Indole-Diterpene Synthetic Studies: Total Synthesis of (-)-21-Isopentenylpaxilline

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Indole-Diterpene Synthetic Studies: Total Synthesis of

(À)-21-Isopentenylpaxilline

by Amos B. Smith III* and Haifeng Cui

Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of

Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

Dedicated to Professor Duilio Arigoni, on the occasion of his 75th birthday, with admiration and respect, for his

many seminal contributions to chemistry and biosynthesis.

An efficient, stereocontrolled total synthesis of the complex indole-diterpene alkaloid (À)-21-isopenten-

ylpaxilline (1) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the

advanced eastern hemisphere (À)-68, involving a highly efficient union of the eastern and western fragments

(À)-68 and 5 exploiting our 2-substituted indole synthesis, application of the Negishi p cycloalkylation tactic as a

new, potentially general protocol for the construction of ring C, and the fragmentation of a b,g-epoxy ketone to

introduce the tertiary OH group at C(13) in the indole diterpene skeleton.

Introduction.

The indole-diterpene alkaloids comprise a diverse group of

architecturally complex, naturally occurring fungal metabolites, belonging to a class

of environmental neurotoxins called tremorgens, which, upon ingestion by vertebrate

animals, result in tremors, limb weakness, ataxia, convulsions, and eventual death.

Fortunately, the symptoms are reversible if the animal is removed from the infected

area [1]. Many tremorgens also display insecticidal and/or antifeedant activity at the

levels produced by the fungi [2][3]. Evolutionary considerations indicate that fungi

have evolved the capacity to produce these defensive compounds to protect the

sclerotium bodies against fungivorous insects [2].

In addition to the similar biological profiles, members of this class share common

structural features, including a core comprised of an indole arising from tryptophan and

a diterpene framework derived from mevalonate-produced isoprene units (Fig. 1). The

diterpene framework is often fused to the indole ring in the form of a trans-anti-trans

5,6,6-fused ring system, with the signature structural element being vicinal quaternary

Me groups disposed anti with an adjacent tertiary OH group.

Fig. 1. Common core structural unit of the indole-diterpene alkaloids

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Paspaline and paspalicine, structurally the simplest members of the indole-

diterpene class, were first reported by the Arigoni group in 1966 [4 7]. Subsequently,

Arigoni and co-workers, in elegant fashion, deduced the biosynthetic pathway, and then

demonstrated that both paspalicine and paspalinine arise from paspaline [8].

Interestingly, paspaline and paspalicine, the parent congeners lacking the tertiary

OH group, were neither tremorgenic nor toxic, suggesting that the tertiary OH group is

critical for tremorgenic activity [9][10].

The indole tremorgens can be grouped into two rapidly growing subclasses; the

structurally simpler congeners include paspaline [4][5], paspalicine [5], paxilline [11],

dehydroxypaxilline [10], paspalinine [12 14], aflatrem [15], and paspalitrems A C

[1]; the architecturally more complex include the penitrems A F [16], janthitrems E

G [17 20], and lolitrems B and C [21]. A considerable expansion of both subclasses

occurred in the early 1990×s, with the most recently discovered members being

pennigritrem [22], the sulpinines A and B [23], secopenitrem B [23], sherinines A and

B [2], terpendole C and M [24][25], paxinorol [26], nodulisporic acid A [27][28],

pepenitremones A C [29], and the thiersinines A and B [30]. The long-standing

interest of our laboratory in the indole-diterpene alkaloids has led to the total syntheses

of (À)-paspaline [31 33], ()-paspalicine [34][35], ()-paspalinine [34][35], and,

most recently, (À)-penitrem D [36].

In 1995, a new congener, (À)-21-isopentenylpaxilline (1; Fig. 2), was reported by

Gloer and Belofsky, along with seven other indole alkaloids isolated from the org.

extracts of the sclerotioid ascostromata of Eupenicillium shearii (NRRL 3324) [2]. The

molecular formula C₃₂H₄₁NO₄was deduced from ¹³C-NMR, DEPT, and LR-FAB-MS

data. Careful analysis of the NMR data indicated that the new metabolite is quite

similar in structure to the known tremorgens paxilline and paspalinine, differing only by

an isopentenyl group. Key HMBC-NMR correlations permitted unambiguous place-

ment of the isopentenyl unit on the aromatic ring at C(21). The absolute configuration

of (À)-21-isopentenylpaxilline (1), however, was not established. Herein, we record

a full account of the first total synthesis of (À)-21-isopentenylpaxilline (1), which

both confirms the Gloer structure and permits assignment of the absolute config-

uration.

Fig. 2. Structure of (À)-21-isopentenylpaxilline (1)

Synthetic Analysis. The core element of (À)-21-isopentenylpaxilline (1), the

common diterpene CDE tricyclic skeleton, suggested that we employ our unified

indole-diterpene strategy, which proved highly successful in our earlier syntheses. The

cornerstone of this unified approach entails elaboration of the NolanÀSprengeler

lactone (À)-2 to the requisite tricyclic skeleton (Fig. 3) [37].

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Fig. 3. NolanÀSprengeler lactone (À)-2

To implement this plan (Scheme 1), we envisioned introduction of the tertiary OH

group at C(13) via a late-stage autooxidation of a,b-unsaturated ketone 3, which, in

turn, would derive from the corresponding protected homoallylic alcohol. We were, of

course, well aware of the known oxidative sensitivity of the indole nucleus. For

example, paxilline and nodulisporic acid A (9), upon standing in air, undergo oxidative

cleavage of the indole ring to furnish eight-membered-ring lactams (Scheme 2) [2][27].

Scheme 1

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Scheme 2

Continuing with our analysis, disconnection of ring C would furnish hydroxy-indole

4. To construct the latter, we planned to take advantage of our 2-substituted-indole

synthetic protocol [38][39], employing the western hemisphere toluidine 5 and the

highly functionalized eastern hemisphere lactone 6. Disconnection of 6, in turn, led to

epoxide 7 and hydrazone 8, readily available in four steps from NolanÀSprengeler

lactone (À)-2. In the forward direction, we would exploit the Stork metallo-enamine

union of 7 and 8, followed by a reductive cyclization, as employed in our indole

synthesis [36] to access the F-ring tetrahydropyran in 6. Thus, (À)-21-isopentenylpaxil-

line (1) would be constructed from three fragments: (À)-2, 5, and 7. Hydrazone 8,

derived from (À)-2, was selected as our initial target.

Hydrazone ()-8 Optimization.

Experience gained during our campaign to

construct (À)-penitrem D [36] demonstrated that the lactone CO group in the

NolanÀSprengeler lactone (À)-2 must be masked during the Stork metallo-enamine

alkylation required to construct the tetrahydropyran ring. Although hydrazone ()-8

could be readily prepared in an efficient manner from (À)-2 [36], a more-direct route

not involving (À)-2 appeared promising (Scheme 3). Toward this end, removal of the

TBS group and hydrolysis of the acetal in ()-11, an advanced intermediate on the way

to (À)-2, was easily achieved to furnish keto alcohol ()-12. Efficient ozonolysis of the

olefin, however, initially proved elusive, affording over-oxidation products due to the

difficulty in monitoring the reaction progress. Use of Sudan III as an indicator, which

undergoes a sharp color change upon olefin cleavage (e.g., red-orange to pale yellow)

solved this problem [40], providing hemiacetal 13 in 89% yield on large scale. Efficient

methylation of the resultant hemiacetal was then achieved in the presence of the ketone

Scheme 3

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by treatment with MeI and Ag₂O in acetone at reflux; a mixture (ca. 1.8 :1) of the a-

and b-methyl acetals (14a and 14b, resp.) resulted in a combined yield of 88%.

Surprisingly, different conditions were required to achieve the Robinson aldol/

dehydration sequence for the structurally similar acetals. Treatment of (À)-14a with

KOH in toluene at reflux readily furnished the a-enone ()-15a in 68% yield, while

()-14b required treatment with sodium dimsylate in THF at reflux to afford the b-

enone ()-15b (62%). Both ()-15a and ()-15b were identical in all respects to

intermediates prepared during our penitrem D synthesis [36]. Acetals ()-15a and ()-

15b were then converted to the corresponding hydrazones (Scheme 4). The overall

sequence was significantly enhanced (ca. 45%) compared to the previous route,

requiring only five steps from ()-11, vs. seven steps, which proceeded in 22% yield

[36][37]. During this work, we also discovered the feasibility of acid equilibration of

()-15a and ()-15b (ca. 2 :1), an observation that would prove important later in the

synthesis (vide infra).

Scheme 4

Construction of Epoxide ()-7. Synthesis of ()-7 began with known allylic

alcohol (À)-16 (Scheme 5) [41]; ozonolysis furnished methyl ketone ()-17 in 91%

yield. Efforts to protect the secondary OH group as the MTM ether in ()-17, however,

proceeded in low yield. As an alternative, ()-17 was converted to diol (À)-18 by

treatment with MeMgBr; selective protection of the secondary OH group furnished

()-19 in 52% yield for the two steps. The tertiary alcohol was next converted to the

benzyl ether to provide ()-20 (96%); hydrolysis of the acetal, followed by Fraser-Reid

[42] epoxide construction (NaH, tosylimidazole (Tsimid), À78 to 08), completed the

preparation of ()-7 (91%).

Union of Hydrazones ()-8a and ()-8b with Epoxide ()-7: A Difficult

Transformation. In our penitrem D synthesis [36], the Stork metallo-enamine union

of hydrazones ()-8a and ()-8b with epoxide (À)-22 proved quite successful

(Scheme 6). We, thus, anticipated that union of the same hydrazone with epoxide

()-7 would be straightforward [43][44]. Surprisingly, the conditions employed in the

penitrem D venture [36] furnished none of the coupled product. This result was

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Scheme 5

Scheme 6

remarkable, given only the minor modification of the epoxide structure. To develop

viable conditions for this union, we turned to the literature.

In 1998, Overman and Rucker [45] reported that high concentrations of hydrazone

25 and electrophile 26 (Scheme 7), in conjunction with the use of hexamethylphos-

phoric triamide (HMPA), permitted efficient construction of 27 (> 90%). LiNEt₂was

the base of choice for deprotonation and metalloenamine equilibration. Unfortunately,

these conditions did not improve the required alkylation of 8a or 8b with ()-7, due

presumably to our inability to effect equilibration of the kinetic anion of the 5,6,6-

tricyclic hydrazone. An associated problem was also the difficulty in recovering the

starting hydrazones.

Scheme 7

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To conserve valuable material, we decided to screen a series of the coupling

protocols with model hydrazone ()-23 [43][44]. In addition to epoxide ()-7, we

would also explore iodide ()-28 as an alternate electrophile; the latter was prepared in

two steps from ()-7 (Scheme 8). Results from this study are summarized in Table 1.

Unfortunately, under the best conditions, the yield of ()-30 was only modest.

Scheme 8

Table 1. Optimization of Hydrazone ()-23 Coupling.

Entry

Base

T [8]

Cosolvent (10%)

Conc. [m]

Electrophile

Yield [%], (3 steps)

1

2

3

4

5

6

7

LDA

65

r.t.

65

HMPA

DMPU

None

0.1

1.0

()-7

()-28

( )-7

()-28

< 5

0

8

LiNEt₂

36

24

34^a)

< 5

^a) Optimal conditions: LiNEt₂, THF, 1.0m of ()-23 at reflux overnight, N,N'-dimethylpropylenurea (DMPU;

10%), then epoxide ()-7, À788 r.t.

Notwithstanding the modest efficiencies observed in the model study, we explored

the alkylation of hydrazones 8a and 8b individually with ()-7, employing host

hydrazone ()-23, the latter to facilitate equilibration of the metallo-enolates, as

required in the penitrem D synthesis (Scheme 9) [36]. Benzoylation of the desired

alkylation products, followed by hydrolysis of the hydrazone, afforded ()-33a and ()-

33b, respectively, in 23 and 34% yield for the three steps.

Construction of cis-Pyran (À)-39. After accumulating sufficient 33a and 33b, we

proceeded with the synthesis. The next task entailed installation of the lactone CO

group prior to cis-pyran formation. Hydrolysis of the b-acetal ()-33b proceeded to

give an epimeric mixture of lactols 34 (70%), in conjunction with minor amounts of 35

and 36; however, these by-products could be recycled into (À)-39. On the other hand,

hydrolysis of the a congener ()-33a furnished predominately dienyl ether 35 (62%).

Indeed, no more than 30% of the desired 34 could be obtained under a variety of

conditions. Fortunately, this problem could be circumvented by isomerization of ()-

15a to ()-15b as described earlier (Scheme 4), thereby significantly enhancing

throughput of the a-isomer. Treatment of 34 with N-iodosuccinimide (NIS) and a

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Scheme 9

catalytic amount of tetrabutylammoniun iodide (TBAI) led to lactone ()-37 in 91%

yield (Scheme 10) [46][47].

Scheme 10

Generation of the tetrahydropyran F ring now called for a cascade of reactions,

involving removal of the MeSCH₂(MTM) group, cyclization to an intermediate

hemiacetal and capture of the derived carbocation 38 with a silyl hydride. A similar

tactic, initially developed by Nicolaou and co-workers for the construction of oxepanes

[48], had been exploited with great success in our penitrem D venture [36]. Toward this

end, treatment of ()-37 with TfOH in Et₃SiH, employing CH₂Cl₂as solvent with

careful temperature control (À408 !À 58), provided the desired cis-pyran (À)-39

initially in 32% yield, along with 30% of an intermediate identified as (À)-40

(Scheme 11).

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Scheme 11

Although (À)-40 could be resubmitted to the same reaction conditions, this

procedure both was tedious and resulted in low yields. To improve the yield of (À)-39,

we screened a series of conditions (Table 2), identifying the problem to be the

reduction step. Switching the silane from Et₃SiH to the less sterically demanding

EtMe₂SiH proved rewarding; lactone (À)-39 was obtained in 81% yield.

Table 2. Optimization of cis-Pyran (À)-39 Formation

Entry

Acid

Solvent (1 : 1)

T [8]

Yield [%]

1

2

3

4

5

HClO₄

TfOH

TfOH/MeCN

Toluene/Et₃SiH

CH₂Cl₂/Et₃SiH

Toluene/Et₃SiH

CH₂Cl₂/EtMe₂SiH

À 78 ! r.t.

À 40 ! 0

No reaction

25

22

35

81

À 40 ! 0

À 60 !À 5

À 50 !À 20

Completion of Eastern Hemisphere ()-6. All that remained to complete 6 was

protecting-group adjustment. To this end, removal of the Bn group in (À)-39 with 2,3-

dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), followed by hydrolysis of the ester

with K₂CO₃in MeOH, furnished diol ()-42 as a crystalline solid (92% yield, two steps;

Scheme 12); single-crystal X-ray-analysis confirmed the structure and relative config-

uration. Protection of the diol as the bis-TES (Et₃Si) ether then completed construction

of eastern hemisphere ()-6.

Autooxidation: A Strategic Decision. From the outset, introduction of the tertiary

allylic OH group at C(13) of (À)-21-isopentenylpaxilline (1) was envisioned to be

achieved late in the overall synthetic sequence via autooxidation of an appropriate b,g-

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Scheme 12

unsaturated ketone [49][50]. However, given the ease with which highly substituted

indoles are oxidized, we thought it prudent to examine at this juncture the feasibility of

performing the autooxidation before introduction of the indole. We therefore removed

the Bz moiety of (À)-39 (Scheme 13) and subjected the derived alcohol to

DessÀMartin oxidation to afford ketone 44, which, without purification, was exposed

Scheme 13

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for 18 h to aeration in acetone over silica gel; autooxidation furnished ()-45 as a

stable, fully characterizable hydroperoxide in 62% yield for the two steps. Reduction

with PPh₃provided hydroxy enone ()-46 (96%). The relative configuration at the

stereogenic center carrying the newly introduced OH group, however, was not

confirmed at this stage (vide infra).

Construction of the Western Hemisphere Toluidine 5. We began with commer-

cially available 4-bromo-2-methylaniline (47; Scheme 14); N-protection as the bis-TMS

(Me₃Si) ether (48), followed by Li/Br exchange and alkylation with prenyl bromide

readily installed the isopentenyl group para to the amino group to provide 49. Removal

of the silyl groups (1n HCl, EtOH) then afforded toluidine 5; the overall yield for the

three-step sequence was 69%.

Scheme 14

C-Ring Construction: Two Model Studies. Construction of ring C in (À)-21-

isopentenylpaxilline (1) was viewed as a significant challenge. Previous model work by

Haseltine in our laboratory entailed blocking the indole N-atom in 50 as a p-

methoxybenzyl (PMB) ether, followed by heating to 1758 to effect ring closure

(Scheme 15) [51]. Such a scenario, however, was not expected to be feasible here. First,

the fully elaborated system would not in all likelihood tolerate high temperature;

second, oxidative removal of the PMB group would raise the specter of indole

oxidation. A milder protocol for C-ring construction was, therefore, sought.

Scheme 15

In 1998, Negishi et al. introduced a s-cycloalkylation tactic [52] employing

alkenylmetals to construct three- to seven-membered rings in high yield. Based on

this precedent, incorporation of a halogen at C(3) of the indole, followed by Li/halogen

exchange would lead to an alkenyl-lithium, which we anticipated would rapidly lead to

C-ring construction, assuming the availability of an appropriate side-chain electrophile.

Two model studies were undertaken. The first called for iodo bromide 55, readily

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prepared via our indole synthesis with butyrolactone [38][39]. Conversion of the OH

group to the corresponding Br derivative, followed by treatment with NIS, generated

55. Protection of the indole N-atom with a TBS ((t-Bu)Me₂Si) group, followed by Li/I

exchange (BuLi; À788) led, as expected, to C(3)-alkylation; removal of the silyl group

(TBAF (Bu₄NF)) generated 57 in 72% yield for the two steps. Not surprisingly, indole

57 proved unstable in air to silica-gel chromatography; lactam 58 was obtained in

nearly quantitative yield (Scheme 16).

Scheme 16

Intrigued by the possibility of a more direct route to 57, methanesulfonate 59,

readily available from 53, was treated with various Grignard reagents (i.e., a p-

cycloalkylation). Best results, albeit modest, were obtained with t-BuMgCl (1.5 equiv.)

in toluene at reflux; these conditions furnished indole 57 in an unoptimized yield of

30% for the two steps (Scheme 17).

Scheme 17

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Union of the Eastern and Western Hemispheres. Having devised two potentially

viable approaches for C-ring construction, we turned to the union of toluidine 5 with

advanced lactone ()-6, exploiting our 2-substituted-indole construction (Scheme 18)

[38][39]. Best conditions involved use of MeLi instead of BuLi to install the TMS,

followed by treatment with s-BuLi and addition of ()-6 at 08; amino ketone 60, not the

expected indole 61, resulted. We have noticed that, in structurally complex cases (e.g.,

the penitrem synthesis), our indole protocol does not proceed to completion, but

instead furnishes a mixture of the corresponding amino ketone and indole, or only the

amino ketone. In general, heating the resultant mixture completes the indole-ring

construction. In the case at hand, heating 60 in benzene at reflux over a 2-day period

furnished ()-61 in 81% yield for the two-step sequence.

Scheme 18

C-Ring Construction. Having achieved the union of the eastern and western

hemispheres, we turned our attention to construct ring C, exploiting the Negishi s-

cycloalkylation. All attempts to convert the primary OH group in indole ()-61 to the

corresponding Br substituent, as readily achieved in our model study, however, proved

unrewarding, presumably due to the steric encumbrance of the OH group. We were,

however, able to prepare methanesulfonate ()-62 in 93% yield. The next step in the

Negishi s-cycloalkylation protocol calls for introduction of the I-substituent at C(3).

This reaction also was not straightforward. We, therefore, turned to the second tactic,

involving the treatment of ()-62 with Grignard reagents (i.e., p-cycloalkylation). Due

to interference of the indole N-atom, we anticipated at best modest efficiency. Not

surprisingly, with MeMgBr, no reaction took place at room temperature. However,

upon heating in toluene at reflux, two products were observed; the desired hexacycle

()-63 was isolated in 25% yield, accompanied by the product resulting from the ring

closure on the indole N-atom. Pleasingly, further investigation revealed that t-BuMgCl,

possessing a higher pK_bvalue and a smaller counterion, improved the yield of carbon

alkylation to the level of 68%. (Scheme 19).

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Scheme 19

At this juncture, autooxidation to introduce the tertiary OH group at C(13) was the

remaining key transformation to complete the synthesis of (À)-21-isopentenylpaxilline

(1). This transformation required conversion of ()-63 to the corresponding a,b-

unsaturated ketone. To our surprise, we were not able to effect this simple oxidation.

Although we could obtain the monoprotected secondary alcohol ()-64 (Scheme 20),

oxidation employing a variety of conditions, including DessÀMartin [53], Moffatt [54],

TPAP/NMO, IBX [55][56] etc., led either to recovery of starting material or to

complete decomposition. We reasoned that the steric bulk of the TES (Et₃Si) group

played a significant role, preventing the desired oxidation.

Scheme 20

A Second-Generation End-Game Strategy. Given our inability to achieve the

late-stage oxidation, we devised an alternate end-game (Scheme 21). We reasoned that

the g-hydroxy-a,b-enone functionality in (À)-1 could instead be installed via

fragmentation of b,g-epoxy ketone 66, available from 67 via t-BuMgCl-mediated

ring-C closure, followed by removal of the TES group and oxidation of the derived

alcohol to ketone 66. The risk of proposing another late-stage oxidation, given the

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difficulty experienced with ()-64, however, did not go unnoticed! Notwithstanding

this concern, indole 67 was envisioned to derive from a new eastern hemisphere (i.e.,

68), again exploiting our 2-subsititued-indole protocol with toluidine 5. The requisite

configuration of the tetrasubstituted epoxide in 68, required for a-installation of the

tertiary allylic OH group in (À)-1, would arise from the expected facial selectivity upon

epoxidation of (À)-39 prepared earlier (Table 2).

Scheme 21

With this goal in mind, attempted epoxidation of (À)-39 (Scheme 22) with m-

chloroperbenzoic acid (m-CPBA) in CH₂Cl₂/H₂O initially proceeded with low

diastereoselectivity. Other epoxidation conditions led either to decomposition or to

no reaction. After considerable experimentation, we discovered that the solvent played

a critical role. Best results were obtained with toluene, which afforded the desired a-

epoxide (À)-69a in 77% yield, in conjunction with 13% of the b-diastereoisomer (69b).

Removal of the Bz group was next achieved (e.g., KOH/MeOH/H₂O), albeit with

partial lactone hydrolysis; reinstallation of the lactone with 1-[3-(dimethylamino)-

propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and 4-(dimethylamino)pyridine

(DMAP) furnished alcohol ()-70 in 91% yield for the two steps. To confirm the

epoxide configuration in (À)-69a, transfer hydrogenation of ()-70 removed the Bn

group to furnish ()-71 as a crystalline solid; single-crystal X-ray analysis confirmed

the relative configuration. Silylation of ()-70 then completed construction of (À)-68,

the new eastern hemisphere.

Again cognizant of the potential difficulty with the proposed late-stage oxidation of

the OH group at C(13), alcohol ()-70 appeared to be an excellent model system to

explore this oxidation. Extensive experimentation eventually revealed the oxidant

Ph₃BiCO₃. Developed by Barton and co-workers, this hypervalent reagent permits

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Scheme 22

oxidation under nearly neutral conditions, and, importantly, it is known to tolerate the

indole nucleus [57]. Fortuitously, in the case at hand, treatment of ()-70 in benzene at

reflux led not only to OH oxidation, but also to the desired epoxide fragmentation to

furnish ()-46 (Scheme 23), the latter identical in all respects to that prepared

previously via autooxidation of 44 (Scheme 13). The relative configuration of ()-46

was thus established, given the X-ray structure of ()-71.

Scheme 23

Total Synthesis of (À)-21-Isopentenylpaxilline (1). With (À)-68, the new eastern

hemisphere in hand, we turned again to our 2-substituted indole protocol (Scheme 24)

[38][39]. Treatment of the derived TMS derivative of 5 with s-BuLi, followed by the

addition of (À)-68, as with ()-6 (Scheme 18), resulted only in acylation at the highly

hindered lactone CO group, to afford the corresponding amino ketone. As before,

completion of the indole-ring construction was readily achieved by heating in toluene

at reflux to furnish (À)-72 in 76% yield for the two steps. Mesylation of the derived

primary alcohol then afforded (À)-67 (90%), substrate for the ring-C closure. In the

event, treatment with t-BuMgCl smoothly furnished (À)-73 in 73% yield. Removal of

the TES group (TBAF, 93%) then set the stage for the critical Ph₃BiCO₃oxidation/

fragmentation reaction sequence. Pleasantly, g-hydroxy-a,b-enone ()-75 was ob-

tained in 69% yield.

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The final challenge to complete the total synthesis of (À)-1 entailed removal of the

Bn group in ()-75. The difficulty here was possible concomitant reduction of the

C(21)-isopentenyl moiety. After considerable experimentation, transfer hydrogenation

furnished 21-isopentenylpaxilline ((À)-1), along with a minor amount of the over-

reduced product. Normal-phase high-pressure liquid chromatography afforded syn-

1

thetic (À)-1 in 70% yield, identical in all respects (i.e., 500-MHz H-NMR, 125-MHz

¹³C-NMR, HR-MS data, and chiroptical properties) to a sample of the natural product

kindly provided by Prof. Gloer.

Scheme 24

In summary, the first total synthesis and assignment of absolute configuration of

(À)-21-isopentenylpaxilline (1) have been achieved. Key elements of the synthesis

include the stereocontrolled construction of advanced eastern hemisphere (À)-68,

involving a highly efficient union of eastern and western fragments (À)-68 and 5,

exploiting our 2-substituted-indole synthesis, application of the Negishi p-cycloalkyl-

ation tactic as a new, potentially general protocol for the construction of ring C, and the

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fragmentation of an b,g-epoxy ketone to introduce the tertiary OH group at C(13) in

the indole diterpene skeleton.

Experimental Part

General. All non-aq. reactions were carried out in oven- or flame-dried glassware under Ar, unless

otherwise noted. All solvents were reagent-grade. Et₂O and THF were freshly distilled from Na/benzophenone

ketyl under Ar. The Ar was deoxygenated by passing it through an OXICLEAR^TMtube from Aldrich. CH₂Cl₂,

benzene, toluene, (i-Pr)₂NH, and Et₂NH were freshly distilled from CaH₂. Et₃N and N,N'-dimethylpropylenur-

ea (DMPU) were distilled from CaH₂and stored over activated 4-ä molecular sieves. Anh. pyridine and DMSO

were purchased from Aldrich and used without purification. MeLi, BuLi, s-BuLi and t-BuLi were purchased

from Aldrich, and standardized by titration with Ph₂CHCOOH or N-pivaloyl-o-toluidine. All other

commercially available reagents were used as received. Except as indicated otherwise, reaction mixtures were

magnetically stirred and monitored by TLC with 0.25-mm E. Merck pre-coated silica-gel plates. Flash

chromatography (FC) was performed with silica gel 60 (particle size 230 400 mesh) supplied by E. Merck.

Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise stated. High-

performance liquid chromatography (HPLC) was performed with a Waters component anal. system. Optical

rotations were obtained with a Perkin-Elmer model 241 polarimeter with a Na lamp, and are reported as follows:

[a]²_D⁵(c (g/100 ml), solvent). IR Spectra were recorded with a Perkin-Elmer model 283B spectrometer with

polystyrene as external standard or a Perkin-Elmer 1600 series FTIR spectrometer or JascoFT/IR-480 plus

1

spectrometer, and are reported in cm^À1(abs.). H- and ¹³C-NMR spectra were recorded on a Bruker AM-500

spectrometer. Chemical shifts (d) are reported in ppm with the solvent resonance as the internal standard

relative to CHCl₃(d 7.26), benzene (d 7.15), or CH₂Cl₂(d 2.05) for ¹H, and CHCl₃(d 77.0), benzene (d 128.0), or

CH₂Cl₂(d 2.05) for ¹³C. High-resolution mass spectra (HR-MS) were measured at the University of

Pennsylvania Mass Spectrometry Service Center on either a VG Micromass 70/70 H or VG ZAB-E

spectrometer. Microanalyses were performed at the University of Pennsylvania.

Preparations. ()-(4R,4aS,8aR)-3,4,4a,7,8,8a-Hexahydro-4-(hydroxymethyl)-4a,6,8a-trimethylnaphthalen-

1(2H)-one (()-12). A soln. of ()-11 (1.50 g, 3.94mmol) in acetone (40 ml) and H ₂O (0.8 ml) was treated

with TsOH (76 mg, 0.4mmol); this mixture was then stirred at r.t. for 16 h. The reaction was quenched with

Et₃N (50 ml), and then the mixture was concentrated in vacuo. FC (hexanes/AcOEt, 2 :1) provided ()-12

(815 mg, 93%). Colorless crystals. M.p. 58 608. [a]²_D⁵ 149 (c 1.14, CHCl₃). IR (neat): 3446s (br.), 2959s,

2833m, 1699s, 1447m, 1373m, 1061m, 997m, 817w. ¹H-NMR (500 MHz, CDCl₃) 5.55 (s, 1 H); 4.01 (dd, J 10.4,

3.2, 1 H); 3.43 (dd, J 10.2, 8.0, 1 H); 2.73 2.78 (m, 1 H); 2.21 2.26 (m, 3 H); 1.90 1.98 (m, 3 H); 1.59 1.63

(m, 4H); 1.47 1.51 ( m, 1 H); 1.40 (br. s, 1 H); 1.16 (s, 3 H); 0.78 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 216.3;

132.5; 125.9; 64.2; 50.0; 42.2; 39.4; 35.6; 26.5; 25.8; 24.0; 23.4; 19.9; 19.6. HR-ESI-MS: 222.1616 (M , C₁₄H₂₂O₂

;

calc. 222.1620).

(À)-(3R,3aS,4R)-3,3a,4,5,6,7-Hexahydro-3-methoxy-3a,4-dimethyl-4-(3-oxobutyl)[2]benzofuran-5(1H)-

one ((À)-14a) and ()-(3S,3aS,4R)-3,3a,4,5,6,7-Hexahydro-3-methoxy-3a,4-dimethyl-4-(3-oxobutyl)[2]benzo-

furan-5(1H)-one (()-14b). A soln. of ()-12 (2.26 g, 10.2 mmol) in MeOH (120 ml) was added Sudan III

(5 mg), the resulting orange soln. was cooled to À788 and then bubbled in O₃/O₂for 25 min; Ar was then

bubbled in for 5 min, and Me₂S (1.5 ml) was added. 10 min later, this mixture was warmed to r.t. and stirred for

3 h. The mixture was concentrated in vacuo. FC (hexanes/AcOEt, 1:1) provided a mixture of lactols (2.29 g,

89%).

Under Ar, a soln. of the above lactols (35.0 mg, 137 mmol) in acetone (2 ml) was treated with Ag₂O

(100 mg) and MeI (300 ml), this suspension was then heated to reflux for 3.5 h. After cooling to r.t., this mixture

was diluted with acetone (5 ml) and then filtered. The filtrate was concentrated in vacuo. Gradient FC (hexanes/

AcOEt 2 :1 ! hexanes/AcOEt 1:1) provided (À)-14a (20.8 mg, 57%) as colorless crystals and ()-14b (11.5 mg,

31%) as a colorless oil.

Data of (À)-14a: colorless crystals. M.p. 98 1008. [a]²_D⁵ À11 (c 1.15, CHCl₃); IR (neat): 2949s, 1726s,

1703s, 1379w, 1090w, 1007m. ¹H-NMR (500 MHz, CDCl₃): 4.89 (s, 1 H); 3.87 (t, J 7.5, 1 H); 3.64( dd, J 11.0,

7.7, 1 H); 3.45 (s, 3 H); 2.87 2.92 (m, 1 H); 2.62 2.68 (m, 1 H); 2.47 2.54 (m, 1 H); 2.38 2.43 (m, 1 H); 2.26

(ddd, J 15.6, 5.3, 1.3, 1 H); 2.13 (s, 3 H); 2.01 2.07 (m, 1 H); 1.77 1.82 (m, 1 H); 1.59 1.71 (m, 2 H); 1.20

(s, 3 H); 0.85 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 214.6; 209.0; 106.0; 67.8; 57.0; 53.0; 50.8; 40.0; 39.7; 36.8;

29.8; 26.0; 20.9; 16.8; 10.0. HR-ESI-MS: 291.1578 ([M Na] , C₁₅H₂₄NaO₆; calc. 291.1572).

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Helvetica Chimica Acta Vol. 86 (2003)

Data of ()-14b: colorless oil. [a]²_D⁵ 88 (c 1.50, CHCl₃); IR (neat): 2952s, 1725s, 1705s, 1375w, 1091m,

1008m. ¹H-NMR (500 MHz, CDCl₃): 4.55 (s, 1 H); 4.05 (t, J 8.2, 1 H); 3.48 (dd, J 10.2, 8.0, 1 H); 3.30

(s, 3 H); 3.12 3.20 (m, 1 H); 2.69 2.74( m, 1 H); 2.57 2.63 (m, 1 H); 2.29 2.36 (m, 1 H); 2.21 (ddd, J 15.2,

5.4, 1.5, 1 H); 2.15 (s, 3 H); 2.04 2.11 ( m, 1 H); 1.87 1.92 (m, 1 H); 1.56 1.64( m, 2 H); 1.29 (s, 3 H); 0.79

(s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 214.9; 209.1; 110.5; 68.8; 54.4; 54.1; 52.2; 39.3; 36.6; 36.4; 29.9; 26.9; 21.3;

19.4; 15.5. HR-ESI-MS: 291.1570 ([M Na] , C₁₅H₂₄NaO₆; calc. 291.1572).

()-(1R,9aS,9bS)-3,3a,4,5,8,9,9a,9b-Octahydro-1-methoxy-9a,9b-dimethylnaphtho[1,2-c]furan-7(1H)-one

(()-15a). Under Ar, a soln. of (À)-14a (52.8 mg, 197 mmol) in toluene (8 ml) was treated with an aq. KOH soln.

(8.8 mg of KOH in 300 ml H₂O, 157 mmol). This mixture was then heated to reflux by using a Dean-Stark trap for

2 h. After cooling to r.t., this mixture was diluted with AcOEt (20 ml), washed with H₂O (5 ml), and brine

(5 ml). The org. layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. FC (Et₂O) provided ()-15a

(33.7 mg, 68%). White solid. M.p. 114 117 8. [a]_D²⁵ 147 (c 1.04, CHCl₃). IR (CHCl₃): 2930s, 1660s, 1230m,

1100m, 1080m, 990s, 970m. ¹H-NMR (500 MHz, CDCl₃): 5.85 (d, J 2.0, 1 H); 4.94 (s, 1 H); 3.89 (t, J 7.6,

1 H); 3.68 (dd, J 7.7, 10.9, 1 H); 3.48 (s, 3 H); 2.65 (m, 1 H); 2.52 2.42 (m, 2 H); 2.14 2.34 ( m, 2 H); 2.29

(dt, J 4.7, 14.4, 1 H); 1.70 1.64 (m, 2 H); 1.58 (dq, J 5.2, 12.5, 1 H); 1.38 (s, 3 H): 0.89 (s, 3 H). ¹³C-NMR

(125 MHz, CDCl₃): 198.4; 168.2; 126.8; 106.7; 68.2; 57.2; 48.0; 41.7; 40.9; 33.8; 32.0; 30.4; 21.1; 18.0; 10.4. HR-CI-

MS (CH₄): 251.1638 ([M H] , C₁₅H₂₃O₃; calc. 251.1647).

()-(1S,9aS,9bS)-3,3a,4,5,8,9,9a,9b-Octahydro-1-methoxy-9a,9b-dimethylnaphtho[1,2-c]furan-7(1H)-one

(()-15b). Under Ar, DMSO (2.7 ml) was treated with NaH (92.3 mg), this suspension was then heated to 658

for 1.5 h. A clear soln. was formed, which was cooled to r.t. A soln. of ()-14b (253 mg, 0.942 mmol) in THF

(5 ml) under Ar was treated with the above base (1.4ml). After heating to reflux for 5 h, this mixture was cooled

to r.t., and the reaction was quenched with sat. aq. NH₄Cl soln. (3 ml). This mixture was then extracted with

Et₂O (3 Â 10 ml), and all the org. layers were combined and washed with brine (5 ml). The org. layer was then

dried (Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/AcOEt 2 :1)

provided ()-15b (146 mg, 62%). Colorless crystals. M.p. 111 1138. [a]²_D⁵ 273 (c 1.32, CHCl₃). IR

(CHCl₃): 2940s, 1660s, 1235m, 1090s, 990s, 970m 930m. ¹H-NMR (500 MHz, CDCl₃): 5.80 (d, J 2.1, 1 H); 4.58

(s, 1 H); 4.06 (t, J 8.2, 1 H); 3.52 (dd, J 8.1, 10.0, 1 H); 3.33 (s, 3 H); 2.92 (m, 1 H); 2.59 2.49 (m, 2 H);

2.39 2.30 (m, 3 H); 1.75 1.75 (m, 2 H); 1.53 (dq, J 5.3, 12.8, 1 H); 1.49 (s, 3 H); 0.85 (s, 3 H). ¹³C-NMR

(125 MHz, CDCl₃): 198.7; 170.3; 125.5; 110.7; 69.4; 54.6; 50.3; 43.0; 36.9; 33.9; 31.8; 30.2; 22.0; 20.3; 17.2. HR-CI-

MS (CH₄): 273.1460 ([M Na] , C₁₅H₂₂NaO₃; calc. 273.1467).

()-(1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-hydroxypropan-2-one (()-17). To a soln. of (À)-16

(4.92 g, 28.6 mmol) in CH₂Cl₂(300 ml) at À788 was bubbled O₂/O₃for 1 h. After quenching with PPh₃(8.26 g,

31.5 mmol) at À788 and stirring for 30 min, the mixture was warmed to r.t. under Ar and then concentrated.

Gradient FC (hexanes/AcOEt 2 :1 ! hexanes/AcOEt 1:1) provided ()-17 (4.54 g, 91%). Colorless oil. [a]_D²⁵

43.8 (c 0.95, CHCl₃). IR (CHCl₃): 3460s (br.), 2975s, 2880m, 1735s, 1370m, 1250m, 1230m, 1120m, 1070m,

845m. ¹H-NMR (500 MHz, CDCl₃): 4.44 (ddd, J 6.9, 6.1, 2.8, 1 H); 4.06 4.09 (m, 2 H); 3.98 (dd, J 8.3, 6.9,

1 H); 3.44 (d, J 6.1, 1 H); 2.23 (s, 3 H); 1.36 (s, 3 H); 1.31 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 207.0; 109.8;

76.3; 75.5; 65.5; 26.0; 25.2. HR-CI-MS (CH₄): 159.0693 ([M À Me] , C₇H₁₁O₄; calc. 159.0657).

(À)-(1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-methylpropane-1,2-diol ((À)-18). Under Ar, a soln. of

()-17 (182.4mg, 1.05 mmol) in THF (10 ml) at À788 was treated with MeMgBr (3.0m in Et₂O, 1.05 ml,

3.15 mmol), this mixture was then warmed to r.t. over 1 h. After quenching with sat. aq. NH₄Cl soln. (5 ml), the

mixture was extracted with Et₂O (3 Â 30 ml), and the org. layers were washed with brine, dried (MgSO₄),

filtered, and concentrated. Gradient FC (hexanes/AcOEt 2 :1 ! hexanes/AcOEt 1 :1) provided (À)-18

(179.7 mg, 90%). Colorless oil. [a]²_D⁵ À7.8 (c 1.14, CHCl₃). IR (CHCl₃): 3510s (br.), 2970s, 2920m, 1380m,

1365m, 1250m, 1140m, 1055m, 865w. ¹H-NMR (500 MHz, CDCl₃): 4.28 (ddd, J 8.1, 7.7, 3.1, 1 H); 4.02 (dd, J

8.1, 6.5, 1 H); 3.92 (dd, J 7.7, 6.5, 1 H); 3.21 (dd, J 8.3, 3.1, 1 H); 2.68 (d, J 8.3, 1 H); 2.55 (s, 1 H); 1.40

(s, 3 H); 1.35 (s, 3 H); 1.24( s, 3 H); 1.22 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 109.3; 75.3; 74.9; 72.5; 66.7; 26.3;

26.2; 26.1; 25.4. HR-CI-MS (CH₄): 191.1291 ([M H] , C₉H₁₉O₄; calc. 191.1283).

()-(1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-methyl-1-[(methylsulfanyl)methoxy]propan-2-ol

(()-19). Diol (À)-18 (10.9 g, 57.3 mmol) was treated with DMSO (203 ml), glacial AcOH (332 ml), and Ac₂O

(135 ml) at r.t. After 38 h, the resulting soln. was poured into cold sat. aq. NaHCO₃soln. and stirred for 2 h. The

mixture was extracted with Et₂O (3 Â 500 ml), and the combined org. layers were washed with brine, dried

(MgSO₄), and concentrated. Gradient FC (hexanes/AcOEt 20 :1 ! hexanes/AcOEt 5 :1) provided ()-19

(8.3 g, 58%). Colorless oil. [a]²_D⁵ 114( c 0.95, CHCl₃). IR (CHCl₃): 3480s (br.), 2970s, 2910s, 1375m,

1355m, 1235m, 1150m, 1060m, 1040m, 900w. ¹H-NMR (500 MHz, CDCl₃): 4.88 (dd, J 17.2, 11.6, 2 H); 4.24

(app. ddd, J 8.4, 8.2, 6.8, 1 H); 4.02 (dd, J 8.4, 6.2, 1 H); 3.77 (dd, J 8.2, 6.2, 1 H); 3.34( d, J 6.8, 1 H); 2.51

Helvetica Chimica Acta Vol. 86 (2003)

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(br. s, 1 H); 2.18 (s, 3 H); 1.37 (s, 3 H); 1.32 (s, 3 H); 1.22 (s, 3 H); 1.18 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃):

108.3; 84.2; 77.3; 76.7; 72.1; 67.2; 27.1; 26.3; 25.8; 25.5;14.8. HR-CI-MS (CH₄): 251.1306 ([M H] , C₁₁H₂₃O₄S ;

calc. 251.1317).

()-(4R)-4-{(1S)-2-(Benzyloxy)-2-methyl-1-[(methylsulfanyl)methoxy]propyl}-2,2-dimethyl-1,3-dioxolane

(()-20). Under Ar, to a suspension of NaH (60% suspension in mineral oil, 39 mg, 0.955 mmol) in THF

(1.2 ml) at 08 was added dropwise a soln. of ()-19 (47.8 mg, 0.191 mmol) in THF (1 ml), and this mixture was

warmed to r.t. and stirred for 1 h. A soln. of BnBr (0.5m in THF, 770 ml, 0.382 mmol) and Bu₄NI (TBAI; 4mg,

0.01 mmol) was then added, and the mixture was stirred overnight. Sat. aq. NH₄Cl soln. (3 ml) was added to

quench the reaction, the entire mixture was extracted with Et₂O (3 Â 5 ml), and the combined org. layers were

washed with brine, dried (MgSO₄) filtered, and concentrated. Gradient FC (hexanes/AcOEt 20 :1 ! hexanes/

AcOEt 5 :1) provided ()-20 (62.2 mg, 96%). Pale yellow oil. [a]²_D⁵ 107 (c 0.85, CHCl₃). IR (CHCl₃):

1

2970s, 2920m, 1450w, 1375m, 1365m, 1230m, 1155m, 1060s. H-NMR (500 MHz, CDCl₃): 7.23 7.33 (m, 5 H);

4.94 (dd, J 15.3, 11.4, 2 H); 4.42 (dd, J 12.0, 11.6, 2 H); 4.21 4.25 (m, 1 H); 3.95 (dd, J 9.0, 6.0, 1 H); 3.68

(t, J 8.7, 1 H); 3.53 (d, J 7.9, 1 H); 2.19 (s, 3 H); 1.37 (s, 3 H); 1.35 (s, 3 H); 1.33 (s, 3 H); 1.26 (s, 3 H).

¹³C-NMR (125 MHz, CDCl₃): 138.9; 128.3; 127.5; 127.3; 107.8; 83.0; 77.6; 76.9; 68.1; 63.9; 26.6; 25.9; 23.6; 20.3;

14.9. HR-CI-MS (CH₄): 341.1778 ([M H] , C₁₈H₂₉O₄S ; calc. 341.1787).

(À)-(2R,3S)-4-(Benzyloxy)-4-methyl-3-[(methylsulfanyl)methoxy]pentane-1,2-diol ((À)-21). To a soln. of

()-20 (4.80 g, 14.1 mmol) in MeOH (105 ml) and H₂O (15 ml) was added ()-camphorsulfonic acid (160 mg,

0.71 mmol) at r.t. and the resultant mixture was stirred for 2.5 h at 658. The mixture was cooled to r.t., poured

into sat. aq. NaHCO₃soln. (5 ml) and AcOEt (40 ml), extracted with AcOEt (3 Â 100 ml), washed with brine

(70 ml), dried (MgSO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 2 :1 ! hexanes/

AcOEt 1:1) provided (À)-21 (3.77 g, 90%). Colorless oil. [a]²_D⁵ À68.3 (c 1.22, CHCl₃). IR (neat):

3433s (br.), 2922s, 1388m, 1154m, 1057s, 735m, 697m. ¹H-NMR (500 MHz, CDCl₃): 7.26 7.33 (m, 5 H); 4.88

(dd, J 21.1, 11.6, 2 H); 4.49 (s, 2 H); 3.92 3.98 (m, 1 H); 3.64 3.70 ( m, 2 H); 3.53 (d, J 2.8, 1 H); 3.00

(d, J 6.1, 1 H); 2.46 (t, J 5.3, 1 H); 2.23 (s, 3 H); 1.4 1 (s, 3 H); 1.35 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃):

138.8; 128.4; 127.4; 127.3; 82.1; 79.3; 77.6; 70.7; 64.9; 63.9; 22.9; 21.4; 15.0. HR-CI-MS (NH ₃): 323. 1289 ([M

Na] , C₁₅H₂₄NaO₄S ; calc. 323.1293).

()-(2R)-2-{(1S)-2-(Benzyloxy)-2-methyl-1-[(methylsulfanyl)methoxy]propyl}oxirane (()-7). Under Ar,

a soln. of (À)-21 (772 mg, 2.57 mmol) in THF (50 ml) was treated with NaH (308 mg, 12.9 mmol) at 08. After

1 h, the resulting mixture was cooled to À788, and then a 1-tosyl-1H-imidazole soln. (629 mg, 2.83 mmol) in

THF (5 ml) was added via a cannula. After 10 min, the mixture was allowed to warm to 08 and stirred for 1.5 h.

Sat. aq. NH₄Cl soln. (15 ml) was added, the aq. layer was extracted with Et₂O (3 Â 30 ml), and all org. layers

were combined, washed with brine (50 ml), dried with MgSO₄, filtered, and concentrated. FC (hexanes/AcOEt

5 :1) afforded ()-7 (658 mg, 91%). Pale yellow oil. [a]²_D⁵ 136 (c 1.06, CHCl₃). IR (CHCl₃): 2980s, 2920s,

1385m, 1350m, 1230m, 1160m, 1050s, 965w, 84 0m. ¹H-NMR (500 MHz, CDCl₃): 7.24 7.35 ( m, 5 H); 4.94

(dd, J 16.9, 11.5, 2 H); 4.55 (dd, J 23.6, 11.6, 2 H); 3.31 (d, J 7.5, 1 H); 3.18 (ddd, J 7.5, 4.3, 2.8, 1 H); 2.80

(dd, J 4.8, 4.3, 1 H); 2.64 (dd, J 4.9, 2.8, 1 H); 2.18 (s, 3 H); 1.37 (s, 3 H); 1.36 (s, 3 H). ¹³C-NMR (125 MHz,

CDCl₃): 139.5; 128.2; 127.1; 126.9; 82.8; 77.4; 75.0; 64.0; 52.4; 44.3; 23.6; 21.6; 14.4. HR-CI-MS (NH₃): 283.1363

([M H] , C₁₅H₂₃O₃S ; calc. 283.1368).

()-Benzyl (2S,3S)-4-Iodo-1,1-dimethyl-2-[(methylsulfanyl)methoxy]-3-[(triethylsilyl)oxy]butyl Ether

(()-28). Under Ar, a soln. of ()-7 (22.8 mg, 0.089 mmol) in THF (5 ml) was treated with LiI (30 mg,

0.226 mmol) and AcOH (14 ml, 0.244 mmol) at 08. After 15 min, the resulting mixture was warmed to r.t. and

stirred for 3 h. This mixture was then charged with Et₂O (10 ml), washed with sat. aq. Na₂SO₃soln. (5 ml) and

brine (5 ml), dried (MgSO₄), filtered, and concentrated. This material was used without purification in the next

step.

Under Ar, the soln. of iodohydrin (30.2 mg, 73.6 mmol) in CH₂Cl₂(2 ml) was treated with 2,6-lutidine

(31 ml, 0.265 mmol) and TESOTf (47 ml, 0.206 mmol) at 08. After 15 min, this mixture was charged with Et₂O

(10 ml), washed with sat. aq. NH₄Cl soln. (5 ml) and brine (5 ml), dried (MgSO₄), filtered, and concentrated.

FC (hexanes/AcOEt 20 :1) afforded ()-28 (36.5 mg, 86% yield for 2 steps). Pale yellow oil. [a]²_D⁵ 14( c

1.14, CH₂Cl₂). IR (neat): 2954s, 2876s, 1456w, 1180w, 1092s, 1006w, 732s. ¹H-NMR (500 MHz, C₆D₆): 7.29 (d, J

7.5, 2 H); 7.20 (t, J 7.7, 2 H); 7.10 (t, J 7.4, 1 H); 4.89 (dd, J 45.1, 11.6, 2 H); 4.29 (dd, J 18.5, 11.4, 2 H);

3.90 (app. dd, J 10.0, 4.4, 1 H); 3.76 (d, J 5.8, 1 H); 3.44 (ddd, J 19.3, 10.1, 4.5, 2 H); 1.93 (s, 3 H); 1.32

(s, 3 H); 1.19 (s, 3 H); 0.99 (t, J 8.8, 9 H); 0.62 (q, J 7.9, 6 H). ¹³C-NMR (125 MHz, C₆D₆): 139.7; 128.6; 127.5;

127.4; 82.3; 78.3; 72.0; 64.0; 24.0; 21.1; 16.3; 14.7; 7.2; 5.6. HR-ESI-MS: 547.1173 ([M Na] , C₂₁H₃₇INaO₃Si ;

calc. 547.1175).

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Helvetica Chimica Acta Vol. 86 (2003)

()-(1R,2S)-3-(Benzyloxy)-1-{[(4aS)-2,3,4,4a,5,6,7,8-octahydro-4a-methyl-2-oxo-naphthalen-1-yl]methyl}-

3-methyl-2-[(methylsulfanyl)methoxy]butyl Benzenecarboxylate (()-30). Under Ar, a 1.5m soln. of LiNEt₂in

THF and hexanes (0.6 ml) was added to ()-23 (140 mg, 0.68 mmol) in THF (300 ml) at À408 and gradually

heated to 658 over a 2 h period. The resulting mixture was stirred for 12 h at 658, cooled to À788, and then

DMPU (150 ml) and ()-7 (271 mg, 0.97 mmol) were added. The mixture was warmed to r.t., stirred for 3 h, the

reaction was quenched with H₂O (6 ml), and the mixture was extracted with AcOEt (3 Â 10 ml). The combined

org. layers were washed with brine (5 ml), dried (MgSO₄), filtered, and concentrated. This material was used

without purification in the next step.

The above alcohol mixture in CH₂Cl₂(5 ml) was treated with 4-(dimethylamino)pyridine (56 mg,

0.44 mmol) and BzCl (40 ml, 0.33 mmol) at r.t. The mixture was stirred for 18 h, diluted with AcOEt (10 ml),

washed sequentially with H₂O (5 ml) and brine (5 ml), dried (MgSO₄), filtered, and concentrated. Gradient FC

(95% hexanes/AcOEt ! 80% hexanes/AcOEt ! 65% hexanes/AcOEt) provided a mixture of benzoates.

A soln. of the crude benzoate (211 mg) in benzene (3 ml) was treated with AcONa/AcOH buffer (3 ml) at

658. After 15 h, the mixture was cooled to r.t., the reaction was quenched with sat. aq. NaHCO₃(1 ml), and the

mixture was extracted with AcOEt (3 Â 10 ml). The combined org. layers were washed with brine (5 ml), dried

(MgSO₄), filtered, and concentrated. Gradient FC (95% hexanes/AcOEt ! 80% hexanes/AcOEt) provided

()-30 (127 mg, 34% yield for 3 steps). Pale yellow oil. [a]²_D⁵ 134( c 0.89, CHCl₃). IR (neat): 2927s, 1716s,

1664s, 1602s, 1451m, 1274s, 1026m, 711m. ¹H-NMR (500 MHz, CDCl₃): 7.96 7.98 (m, 2 H); 7.49 7.52 (m, 1 H);

7.39 (app. t, J 7.1, 2 H); 7.20 7.31 (m, 5 H); 5.57 (dt, J 10.7, 3.5, 1 H); 4.95 (dd, J 19.2, 11.3, 2 H); 4.47

(s, 2 H); 3.80 (d, J 3.3, 1 H); 3.07 (dd, J 13.8, 10.7, 1 H); 2.67 2.72 (m, 2 H); 2.22 2.33 (m, 2 H); 2.18

(s, 3 H); 1.99 2.06 (m, 1 H); 1.69 (dt, J 13.7, 4.9, 1 H); 1.57 1.61 (m, 1 H); 1.46 1.54 (m, 2 H); 1.37 1.40

(m, 1 H); 1.33 (s, 3 H); 1.28 (s, 3 H); 1.22 1.25 (m, 1 H); 1.04( s, 3 H); 0.94 1.00 ( dt, J 13.4, 3.8, 1 H); 0.77

0.86 (m, 1 H). ¹³C-NMR (125 MHz, CDCl₃): 198.5; 165.7; 165.0; 139.3; 132.8; 130.4; 129.8; 129.2; 128.4; 128.2;

127.4; 127.1; 82.7; 78.8; 76.9; 72.4; 63.6; 41.7; 37.4; 36.2; 33.8; 30.3; 29.7; 29.5; 27.5; 26.5; 22.9; 22.3; 21.2; 21.1; 14.8.

HR-ESI-MS: 551.2819 ([M H] , C₃₃H₄₃O₅S ; calc. 551.2831).

()-(1R,2S)-3-(Benzyloxy)-1-{[(1S,9aS,9bS)-1,3,3a,4,5,7,8,9,9a,9b-decahydro-1-methoxy-9a,9b-dimethyl-7-

oxonaphtho[1,2-c]furan-6-yl]methyl}-3-methyl-2-[(methylsulfanyl)methoxy]butyl Benzenecarboxylate (()-

33b). Under Ar, a 1.5m soln. of LiNEt₂in THF and hexanes (6.5 ml) was added to a mixture of 8b (832 mg,

2.85 mmol) and the ()-23 (924 mg, 4.48 mmol) in THF (2 ml) at À 408 and gradually heated to 658 over a 2 h

period. The resulting mixture was stirred for 12 h at 658, cooled to À788, and then DMPU (1.5 ml) and epoxide

()-7 (1.95 g, 6.94mmol) were added. The mixture was warmed to r.t., stirred for 3 h, the reaction was quenched

with H₂O (60 ml), and the mixture was extracted with AcOEt (3 Â 60 ml). The combined org. layers were

washed with brine (60 ml), dried (MgSO₄), filtered, and concentrated. This material was used without

purification in the next step.

The alcohol mixture in CH₂Cl₂(80 ml) was treated with DMAP (2.7 g, 20.5 mmol) and BzCl (1.87 ml,

16.2 mmol) at r.t. The mixture was stirred for 18 h, diluted with AcOEt (100 ml), washed with H₂O (50 ml) and

brine (50 ml), dried (MgSO₄), filtered, and concentrated. Gradient FC (95% hexanes/AcOEt ! 80% hexanes/

AcOEt ! 50% hexanes/AcOEt) provided a mixture of benzoates.

A soln. of the crude benzoates (1.12 g) in benzene (35 ml) was treated with AcONa/AcOH buffer¹) (25 ml)

at 658. After 45 h, the mixture was cooled to r.t., the reaction was quenched with sat. aq. NaHCO₃soln. (10 ml),

and the mixture was extracted with AcOEt (3 Â 100 ml). The combined org. layers were washed with brine

(50 ml), dried (MgSO₄), filtered, and concentrated. Gradient FC (95% hexanes/AcOEt ! 80% hexanes/

AcOEt ! 65% hexanes/AcOEt) provided ()-33b (615 mg, 34% yield for 3 steps). Colorless oil. [a]²_D⁵ 203

(c 1.15, CHCl₃). IR (neat): 2945s, 2879s, 1717s, 1662s, 1451m, 1272s, 1094m, 713m. ¹H-NMR (500 MHz,

CDCl₃): 7.95 (d, J 7.1, 2 H); 7.51 (t, J 7.4, 1 H); 7.38 (t, J 7.8, 2 H); 7.22 7.32 (m, 5 H); 5.16 (dt, J 10.8, 3.6,

1 H); 4.93 (dd, J 17.5, 11.4, 2 H); 4.48 (s, 2 H); 4 .4 2 s(, 1 H); 3.92 (t, J 8.1, 1 H); 3.76 (d, J 3.8, 1 H); 3.21

3.25 (m, 4H); 3.17 ( dd, J 14.0, 10.9, 1 H); 2.72 2.79 (m, 2 H); 2.66 (dd, J 10.7, 3.3, 1 H); 2.18 2.31

(m, 7 H); 1.51 1.61 (m, 2 H); 1.33 (s, 3 H); 1.31 (s, 3 H); 1.30 (s, 3 H); 0.99 (ddd, J 25.2, 12.9, 5.4, 1 H); 0.48

(s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 197.8; 165.6; 165.0; 139.3; 132.9; 130.4; 130.3; 129.7; 128.4; 128.2; 127.4;

127.1; 110.8; 82.9; 78.6; 76.9; 72.1; 69.6; 63.7; 54.5; 50.4; 43.4; 35.9; 33.7; 30.1; 29.7; 26.7; 23.2; 21.7; 20.9; 20.5;

17.0; 14.8. HR-ESI-MS: 659.3039 ([M Na] , C₃₇H₄₈NaO₇S ; calc. 659.3018).

()-(1R,2S)-3-(Benzyloxy)-1-{[(1R,9aS,9bS)-1,3,3a,4,5,7,8,9,9a,9b-decahydro-1-methoxy-9a,9b-dimethyl-

7-oxonaphtho[1,2-c]furan-6-yl]methyl}-3-methyl-2-[(methylsulfanyl)methoxy]butyl Benzenecarboxylate (()-

1

)

Use of toluene, instead of benzene, as with 60 (Scheme 18), accelerated the reaction.

Helvetica Chimica Acta Vol. 86 (2003)

3929

33a). Under Ar, a 1.5m soln. of LiNEt₂in THF and hexanes (1.5 ml) was added to a mixture of 8a (186 mg,

0.637 mmol) and the ()-23 (160 mg, 0.776 mmol) in THF (0.5 ml) at À408 and gradually heated to 658 over a

2 h period. The resulting mixture was stirred for 12 h at 658, cooled to À788, and then DMPU (1.5 ml) and

epoxide ()-7 (398 mg, 1.41 mmol) were added. The mixture was warmed to r.t., stirred for 3 h, the reaction was

quenched with H₂O (10 ml), and the mixture was extracted with AcOEt (3 Â 20 ml). The combined org. layers

were washed with brine (10 ml), dried (MgSO₄), filtered, and concentrated. This material was used without

purification in the next step.

The alcohol mixture in CH₂Cl₂(20 ml) was treated with DMAP (530 mg, 4.23 mmol) and BzCl (0.33 ml,

2.82 mmol) at r.t. The mixture was stirred for 18 h, diluted with AcOEt (30 ml), washed with H₂O (10 ml) and

brine (10 ml), dried (MgSO₄), filtered, and concentrated. Gradient FC (90% hexanes/Et₂O ! 75% hexanes/

Et₂O ! 50% hexanes/Et₂O) provided a mixture of benzoates.

A soln. of the crude benzoates (214mg) in benzene (5 ml) was treated with AcONa/AcOH buffer ¹) (5 ml)

at 658. After 25 h, the mixture was cooled to r.t., the reaction was quenched with sat. aq. NaHCO₃soln. (5 ml),

and the mixture was extracted with AcOEt (3 Â 20 ml). The combined org. layers were washed with brine

(10 ml), dried (MgSO₄), filtered, and concentrated. Gradient FC (85% hexanes/AcOEt ! 65% hexanes/

AcOEt) provided ()-33a (91.4mg, 23% yield for 3 steps). Colorless oil. [ a]²_D⁵ 144 (c 0.24, CHCl₃). IR

(neat): 2937s, 1715s, 1664s, 1451w, 1273s, 1114w, 713m. ¹H-NMR (500 MHz, CDCl₃): 7.97 (d, J 8.3, 2 H); 7.53

(t, J 7.4, 1 H); 7.40 (t, J 7.7, 2 H); 7.24 7.34 ( m, 5 H); 5.63 (dt, J 10.9, 3.4, 1 H); 4.95 (dd, J 14.8, 11.4,

2 H); 4.80 (s, 1 H); 4.50 (s, 2 H); 3.79 (d, J 3.4, 1 H); 3.76 (t, J 7.5, 1 H); 3.43 (dd, J 10.8, 7.7, 1 H); 3.40

(s, 3 H); 3.22 (dd, J 13.9, 11.1, 1 H); 2.79 (dd, J 16.5, 4.5, 1 H); 2.67 (dd, J 14.0, 3.3, 1 H); 2.47 2.54

(m, 1 H); 2.13 2.33 (m, 7 H); 1.47 1.50 (m, 1 H); 1.38 1.43 (m, 1 H); 1.36 (s, 3 H); 1.32 (s, 3 H); 1.19 (s, 3 H);

1.04( ddd, J 25.6, 12.8, 5.1, 1 H); 0.55 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 197.6; 165.6; 163.2; 139.3; 133.0;

132.0; 130.2; 129.8; 128.4; 128.3; 127.5; 127.2; 107.0; 82.9; 78.7; 76.9; 71.9; 68.5; 63.7; 57.1; 48.3; 42.2; 39.4; 33.7;

30.2; 30.0; 27.0; 23.1; 21.0; 20.9; 18.5; 14.8; 10.4. HR-ESI-MS: 659.3034 ([M Na] , C₃₇H₄₈NaO₇S ; calc.

659.3018).

()-(1R,2S)-3-(Benzyloxy)-1-{[(9aS,9bS)-1,3,3a,4,5,7,8,9,9a,9b-decahydro-9a,9b-dimethyl-1,7-dioxonaph-

tho[1,2-c]furan-6-yl]methyl}-3-methyl-2-[(methylsulfanyl)methoxy]butyl Benzenecarboxylate (()-37). Under

Ar, a soln. of ()-33b (502 mg, 0.788 mmol) in MeCN (36 ml) and H₂O (9 ml) was treated with HClO₄(70% in

H₂O, 240 ml) at 558. After 75 min, the mixture was cooled to r.t., the reaction was quenched with sat. aq.

NaHCO₃(5 ml), and the mixture was extracted with AcOEt (3 Â 30 ml). The combined org. layers were washed

with brine (20 ml), dried (Na₂SO₄), filtered, and concentrated in vacuo. FC afforded a mixture of aldehyde and

hemiacetals 34 (343 mg, 70%) as a colorless oil, pyran 35 (94mg, 16%) as a colorless oil, and alcohol 36 (26 mg,

8%) as a colorless oil. The alcohol 36 was further treated with HCl (1n, 0.3 ml) in THF (5 ml) and afforded

additional 35 (23 mg, 90%).

Under Ar, to a soln. of NIS (233 mg, 1.04mmol) and TBAI (76 mg, 0.207 mmol) in CH ₂Cl₂(5 ml) at 08 was

added a mixture of aldehyde and hemiacetals 34b (129 mg, 0.207 mmol) in CH₂Cl₂(3 ml). This mixture was then

warmed to r.t. for 1 h. The mixture was diluted with Et₂O (20 ml), washed with sat. aq. Na₂S₂O₃soln. (10 ml),

brine (5 ml), dried (Na₂SO₄), filtered, and concentrated in vacuo. FC (hexanes/AcOEt 5 :1) afforded ()-37

(113 mg, 91% yield). Colorless crystals. M.p. 107 1098. [a]²_D⁵ 135 (c 1.51, CHCl₃). IR (neat): 2978m,

1772s, 1714s, 1665s, 1451w, 1273s, 1069w, 1026w, 713m. ¹H-NMR (500 MHz, CDCl₃): 7.97 7.99 (m, 2 H); 7.53

7.56 (m, 1 H); 7.4 1 (t, J 7.9, 2 H); 7.22 7.33 (m, 5 H); 5.61 (dt, J 10.7, 3.5, 1 H); 4.96 (dd, J 18.9, 11.4, 2 H);

4.49 (s, 2 H); 4.17 (dd, J 8.6, 7.3, 1 H); 3.79 (d, J 3.4, 1 H); 3.74 (dd, J 11.2, 8.7, 1 H); 2.83 2.87 (m, 1 H);

2.71 2.80 (m, 2 H); 2.06 2.40 (m, 7 H); 1.42 1.51 (m, 1 H); 1.35 (s, 3 H); 1.30 (s, 3 H); 1.19 (s, 3 H); 1.05

(ddd, J 25.7, 12.9, 5.0, 1 H); 0.72 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 197.3; 178.3; 165.6; 160.3; 139.3; 133.7;

133.1; 130.1; 129.7; 128.5; 128.2; 127.5; 127.2; 83.0; 78.7; 77.0; 71.9; 68.7; 63.7; 47.2; 42.1; 38.6; 33.4; 30.3; 27.9; 26.8;

23.1; 20.9; 20.2; 19.1; 14.8; 13.2. HR-ESI-MS: 643.2727 ([M Na] , C₃₆H₄₄NaO₇S ; 643.2705).

(À)-(2S,3R,9aS,9b S,11aS)-2-[1-(Benzyloxy)-1-methylethyl]-3,4,5,6,6a,7,9,9a,9b,10,11,11a-dodecahydro-

9a,9b-dimethyl-9-oxo-2H-[2]benzofuro[5,4-f][1]benzopyran-3-yl Benzenecarboxylate ((À)-39). To a soln. of

()-37 (220 mg, 0.354mmol) in CH ₂Cl₂(7 ml) and Et₃SiH (7 ml) was added CF₃SO₃H (TfOH; 73 ml,

1.06 mmol) in MeCN (0.8 ml) at À508, and the resultant mixture was allowed to warm to À208. After 1 h, the

reaction was cooled to À408, quenched with sat. aq. NaHCO₃soln. (3 ml), and slowly warmed to r.t. This

mixture was then extracted with Et₂O (2 Â 20 ml); the combined org. layers were dried (Na₂SO₄), filtered, and

concentrated in vacuo. FC (hexanes/AcOEt 5 :1) provided (À)-39 (156 mg, 81% yield). Colorless oil. [a]_D²⁵

À7.5 (c 1.47, CHCl₃). IR (neat): 2978m, 1772s, 1713s, 1451w, 1272s, 1070m. ¹H-NMR (500 MHz, CDCl₃): 7.99

8.01 (m, 2 H); 7.53 7.57 (m, 1 H); 7.4 2 (t, J 7.7, 2 H); 7.22 7.31 (m, 5 H); 5.54(app. dd, J 3.1, 2.8, 1 H); 4.54

(s, 2 H); 4.17 (dd, J 8.5, 7.5, 1 H); 4.06 (t, J 7.8, 1 H); 3.89 (dd, J 11.3, 8.6, 1 H); 3.60 (s, 1 H); 3.28 (dd,

3930

Helvetica Chimica Acta Vol. 86 (2003)

J 15.1, 3.8, 1 H); 2.72 2.79 (m, 1 H); 2.52 2.55 (m, 1 H); 2.10 2.17 (m, 3 H); 1.78 1.92 (m, 2 H); 1.52 1.59

(m, 2 H); 1.38 (s, 3 H); 1.29 1.37 (m, 1 H); 1.27 (s, 3 H); 1.25 (s, 3 H); 1.01 (s, 3 H). ¹³C-NMR (125 MHz,

CDCl₃): 179.4; 165.8; 139.8; 136.0; 132.9; 130.7; 129.6; 128.6; 128.4; 128.2; 127.1; 127.0; 82.8; 76.1; 69.6; 69.0;

64.2; 47.6; 41.7; 39.4; 32.6; 26.8; 25.4; 24.0; 23.7; 22.0; 21.2; 20.5; 13.2. HR-ESI-MS: 567.2736 ([M Na] ,

C₃₄H₄₀NaO₆; calc. 567.2723).

()-(2S,3R,9aS,9bS,11aS)-3,4,5,6,6a,7,9,9a,9b,10,11,11a-Dodecahydro-2-(1-hydroxy-1-methylethyl)-9a,9b-

dimethyl-9-oxo-2H-[2]benzofuro[5,4-f][1]benzopyran-3-yl Benzenecarboxylate (()-41). Under Ar, a suspen-

sion of (À)-39 (58.0 mg, 107 mmol) in CH₂Cl₂(5 ml) and H₂O (0.5 ml) was treated with DDQ (43.5 mg,

192 mmol) at r.t. for 3.5 h. This mixture was then diluted with Et₂O (10 ml), washed sequentially with sat. aq.

NaHCO₃soln. (3 ml), and brine (3 ml). The org. layer was dried (Na₂SO₄), filtered, and concentrated in vacuo.

Gradient FC (hexanes/AcOEt 2 :1 ! hexanes/AcOEt 1:1) provided ()-41 (45.8 mg, 95%). Colorless oil.

[a]²_D⁵ 33 (c 0.74, CHCl₃). IR (neat): 3512s (br.), 2977s, 1771s, 1713s, 1450w, 1345w, 1280s, 1118w, 1071m,

1

1048m, 714m. H-NMR (500 MHz, CDCl₃): 7.96 7.98 (m, 2 H); 7.54 7.57 ( m, 1 H); 7.41 7.44 (m, 2 H); 5.41

(dd, J 2.7, 1.8, 1 H); 4.18 (dd, J 8.6, 7.3, 1 H); 4.09 4.14 (m, 1 H); 3.89 (dd, J 11.3, 8.6, 1 H); 3.45 (s, 1 H);

3.26 (dd, J 15.1, 3.8, 1 H); 2.74 2.81 ( m, 1 H); 2.60 (s, 1 H); 2.51 2.57 (m, 1 H); 2.09 2.20 (m, 3 H); 1.76

1.91 (m, 2 H); 1.52 1.66 (m, 2 H); 1.35 (ddd, J 25.8, 12.9, 4.6, 1 H); 1.27 (s, 3 H); 1.23 (s, 3 H); 1.22 (s, 3 H);

1.01 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 179.3; 165.9; 136.6; 133.1; 130.3; 129.6; 128.5; 127.9; 83.1; 76.2; 71.7;

69.2; 69.0; 47.6; 41.7; 39.4; 32.6; 26.7; 26.3; 25.8; 25.3; 23.8; 21.2; 20.5; 13.2. HR-ESI-MS: 477.2251 ([M Na] ,

C₂₇H₃₄NaO₆; calc. 477.2253).

()-(2S,3R,9aS,9bS,11aS)-3,4,5,6,6a,7,9,9a,9b,10,11,11a-Dodecahydro-3-hydroxy-2-(1-hydroxy-1-methyl-

ethyl)-9a,9b-dimethyl-2H-[2]benzofuro[5,4-f][1]benzopyran-9-one (()-42). A soln. of ()-41 (45.2 mg,

99.4 mmol) in MeOH (2.7 ml) and H₂O (0.3 ml) was treated with K₂CO₃(21 mg, 149 mmol) at r.t. for 15 h.

This reaction was quenched with sat. aq. NH₄Cl soln. (1 ml), and then the mixture was concentrated. The residue

was extracted with AcOEt (2 Â 10 ml), the combined org. layers were washed with brine (3 ml) and dried

(Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 1:2 ! AcOEt) provided ()-42

(33.8 mg, 97%). Colorless crystals. M.p. 201 2038. [a]²_D⁵ 52 (c 0.53, CHCl₃). IR (neat): 3253s (br.),

2969m, 1761s, 1447w, 1231w, 1082m, 984m. ¹H-NMR (500 MHz, CDCl₃): 4.24 (dd, J 8.3, 7.4, 1 H); 4.16 (app.

d, J 3.4, 1 H); 3.98 4.02 (m, 1 H); 3.93 (dd, J 11.3, 8.6, 1 H); 3.39 (d, J 4.5, 1 H); 3.11 (s, 1 H); 2.99

(dd, J 14.9, 3.3, 1 H); 2.87 2.93 (m, 1 H); 2.77 (ddd, J 15.3, 4.7, 2.0, 1 H); 2.64 (s, 1 H); 2.13 (app. dd, J

11.0, 3.8, 1 H); 1.97 2.07 (m, 3 H); 1.68 1.82 (m, 3 H); 1.4 1 (ddd, J 25.8, 12.9, 4.6, 1 H); 1.30 (s, 9 H); 1.01

(s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 179.4; 136.3; 128.6; 81.3; 76.7; 73.0; 69.1; 66.9; 47.9; 42.0; 39.5; 34.8; 27.6;

27.0; 25.3; 25.0; 24.0; 21.4; 21.0; 13.2. HR-ESI-MS: 373.1996 ([M Na] , C₂₀H₃₀NaO₅; calc. 373.1991).

()-(2S,3R,9aS,9bS,11aS)-3,4,5,6,6a,7,9,9a,9b,10,11,11a-Dodecahydro-9a,9b-dimethyl-2-{1-methyl-1-[(tri-

ethylsilyl)oxy]ethyl}-3-[(tri-ethylsilyl)oxy]-2H-[2]benzofuro[5,4-f][1]benzopyran-9-one (()-6). Under Ar, a

soln. of ()-42 (2.7 mg, 7.7 mmol) in CH₂Cl₂(1 ml) was treated with 2,6-lutidine (10 ml) and TESOTf (10 ml), the

resultant soln. was stirred at r.t. for 15 min. After diluting with Et₂O (10 ml), the mixture was washed

sequentially with sat. aq. NH₄Cl soln. (2 ml) and brine (2 ml). The org. layer was then dried (Na₂SO₄), filtered,

and concentrated in vacuo. FC (hexanes/AcOEt 20 :1) provided ()-6 (4.1 mg, 92%). Colorless oil. [a]²_D⁵ 16

(c 0.93, CHCl₃). IR (neat): 2954s, 2875s, 1776s, 1458w, 1375w, 1231m, 1045m, 1006m, 74 m0 . ¹H-NMR

(500 MHz, CDCl₃): 4.21 4.26 (m, 2 H); 3.92 (dd, J 11.3, 8.5, 1 H); 3.89 (t, J 7.9, 1 H); 3.01 (s, 1 H); 2.80

2.92 (m, 2 H); 2.67 (ddd, J 14.9, 4.5, 1.8, 1 H); 2.07 2.13 (m, 2 H); 1.91 1.99 (m, 2 H); 1.68 1.86 (m, 3 H);

1.40 (ddd, J 25.8, 12.9, 4.6, 1 H); 1.28 (s, 3 H); 1.26 (s, 3 H); 1.20 (s, 3 H); 1.02 (s, 3 H); 0.92 0.98 (m, 18 H);

0.56 0.61 (m, 12 H). ¹³C-NMR (125 MHz, CDCl₃): 179.5; 133.0; 130.5; 85.6; 76.7; 75.3; 69.1; 66.7; 47.9; 42.1;

39.5; 36.3; 28.2; 27.4; 26.3; 25.4; 24.1; 21.6; 21.1; 13.3; 7.1; 6.9; 6.8; 5.3. HR-ESI-MS: 601.3733 ([ M Na] ,

C₃₂H₅₈NaO₅Si₂; calc. 601.3721).

()-(2S,3R,9aS,9bS,11aS)-2-[1-(Benzyloxy)-1-methylethyl]-3,4,5,6,6a,7,9,9a,9b,10,11,11a-dodecahydro-3-

hydroxy-9a,9b-dimethyl-2H-[2]benzofuro[5,4-f][1]benzopyran-9-one (()-43). Under Ar, a soln. of (À)-39

(24.4 mg, 44.8 mmol) in MeOH (2 ml) and H₂O (0.5 ml) was treated with KOH (12.5 mg, 244 mmol), the

resultant mixture was then heated to reflux for 6 h. After cooling to r.t., sat. aq. NH₄Cl soln. (5 ml) was added.

This mixture was then extracted with CH₂Cl₂(3 Â 20 ml), the combined org. layers were washed with brine

(10 ml), dried (Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/

AcOEt 2 :1 ! hexanes/AcOEt 1:1) provided ()-43 (15.9 mg, 81%, 2 steps). Colorless oil. [a]²_D⁵ 26 (c

1.11, CHCl₃). IR (neat): 3465s (br.), 2977s, 1771s, 1452w, 1377w, 1230w, 1047m, 738w, 697w. ¹H-NMR

(500 MHz, CDCl₃): 7.22 7.32 (m, 5 H); 4.60 (dd, J 56.0, 11.5, 2 H); 4.22 4.26 (m, 2 H); 3.91 3.95 (m, 2 H);

3.61 (d, J 4.2, 1 H); 3.20 (s, 1 H); 2.97 (dd, J 14.8, 3.4, 1 H); 2.87 2.93 (m, 1 H); 2.74 2.79 ( m, 1 H); 1.99

2.16 (m, 4H); 1.67 1.81 ( m, 3 H); 1.4 3 (s, 3 H); 1.38 (s, 3 H); 1.31 (s, 3 H); 1.02 (s, 3 H). ¹³C-NMR (125 MHz,

Helvetica Chimica Acta Vol. 86 (2003)

3931

CDCl₃): 179.5; 139.3; 135.5; 129.2; 128.3; 127.4; 127.2; 83.2; 78.2; 77.1; 69.1; 66.4; 65.2; 47.9; 42.0; 39.5; 35.1; 27.1;

25.4; 24.2; 24.0; 22.4; 21.4; 21.1; 13.2. HR-ESI-MS: 441.2657 ([M H] , C₂₇H₃₇O₅; calc. 441.2641).

()-(2R,4bS,9aS,9bR,11aS)-2-[1-(Benzyloxy)-1-methylethyl]-5,6,6a,7,9,9a,9b,10,11,11a-decahydro-4b-(hy-

droperoxy)-9a,9b-dimethyl-2H-[2]benzofuro[5,4-f][1]benzopyran-3,9(4bH)-dione (()-45). Under Ar, a soln.

of ()-43 (3.9 mg, 8.9 mmol) in CH₂Cl₂(1 ml) was treated with DMP (15% soln. in CH₂Cl₂, 60 ml), the resultant

cloudy soln. was then stirred at r.t. for 1 h. This mixture was then diluted with Et₂O (10 ml), washed sequentially

with sat. aq. Na₂SO₃soln. (3 ml) and brine (3 ml). The org. layer was dried (Na₂SO₄), filtered, and concentrated

in vacuo. This crude material was used without further purification.

Under air, a soln. of the above ketone in acetone (2 ml) was treated with silica gel (200 mg). After 16 h

stirring at r.t., this mixture was diluted with Et₂O (10 ml), filtered through a Celite pad, and concentrated in

vacuo. Gradient FC (hexanes/AcOEt 2 :1 ! hexanes/AcOEt 1:1) provided ()-45 (2.5 mg, 62%, 2 steps).

Colorless oil. [a]²_D⁵ 24( c 0.28, CHCl₃). IR (neat): 3329s (br.), 2975s, 1772s, 1684s, 1454w, 1382w, 1131w,

1

1068w, 985w. H-NMR (500 MHz, CDCl₃): 7.63 (s, 1 H); 7.22 7.37 (m, 5 H); 5.85 (d, J 2.0, 1 H); 4.54 4.59

(m, 3 H); 4.23 (dd, J 8.1, 7.3, 1 H); 4.05 (dd, J 11.4, 8.4, 1 H); 3.93 (d, J 1.6, 1 H); 2.67 2.74( m, 1 H);

2.22 2.31 (m, 3 H); 1.86 1.97 (m, 2 H); 1.66 1.73 (m, 2 H); 1.59 (app. dt, J 8.6, 5.4, 1 H); 1.48 (s, 3 H); 1.39

(s, 3 H); 1.34( s, 3 H); 1.07 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 194.8; 178.5; 160.8; 139.7; 128.2; 127.4; 127.2;

124.6; 89.3; 82.9; 77.2; 73.0; 68.9; 64.6; 47.7; 44.4; 40.7; 28.7; 25.3; 23.9; 23.1; 22.4; 18.7; 17.5; 12.9. HR-ESI-MS:

493.2167 ([M Na] , C₂₇H₃₄NaO₇; calc. 493.2202).

()-(2R,4bS,9aS,9bR,11aS)-2-[1-(Benzyloxy)-1-methylethyl]-5,6,6a,7,9,9a,9b,10,11,11a-decahydro-4b-hy-

droxy-9a,9b-dimethyl-2H-[2]benzofuro[5,4-f][1]benzopyran-3,9(4bH)-dione (()-46). Under Ar, a soln. of

()-45 (2.7 mg, 5.7 mmol) in benzene (1.5 ml) was treated with PPh₃(3 mg, 12 mmol) at r.t. for 3 h. This mixture

was diluted with Et₂O (10 ml), washed sequentially with sat. aq. NaHCO₃soln. (3 ml) and brine (3 ml). The org.

layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 2 :1 ! hexanes/

AcOEt 1 :1) provided ()-46 (2.5 mg, 96%). White solid. M.p. 176 1788. [a]²_D⁵ 25 (c 0.21, CHCl₃). IR

(neat): 3465s (br.), 2942s, 1749s, 1683s, 1453w, 1380w, 1068w, 737w. ¹H-NMR (500 MHz, CDCl₃): 7.36 (d, J 7.3,

2 H); 7.32 (t, J 7.5, 2 H); 7.23 (d, J 7.3, 1 H); 5.83 (d, J 2.1, 1 H); 4.69 (dd, J 10.1, 8.2, 1 H); 4.55 (dd, J

17.7, 11.4, 2 H); 4.23 (dd, J 8.2, 7.0, 1 H); 4.07 (dd, J 11.6, 8.3, 1 H); 3.91 (d, J 1.7, 1 H); 2.68 2.74( m, 1 H);

2.42 (ddd, J 22.5, 13.6, 4.8, 1 H); 2.20 2.26 (m, 1 H); 1.83 2.03 (m, 4H); 1.61 1.72 ( m, 2 H); 1.4 9 (s, 3 H);

1.48 (s, 3 H); 1.38 (s, 3 H); 1.16 (s, 1 H); 1.02 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 195.4; 178.7; 164.5; 139.7;

128.2; 127.4; 127.1; 123.0; 83.2; 77.9; 77.2; 72.6; 68.8; 64.6; 47.7; 42.1; 40.6; 32.8; 28.2; 24.0; 23.2; 22.6; 17.8; 17.6;

12.5. HR-ESI-MS: 477.2274 ([M Na] , C₂₇H₃₄NaO₆; calc. 477.2253).

4-Bromo-2-methyl-N,N-bis(trimethylsilyl)benzenamine (48). Under Ar, a soln. of 4-bromo-2-methylaniline

(1.52 g, 8.2 mmol) in THF (35 ml) at 08 was treated with MeLi (1.4m soln. in Et₂O, 12.2 ml, 17.2 mmol), dropwise

over 5 min. The resultant opaque mixture was stirred at 08 for 3 h, and TMSCl (2.2 ml, 17.2 mmol) was

introduced via cannula, dropwise over 5 min. The resultant white suspension was then warmed to r.t. and stirred

overnight. Et₂O (100 ml) was then added, followed by brine (20 ml). After separation, the org. layer was dried

(MgSO₄). Evaporation of solvent afforded a yellow oil. Bulb-to-bulb distillation provided 48 (2.2 g, 84% yield),

Pale yellow oil. IR (neat): 2954s, 2899w, 1473s, 1391m, 1263s, 1252s, 1225s, 1184m, 1119m, 962s, 930s, 839s.

¹H-NMR (500 MHz, C₆D₆): 7.21 (d, J 2.3, 1 H); 7.09 (dd, J 8.3, 2.4, 1 H); 6.52 (d, J 8.3, 1 H); 1.94( s, 3 H);

0.00 (s, 18 H). ¹³C-NMR (125 MHz, C₆D₆): 145.9; 139.5; 133.6; 132.3; 129.5; 117.6; 18.9; 1.9. HR-ESI-MS:

330.0709 ([M H] , C₁₃H₂₅BrNSi₂; calc. 330.0695).

2-Methyl-4-(3-methylbut-2-enyl)benzenamine (5). Under Ar, a soln. of 48 (183 mg, 0.555 mmol) in THF

(11 ml) at À788 was treated with t-BuLi (1.7m soln. in pentane; 650 ml, 1.11 mmol). The resultant yellow soln.

was stirred at À788 for 10 min, and prenyl bromide (140 ml, 1.11 mmol) was introduced dropwise via syringe

over 5 min. The resultant orange suspension was then warmed to r.t. and stirred for 2 h. Et₂O (50 ml), then brine

(10 ml) was added. After separation, the org. layer was dried (MgSO₄). Evaporation of solvent afforded a

yellow oil, which was dissolved in MeOH (2 ml), to this soln., 1n aq. HCl soln. (3 ml) was added. After stirring at

r.t. for 1 h, 10% aq. NaOH soln. was added until pH 11. The mixture was extracted with Et₂O (3 Â 20 ml).

Combined extracts were washed with brine (10 ml), dried (Na₂SO₄), and concentrated in vacuo. Bulb-to-bulb

distillation provided 5 (79.8 mg, 82% yield). Yellow oil. IR (neat): 3370m (br.), 2913s (br.), 1623s, 1506s,

1447m, 1277m, 814m. ¹H-NMR (500 MHz, CDCl₃): 6.85 6.87 (m, 2 H); 6.61 (d, J 7.8, 1 H); 5.29 5.33

(m, 1 H); 3.49 (br. s, 2 H); 3.23 (d, J 7.3, 2 H); 2.16 (s, 3 H); 1.73 (d, J 10.2, 2 H). ¹³C-NMR (125 MHz,

CDCl₃): 142.3; 131.9; 131.6; 130.3; 126.6; 124.1; 122.5; 115.1; 33.5; 25.7; 17.7; 17.4. HR-CI-MS (CH₄): 175.1359

(M , C₁₂H₁₇N ; calc. 175.1361).

3-[5-(3-Methylbut-2-enyl)-1H-indol-2-yl]propan-1-ol (53). Under Ar, a soln. of 5 (275 mg, 1.57 mmol) in

Et₂O (6 ml) was treated with MeLi (1.4m soln. in Et₂O; 1.32 ml, 1.85 mmol) at 08. After 30 min, the mixture was

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Helvetica Chimica Acta Vol. 86 (2003)

treated with TMSCl (220 ml, 1.72 mmol) for 1 h at 08. The mixture was then treated with s-BuLi (2.58 ml,

2.84mmol) at r.t. for 70 min and cooled to À788; neat g-butyrolactone (50 ml, 0.66 mmol) was added, and the

mixture was warmed to r.t. The reaction was quenched with sat. aq. NH₄Cl (3 ml), and the mixture was

extracted with AcOEt (3 Â 30 ml). The combined org. layers were washed with brine (10 ml), dried (MgSO₄),

filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/AcOEt 2 :1) provided 53

(116.6 mg, 73%). Yellow crystals. M.p. 66 688. IR (neat): 3397s (br.), 2924s (br.), 1586m, 1479s, 1452s, 1050s,

800s. ¹H-NMR (500 MHz, C₆D₆): 7.57 (s, 1 H); 7.41 (br. s, 1 H); 7.14 7.20 ( m, 2 H); 6.23 (s, 1 H); 5.60 5.63

(m, 1 H); 3.59 (d, J 7.3, 2 H); 3.32 (t, J 6.0, 2 H); 2.51 (t, J 7.4, 2 H); 1.72 (s, 3 H); 1.70 (s, 3 H); 1.58 1.63

(m, 2 H); 1.32 (br. s, 1 H). ¹³C-NMR (125 MHz, C₆D₆): 138.9; 134.9; 132.8; 130.8; 129.6; 125.2; 121.9; 119.2;

110.3; 99.4; 61.5; 34.8; 31.8; 25.5; 24.4; 17.5. HR-ESI-MS: 266.1517 ([M Na] , C₁₆H₂₁NNaO ; calc. 266.1521).

2-(3-Bromopropyl)-5-(3-methylbut-2-enyl)-1H-indole (54). Under Ar, a soln. of 53 (70.1 mg, 0.288 mmol)

in CH₂Cl₂(5 ml) was treated with PPh₃(92 mg, 0.345 mmol) and CBr₄(114mg, 0.345 mmol). After 20 min, the

mixture was concentrated in vacuo. Gradient FC (hexanes/AcOEt 20 :1 ! hexanes/AcOEt 10 :1) provided 54

(69.9 mg, 79%). Yellow oil. IR (neat): 3400s (br.), 2912m (br.), 1476m, 1452m, 1293m, 800m. ¹H-NMR

(500 MHz, C₆D₆): 7.50 (s, 1 H); 7.15 7.17 (m, 1 H); 7.03 (d, J 8.2, 1 H); 6.53 (br. s, 1 H); 6.09 (d, J 1.1, 1 H);

5.56 5.60 (m, 1 H); 3.55 (d, J 7.3, 2 H); 2.90 (t, J 6.5, 2 H); 2.24( t, J 7.2, 2 H); 1.70 (s, 3 H); 1.67 (s, 3 H);

1.62 1.68 (m, 2 H). ¹³C-NMR (125 MHz, C₆D₆): 137.3; 135.1; 133.2; 131.2; 129.8; 125.5; 122.5; 119.6; 110.6;

100.1; 35.0; 33.0; 32.2; 26.5; 25.9; 17.8. HR-CI-MS (CH₄): 305.0772 (M , C₁₆H₂₀BrN ; calc. 305.0779).

2-(3-Bromopropyl)-3-iodo-5-(3-methylbut-2-enyl)-1H-indole (55). Under Ar, a soln. of 54 (56.0 mg,

0.183 mmol) in acetone (3 ml) was treated with NIS (44.4 mg, 0.197 mmol). After 20 min, the mixture was

concentrated in vacuo, redissolved in Et₂O (15 ml), washed sequentially with sat. aq. Na₂S₂O₃(5 ml) and brine

(5 ml), dried (MgSO₄), filtered, and concentrated. Gradient FC (hexanes/AcOEt 20 :1 ! hexanes/AcOEt

10 :1) provided 55 (70.7 mg, 90%). Yellow oil. IR (neat): 3397s (br.), 2911m, 1477m, 1450s, 1246m, 1230m,

802m. ¹H-NMR (500 MHz, C₆D₆): 7.46 (s, 1 H); 7.13 (dd, J 8.2, 1.4, 1 H); 6.90 (d, J 8.2, 1 H); 6.82

(br. s, 1 H); 5.47 5.51 (m, 1 H); 3.47 (d, J 7.3, 2 H); 2.82 (t, J 6.5, 2 H); 2.46 (t, J 7.4, 2 H); 1.65 (s, 3 H);

1.63 (s, 3 H); 1.61 1.66 (m, 2 H). ¹³C-NMR (125 MHz, C₆D₆): 138.2; 134.9; 134.7; 131.6; 131.5; 125.0; 123.9;

120.1; 111.1; 59.2; 34.9; 32.8; 32.1; 27.0; 25.8; 17.8. HR-CI-MS (CH₄): 430.9726 (M , C₁₆H₁₉BrIN ; calc.

430.9746).

1,2,3,4-Tetrahydro-7-(3-methylbut-2-enyl)cyclopenta[b]indole (57). Under Ar, a soln. of 55 (63.2 mg,

0.146 mmol) in THF (2 ml) at À1008 was treated with KHMDS (potassium 1,1,1,3,3,3-hexamethyldisilazide;

0.5m soln. in toluene, 580 ml, 0.292 mmol). After 10 min, TBSOTf (100 ml, 0.438 mmol) was added dropwise at

À1008, and the soln. was warmed slowly to À788 over 10 min. Et₂O (10 ml, with 200 ml Et₃N) was then added,

and the mixture was warmed to r.t. and stirred under air for 30 min. This mixture was then extracted with AcOEt

(3 Â 10 ml), the combined org. layers were dried (MgSO₄), filtered, and concentrated. FC (1% Et₂O/hexanes)

provided 56 (64.3 mg, 81%) as a yellow oil. Under Ar, a soln. of 56 (30.8 mg, 56.3 mmol) in THF (2 ml) at À788

was treated with BuLi (2.5m in hexanes, 26 ml, 67 ml) for 5 min, then slowly warmed to r.t. over 45 min. This

mixture was then treated with TBAF (1.0m in THF; 110 ml, 110 mmol) for 10 min. The reaction was then

quenched with brine (5 ml), and the mixture was extracted with Et₂O (3 Â 10 ml). The combined org. layers

were washed with brine, dried (MgSO₄), filtered, and concentrated. Gradient FC (hexanes/AcOEt 20 :1 !

hexanes/AcOEt 10 :1) provided 57 (9.1 mg, 72%). Yellow oil. IR (neat): 3402s (br.), 2911s, 2851s, 1453m, 799m.

¹H-NMR (500 MHz, C₆D₆): 7.47 (s, 1 H); 7.13 (dd, J 8.3, 1.6, 1 H); 7.03 (d, J 8.2, 1 H); 6.43 (br. s, 1 H); 5.58

5.62 (m, 1 H); 3.57 (d, J 7.1, 2 H); 2.75 (app. t, J 6.9, 2 H); 2.42 (dd, J 7.0, 6.3, 2 H); 2.22 2.28 (m, 2 H):

1.68 (s, 3 H); 1.66 (s, 3 H). ¹³C-NMR (125 MHz, C₆D₆): 143.4; 140.3; 132.9; 131.0; 125.8; 125.7; 121.6; 119.4;

118.3; 111.4; 35.2; 28.9; 25.8; 24.8; 17.8. HR-CI-MS (CH ₄): 226.1596 (M , C₁₆H₁₉N ; calc. 226.1596).

4,5-Dihydro-8-(3-methylbut-2-enyl)-1-benzazocine-2,6(1H,3H)-dione (58). Compound 57 (5.2 mg,

23.1 mmol) was treated with silica gel (20 mg); after 10 min, this mixture was dissolved in Et₂O (5 ml), filtered,

and concentrated. FC (hexanes/AcOEt 5 :1) provided 58 (6.0 mg, 100%). Colorless crystals. M.p. 125 1278. IR

(neat): 3208s, 3106s, 2967s, 1674s, 1652s, 1492m, 1456m, 1404m, 1383m, 1238m, 831m. ¹H-NMR (500 MHz,

C₆D₆): 9.17 (br. s, 1 H); 8.24( d, J 2.2, 1 H); 6.98 (dd, J 8.1, 2.2, 1 H); 6.78 (d, J 8.1, 1 H); 5.23 5.27

(m, 1 H); 3.14( d, J 7.4, 2 H); 2.72 (br. s, 2 H); 2.10 (t, J 6.9, 2 H); 1.78 1.83 (m, 2 H); 1.59 (s, 3 H); 1.50

(s, 3 H). ¹³C-NMR (125 MHz, C₆D₆): 198.5; 174.6; 139.2; 136.6; 133.6; 132.9; 130.6; 130.5; 125.0; 122.6; 38.7;

33.4; 30.7; 25.4; 25.1; 17.4. HR-CI-MS (CH ₄): 257.1407 (M , C₁₆H₁₉NO₂; calc. 254.1416).

3-[5-(3-Methylbut-2-enyl)-1H-indol-2-yl]propyl Methanesulfonate (59). Under Ar, a soln. of 53 (20.9 mg,

85.9 mmol) in CH₂Cl₂(2 ml) at 08 was treated with DMAP (17 mg, 0.138 mmol) and MsCl (8 ml, 0.103 mmol) for

20 min. Sat. aq. NaHCO₃soln. (1 ml) was added, and the mixture was extracted with Et₂O (10 ml). The

org. layer was washed with brine, dried (MgSO₄), filtered, and concentrated. Gradient FC (hexanes/AcOEt

Helvetica Chimica Acta Vol. 86 (2003)

3933

2 :1 ! hexanes/AcOEt 1:1, containing 0.2% Et₃N) provided 59 (26.4mg, 97%). Yellow oil. IR (neat):

1

3398s (br.), 2928m, 1479m, 1452m, 1350s, 1174s, 971m, 927m. H-NMR (500 MHz, C₆D₆): 7.53 (s, 1 H); 7.13

7.18 (m, 1 H); 7.03 (br. s, 1 H); 6.13 (t, J 0.6, 1 H); 5.56 5.60 (m, 1 H); 3.75 (t, J 6.1, 2 H); 3.56 (d, J 7.3,

2 H); 2.37 (t, J 7.3, 2 H); 2.14( s, 3 H); 1.70 (s, 3 H); 1.67 (s, 3 H); 1.55 1.61 (m, 2 H). ¹³C-NMR (125 MHz,

C₆D₆): 137.5; 135.2; 133.3; 131.2; 129.7; 125.4; 122.6; 119.6; 110.7; 100.0; 68.7; 36.4; 35.0; 29.0; 25.8; 24.0; 17.8.

HR-ESI-MS: 344.1285 ([M Na] , C₁₇H₂₃NNaO₃S ; calc. 344.1296).

()-{(2R,3S,4aS,6aS,7S)-2,3,4a,5,6,6a,7,8,9,10-Decahydro-6a,7-dimethyl-7-[5-(3-methylbut-2-enyl)-1H-in-

dol-2-yl]-3-{1-methyl-1-[(triethylsilyl)oxy]ethyl}-2-[(triethylsilyl)oxy]-1H-benzo[f][1]benzopyran-8-yl}metha-

nol (()-61). Under Ar, a soln. of 5 (206 mg, 1.18 mmol) in Et₂O (4ml) was treated with MeLi (1.6 m in Et₂O,

898 ml, 0.898 mmol) at 08 for 30 min, TMSCl (155 ml, 1.53 mmol) was then added, and the resulting white

suspension was stirred at 08 for 60 min. s-BuLi (1.3m in cyclohexane; 1.72 ml, 2.23 mmol) was then added

dropwise over a period of 5 min, and this suspension was warmed to r.t. for 80 min.

Under Ar, a soln. of ()-6 (41.9 mg, 72.3 mmol) in Et₂O (1 ml) was treated with the above base soln. (1.7 ml)

at 08 for 10 min, then warmed to r.t. for 30 min. The reaction was quenched with sat. aq. NH₄Cl soln. (1 ml), and

the mixture was diluted with Et₂O (10 ml) and washed with brine (5 ml). The org. layer was dried (Na₂SO₄),

filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/AcOEt 1:1) provided a crude

alcohol (48.9 mg) as a yellow oil.

Under Ar, a soln. of the above crude alcohol in benzene (5 ml) was heated to reflux for 48 h. After cooling

to r.t., the mixture was concentrated in vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/AcOEt 2 :1)

provided ()-61 (43.1 mg, 81% for 2 steps). Colorless oil. [a]²_D⁵ 56.5 (c 0.29, CHCl₃). IR (neat):

1

3348m (br.), 2954s, 2875s, 1456w, 1170w, 1097m, 1004w, 74 1m. H-NMR (500 MHz, CDCl₃): 8.09 (br. s, 1 H);

7.34( s, 1 H); 7.24( d, J 8.3, 1 H); 6.97 (dd, J 8.3, 1.6, 1 H); 6.28 (d, J 1.7, 1 H); 5.38 5.42 (m, 1 H); 4.25

(t, J 2.7, 1 H); 3.90 (app. dd, J 10.1, 5.2, 1 H); 3.41 3.46 (m, 3 H); 3.24( dd, J 10.2, 7.8, 1 H); 3.03 (s, 1 H);

2.89 (dd, J 15.3, 2.9, 1 H); 2.68 2.72 (m, 1 H); 2.51 2.57 (m, 1 H); 2.08 2.13 (m, 3 H); 1.75 1.83 (m, 7 H);

1.56 1.62 (m, 3 H); 1.38 1.43 (m, 1 H); 1.27 (s, 3 H); 1.25 (s, 3 H); 1.20 (s, 3 H); 1.14( s, 3 H); 0.93 0.98

(m, 18 H); 0.57 0.62 (m, 12 H). ¹³C-NMR (125 MHz, CDCl₃): 142.2; 134.9; 134.0; 133.0; 131.5; 128.1; 127.3;

124.5; 122.1; 118.8; 110.3; 102.2; 85.4; 76.6; 75.4; 66.6; 66.2; 45.7; 44.1; 42.3; 35.7; 34.4; 29.3; 28.1; 26.4; 26.3; 26.1;

25.8; 23.8; 22.5; 17.8; 15.9; 7.0; 6.9; 6.8; 5.4. HR-ESI-MS: 758.4998 ([M Na] , C₄₄H₇₃NNaO₄Si₂; calc.

758.4976).

()-{(2R,3S,4aS,6aS,7S)-2,3,4a,5,6,6a,7,8,9,10-Decahydro-6a,7-dimethyl-7-[5-(3-methylbut-2-enyl)-1H-in-

dol-2-yl]-3-{1-methyl-1-[(triethylsilyl)oxy]ethyl}-2-[(triethylsilyl)oxy]-1H-benzo[f][1]benzopyran-8-yl}methyl

Methanesulfonate (()-62). Under Ar, a soln. of ()-61 (6.4mg, 8.7 mmol) in CH₂Cl₂(1 ml) was treated with

DMAP (8.5 mg, 69.5 mmol) and MsCl (4 ml, 52.1 mmol) at 08, this mixture was then warmed to r.t. for 30 min.

After diluting with Et₂O (5 ml), the mixture was washed with sat. aq. NaHCO₃soln. (1 ml), dried (Na₂SO₄),

filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 20 :1 ! hexanes/AcOEt 5 :1) provided ()-

62 (6.4mg, 93%). Yellow oil. [ a]²_D⁵ 37 (c 0.30, CHCl₃). IR (neat): 3418s (br.), 2955s, 1457w, 1356m, 1173s,

1097m, 950m, 74 1m. ¹H-NMR (500 MHz, CDCl₃): 8.31 (br. s, 1 H); 7.34( s, 1 H); 7.28 (d, J 8.3, 1 H); 6.99

(dd, J 8.3, 1.4, 1 H); 6.28 (s, 1 H); 5.38 5.42 (m, 1 H); 4.26 (t, J 2.5, 1 H); 4.04 (br. s, 1 H); 3.90 (app. dd, J

9.8, 5.2, 1 H); 3.82 (t, J 9.6, 1 H); 3.42 (d, J 7.3, 2 H); 3.03 (s, 1 H); 2.87 2.91 (m, 2 H); 2.85 (s, 3 H); 2.73

(app. dd, J 14.8, 3.3, 1 H); 2.08 2.21 (m, 3 H); 1.75 1.84( m, 8 H); 1.43 1.62 (m, 3 H); 1.27 (s, 3 H); 1.22

(s, 3 H); 1.20 (s, 3 H); 1.17 (s, 3 H); 0.93 0.99 (m, 18 H); 0.56 0.62 (m, 12 H). ¹³C-NMR (125 MHz, CDCl₃):

140.6; 134.0; 133.2; 131.6; 128.0; 124.4; 122.5; 118.8; 110.5; 102.6; 85.5; 76.4; 75.4; 74.4; 66.6; 45.5; 44.2; 39.5;

37.1; 35.8; 34.4; 29.1; 28.0; 26.4; 26.2; 25.8; 25.3; 23.4; 22.3; 17.8; 7.2; 7.0; 6.8; 5.3. HR-ESI-MS: 836.4731 ([ M

Na] , C₄₅H₇₅NNaO₅SSi₂; calc. 836.4719).

()-(2S,3R,12bS,12cS,14aS)-3,4,5,6,6a,7,12,12b,12c,13,14,14a-Dodecahydro-12b,12c-dimethyl-9-(3-methyl-

but-2-enyl)-2-{1-methyl-1-[(triethylsilyl)oxy]ethyl}-2H-[1]benzopyrano[5',6':6,7]indeno[1,2-b]indol-3-ol (()-

64), and ()-(2S,3R,12bS,12cS,14aS)-3,4,5,6,6a,7,12,12 b,12c,13,14,14a-Dodecahydro-2-(1-hydroxy-1-methyleth-

yl)-12b,12c-dimethyl-9-(3-methylbut-2-enyl)-2H-[1]benzopyrano[5',6':6,7]indeno[1,2-b]indol-3-ol (()-65).

Under Ar, a soln. of ()-63 (4.7 mg, 6.5 mmol) in CH₂Cl₂(1 ml) was treated with CBr₄(1.9 mg, 5.8 mmol) and

PPh₃(1.7 mg, 6.5 mmol) at 08 for 30 min. The mixture was then diluted with Et₂O (5 ml), washed sequentially

with sat. aq. NaHCO₃soln. (1 ml) and brine (1 ml). The org. layer was then dried (Na₂SO₄), filtered, and

concentrated in vacuo. Gradient FC (hexanes/AcOEt 20 :1 ! hexanes/AcOEt 5 :1 ! hexanes/AcOEt 2 :1,

containing 0.5% Et₃N) afforded ()-64 (2.3 mg, 60%) as a colorless oil and ()-65 (1.3 mg, 40%) as a colorless

oil.

Data of ()-64: [a]_D²⁵ 17 (c 0.10, CHCl₃). IR (neat): 3433m (br.), 3264s (br.), 2963s, 1456m, 1096m,

1079m, 953w, 74 m5 . ¹H-NMR (500 MHz, C₆D₆): 7.63 (s, 1 H); 7.29 7.33 (m, 2 H); 7.09 (br. s, 1 H); 5.73

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Helvetica Chimica Acta Vol. 86 (2003)

(t, J 7.3, 1 H); 4.27 (t, J 2.9, 1 H); 3.92 (app. t, J 7.9, 1 H); 3.70 (d, J 7.3, 1 H); 3.54( s, 1 H); 3.07 (s, 1 H);

3.00 3.05 (m, 1 H); 2.89 (dd, J 15.1, 3.2, 1 H); 2.82 (dd, J 13.2, 6.5, 1 H); 2.68 2.71 (m, 1 H); 2.46 (dd, J

13.1, 10.4, 1 H); 2.04 2.11 (m, 3 H); 1.83 1.93 (m, 2 H); 1.80 (s, 3 H); 1.79 (s, 3 H); 1.63 1.68 (m, 5 H); 1.49

(s, 3 H); 1.23 (s, 3 H); 1.10 (t, J 8.0, 9 H); 0.89 (s, 3 H); 0.71 (q, J 8.0, 6 H); 0.50 (br. s, 1 H). ¹³C-NMR

(125 MHz, C₆D₆): 149.4; 139.5; 136.1; 133.3; 131.1; 127.5; 126.2; 125.7; 122.0; 118.6; 118.5; 111.8; 83.3; 76.9; 72.0;

68.4; 51.2; 48.2; 43.0; 35.5; 35.2; 30.4; 27.8; 27.5; 27.4; 26.3; 25.9; 25.7; 25.5; 22.3; 16.4; 7.1; 5.6. HR-ESI-MS:

626.4001 ([M Na] , C₃₈H₅₇NNaO₃Si ; calc. 626.4005).

Data of ()-65: [a]_D²⁵ 39 (c 0.16, CHCl₃). IR (neat): 3435s (br.), 3335s (br.), 2968s, 2923s, 1453m,

1092m, 1076m, 755w. ¹H-NMR (500 MHz, C₆D₆): 7.52 (s, 1 H); 7.18 7.23 (m, 2 H); 7.01 (br. s, 1 H); 5.61 5.64

(m, 1 H); 4.03 (app. t, J 2.7, 1 H); 3.82 (app. t, J 7.9, 1 H); 3.59 (d, J 7.2, 2 H); 3.47 (br. s, 1 H); 2.99 (dd, J

14.7, 3.5, 1 H); 2.88 2.92 (m, 1 H) 2.85 (d, J 0.8, 1 H); 2.65 2.69 (m, 2 H); 2.32 (dd, J 13.3, 10.4, 1 H);

1.89 2.02 (m, 3 H); 1.69 1.81 (m, 8 H); 1.49 1.53 (m, 2 H); 1.30 (s, 3 H); 1.23 (s, 3 H); 1.13 (s, 3 H); 1.02 1.07

(m, 1 H); 0.77 (s, 3 H). ¹³C-NMR (125 MHz, C₆D₆): 149.4; 139.5; 138.5; 133.3; 131.1; 126.8; 126.3; 125.7; 122.0;

118.8; 118.5; 111.7; 82.0; 76.9; 72.9; 67.0; 51.2; 48.3; 42.9; 35.2; 34.9; 30.3; 27.8; 27.7; 26.3; 25.9; 25.6; 25.5; 25.3;

22.1; 17.8; 16.3. HR-ESI-MS: 512.3120 ([M Na] , C₃₂H₄₃NNaO₃; calc. 512.3141).

(À)-(2S,3R,4aR,5aS,10aS,10bR,12aS)-2-[1-(Benzyloxy)-1-methylethyl]-3,4,6,7,7a,8,10,10a,10b,11,12,12a-

dodecahydro-10a,10b-dimethyl-10-oxo-2H-[2]benzofuro[5,4-f]oxireno[2,3-e][1]benzopyran-3-yl Benzenecar-

boxylate ((À)-69a). A soln. of (À)-39 (68 mg, 0.125 mmol) in toluene (6 ml) was treated with NaHCO₃

(84mg, 1.00 mmol) and a soln. of m-CPBA in toluene (1.5 ml) at r.t. for 48 h. This mixture was then diluted

with AcOEt (20 ml), washed with sat. aq. Na₂CO₃soln. (5 ml) and brine (5 ml), the org. layer was then dried

(Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/Et₂O/CH₂Cl₂3 :1:1 ! hexanes/AcOEt

2 :1) provided (À)-69a (53.7 mg, 77%). Colorless oil. [a]²_D⁵ À19.2 (c 1.10, CHCl₃). IR (neat): 2980m, 1771s,

1

1715s, 1451w, 1272s, 1112w, 1072w, 1053m, 713w. H-NMR (500 MHz, CDCl₃): 8.08 (app. d, J 8.0, 2 H); 7.60

(t, J 7.4, 1 H); 7.47 (t, J 7.8, 2 H); 7.21 7.31 (m, 5 H); 5.61 (d, J 2.8, 1 H); 4.51 (s, 2 H); 4.13 (dd, J 8.4, 7.5,

1 H); 3.88 3.96 (m, 2 H); 3.55 (s, 1 H); 2.54 2.59 ( m, 1 H); 2.28 (dd, J 15.0, 3.7, 1 H); 2.17 2.21 (m, 1 H);

1.94 2.01 ( m, 2 H); 1.78 1.85 (m, 2 H); 1.43 1.64 (m, 3 H); 1.4 2 (s, 3 H); 1.36 (s, 3 H); 1.35 1.38 (m, 1 H);

1.33 (s, 3 H); 1.21 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 178.5; 165.3; 139.5; 133.3; 130.0; 129.7; 128.6; 128.2;

127.0; 126.9; 83.2; 77.2; 76.4; 73.6; 69.0; 68.7; 68.6; 64.1; 58.1; 47.1; 39.7; 39.5; 33.1; 26.6; 24.7; 24.3; 22.0; 21.6; 19.1;

17.4; 11.6. HR-ESI-MS: 583.2654 ([ M Na] , C₃₄H₄₀NaO₇; calc. 583.2672).

()-(2S,3R,4aR,5aS,10aS,10bR,12aS)-2-[1-(Benzyloxy)-1-methylethyl]-3,4,6,7,7a,8,10,10a,10b,11,12,12a-

dodecahydro-3-hydroxy-10a,10b-dimethyl-2H-[2]benzofuro[5,4-f]oxireno[2,3-e][1]benzopyran-10-one (()-

70). Under Ar, a soln. of (À)-69a (21.8 mg, 38.9 mmol) in MeOH (4ml) and H ₂O (0.5 ml) was treated with

KOH (17.5 mg, 311 mmol), the resultant mixture was then heated to reflux for 42 h. After cooling to r.t., sat. aq.

NH₄Cl soln. (5 ml) was added. This mixture was then extracted with CH₂Cl₂(3 Â 20 ml), and the combined org.

layers were washed with brine (10 ml), dried (Na₂SO₄), filtered, and concentrated in vacuo. This crude material

was used without further purification.

Under Ar, a soln. of the above alcohols in CH₂Cl₂(5 ml) was treated with DMAP (5 mg) and EDCI

(15 mg). After 20-min stirring at r.t., this mixture was diluted with Et₂O (20 ml), and then washed with sat. aq.

Na₂CO₃soln. (5 ml) and brine (5 ml). The org. layer was then dried (Na₂SO₄), filtered, and concentrated in

vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/AcOEt 1 :1 ! hexanes/AcOEt 1:2) provided ()-70

(16.1 mg, 91%, 2 steps). Colorless oil. [a]²_D⁵ 3.5 (c 0.80, CHCl₃). IR (neat): 3457s (br.), 2981s, 1773s,

1449w, 1252w, 1055m, 977w, 737w. ¹H-NMR (500 MHz, CDCl₃): 7.24 7.33 ( m, 5 H); 4.66 (dd, J 19.3, 7.4, 2 H);

4.42 (s, 1 H); 4.29 (s, 1 H); 4.24 (t, J 7.8, 1 H); 4.01 (dd, J 11.3, 8.6, 1 H); 3.78 (app. dd, J 9.9, 4.5, 1 H); 3.12

(s, 1 H); 2.83 2.88 (m, 1 H); 2.13 2.21 (m, 2 H); 1.95 2.04( m, 2 H); 1.72 1.85 (m, 5 H); 1.52 1.57 (m, 1 H);

1.45 (s, 3 H); 1.37 (s, 3 H); 1.36 (s, 3 H); 1.25 (s, 3 H). ¹³C-NMR (125 MHz, CDCl₃): 178.9; 139.0; 128.3; 127.3;

127.0; 83.3; 78.6; 77.2; 73.7; 68.9; 68.6; 66.4; 65.4; 58.3; 47.3; 39.7; 39.4; 35.3; 27.2; 25.0; 24.8; 22.5; 21.7; 19.3; 17.1;

11.7. HR-ESI-MS: 479.2404 ([M Na] , C₂₇H₃₆NaO₆; calc. 479.2410).

()-(2S,3R,4aR,5aS,10aS,10bR,12aS)-3,4,6,7,7a,8,10,10a,10b,11,12,12a-Dodecahydro-3-hydroxy-2-(1-hy-

droxy-1-methylethyl)-10a,10b-dimethyl-2H-[2]benzofuro[5,4-f]oxireno[2,3-e][1]benzopyran-10-one (()-71).

Under Ar, a soln. of ()-70 (14.1 mg, 30.9 mmol) in MeOH (3 ml) was treated with 1-methylcyclohexa-1,4-

diene (20 mmol) and 10% Pd/C (7 mg), the resultant mixture was then heated to reflux for 30 min. After cooling

to r.t., this mixture was filtered and concentrated in vacuo. FC (hexanes/AcOEt 1:4) provided ()-71 (10.8 mg,

96%). Colorless crystals. M.p. 221 2238. [a]²_D⁵ 23 (c 0.35, CHCl₃). IR (neat): 3489s (br.), 3447s (br.),

2973s, 1769s, 1444w, 1348w, 1253w, 1084m, 1053m, 821w. ¹H-NMR (500 MHz, CDCl₃): 4.26 (dd, J 8.5, 7.2,

1 H); 4.20 4.21 (m, 1 H); 4.00 4.04 (m, 2 H); 3.88 (dd, J 9.9, 5.0, 1 H); 3.09 (s, 1 H); 2.83 2.90 (m, 1 H);

2.35 (s, 1 H); 2.11 2.22 (m, 2 H); 1.94 2.06 ( m, 2 H); 1.80 1.84( ddd, J 13.2, 6.5, 1.8, 1 H); 1.64 1.77

Helvetica Chimica Acta Vol. 86 (2003)

3935

(m, 4H); 1.55 1.59 ( m, 1 H); 1.34( s, 3 H); 1.33 (s, 3 H); 1.31 (s, 3 H); 1.25 (s, 3 H). ¹³C-NMR (125 MHz,

CDCl₃): 178.8; 81.0; 73.6; 73.5; 68.9; 68.7; 66.6; 58.0; 47.3; 39.7; 39.5; 35.0; 28.3; 27.1; 24.8; 24.5; 21.7; 19.3; 17.3;

11.7. HR-ESI-MS: 389.1925 ([M Na] , C₂₀H₃₀NaO₆; calc. 389.1940).

(À)-(2S,3R,4aR,5aS,10aS,10bR,12aS)-2-[1-(Benzyloxy)-1-methylethyl]-3,4,6,7,7a,8,10,10a,10b,11,12,12a-

dodecahydro-10a,10b-dimethyl-3-[(triethylsilyl)oxy]-2H-[2]benzofuro[5,4-f]oxireno[2,3-e][1]benzopyran-10-

one ((À)-68). Under Ar, a soln. of ()-70 (15.9 mg, 34.8 mmol) in CH₂Cl₂(2 ml) was treated with 2,6-lutidine

(12 ml, 104 mmol) and TESOTf (16 ml, 70 mmol), the resultant soln. was stirred at r.t. for 20 min. After diluting

with Et₂O (15 ml), the mixture was washed with sat. aq. NH₄Cl soln. (5 ml) and brine (5 ml). The org. layer was

then dried (Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 20 :1 ! hexanes/

AcOEt 5 :1) provided (À)-68 (18.5 mg, 94%). Colorless oil. [a]²_D⁵ À15.1 (c 0.87, CHCl₃). IR (neat): 2951s,

2876s, 1776s, 1452w, 1380w, 1233w, 1090m, 1053m, 737m. ¹H-NMR (500 MHz, CDCl₃): 7.32 (app. d, J 4.5, 4 H);

7.23 7.25 (m, 1 H); 4.52 (dd, J 19.2, 11.4, 2 H); 4.33 (app. dd, J 3.0, 2.2, 1 H); 4.26 (dd, J 8.5, 3.2, 1 H); 4.03

(dd, J 11.4, 8.5, 1 H); 3.72 (dd, J 9.6, 5.9, 1 H); 3.20 (d, J 0.9, 1 H); 2.84 2.90 ( m, 1 H); 2.03 2.10

(m, 2 H); 1.92 (ddd, J 27.4, 13.6, 5.3, 1 H); 1.84 (app. dd, J 6.2, 3.1, 1 H); 1.67 1.81 (m, 4H); 1.50 1.54

(m, 1 H); 1.35 (s, 3 H); 1.33 (s, 6 H); 1.25 (s, 3 H); 0.92 (t, J 7.9, 9 H); 0.60 (q, J 7.8, 6 H). ¹³C-NMR

(125 MHz, CDCl₃): 178.7;139.8; 128.1; 127.4; 127.0; 84.3; 76.9; 73.8; 69.4; 68.8; 66.2; 63.8; 58.6; 47.3; 39.7; 39.7;

37.2; 27.9; 24.8; 24.6; 21.8; 20.9; 19.4; 17.3; 11.7; 7.0; 5.2. HR-ESI-MS: 593.3263 ([M Na] , C₃₃H₅₀O₆NaSi ; calc.

593.3274).

(À)-{(2R,3S,4aS,6aR,7S,10aS,11aR)-3-[1-(Benzyloxy)-1-methylethyl]-2,3,4a,5,6,6a,7,8,9,10-decahydro-

6a,7-dimethyl-7-[5-(3-methylbut-2-enyl)-1H-indol-2-yl]-2-[(triethylsilyl)oxy]-1H-benzo[f]oxireno[2,3-e][1]-

benzopyran-8-yl}methanol ((À)-72). Under Ar, a soln. of 5 (253.8 mg, 1.45 mmol) in Et₂O (6 ml) was treated

with MeLi (1.6m in Et₂O, 1.00 ml, 1.60 mmol) at 08 for 30 min, TMSCl (197 ml, 1.53 mmol) was then added, and

the resulting white suspension was stirred at 08 for 60 min. s-BuLi (1.3m in cyclohexane, 2.14ml, 2.79 mmol) was

then added dropwise over a period of 5 min, and the suspension was warmed to r.t. for 80 min.

Under Ar, a soln. of (À)-68 (39.8 mg, 69.7 mmol) in Et₂O (2 ml) was treated with the above base soln.

(1.8 ml) at 08 for 10 min, then warmed to r.t. for 15 min. The reaction was quenched with sat. aq. NH₄Cl soln.

(1 ml), and the mixture was diluted with Et₂O (15 ml) and washed with brine (5 ml). The org. layer was dried

(Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/AcOEt 1 :1)

provided a crude alcohol (52.1 mg) as a yellow oil.

Under Ar, a soln. of the above crude alcohol in toluene (3 ml) was heated to reflux for 40 h. After cooling to

r.t., the mixture was concentrated in vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/AcOEt 1:1) provided

(À)-72 (38.9 mg, 76% for 2 steps). Yellow oil. [a]_D²⁵ À38.7 (c 0.52, CHCl₃). IR (neat): 3363s (br.), 2935s,

2875s, 1453m, 1377m, 1166w, 1094s, 1004m, 736m. ¹H-NMR (500 MHz, CDCl₃): 8.03 (br. s, 1 H); 7.34( s, 1 H);

7.23 7.31 (m, 6 H); 6.98 (dd, J 8.3, 1.4, 1 H); 6.30 (d, J 1.5, 1 H); 5.38 5.42 (m, 1 H); 4.50 (dd, J 23.3, 11.4,

2 H); 4.33 (t, J 2.6, 1 H); 3.70 (dd, J 8.8, 7.2, 1 H); 3.41 3.45 (m, 3 H); 3.32 (t, J 8.5, 1 H); 3.20 (s, 1 H);

2.52 2.55 (m, 1 H); 2.15 2.20 (m, 2 H); 1.80 1.97 (m, 4H); 1.76 ( s, 3 H); 1.74( s, 3 H); 1.68 1.72 (m, 1 H);

1.55 1.60 (m, 1 H); 1.38 1.47 (m, 1 H); 1.36 (s, 3 H); 1.32 (s, 3 H); 1.30 (s, 3 H); 1.22 (s, 3 H); 0.94( t, J 7.9,

9 H); 0.81 0.84( m, 1 H); 0.62 (q, J 7.9, 6 H). ¹³C-NMR (125 MHz, CDCl₃): 142.3; 139.9; 133.8; 133.0; 131.6;

128.1; 127.4; 127.0; 124.4; 122.2; 118.8; 110.3; 102.2; 83.8; 76.9; 73.7; 70.9; 66.1; 65.8; 63.8; 59.2; 45.3; 42.5; 41.4;

36.8; 34.4; 26.2; 25.8; 24.8; 24.5; 23.2; 23.1; 21.0; 20.6; 17.8; 15.0; 7.1; 5.3. HR-ESI-MS: 750.4505 ([M Na] ,

C₄₅H₆₅NNaO₅Si ; calc. 750.4530).

(À)-{(2R,3S,4aS,6aR,7S,10aS,11aR)-3-[1-(Benzyloxy)-1-methylethyl]-2,3,4a,5,6,6a,7,8,9,10-decahydro-

6a,7-dimethyl-7-[5-(3-methylbut-2-enyl)-1H-indol-2-yl]-2-[(triethylsilyl)oxy]-1H-benzo[f]oxireno[2,3-e][1]benzo-

pyran-8-yl}methyl Methanesulfonate ((À)-67). Under Ar, a soln. of (À)-72 (10.3 mg, 14.1 mmol) in CH₂Cl₂(2 ml)

was treated with DMAP (6.1 mg, 49.4 mmol) and MsCl (2.7 ml, 35.3 mmol) at 08; this mixture was then warmed to

r.t. for 20 min. After diluting with Et₂O (5 ml), the mixture was washed with sat. aq. NaHCO₃soln. (1 ml), dried

(Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 5 :1 ! hexanes/AcOEt 2 :1)

provided (À)-67 (11.1 mg, 90%). Yellow oil. [a]_D²⁵ À48.7 (c 0.55, CHCl₃). IR (neat): 3415m, 2936s, 2876s,

1456m, 1356s, 1177s, 1094m, 952m, 734m. ¹H-NMR (500 MHz, CDCl₃): 8.29 (br. s, 1 H); 7.35 (s, 1 H); 7.23 7.35

(m, 6 H); 7.00 (dd, J 8.3, 1.5, 1 H); 6.30 (d, J 1.2, 1 H); 5.38 5.42 (m, 1 H); 4.50 (dd, J 23.3, 11.4, 2 H); 4.33

(t, J 2.7, 1 H); 4.02 (br. s, 1 H); 3.90 (t, J 9.5, 1 H); 3.70 (app. dd, J 8.5, 7.4, 1 H); 3.43 (d, J 7.4, 2 H); 3.20

(s, 1 H); 2.84 2.86 ( m, 4H); 2.12 2.23 ( m, 2 H); 1.71 1.97 (m, 11 H); 1.57 1.61 (m, 1 H); 1.38 1.44

(m, 4H); 1.32 ( s, 3 H); 1.30 (s, 3 H); 1.18 (s, 3 H); 0.94( t, J 7.9, 9 H); 0.62 (q, J 7.9, 6 H). ¹³C-NMR

(125 MHz, CDCl₃): 139.9; 133.3; 131.7; 128.1; 127.4; 127.0; 124.3; 122.6; 118.9; 110.5; 83.8; 76.9; 74.2; 73.6; 70.5;

66.0; 63.8; 59.3; 45.2; 41.6; 39.8; 37.0; 36.8; 34.4; 25.8; 24.8; 24.5; 22.6; 21.0; 20.4; 17.8; 7.1; 5.3. HR-ESI-MS:

828.4313 ([M Na] , C₄₆H₆₇NNaO₇SS_i; calc. 828.4305).

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Helvetica Chimica Acta Vol. 86 (2003)

( À )-(2S,3R,4aR,5aS,13bS,13cR,15aS)-2-[1-(Benzyloxy)-1-methylethyl]-3,4,6,7,7a,8,13,13b,13c,14,15,15a-

dodecahydro-13b,13c-dimethyl-10-(3-methylbut-2-enyl)-3-[(triethylsilyl)oxy]-2H-oxireno[2'',3'':4a',5'][1]ben-

zopyrano[5',6':6,7]indeno[1,2-b]indole ((À)-73). Under Ar, a soln. of (À)-67 (4.4 mg, 5.5 mmol) in toluene

(1.5 ml) was treated with t-BuMgCl (2.0m in Et₂O, 10 ml, 20 mmol) at r.t. After 5 min, this mixture was heated to

reflux for 5 min. The mixture was then cooled to r.t., the reaction was quenched with sat. aq. NH₄Cl soln. (1 ml),

and the mixture was diluted with AcOEt (8 ml) and washed with brine (3 ml). The org. layer was dried

(Na₂SO₄), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt 30 :1 ! hexanes/AcOEt 20 :1,

containing 0.5% Et₃N) provided (À)-73 (2.8 mg, 73%). Yellow oil. [a]²_D⁵ À21.4( c 0.56, CHCl₃). IR (neat):

3424m (br.), 3366m (br.), 2932s, 2875s, 1454s, 1375m, 1304w, 1238w, 1165m, 1091s, 1002w, 734s. ¹H-NMR

(500 MHz, C₆D₆): 7.51 (s, 1 H); 7.39 (d, J 7.4, 2 H); 7.25 (t, J 7.6, 2 H); 7.14 7.19 ( m, 3 H); 6.93 (s, 1 H);

5.61 5.65 (m, 1 H); 4 .4 1d(d, J 19.0, 11.4, 2 H); 4.33 (t, J 2.7, 1 H); 3.84( dd, J 9.5, 6.1, 1 H); 3.59 (d, J 7.3,

2 H); 3.17 (s, 1 H); 2.95 3.01 (m, 1 H); 2.65 (dd, J 13.2, 6.5, 1 H); 2.39 (dd, J 13.2, 10.5, 1 H); 2.30 (ddd, J

19.1, 13.7, 5.2, 1 H); 2.10 2.20 (m, 2 H); 1.89 1.96 (m, 3 H); 1.69 1.74( m, 7 H); 1.54 1.60 ( m, 2 H); 1.46

(s, 3 H); 1.4 2 (s, 3 H); 1.35 (s, 3 H); 1.20 (s, 3 H); 0.97 (t, J 7.9, 9 H); 0.68 0.72 (m, 1 H); 0.63 (q, J 7.9, 6 H).

¹³C-NMR (125 MHz, C₆D₆): 150.1; 140.4; 139.2; 133.3; 129.7; 127.4; 126.2; 125.7; 121.9; 118.5; 118.2; 111.9; 84.8;

77.0; 74.9; 69.8; 66.5; 64.0; 58.4; 50.7; 49.0; 40.7; 37.2; 35.2; 30.0; 27.5; 26.6; 25.9; 25.7; 25.3; 23.2; 20.9; 19.1; 17.8;

15.5; 7.3; 5.6. HR-ESI-MS: 732.4449 ([M Na] , C₄₅H₆₃NNaO₄Si ; calc. 732.4424).

(À)-(2S,3R,4aR,5aS,13bS,13cR,15aS)-2-[1-(Benzyloxy)-1-methylethyl]-3,4,6,7,7a,8,13,13b,13c,14,15,15a-

dodecahydro-13b,13c-dimethyl-10-(3-methylbut-2-enyl)-2H-oxireno[2'',3'':4a',5'][1]benzopyrano[5',6':6,7]inde-

no[1,2-b]indol-3-ol ((À)-74). Under Ar, a soln. of (À)-73 (16.2 mg, 22.8 mmol) in THF (3 ml) was treated with

TBAF (1.0m in THF; 110 ml, 110 mmol) at r.t. for 1 h. The mixture was then diluted with Et₂O (20 ml) and

washed with brine (5 ml). The org. layer was then dried (Na₂SO₄), filtered, and concentrated in vacuo. FC

(hexanes/AcOEt 3 :1, containing 0.5% Et₃N) provided (À)-74 (12.7 mg, 93%). Colorless oil. [a]²_D⁵ À43.5 (c

0.20, CH₂Cl₂). IR (neat): 3440m (br.), 3366m (br.), 2930s, 1453s, 1374m, 1305m, 1163w, 1081m, 801m, 737m.

¹H-NMR (500 MHz, CD₂Cl₂): 7.76 (br. s, 1 H); 7.26 7.31 (m, 4H); 7.19 7.23 ( m, 3 H); 6.88 (dd, J 8.4, 1.4,

1 H); 5.34 5.38 ( m, 1 H); 5.32 (d, J 1.1, 1 H); 4.66 (dd, J 83.1, 11.3, 2 H); 4.27 4.28 (m, 1 H); 4.11 (t, J

1.4, 1 H); 3.39 (d, J 7.4, 2 H); 3.17 (s, 1 H); 2.98 3.04( m, 1 H); 2.71 (dd, J 13.4, 6.5, 1 H); 2.38 (dd, J 13.4,

10.5, 1 H); 2.30 2.37 (m, 1 H); 2.20 2.27 (m, 2 H); 2.06 (dd, J 14.1, 2.8, 1 H); 1.82 1.92 (m, 2 H); 1.72 1.79

(m, 8 H); 1.51 1.54( m, 1 H); 1.4 5 (s, 3 H); 1.37 (s, 3 H); 1.36 (s, 3 H); 1.16 1.20 (m, 1 H); 1.06 (s, 3 H).

¹³C-NMR (125 MHz, CD₂Cl₂): 150.7; 139.7; 138.9; 133.4; 131.6; 128.7; 127.7; 127.6; 125.7; 125.1; 121.6; 118.2;

117.8; 111.5; 83.9; 78.9; 74.5; 69.3; 66.7; 65.8; 58.6; 50.7; 48.7; 40.9; 35.6; 34.8; 29.0; 27.6; 26.7; 25.8; 25.7; 25.0;

23.2; 22.6; 18.9; 17.9; 15.3. HR-ESI-MS: 618.3586 ([M Na] , C₃₉H₄₉NNaO₄; calc. 618.3559).

()-(2R,4bS,12bS,12cR,14aS)-2-[1-(Benzyloxy)-1-methylethyl]-5,6,6a,7,12,12b,12c,13,14,14a-decahydro-

4b-hydroxy-12b,12c-dimethyl-9-(3-methylbut-2-enyl)-2H-[1]benzopyrano[5',6':6,7]indeno[1,2-b]indol-3(4bH)-

one (()-75). Under Ar, a soln. of (À)-74 (4.8 mg, 8.1 mmol) in benzene (2 ml) was treated with Ph₃BiCO₃

(32 mg, 64.5 mmol), this mixture was then heated to reflux for 3.5 h. The mixture was then cooled to r.t., diluted

with Et₂O (10 ml), filtered, and concentrated in vacuo. Gradient FC (hexanes/AcOEt, 5 :1 ! hexanes/AcOEt

3 :1, containing 0.5% Et₃N) provided ()-75 (3.3 mg, 69%). Yellow oil. [a]²_D⁵ 21.3 (c 0.15, CH₂Cl₂). IR

(neat): 3401s (br.), 2928s, 1675s, 1452s, 1374w, 1305w, 1126m, 697w. ¹H-NMR (500 MHz, C₆D₆): 7.52 7.54

(m, 2 H); 7.24 7.27 ( m, 1 H); 7.13 7.19 (m, 5 H); 6.86 (s, 1 H); 5.67 (d, J 2.1, 1 H); 5.61 5.64( m, 1 H); 4.59

(s, 2 H); 4.52 (dd, J 10.0, 8.2, 1 H); 3.88 (d, J 1.7, 1 H); 3.59 (d, J 7.2, 2 H); 2.62 (dd, J 12.7, 6.0, 1 H);

2.36 2.54( m, 3 H); 2.11 2.16 (m, 1 H); 1.85 1.93 (m, 1 H); 1.71 (s, 3 H); 1.69 (s, 3 H); 1.67 (s, 3 H); 1.61

(s, 3 H); 1.22 1.35 (m, 7 H); 0.77 0.97 (m, 2 H); 0.74( s, 3 H). ¹³C-NMR (125 MHz, C₆D₆): 194.9; 164.8; 151.9;

140.7; 139.0; 133.4; 131.1; 127.3; 126.2; 125.7; 121.9; 120.7; 118.4; 117.3; 111.8; 83.9; 77.2; 76.8; 73.1; 64.6; 50.9;

49.4; 42.9; 35.2; 33.7; 28.9; 27.9; 27.4; 25.9; 23.5; 22.6; 21.0; 19.5; 17.8; 16.4. HR-ESI-MS: 616.3385 ([M Na] ,

C₃₉H₄₇NNaO₄; calc. 616.3403).

(À)-(2R,4bS,12bS,12cR,14aS)-5,6,6a,7,12,12b,12c,13,14,14a-Decahydro-4b-hydroxy-2-(1-hydroxy-1-methyl-

ethyl)-12b,12c-dimethyl-9-(3-methylbut-2-enyl)-2H-[1]benzopyrano[5',6 ':6,7]indeno[1,2-b]indol-3(4bH)-one

((À)-21-Isopentenylpaxilline; (À)-1; synthetic). Under Ar, a soln. of ()-75 (0.7 mg, 1.2 mmol) in MeOH

(1 ml) was treated with 1-methylcyclohexa-1,4-diene (10 mmol) and 10% Pd/C (7 mg), the resultant mixture was

then heated to reflux for 1.5 h. After cooling to r.t., the mixture was filtered and concentrated in vacuo. Gradient

normal-phase HPLC separation (hexanes/AcOEt 3 :1 ! hexanes/AcOEt 3 :2 ! hexanes/AcOEt 1:1, contain-

ing 0.1% Et₂NH) provided (À)-1 (0.4mg, 70%). Colorless oil: [ a]²_D⁵ À17 (c 0.03, C₆D₆). ¹H-NMR

(500 MHz, CDCl₃): 7.51 (s, 1 H); 7.23 (s, 1 H); 6.81 (br. s, 1 H); 5.60 5.63 (m, 2 H); 4.42 4.47 (m, 2 H); 3.74

(d, J 1.9, 1 H); 3.58 (d, J 7.4, 1 H); 2.62 (dd, J 12.7, 6.0, 1 H); 2.34 2.50 ( m, 3 H); 2.04 2.09 ( m, 1 H);

1.71 1.79 (m, 1 H); 1.69 (s, 3 H); 1.68 (s, 3 H); 1.64 1.67 ( m, 1 H); 1.59 (s, 3 H); 1.55 (s, 3 H); 1.24 1.29

Helvetica Chimica Acta Vol. 86 (2003)

3937

(m, 5 H); 0.87 0.93 (m, 1 H); 0.74 0.79 ( m, 2 H); 0.70 (s, 3 H). ¹³C-NMR (125 MHz, C₆D₆, resolved peaks):

198.8; 167.0; 138.8; 125.4; 121.7; 119.6; 118.2; 111.5; 84.0; 72.7; 49.1; 34.9; 33.4; 28.5; 27.6; 27.1; 27.0; 25.6; 24.4;

20.6; 19.1; 16.1. HR-ESI-MS: 526.2928 ([M Na] , C₃₂H₄₁NNaO₄; calc. 526.2933).

(À)-21-Isopentenylpaxilline ((À)-1; natural). Yellow oil. [a]²_D⁵ À12 (c 0.30, CHCl₃). ¹H-NMR

(500 MHz, C₆D₆): 7.51 (s, 1 H); 7.23 (s, 1 H); 6.81 (br. s, 1 H); 5.60 5.63 (m, 2 H); 4.51 (s, 1 H); 4.44 (dd, J

10.8, 8.1, 1 H); 3.74( d, J 1.9, 1 H); 3.58 (d, J 7.4, 1 H); 2.62 (dd, J 12.7, 6.0, 1 H); 2.34 2.50 ( m, 3 H);

2.04 2.09 ( m, 1 H); 1.71 1.79 (m, 1 H); 1.69 (s, 3 H); 1.68 (s, 3 H); 1.64 1.67 ( m, 1 H); 1.59 (s, 3 H); 1.55

(s, 3 H); 1.24 1.29 ( m, 5 H); 0.87 0.93 (m, 1 H); 0.74 0.79 ( m, 2 H); 0.70 (s, 3 H). ¹³C-NMR (125 MHz, C₆D₆,

resolved peaks): 198.8; 167.0; 138.8; 125.3; 121.7; 119.6; 118.2; 111.5; 84.0; 72.7; 49.1; 34.9; 33.4; 28.5; 27.6; 27.1;

27.0; 25.6; 24.4; 20.6; 19.1; 16.1. HR-ESI-MS: 526.2926 ([M Na] , C₃₂H₄₁NNaO₄; calc. 526.2933).

Financial support was provided by the National Institutes of Health (Institute of General Medical Science)

through grant GM-29028. We thank Prof. J. B. Gloer (University of Iowa) for providing a generous sample of

natural (À)-21-isopentenylpaxilline. We also wish to thank Dr. G. Furst, Dr. R. K. Kohli and Dr. P. J. Caroll,

Directors of the University of Pennsylvania Spectroscopic Facilities, for assistance in obtaining NMR spectra,

high-resolution mass spectra, and X-ray crystallographic analyses, respectively.

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Article Doi

Indole-Diterpene Synthetic Studies: Total Synthesis of (-)-21-Isopentenylpaxilline

DOI: 10.1002/hlca.200390328

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