 311

(1), 286 (5.6), 285 (25), 281 (3), 255 (6.6), 249 (4), 227 (3), 201 (3), 174

(7), 173 (7), 115 (8), 85 (100).

Methyl (1␣,3␣,3a␣,10a␣,10b␣)-3-Hydroxy-7-methoxy-1,5-dimethyl-

4-oxo-1,2,3,3a,6,9,10,10b-octahydro-cyclohept[bc]acenaphthylene-

10a(4H)-carboxylate (43)

K₂CO₃(15 mg) and NaHCO₃(15 mg) were added to a solution of

the aldehyde (42) (220 mg, 0.614 mmol) in methanol (5 ml). After the

resulting suspension was stirred at room temperature for 4 h, volatile

components were removed under vacuum. The residue was diluted with

ether, washed with water and brine, and dried over MgSO₄.

Concentration under vacuum gave a pale yellow solid which was puri-

fied by flash chromatography (33% pentane in diethyl ether) to afford

a 6 : 1 mixture of the 3␣-carbinol (43) (161 mg, 73%; R_F0.42) and its

3␤-epimer (22 mg, 10%; R_F0.52).

3␣-Hydroxy epimer (43) (Found: M^+•, 358.1780. C₂₁H₂₆O₅requires

M^+•, 358.1780). ␯ 3600–3300, 2965, 1720s, 1695s, 1635, 1570,

max

1260, 1075 cm^{–1. 1}H n.m.r. (500 MHz) ␦ 0.98, d, J_Me,17.0 Hz, 1-Me;

1.64, ddd, J_gem12.2, J_2␣,112.3, J_2␣,310.5 Hz, H 2␣; 1.78–1.67, m, H 2␤,

H10␤; 1.87, ddq, J_1,2␣12.3, J_1,Me7.0 Hz, J_1,2␤3.1 Hz, H 1; 2.20, br d,

J

_gem12.5 Hz, H6; 2.43, br s, 5-Me; 2.33–2.52, m, H9, H10␣; 2.77, br

s, 3-OH; 2.82, dd, J_3a,39.9, J_3a,10b7.3 H3a; 2.93, dd, J_gem12.5, J_6,82.0

Hz, H6; 3.30, br d, J_10b,3a7.3 Hz, H10b; 3.34, ddd, J_3,2␣10.5, J_3,3a9.9,

J_3,2␤4.8 Hz, H 3; 3.68, 3.71, 2×s, OMe; 5.14, br s, H8. ¹³C n.m.r. (75

MHz) ␦ 16.4, 1-Me; 20.6, 5-Me; 26.4, C 9+C 10; 28.8, C 1; 35.9, C 2;

42.0, C 6; 42.5, C 10b; 45.7, C 10a; 51.4, 56.0, OMe; 57.8, C 3a; 69.2,

C 3; 99.1, C 8; 130.3, 130.5; 133.4, C 4a, C 8a, C 10c; 139.2, C 5; 147.0,

C 7; 176.0, CO; 208.8, C 4. Mass spectrum m/z 359 (M+1, 19.6%), 358

(M, 92.4), 340 (52), 326 (21), 325 (17), 285 (22), 281 (100), 280 (48),

265 (27), 253 (20), 227 (19), 165 (17), 141 (22), 128 (26), 115 (34).

3␤-Hydroxy epimer: ¹H n.m.r. (300 MHz) ␦ 0.98, d, J_Me,17.0 Hz, 1-

Me; 1.36, d, J_OH,36.5 Hz, 3-OH; 1.67, ddd, J_gem13.9, J_2␤,13.8, J_2␤,33.5

Hz, H2␤; 1.76, m, H 2␣; 1.76, m, H10; 2.24, br d, J_gem12.6 Hz, H6;

2.32, ddq, J_1,2␣11.4, J_1,Me7.0, J_1,2␤3.8 Hz, H 1; 2.46, br s, 5-Me;

2.68–2.33, m, H 9, H10; 2.92, dd, J_gem12.6, J_6,82.1 Hz, H 6; 3.07, dd,

Methyl (2a␤,3␣,5␣,5a␣,7a␤)-3-Hydroxy-5,11-dimethyl-1,9-dioxo-

1,2,4,5,6,7,7a,8-octahydro-3H-indeno[4,5-cd]azulene-5a(9H)-

carboxylate (41)

A solution of the enone (40) (70 mg, 0.17 mmol) in dry

dichloromethane (2 ml) was treated at –78° with a threefold excess (17

␮l) of Me₂BBr. The reaction mixture was quenched after c. 15 s and

workup as previously described afforded a dark yellow oil. Flash chro-

matography gave dione (41) as the major product (28 mg, 47%) as an

amorphous white solid. ¹H n.m.r. (300 MHz) ␦ 1.02, d, J_Me,56.6 Hz, 5-

Me; 1.54, br ddd, J_7␤,7␣≈ 12–14, J_7␤,7a12.5, J_7␤,6␣≈ 10–12 Hz, H7␤; 1.67,

m, H 6␤; 1.85, d, J_gem16.3 Hz, H 2; 2.19, s, 11-Me; 2.20–1.83, m, H 4,

H5, H 6␣, H 7␣; 2.54, d, J_8␤,7a12.1 Hz, H 8␤; 2.55, dd, J_8␣,7a6.6, J_8␣,100.9

Hz, H 8␣; 2.82, d, J_gem16.3 Hz, H2; 3.04, dddd, J_7a,7␤12.5, J_7a,8␤12.1,

J_7a,7␣7.5, J_7a,8␣6.6 Hz, H 7a; 3.69, s, OMe; 3.72, m, H 3; 4.26, br d, J_OH,3

≈ 4.2 Hz, 3-OH; 5.94, d, J_10,8␣0.9 Hz, H10. ¹³C n.m.r. (75 MHz) ␦ 14.0,

5-Me; 22.9, C 6; 23.2, 11-Me; 28.9, C 7; 33.0, C5; 36.1, C7a; 40.8, C2;

48.0, C4; 49.1, C 8; 51.2, OMe; 56.9, 58.2, C 5a, C 2a; 78.4, C3; 130.7,

C 10; 136.3, C11a; 146.1, C11b; 174.2, CO; 180.5, C 11; 201.2, C 9;

204.2, C1. Mass spectrum m/z 344 (M, 27%), 273 (100), 225 (29), 213

(48), 185 (24), 141 (25), 128 (28), 115 (29), 91 (31), 77 (32).

J

_3a,10b7.9, J_3a,35.3 Hz, H 3a; 3.19, m, H 10b; 3.57, 3.70, 2×s, OMe; 4.36,

dddd, J_3,OH6.5, J_3,3a5.3, J_3,2␤3.5, J_3,2␣2.6 Hz, H 3; 5.16, br s, 1H, H 8.

¹³C n.m.r. (75 MHz) ␦ 16.4, 1-Me; 20.8, 5-Me; 22.3, C 1; 26.6, 27.3,

C 9, C 10; 36.6, C 2; 40.4, C 10b; 42.0, C 6; 45.8, C 10a; 51.4, OMe;

54.2, C 3a; 56.0, OMe; 67.9, C 3; 99.0, C 8; 129.4, 132.6, 135.0, C 4a,

C 8a, C 10c; 137.5, C 5; 147.1, C 7; 176.1, CO; 208.3, C 4.

Methyl (1␣,3␣,3a␣,4␤,10a␣,10b␣)-3,4-Dihydroxy-7-methoxy-1,5-

dimethyl-2,3,3a,4,6,9,10,10b-octahydrocyclohept[bc]acenaphth-

ylene-10a(1H)-carboxylate

A solution of the hydroxy ketone (43) (126 mg, 0.352 mmol) and a

catalytic amount (c. 5 mg) of CeCl₃·H₂O in MeOH (5 ml) were cooled

to 0° and NaBH₄(20 mg) was added. After 10 min, the solution was

diluted with 0.1 ^MHCl and extracted with ether. The combined ether

extracts were washed with water and brine, and dried over MgSO₄.

Evaporation of solvent afforded the title diol as a colourless foam (127

mg, 100%), which was used without further purification (Found: M^+•,

360.1936. C₂₁H₂₈O₅requires M^+•, 360.1937). ␯_max3660–3200, 2960,

1720s, 1585, 1080, 910 cm^–1. ¹H n.m.r. (300 MHz) ␦ 0.94, d, J_Me,16.9

Hz, 1-Me; 1.76–1.52, m, H2, H10␤; 1.86, ddq, J_1,28.1, J_1,Me6.9, J_1,2

5.6 Hz, H1; 2.09, br s, 5-Me; 2.44–2.12, m, H 9, H10␣; 2.50, br d, J_gem

13.6 Hz, H6; 2.63, dd, J_gem13.6, J_6,82.2 Hz, H6; 2.68, br d, J_OH,45.3

Methyl [3´R-(2a␣,3␣)]-7-Methoxy-9-methyl-1-oxo-3-(1´-oxobut-3´-

yl)-2,2a,3,4,5,8-hexahydro-1H-benz[ cd]azulene-3-carboxylate (42)

To a solution of the acetal (40) (500 mg, 1.24 mmol) in dry acetone

(20 ml) under nitrogen was quickly added a catalytic amount (20 mg)

of Pt^II(dppe)(OTf)₂(see Note Added in Proof on p. 1108). The resulting

homogeneous mixture was stirred at ambient temperature for 30 min.

The progress of the reaction was monitored by t.l.c. and if starting mate-

rial remained after this time, another aliquot of catalyst was added. The

solution was diluted with ether, washed with water and brine, and dried

over MgSO₄. Removal of solvent in vacuum afforded a pale yellow oil

which was chromatographed (20% ethyl acetate in pentane) to give the

Studies on the Synthesis of Harringtonolide

1107

Hz, 4-OH; 2.81, ddd, J_3a,39.8, J_3a,10b≈ 7, J_3a,46.8 Hz, H 3a; 2.84, br d,

X-Ray Structure Determination for Enone (13)

J

_10b,3a≈ 7 Hz, H10b; 3.20, br d, J_OH,32.6 Hz, 3-OH; 3.55, s, OMe; 3.61,

Crystal data. C₁₈H₂₀O₄, M_r300.35, monoclinic, P2₁/n,

a

10.898(2), b 9.065(2), c 15.544(3) Å, ␤ 97.57(1)° , V 1522.2 Å³, Z 4, D_x

1.310 Mg m^–3, λ(Mo K␣) 0.71069 Å, ␮ 0.09 mm^–1, F(000) 640, T 293

K, R 0.048 for 1760 observed reflections. The ester group and bridge-

head H are cis.

m, H3; 3.71, s, OMe; 4.93, br s, H8; 5.03, br dd, J_4,3a6.8, J_4,OH5.3 Hz,

H4. ¹³C n.m.r. (75 MHz), ␦ 16.4, 1-Me; 21.2, 5-Me; 26.6, 26.9, C 9,

C 10; 28.5, C 1; 37.1, C 2; 40.0, C 6; 44.6, C 10b; 46.2, C 10a; 50.0,

C 3a; 51.3, 55.5, OMe; 68.9, C 3; 75.0, C 4; 97.7, C 8; 128.1, 129.6,

132.2, 136.0, C 4a, C 5, C 8a, C 10c; 149.6, C 7; 176.4, CO. Mass spec-

trum m/z 361 (M+1, 7.2%), 360 (M, 29.6), 342 (37), 283 (18), 282 (10),

281 (11), 269 (13), 267 (19), 265 (12), 239 (12), 165 (11), 148 (22), 141

(15), 128 (15), 115 (17), 91 (24).

Data collection and processing. Colourless multi-facetted crystal

of size 0.3 by 0.4 by 0.5 mm were used, in addition to a Philips PW

1100/20 diffractometer and a graphite monochromator. Lattice parame-

ters were obtained from least-squares analysis of setting angles of 25

reflections with 40 < 2␪ < 48°, λ(Mo K␣) 0.70930 Å. ␪–2␪ scans of ␪

width (1.2+0.346tan␪)° and of ␪ scan rate 4.1° min^–1with backgrounds

of 5 s on each side of every scan, 2␪_max50° with –12 < h < 12, 0 < k <

10, 0 < l < 18, 2689 unique reflections, 929 with I < 3␴(I) regarded as

unobserved. Three check reflections measured at intervals of 120 min

showed no systematic variations in intensity; there was no absorption

correction in view of the small ␮. Structure solution was by direct

methods.²³Full matrix least-squares refinement with anisotropic dis-

placement factors was used for all non-H atoms; H atom positions were

calculated from ⌬F map and the coordinates refined.²⁴Refinement on

F, using 259 parameters, gave R 0.048, R_w0.057, S 1.61. The weighting

scheme used was w = [␴²(F)+(0.0006)F ²]^–1. max. ⌬/␴ 0.25; max. and

min. heights in the final ⌬p map were 0.25 and –0.25 e Å^–3respectively.

Neutral-atom scattering factors with anomalous dispersion corrections

were used throughout.²⁵

(1␣,3␣,3a␣,4␤,10a␣,10b␣)-3,4-Dihydroxy-7-methoxy-1,5-dimethyl-

2,3,3a,4,6,9,10,10b-octahydrocyclohept[bc]acenaphthylene-10a(1H)-

carboxylic Acid 10a,3-Lactone (44)

A solution of the diol prepared above (147 mg) and anhydrous

K₂CO₃(10 mg) in MeOH–H₂O (2: 1, 7 ml) was heated under a nitrogen

atmosphere at reflux for 5 h. The cooled reaction mixture was diluted

with water, then extracted with ether, washed with water and brine, and

dried over MgSO₄. Removal of solvent afforded a 1: 3 mixture of the

desired lactone (44) and unreacted starting material as a yellow oil.

Flash chromatography (25% ethyl acetate in pentane) gave lactone (44)

as a pale yellow oil (30 mg, 23%) (Found: M^+•, 328.1675. C₂₀H₂₄O₄

requires M^+•, 328.1672) plus recovered diol (86 mg, 65%). ¹H n.m.r. ␦

(500 MHz) 0.96, d, J_Me,17.0 Hz, 1-Me; 1.19, d, J_OH,44.6 Hz, 4-OH;

1.37, dddd, J_gem14.2, J_2,17.9, J_2,33.3, J_2,3a1.5 Hz, pro-S H 2; 1.82, ddd,

J

_gem14.2, J_10b,912.6 J_10b,97.7 Hz, H 10b; 2.02, s, 5-Me; 2.19, br dd, J_gem

14.2, J_10a,97.3 Hz, H 10a; 2.22, m, H 1; 2.25, br d, J_gem13.1 Hz, H 6;

2.38, br ddd, J_gem18.1, J_9,10␤12.6, J_9,10␣7.3 Hz, H 9; 2.60, br dd, J_gem

18.1, J_9,10␤7.7 Hz, H9; 2.78, ddd, J_gem14.2, J_2,110.1, J_2,32.1 Hz, pro-R

H2; 2.93, br d, J_10b,3a11.9 Hz, H 10b; 2.79, dd, J_gem13.1, J_6,82.1 Hz,

H6; 2.98, dddd, J_3a,10b11.9, J_3a,46.2, J_3a,34.6, J_3a,2(pro-S)1.5 Hz, H3a;

3.60, s, OMe; 4.84, m, H3; 5.10, dd, J_4,3a6.2, J_4,OH4.6 Hz, H4; 5.30, br

s, H 8. ¹³C n.m.r. ␦ (75 MHz) 18.7, 1-Me; 20.4, 5-Me; 23.4, C 10; 24.1,

C 2; 28.0, C 9; 29.5, C 1; 39.5, C 6; 42.2, C 10b; 43.7, C 10a; 46.2, C 3a;

55.6, OMe; 72.2, C 4; 78.1, C 3; 98.8, C 8; 123.7, 129.0; 131.5, 140.6,

C 5, C 4a, C 8a, C 10c; 149.3, C 7; 178.3, CO. Mass spectrum m/z 329

(M+1, 8.1%), 328 (M, 39.6), 327 (17), 314 (3), 313 (15), 297 (2), 269

(3), 209 (8), 149 (29), 133 (10), 119 (20), 118 (12), 105 (47), 91 (100).

Acknowledgments

The authors are most grateful to Dr George Buta for the

provision of an authentic sample of harringtonolide, and to

Bruce Twitchin for technical assistance in the preparation of

early intermediates.

References

1

Buta, J. G., Flippen, J. L., and Lusby, W. R., J. Org. Chem., 1978,

49, 1002.

2

(1␣,3␣,3a␣,4␤,10a␣,10b␣)-3,4-Dihydroxy-1,5-dimethyl-7-oxo-

2,3,3a,4,7,9,10,10b-octahydrocyclohept[bc]acenaphthylene-10a(1H)-

carboxylic Acid 10a,3-Lactone (45)

Sun, N. Z., Xue, Z., Liang, X., and Huang, L., Acta Pharm. Sin.,

1979, 14, 39.

3

Kang, S., Cai, S., Teng, L., Acta Pharmacol. Sin., 1981, 16, 867.

4

Xue, X., Sun, N., and Liang, X., Acta Pharmacol. Sin., 1982, 17,

A solution of Hg(NO₃)₂(5 mg) in H₂O (0.5 ml) was added to a solu-

tion of lactone (44) (15.5 mg) in MeCN (4 ml) under a nitrogen atmo-

sphere at room temperature and the mixture stirred for 18 h. Water (20

ml) was added to the black solution and the product extracted into

dichloromethane and dried (Na₂SO₄). Flash chromatography (ethyl

acetate/hexane, 1 : 1) on silica gel afforded tropone (45) as a grey solid

(11.8 mg, 80%). λ_max240 (logε 4.30), 321 nm (4.05). ␯_max3100, 1760s,

236.

5

Frey, B., Wells, A. P., Rogers, D. H., and Mander, L. N., J. Am.

Chem. Soc., 1998, 120, 1914.

6

Preliminary communication: Rogers, D. H., Morris, J. C., Roden, F.

S., Frey, B., King, G. R., Russkamp, F.-W., Bell, R. A., and Mander,

L. N., Pure Appl. Chem., 1996, 68, 515.

7

1

1620s, 1590, 1530 cm^–1. H n.m.r. (300 MHz), ␦ 0.90, d, J 7.0 Hz, 1-

McKervey, M. A., Tuladhar, S. M., and Twohig, M. F., J. Chem.

Soc., Chem. Commun., 1984, 129; Ye, T., and McKervey, M. A.,

Chem. Rev., 1994, 94, 1091.

Me; 1.7–1.4, m, 3H; 1.91, dt, J 4.6, 7.6 Hz, 1H; 2.40, s, 5-Me;

2.75–2.35, m, 4H; 3.07, ABd, J 10.2 Hz, H10b; 3.15, m, H3a; 4.83, t,

J 4.3 Hz, H 3; 5.67, br t, J 7.1 Hz, H 4; 6.91, 6.95, 2×br s, H6, H8.

8

Hook, J. M., Mander, L. N., and Urech, R., Synthesis, 1979, 373;

Cossey, A. J., Gunter, M. J., and Mander, L. N., Tetrahedron Lett.,

1980, 21, 3309.

(1␣,2␤,3␣,3a␣,4␤,10a␣,10b␣)-3,4-Dihydroxy-2-iodo-1,5-dimethyl-7-

oxo-2,3,3a,4,7,9,10,10b-octahydrocyclohept[bc]acenaphthylene-

10a(1 H)-carboxylic Acid 10a,3-Lactone (46)

9

Mander, L. N., and Sethi, S. P., Tetrahedron Lett., 1983, 24, 5425.

10

Kenny, M. J., Mander, L. N., and Sethi, S. P., Tetrahedron Lett.,

1986, 27, 3923.

11

N-Iodosuccinimide (3 mg) was added to a solution of tropone (45)

(3.5 mg) in dichloromethane (2 ml) under a nitrogen atmosphere at

room temperature and the mixture stirred for 18 h. NaHSO₃solution (1

M, 10 ml) was added to the purple solution and the product extracted

into dichloromethane and dried (Na₂SO₄). Flash chromatography (ethyl

acetate/hexane, 1: 1) on silica gel afforded iodo tropone (46) as a pale

yellow solid (0.8 mg) which decomposed on keeping overnight at 4°. ¹H

n.m.r. (300 MHz) ␦ 1.17, d, J 7.0 Hz, 1-Me; 1.7–1.4, m, 3H; 2.41, s, 5-

Me; 2.80–2.30, m, 3H; 3.12, ABd, J 10.3 Hz, H 10b; 3.15, m, H 3a;

5.06, d, J 3.5 Hz, H 3; 5.23, d, J 9.9 Hz, H 2; 5.67, dd, J_4,4-OH7.0, J_3a,4

4.3 Hz, H4; 6.92, 6.97, 2×br s, H6, H 8.

Frey, B., Mander, L. N., and Hockless, D. C. R., J. Chem. Soc.,

Perkin Trans. 1, 1998, 1555.

12

Corey, E. J., and Chaykovsky, M., J. Am. Chem. Soc., 1964, 84, 867.

13

Kennedy, M., and McKervey, M. A., J. Chem. Soc., Chem.

Commun., 1988, 1028.

14

Agaskar, P. A., Cotton, F. A., Falvello, L. R., and Hahn, S., J. Am.

Chem. Soc., 1986, 108, 1214.

15

Guindon, Y., Yoakim, C., and Morton, H. E., J. Org. Chem., 1984,

49, 3912.

16

Compare: Gorla, F., and Balme, G., Helv. Chim. Acta, 1990, 73,

3336.

1108

D. H. Rogers et al.

17

25

White, J. M., Rogers, D. H., and Mander, L. N., Acta Crystallogr.,

‘International Tables for X-Ray Crystallography’ Vol. 4, pp.

99–101, 149–150 (Kynoch Press: Birmingham, England, 1974).

Sect. C, 1991, 47, 2254.

18

19

Gemal, A. L., and Luche, J.-L., J. Am. Chem. Soc., 1981, 103, 5454.

Heusler, K., and Kalvoda, J., Angew. Chem., Int. Ed. Engl., 1964, 3,

525.

Note Added in Proof

The (dppe)Pt(OTf)₂complex was kindly provided by Dr Hans

Militzer. A recipe is provided below.

20

21

de Armas, P., Concepción, J. I., Francisco, C. J., Salazar, J. A., and

·

Surez, E. J., J. Chem. Soc., Perkin Trans. 1, 1989, 405.

Heusler, K., Kalvoda, J., Wieland, P., Anner, G., and Wettstein, A.,

Helv. Chim. Acta, 1962, 45, 2575; Beebe, T. R., Adkins, R. L.,

Bogardus, C. C., Champney, B., Hii, P. S., Reinking, P., Shadday, W.

D., Weatherford, W. D., III, Webb, M. W., and Yates, W., J. Org.

Chem., 1983, 48, 3126.

(dppe)PtMe₂. dppe (1.79 g, 4.5 mmol) was added to a solution of

CODPtMe₂(Kistner, C. R., Hutchinson, J. H., Doyle, J. R., and Storkie,

T. C., J. Inorg. Chem., 1963, 2, 1255) (1.5 g, 4.5 mmol) in dry CH₂Cl₂

(30 ml) and was stirred at room temperature for 30 min, and then at

reflux for 1 h. Hexane was added and the resulting precipitate filtered

off and dried in vacuum (>95% yield).

22

Furber, M., Kraft-Klaunzer, P., Mander, L. N., Pour, M., Yamauchi,

T., Murofushi, N., Yamane, H., and Schraudolf, H., Aust. J. Chem.,

1995, 48, 427.

(dppe)Pt(OTf)₂. Triflic acid (543 ml, 6.14 mmol) was added drop-

wise to a solution of the (dppe)PtMe₂(1.915 g, 3.07 mmol) in CH₂Cl₂

at –78°C under argon. The solution was allowed to heat to room tem-

perature over 2 h. Ether was then added and the product was isolated by

removing the solvents by decantation and drying under high vacuum (c.

100%).

23

24

‘XTAL2.6 User´s Manual’ (Eds S. R. Hall and J. M. Stewart)

Universities of Western Australia and Maryland, 1989.

SHELX-86. Sheldrick, G. M., in ‘Crystallographic Computing Vol. 3’

(Eds G. M. Sheldrick, C. Krüger and R. Goddard) pp. 175–189

(Oxford University Press: Oxford, England, 1985).

Article Doi

Exploratory studies on the synthesis of the unusual diterpenoid tropone harringtoriolide

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