Use of conjugated dienones in cyclialkylations: The total syntheses of (±)-barbatusol, (±)-pisiferin, (±)-deoxofaveline, (±)-xochitlolone, and (±)-faveline

J . Org. Chem. 1996, 61, 8169-8185

8169

Use of Con ju ga ted Dien on es in Cyclia lk yla tion s: Th e Tota l

Syn th eses of (()-Ba r ba tu sol, (()-P isifer in , (()-Deoxofa velin e,

(()-Xoch itlolon e, a n d (()-F a velin e^†

George Majetich,* Rodgers Hicks, Yong Zhang, Xinrong Tian, Terry Lee Feltman,

J ing Fang, and Sam Duncan, J r.

Department of Chemistry, The University of Georgia, Athens, Georgia 30602

Received April 16, 1996^X

Concise syntheses of five tricyclic diterpenoids are reported. The key reaction in each synthesis is

a cyclialkylation of a functionalized arene with a Lewis acid-activated conjugated dienone to generate

a 6,7,6-fused tricycle.

Recently we reported that tricycles containing a central

cycloheptane ring can be prepared by the Lewis acid-

catalyzed intramolecular alkylation of electron-rich

arenes with conjugated dienones (eq 1).¹The ability of

(1)

F igu r e 1.

Syn th esis of (()-Ba r ba tu sol. Our approach to bar-

batusol features the cyclialkylation of 2-benzyl-dienone

6 to produce tricycle 7 (eq 2).¹⁰Enone 7 is an attractive

synthetic intermediate because it contains the entire

carbocyclic framework of barbatusol, a suitably substi-

tuted “C” ring, and sufficient functionality within the “A”

ring to permit the introduction of the acid-sensitive

trisubstituted C(1),C(10)-double bond.

this method to prepare functionalized 6,7,6-fused tricycles

is the basis for each of the syntheses discussed here

(Figure 1).^2,3The first synthesis discussed is that of (()-

barbatusol (1),⁴a diterpene known to lower blood pres-

sure in mice.⁵We also present the syntheses of (()-

pisiferin (2),⁶(()-deoxofaveline (3),⁷faveline (4),⁸as well

as the first total synthesis of xochitlolone (5).⁹

^†(a) Presented in part at 44th Southeastern-26th Middle Atlantic

Regional Meeting of the American Chemical Society, December 8, 1992;

ORG Abstract No. 411. (b) Taken in part from the MS theses of Terry

Lee Feltman, The University of Georgia, 1993, and Sam Duncan, J r.,

The University of Georgia, 1992. (c) Taken in part from the Ph.D.

Dissertation of Rodgers Hicks, The University of Georgia, 1996.

^XAbstract published in Advance ACS Abstracts, October 15, 1996.

(1) Majetich, G.; Zhang,Y.; Feltman, T. L.; Belfoure, V. Tetrahedron

Lett. 1993, 34, 441.

(2)

(2) For a preliminary account of our barbatusol synthesis, see: (a)

Majetich, G.; Zhang, Y.; Feltman, T. L.; Duncan, S. G., J r. Tetrahedron

Lett. 1993, 34, 445. (b) All structures drawn here represent racemates,

with only one enantiomer shown. (c) Reaction conditions have not been

optimized. (d) All yields are isolated yields.

(3) For a recent application of our cyclialkylation strategy, see:

Wang, X.; Pan, X.; Zhang, C.; Chen, Y. Synth. Commun. 1995, 25, 3413.

(4) For the isolation of barbatusol, see: Kelecom, A. Tetrahedron

1983, 39, 3603.

(5) (a) Steven, R. V.; Bisacchi, G. S. J . Org. Chem. 1982, 47, 2396.

(b) Edwards, J . D.; Cashaw, J . L. Ibid. 1955, 20, 847.

(6) For the isolation of pisiferin, see: (a) Yatagai, M.; Takahashi,

T. Phytochemistry 1980, 19, 1149. (b) Hasegawa, S.; Hirose, Y.; Yatagai,

M.; Takahashi, T. Chem. Lett. 1984, 1837.

Our synthesis began with 3-isopropylveratrole (8).¹¹

The 3-isopropylveratrole was treated with n-butyllithium

to form the anion¹²shown (Scheme 1), which was then

(7) For the isolation of deoxofaveline and faveline, see: Endo, Y.;

Ohta, T.; Nozoe, S. Tetrahedron Lett. 1991, 32, 3083.

(8) Deoxofaveline and faveline have known activity against P-388

murine leukemia cells with IC₅₀’s of 1.0 and 18.6 µg/mL, respectively.⁷

(9) For the isolation of xochitlolone, see: Dominguez, X. A.; Sanchez,

H. V.; Espinosa, G. B.; Villarreal, A. M.; Guerra, N. E. Rev. Quim.

Latin. Amer. 1990, 21, 26.

(10) For the first synthesis of barbatusol, see: Koft, E. Tetrahedron

1987, 43, 5775.

(11) For an efficient, three-step preparation of 3-isopropylveratrole,

see: Majetich, G.; Liu, S. Synth. Commun. 1993, 23, 2331.

(12) (a) Meyer, N.; Seebach, D. Angew. Chem. Int., Ed. Engl. 1978,

17, 521. (b) Taber, D. F.; Dunn, B. S.; Mack, J . F.; Saleh, S. A. J . Org.

Chem. 1985, 50, 1987.

8170 J . Org. Chem., Vol. 61, No. 23, 1996

Majetich et al.

Sch em e 1

Sch em e 2

quenched with gaseous formaldehyde (generated by

heating paraformaldehyde to 135 °C) to yield the benzylic

alcohol 9 in 86% yield.¹³Alcohol 9 was treated with

phosphorus tribromide to produce bromide 10 in 95%

yield.

The next step required the alkylation of 4,4-dimethyl-

1,3-cyclohexanedione (11) with bromide 10. The use of

typical conditions for the C-alkylation of cyclic 1,3-diones

gave either O-alkylation or bis-alkylation. However, the

use of a concentrated solution of compounds 11 and 10

in a 20% aqueous solution of potassium carbonate yielded

mono-alkylated dione 12 in 65% yield, or 98% based on

unreacted 11 (Scheme 2).¹⁴Treatment of dione 12 with

sodium hydride and dimethyl sulfate in DMF gave a

single enol ether, which we assumed to be compound 13

because of the steric congestion of the gem-dimethyls at

C(4). The specificity of this O-alkylation was easily

confirmed. Kinetically controlled bis-alkylation¹⁵of enone

15 resulted in the exclusive formation of 13, confirming

this structural assignment. The preparation of 15 is

straightforward, as shown in Scheme 2.

proton of dimethoxybarbatusol, an intermediate in Koft’s

synthesis.¹⁷Our mechanistic analysis of these results

is discussed in a separate section.

Sch em e 3

1,2-Addition of vinylmagnesium bromide to 13, fol-

lowed by mild acid hydrolysis, completed the preparation

of cyclization precursor 6 (Scheme 3). Not surprisingly,

the presence of the gem-dimethyls at C(6) necessitated

activation of the carbonyl by using cerium chloride¹⁶to

facilitate Grignard addition.

In our preliminary studies, a simplified analogue of 6,

devoid of the gem-dimethyl and isopropyl substitutents,

cyclized easily and in high yield, regardless of the Lewis

acid employed. We expected the cyclization of 6 to be

straightforward; instead, this cyclization proved to be

catalyst dependent. Mild Lewis acids, such as trimethyl-

aluminum or zinc bromide, failed to promote cyclialkyl-

ation. The use of boron trifluoride etherate gave a 4.5:1

ratio of enones 16 and 7, respectively, while the use of

titanium tetrachloride gave the same mixture of isomers

with opposite selectivity. Further experiments revealed

that reexposure of enone 16 to excess Lewis acid does

not result in the formation of enone 7, nor does 7

rearrange to isomer 16 under identical conditions. We

were unable to rigorously establish the structures of

enones 7 and 16 using 2D NMR techniques. However,

our structural assignment for these enones was based

on a comparison of the chemical shift of the aromatic

proton absorption for enones 7 and 16 with the aromatic

We verified our structural assignments for enone 7 by

completing the synthesis of barbatusol. This was achieved

by using a modified Wolff-Kishner reduction of enone

7,¹⁸reducing the C(1) carbonyl and resulting in the

migration of the C(5),C(10)-double bond to the C(1),C(10)-

position (cf. 17, Scheme 4). During the isolation of

barbatusol, Kelecom and co-workers observed that the

C(1),C(10)-double bond readily becomes conjugated upon

exposure to acidic conditions. Koft found that the de-

methylation of 17 could not be achieved without double

(13) Lower yields of benzyl alcohol 9 were obtained when paraform-

aldehyde was used.

(14) Stetter, H.; Dierichs, W. Chem. Ber. 1952, 85, 1061.

(15) Stork, G.; Danheiser, R. J . Org. Chem. 1973, 38, 1775.

(16) Imamoto, T.; Kusumoto, T.; Yokoyama, M. J . Chem. Soc., Chem.

Commun. 1982, 1042.

(17) A single crystal X-ray diffraction study confirmed our structural

assignment for tricyclic enone 16 after our synthesis of barbatusol had

been achieved.

(18) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J . Am. Chem.

Soc. 1973, 95, 3662.

Use of Conjugated Dienones in Cyclialkylations

J . Org. Chem., Vol. 61, No. 23, 1996 8171

Sch em e 4

bond isomerization using acidic reagents [BBr₃, TMSI,

or HI].¹⁰Nevertheless, Koft established that demethyl-

ation of the methyl ethers could be achieved without

isomerization using basic conditions developed by Feutrill

and Mirrington.¹⁹Thus, heating dimethyl ether 17 with

EtSNa in DMF resulted in the isolation of racemic

barbatusol in 65% yield, along with a 25% yield of an

inseparable mixture of mono-methylated products (18a

and 18b). The NMR, infrared, and mass spectra of 1

were all identical with those reported by both Koft and

Kelecom,^4,10thereby confirming our synthesis. In the

course of this investigation we found that warm solutions

of L-Selectride or Super-Hydride in THF efficiently

demethylate methyl phenyl ethers.²⁰Although this new

deprotection method is quite general, treatment of 17

with excess L-Selectride followed by heating for 48 h at

reflux gave only a 45% yield of barbatusol, along with a

46% yield of phenols 18a and 18b. Further demethyl-

ation of 18a and 18b was not examined.

F u n d a m en ta l Mech a n istic Stu d ies. We sought to

learn what structural features, if any, were responsible

for the formation of the rearranged products in the

cyclialkylation of 6. Benzyl-dienone 19 was prepared in

order to test whether the gem-dimethyl moiety at C(4)

in 6 was influencing the product distribution. This

premise proved to be wrong as can be seen in eq 3.

Thus, we were not surprised that the use of TiCl₄gave

only enone 25, albeit in poor yield. Substrates 26 and

28 contain trisubstituted arenes, which differ only in the

position of the methoxy group. The cyclization of 26

proceeds without the formation of rearranged products,

but this is not the case with substrate 28, which gives

spiro-fused dienone 29 in 65% yield. Reexposure of

tricycle 29 to either protic or Lewis acids does not result

in further reaction.

Sch em e 5

(3)

We were curious whether substrate 22, a 4-benzyl-

dienone, would also generate a mixture of cyclialkylation

products. Instead, this cyclialkylation furnished only

tricycle 23, regardless of the catalyst used (eq 4).

Substituted 4-benzyl-dienones and most 2-benzyl-di-

enones undergo rapid cycloheptane annulation when the

“3” position of the arene bears an electron-donating

group. The mechanism shown in Scheme 6 for the

cyclization of substrate 26 is representative of such

substrates. Electrophilic addition of the activated con-

jugated dienone (ii) occurs para to the methoxy group to

form a seven-membered ring and a resonance-stabilized

carbocation intermediate (iii), which loses a proton to

reestablish aromaticity. [Cation iii is conceptually si-

miliar to the carbocation intermediate involved in the

dienone-phenol rearrangement.²¹]

(4)

Scheme 5 presents three additional results which

helped us to gain an understanding of these processes.

The failure of dialkyl-substituted arene 24 to cyclize, even

under harsh conditions, indicates that the two alkyl

substitutents alone do not activate the arene sufficiently

to promote cyclization. Chlorinated Lewis acids tend to

promote 1,6-Michael addition of chloride ion when the

cyclialkylation is sluggish or not geometrically possible.

(19) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 1327.

(20) Majetich, G.; Zhang, Y.; Wheless, K. Tetrahedron Lett. 1994,

35, 8727.

Although substrate 28 has an electron-rich arene, the

activating groups direct substitution toward geometri-

8172 J . Org. Chem., Vol. 61, No. 23, 1996

Majetich et al.

Sch em e 6

F igu r e 2.

the “4” isopropyl groups activate positions which are

geometrically precluded to the activated dienone moiety,

we expected the “3” methoxy group to dictate the forma-

tion of only enone 7 (cf. 26 f 27, Schemes 5 and 6).

Instead, cyclization catalyzed by TiCl₄and BF₃-Et₂O

gave mixtures of isomeric enones 7 and 16, a rearranged

product (cf. Scheme 3). Once again, an ipso-attack

mechanism, followed by a skeletal rearrangement, ac-

counts for the production of these enones (Scheme 8).

Ipso-attack by the arene on the electrophilic dienone unit

leads to the formation of cation viii, which can generate

intermediates ix or x by migration of the “a” or “b” bond,

respectively. Since both of these bonds are allylic and

primary, they are equally likely to migrate. In re-

arrangements where there are two or more potential

migrating groups, the geometry of the molecule often

governs which group migrates (for example, a Beckmann

rearrangement). We believe that in the TiCl₄-catalyzed

reaction an eight-membered ring chelate is formed (xi,

Figure 2), and that its geometry favors the migration of

the “b” bond instead of the “a” bond to generate a nine-

membered ring chelate. In contrast, the use of BF₃-Et₂O

as catalyst leads to the formation of a noncyclic complex

xii. As a consequence of minimizing the nonbonded

steric interactions between the Lewis acid and the

carbocyclic framework, this complex assumes a geometry

which presumably favors the migration of the “a” bond.

Th e Syn t h eses of (()-Deoxofa velin e a n d (()-

P isifer in . Our routes to prepare deoxofaveline (3) and

pisiferin (2) closely parallel our barbatusol work and are

therefore presented together in Scheme 9. Our synthesis

of deoxofaveline^23awill be discussed first. 3-Methoxy-4-

methylbenzoic acid (32) was converted to conjugated aryl-

dienone 37, the requisite cyclization precursor in five

steps and 50% overall yield. Cyclialkylation of dienone

37 produced tricycle 38 in excellent yield. Three ad-

ditional transformations were required to complete a

synthesis of 3: (1) a Wolff-Kishner reduction of enone

38; (2) the isomerization of the C(1),C(10)-double bond

of tricycle 39, and (3) the deprotection of the methyl ether.

The use of excess boron tribromide during the demeth-

ylation of 39 should also cause the migration of the

trisubstituted double bond to a styrenyl position, thereby

furnishing 3 directly. This transformation occurs, albeit

in less than 5% yield.

cally inaccessible positions, which precludes cycloheptane

formation (Scheme 7). Nevertheless, treatment of 28

with TiCl₄results in the formation of spiro-fused enone

29. The isolation of tricycle 29 can be explained only via

an ipso-attack mechanism. Six-membered rings form

more easily than seven-membered rings. Thus, ipso-

attack leads to cyclohexane formation via carbocation iv

and its resonance contributors, whereas cycloheptane

formation leads to a less stable carbocation (i.e., vi) and

its various canonical forms.²²Lewis-acid-catalyzed de-

methylation of intermediate iv generates v, which pro-

vides enone 29 on workup.

Sch em e 7

Concurrent with our synthesis of deoxofavaline, a

cyclialkylation-based synthesis of pisiferin was also

underway.^23bIn contrast to our deoxofaveline synthesis

which was trouble free, the deprotection of pisiferin

methyl ether (45) with NaSEt in DMF gave an insepa-

rable mixture of pisiferin in 68% yield along with a 17%

yield of the isomer in which the trisubstituted double

bond had migrated to a styrenyl position, i.e., isopisiferin

(46). Others have also observed that such unwanted

Substrate 6, whose cyclization is the key step in our

barbatusol synthesis, has an arene unit substituted with

four electron-donating groups. Since the “2” methoxy and

(21) (a) Arnold, R. T.; Buckley, J . S., J r. J . Am. Chem. Soc. 1949,

71, 1781. (b) Wilds, A. L.; Djerassi, C. Ibid. 1946, 68, 1712, 1715. (c)

Arnold, R. T.; Buckley, J . S., J r.; Richter, J . Ibid. 1947, 69, 2322.

(22) For a related example of ipso-attack in a similar system, see:

Burnell, R. H.; J ean, M.; Poirier, D. Can. J . Chem. 1987, 65, 775.

(23) (a) For the first synthesis of deoxofaveline, see: Ghosh, A.; Ray,

C.; Ghatak, U. Tetrahedron Lett. 1992, 33, 655. (b) For the first

synthesis of pisiferin, see: Matsumoto, T.; Imai, S.; Yoshinari, T.;

Matsuno, S. Bull. Chem. Soc. J pn. 1986, 59, 3103.

Use of Conjugated Dienones in Cyclialkylations

J . Org. Chem., Vol. 61, No. 23, 1996 8173

Sch em e 8

Sch em e 9

isomers can not be separated. For example, in Kamet-

ani’s synthesis of pisiferin, their synthetic material was

contaminated with about 10% of the C(5),C(10)-double

bond isomer of 2.²⁴Surprisingly, pisiferin could not be

isomerized cleanly into isopisiferin at ambient temper-

atures (cf. 39 f 40),²⁵while more vigorous reaction

conditions produced tetracyclic dienone 50 (eq 5). These

deprotection problems were avoided by unmasking the

methyl ether prior to the Wolff-Kishner reduction (cf.

44) and then acetylating the intermediate phenol (cf. 48).

Syn th eses of (()-Xoch itlolon e a n d (()-F a velin e.

The most direct way to synthesize faveline would involve

a selective benzylic oxidation of deoxofaveline (cf. 39 f

52, Scheme 10).^26,27In practice only the C(1) position was

oxidized independent of the choice of oxidant and whether

or not the C(12) hydroxyl group was protected. Attempts

(24) Kametani, T.; Kondoh, H.; Tsubuki, M.; Honda, T. J . Chem.

Soc., Perkin Trans. 1 1990, 5.

(25) For a synthesis of isopisiferin, see: Deb, S.; Bhattacharjee, G.;

Ghatak, U. R. J . Chem. Soc., Perkin Trans. 1 1990, 1453.

8174 J . Org. Chem., Vol. 61, No. 23, 1996

Majetich et al.

Sch em e 11

(5)

were then made to introduce a hydroxyl group at C(7)

by adding water in Michael-fashion to the quinone

methide, derived from deoxofaveline (Scheme 10);²⁸this

approach, however, was also not successful.

that others were also trying to synthesize faveline. In

their synthesis of faveline methyl ether (57), Ghatak,

Ray, and Ghosh reported that acetate 55 could be

oxidized to ketone 56 in 60% yield (eq 6).²²They also

observed that the demethylation of 57 to faveline was

plagued by many side reactions. Their results prompted

Sch em e 10

(6)

us to prepare substrate 59 with a tertiary hydroxyl group

at C(10), which we expected would permit the desired

benzylic oxidation at C(7) and facilitate the introduction

of the styrenyl double bond (Scheme 12). Toward this

end, alkene 39 was epoxidized and then treated with

excess of L-Selectride to furnish tertiary alcohol 59. Note

that under these reaction conditions deprotection of the

methyl phenyl ether was the major product.²⁰However,

attempts to oxidize the C(7)-methylene of 59 gave com-

plex mixtures of unidentifiable products.

Although enone 51 was not a useful intermediate for

our faveline synthesis, it does possess many of the salient

features of the diterpenoid xochitlolone (5). Indeed, only

three more reactions were required to complete a syn-

thesis of 5 from enone 51. The first two transformations

involved the introduction of an R,â-unsaturated double

bond within the “A” ring, while the last step was the

liberation of the phenol in the presence of the sensitive

dienone unit (Scheme 11). Heating dienone 53 with

sodium ethanethiolate in DMF produced dienone 54,

wherein the C(10),C(20)-double bond unexpectedly isomer-

ized to the C(5),C(10)-position. Instead, treatment with

BBr₃at low temperatures rapidly effected the desired

ether cleavage cleanly. Our synthetic (()-xochitlolone

exhibited spectral data identical to those reported for the

natural material.⁹

Sch em e 12

One of our main objectives thoroughout this project

was to synthesize faveline, because of its promising

antileukemia activity. It was therefore not surprising

(26) For an unsuccessful approach toward faveline, see: Ho, T.-L.;

Chen, C.-K. Tetrahedron 1995, 51, 5819.

(27) For the first synthesis of faveline, see: Ghosh, A. K.; Mukho-

padhyay, C.; Ghatak, U. R. J . Chem. Soc., Perkin Trans. 1 1994, 327.

(28) (a) Zanarotti, A. J . Org. Chem. 1985, 50, 941. (b) Angle, S. R.;

Turnbull, K. D. J . Am. Chem. Soc. 1989, 111, 1136.

We decided to exploit Ghatak’s finding that acetate 55

can be oxidized at C(7) using mild conditions. Hydro-

Use of Conjugated Dienones in Cyclialkylations

J . Org. Chem., Vol. 61, No. 23, 1996 8175

Sch em e 13

boration of deoxofaveline methyl ether (40) gave a 2:1

mixture of benzylic alcohols with the diastereomer 61

having a cis A/B ring fusion as the major isomer (Scheme

13). The alcohols were then separated and acetylated.

It was hoped that thexylborane would improve the

selectivity of the hydroboration. This more bulky borane,

however, reacted only sluggishly with 40.

Exp er im en ta l Section

Gen er a l. All reactions were run under an inert atmosphere

of nitrogen and monitored by TLC analysis until the starting

material was completely consumed. Unless otherwise indi-

cated, all ethereal workups consisted of the following proce-

dure: the reaction was quenched at rt with saturated aqueous

ammonium chloride. The organic solvent was removed under

reduced pressure on a rotary evaporator, and the residue was

taken up in ether, washed with brine, and dried over anhy-

drous magnesium sulfate. Filtration, followed by concentra-

tion at reduced pressure on a rotary evaporator and at 1 torr

to constant weight, afforded a crude residue which was purified

by flash chromatography using NM silica gel 60 (230-400

mesh ASTM) and distilled reagent grade hexanes and diethyl

ether. Microanalysis was performed by Atlantic Microlab, Inc.,

Atlanta, GA. Proton NMR spectra were obtained in CDCl₃

and were calibrated using trace CHCl₃present (δ 7.27) as an

internal reference.

2,3-Dim eth oxy-4-isop r op ylp h en ylm eth yl Alcoh ol (9).

3-Isopropylveratrole (8) (13.25 g, 73.6 mmol) was dissolved in

130 mL of dry ether containing TMEDA (22.2 mL, 147 mmol)

under an atmosphere of nitrogen and was allowed to stir 1.5

h at rt. n-Butyllithium (103 mmol, 42 mL of 2.5 M solution

in hexanes) was added slowly and the mixture was stirred for

90 min at rt, after which it was treated at rt with excess

gaseous formaldehyde (generated from paraformaldehyde via

pyrolysis at 135 °C). Standard ethereal workup, followed by

chromatography (elution with H:E, 5:1), gave 13.65 g (89%) of

2,3-dimethoxy-4-isopropylbenzyl alcohol (9) which was homo-

geneous by TLC analysis (H:E, 1:1, R_f8 ) 0.76, R_f9 ) 0.10):

¹H NMR (250 MHz) δ 1.22 (d, 6 H, J ) 6.8 Hz), 3.25-3.45 (m,

Acetates 62 and 67 were oxidized separately using

pyridinium chlorochromate (PCC) in methylene chloride

at reflux and saponified to provide alcohols 64 and 69.

We have developed neutral conditions for the dehydration

of tertiary and benzylic alcohols in good yield using mild

heating (typically <100 °C).²⁹The application of this

dehydration procedure to benzylic alcohols 64 and 69

produced (()-faveline methyl ether (57) in good yield. We

were able to complete a synthesis of faveline by unmask-

ing both the C(20) hydroxyl group and the C(12) phenol

using sodium ethanethiolate, followed by the dehydration

of alcohols 65 and 70 with potassium hydrogen sulfate

at 140 °C for 4 h. The NMR, infrared, and mass spectra

of our synthetic racemic faveline were identical with

those first reported by Nozoe⁷and more recently by

Ghatak.²⁷

The ability of this cyclialkylation-based annulation

strategy to prepare functionalized tricylic skeletons has

permitted the efficient synthesis of (()-barbatusol (eight

steps, 15% overall yield), (()-pisiferin (nine steps, 11%

overall yield), (()-deoxofaveline (nine steps, 13% overall

yield), (()-xochiotlolone (11 steps, 7% overall yield) and

(()-faveline (13 steps, 2% overall yield). Other applica-

tions of this new annulation strategy for natural product

synthesis have already been achieved,³⁰or are forth-

coming.

(30) For a concise synthesis of the triterpene perovskone featuring

a cyclialkylation strategy, see: (a) Majetich, G.; Zhang, Y. J . Am. Chem.

Soc. 1994, 116, 4979. For a synthesis of (()-nimbidiol featuring a

cyclialkylation strategy, see: (b) Majetich, G.; Siesel, D. Synlett 1995,

559. For cyclialkylations of conjugated dienones and furans, see: (c)

Majetich, G.; Zhang, Y.; Liu, S. Tetrahedron Lett. 1994, 35, 4887. For

the use of cyclialkylations to prepare functionalized hydrophenan-

threnes, see: (d) Majetich, G.; Liu, S.; Siesel, D. Tetrahedron Lett. 1995,

36, 4749.

(29) Majetich, G.; Hicks, R. Carbodiimide-Promoted Dehydration of

Alcohols. Manuscript is in preparation.

(31) Dhekne, V. V.; Rao, A. S. Synth. Commun. 1978, 8, 135.

8176 J . Org. Chem., Vol. 61, No. 23, 1996

Majetich et al.

1 H), 3.86 (s, 3 H), 3.93 (s, 3 H), 4.67 (s, 2 H), 6.95 (d, 1 H, J

) 8.0 Hz), 7.01 (dd, 2 H, J ) 14.6 Hz, 8.0 Hz), 7.07 (d, 1 H, J

) 8.0 Hz); ¹³C NMR (62.9 MHz) 157.0 (s), 150.2 (s), 143.0 (s),

132.1 (s), 123.7 (d), 121.4 (d), 61.6 (t), 60.6 (q), 60.6 (q) (the

two methoxy signals overlap), 26.7 (d), 23.5 (q) ppm; IR (film)

3550-3200, 1620 cm^-1. Anal for C₁₂H₁₈O₃. Calcd: C, 68.53%,

H, 8.63%. Found: 68.44%, H, 8.66%.

g, 15.29 mmol). The reaction mixture was stirred overnight.

Standard ethereal workup provided 3.80 g of a crude residue

which was dissolved in 5 mL of ether and 2 mL of hexanes,

and the resulting solution was stored overnight at -20 °C.

Filtration afforded 3.02 g (65%) of 14 which was homogenous

by TLC analysis (H:E, 4:1, R_f14 ) 0.24): ¹H NMR (300 MHz)

δ 1.19 (d, 6 H, J ) 7.0 Hz), 1.81 (heptet, 2 H, J ) 6.4 Hz), 2.37

(br t, 4 H, J ) 6.4 Hz), 3.26 (heptet, 1 H, J ) 7.0 Hz), 3.54 (s,

1 H), 3.83 (s, 3 H), 4.02 (s, 3 H), 6.94 (d, 1 H, J ) 8 Hz), 7.18

(d, 1 H, J ) 8 Hz); ¹³C NMR (75.5 MHz) 149.7 (s), 148.1 (s),

141.1 (s), 131.8 (s), 126.2 (d), 122.6 (d), 114.7 (s), 61.5 (q), 60.8

(q), 26.6 (t), 23.4 (q), 20.9 (t), 20.4 (t) ppm.

2-(2,3-Dim eth oxy-4-isopr opylph en ylm eth yl)-3-m eth oxy-

2-cycloh exen on e (15). To a suspension of NaH (80% disper-

sion in mineral oil, 125 mg, 4.16 mmol) in 10 mL of DMF at 0

°C was added dione 14 (1.16 g, 3.47 mmol) in 15 mL of DMF

over a 30-min period. Dimethyl sulfate (0.37 mL, 3.82 mmol)

was then added and the resulting mixture stirred overnight.

The reaction was diluted with ether, washed sequentially with

aqueous 10% HCl and saturated aqueous Na₂CO₃, dried over

anhydrous magnesium sulfate, concentrated, and chromato-

graphed (elution with H:E, 3:1) to give 92 mg of 15 (80%) which

was homogeneous by TLC analysis (H:E, 1:1, R_f14 ) 0.24, R_f

15 ) 0.56): ¹H NMR (300 MHz) δ 1.17 (d, 6 H, J ) 6.9 Hz),

2.03 (heptet, 2 H, J ) 7.1 Hz), 2.39 (t, 2 H, J ) 7.1 Hz), 2.62

(t, 2 H, J ) 7.1 Hz), 3.25 (heptet, 1 H, J ) 6.9 Hz), 3.62 (s, 2

H), 3.76 (s, 3 H), 3.84 (s, 3 H), 3.88 (s, 3 H), 6.65 (d, 1 H, J )

8.0 Hz), 6.80 (d, 1 H, J ) 8.0 Hz); ¹³C NMR (75.5 MHz) 197.8

(s), 172.7 (s), 150.8 (s), 150.1 (s), 139.6 (s), 132.1 (s), 123.2 (d),

120.5 (d), 117.9 (s), 60.5 (q), 59.8 (q), 55.1 (q), 36.3 (t), 26.5

(d), 24.8 (t), 23.55 (q), 21.0 (t), 20.7 (t) ppm.

P r ep a r a tion of 13 fr om 15. To a solution of LDA,

prepared from 99 µL (0.70 mmol) of diisopropylamine in 5 mL

of THF and 280 µL (0.70 mmol) of n-butyllithium (2.5 M in

hexanes), at -78 °C was added a solution of 195 mg (0.59

mmol) of 15 in 1 mL of THF over a 10-min period. After an

additional 1 h at -78 °C, iodomethane (110 mg, 0.77 mmol)

was added, and the reaction mixture was allowed to warm

slowly to rt over a 12-h period. Standard ethereal workup,

followed by chromatography (elution with H:E, 5:1), afforded

150 mg (73%) of 2-(2,3-dimethoxy-4-isopropylphenylmethyl)-

3-methoxy-6-methyl-2-cyclohexenone which was homogeneous

by TLC analysis (H:E, 1:1, R_f15 ) 0.35, R_f6-mono-methylated

adduct ) 0.43): ¹H NMR (250 MHz) δ 1.18 (d, 6 H, J ) 7.0

Hz), 1.17 (d, 3 H, J ) 6.5 Hz), 1.69-1.85 (m, 1 H), 2.15 (dt, 1

H, J ) 13.1 Hz, 4.7 Hz), 2.26-2.40 (m, 1 H), 2.52-2.78 (m, 2

H), 3.26 (heptet, 1 H, J ) 6.9 Hz), 3.62 (d, 2 H, J ) 3.7 Hz),

3.78 (s, 3 H), 3.86 (s, 3 H), 3.90 (s, 3 H), 6.63 (d, 1 H, J ) 8.0

Hz), 6.80 (d, 1 H, J ) 8.0 Hz).

To a solution of LDA, prepared from 100 µL (0.70 mmol) of

diisopropylamine in 5 mL of THF and 280 µL (0.70 mmol) of

n-butyllithium (2.5 M in hexanes), at -78 °C was added a

solution of 150 mg (0.43 mmol) of the above alkylated material

in 1 mL of THF over a 10-min period. After an additional 1 h

at -78 °C, iodomethane (110 mg, 0.77 mmol) was added, and

the reaction mixture was allowed to warm slowly to rt over a

3-h period. Standard ethereal workup, followed by chroma-

tography (elution with H:E, 5:1), afforded 127 mg (80%) of

enone 13 which was identical to that previously characterized.

2,3-Dim eth oxy-4-isopr opylph en ylm eth yl Br om ide (10).

To a cooled (0 °C) solution of 2.1 g (10 mmol) of alcohol 9 in

100 mL of dry ether was added phosphorus tribromide (0.96

mL, 10 mmol). Although reaction was essentially complete

after addition was finished, the reaction mixture was allowed

to stir at rt for 2 h. Standard ethereal workup afford 2.58 g

(95%) of bromide 10 which was homogeneous by TLC analysis

(H:E, 2.5:1, R_f9 ) 0.21, R_f10 ) 0.89): ¹H NMR (300 MHz) δ

1.22 (d, 6 H, J ) 6.8 Hz), 3.25-3.40 (m, 1 H), 3.86 (s, 3 H),

3.99 (s, 3 H), 4.56 (s, 2 H), 6.96 (d, 1 H, J ) 8.0 Hz), 7.09 (d,

1 H, J ) 8.0 Hz); ¹³C NMR (75.5 MHz) 151.3 (s), 150.5(s), 144.2

(s), 129.4 (s), 125.6 (d), 121.5 (d), 60.6(q), 60.5 (q) (the two

methoxy signals overlap), 28.6 (t), 26.8 (d), 23.4 (q) ppm; IR

(film) 1461, 1410, 1044, 1012 cm^-1

. Anal, for C₁₂H₁₇BrO₂.

Calcd: C, 52.70%, H, 6.30%. Found: 52.83%, H, 6.23%.

4,4-Dim e t h yl-2-(2,3-d im e t h oxy-4-isop r op ylp h e n yl-

m eth yl)-1,3-cycloh exa n ed ion e (12). To 2.00 g of 4,4-

dimethyl-1,3-cyclohexanedione (11) (13.96 mmol, Aldrich) dis-

solved in 20% aqueous K₂CO₃(3.09 mL, 5.58 mmol) at rt were

added KI (233 mg, 1.40 mmol) and bromide 10 (3.29 g, 15.29

mmol). The reaction mixture was stirred overnight. The

aqueous solution was extracted with ether (150 mL) and then

washed with aqueous 5% NaOH to remove unreacted 11. The

aqueous phase was acidified with aqueous 10% HCl and then

extracted with ether (3 × 75 mL). The combined ethereal

extracts were dried over anhydrous MgSO₄and concentrated.

The crude residue was dissolved in 5 mL of ether and 2 mL of

hexanes, and the resulting solution was stored overnight at

-20 °C. Filtration afforded 3.02 g (65%) of crystalline 12

which was homogenous by TLC analysis (H:E, 4:1, R_f12 )

1

0.24): mp 124-125 °C; H NMR (300 MHz) δ 1.08 (s, 6 H),

1.10-1.25 (m, 6 H), 1.74 (t, 2 H, J ) 6.0 Hz), 2.40 (t, 2 H, J )

6.0 Hz), 3.27 (heptet, 1 H, J ) 7.0 Hz), 3.50 (s, 0.8 H), 3.52 (s,

1.2 H), 3.81 (s, 1.2 H), 3.83 (s, 1.8 H), 4.00 (s, 1.2 H), 4.01 (s,

0.8 H), 6.85-6.95 (m, 1 H), 7.10-7.20 (m, 1 H), 8.93 (s, 0.6

H), 9.09 (s, 0.4 H); ¹³C NMR (75.5 MHz) 202.6, 197.5, 177.6,

170.1, 149.6, 148.2, 140.9, 131.4, 131.3, 126.4 (d), 126.1 (d),

122.6 (d), 122.5 (d), 113.2, 112.7, 61.4 (q), 60.8 (q), 39.5, 35.6,

35.3 (t), 34.1 (t), 33.8 (t), 26.6 (d), 25.8 (d), 25.7 (t), 24.9 (q),

23.5 (q), 21.7 (t), 21.3 (t) ppm; IR (KBr) 3400-3030 (br), 1619

(br) cm^-1. Anal. for C₂₀H₂₈O₄: Calcd: C, 72.22%; H, 8.52%.

Found: C, 72.10%; H, 8.44%. These data represent a mixture

of enols.

6,6-Dim e t h yl-2-(2,3-d im e t h oxy-4-isop r op ylp h e n yl-

m eth yl)-3-m eth oxy-2-cycloh exen on e (13). To a suspension

of NaH (80% dispersion in mineral oil, 125 mg, 4.16 mmol) in

10 mL of DMF at 0 °C was added dione 12 (1.16 g, 3.47 mmol)

in 15 mL of DMF over a 30-min period. Dimethyl sulfate (0.37

mL, 3.82 mmol) was then added, and the resulting mixture

was stirred for 12 h. The reaction mixture was diluted with

ether, washed sequentially with aqueous 10% HCl and satu-

rated aqueous Na₂CO₃, dried over anhydrous magnesium

sulfate, concentrated, and chromatographed (elution with H:E,

3:1) to give 1.18 g of 13 (98%) which was homogeneous by TLC

analysis (H:E, 1:1, R_f12 ) 0.24, R_f13 ) 0.56): ¹H NMR (300

MHz) δ 1.13 (s, 6 H), 1.18 (d, 6 H, J ) 7.0 Hz), 1.88 (t, 2 H, J

) 6.2 Hz), 2.65 (t, 2 H, J ) 6.2 Hz), 3.26 (heptet, 1 H, J ) 7.0

Hz), 3.62 (s, 2 H), 3.76 (s, 3 H), 3.85 (s, 3 H), 3.90 (s, 3 H), 6.59

(d, 1 H, J ) 8.0 Hz), 6.80 (d, 1 H, J ) 8.3 Hz); ¹³C NMR (75.5

MHz) 202.6 (s), 170.6 (s), 150.8 (s), 150.2 (s), 139.6 (s), 132.3

(s), 122.8 (d), 120.6 (d), 115.6 (s), 60.6 (q), 59.9 (q), 54.8 (q),

39.4 (s), 34.3 (t), 26.5 (d), 24.5 (q), 23.5 (q), 22.0 (t), 21.4 (t)

4,4-Dim et h yl-2-(2,3-d im et h oxy,

4-isop r op ylp h en yl-

m eth yl)-3-vin yl-2-cycloh exen on e (6). A solution of 1.18 g

(3.28 mmol) of enone 13 and CeCl₃(161 mg, 0.66 mmol) in 25

mL of ether at rt was treated dropwise with 5.0 mL (5.00

mmol) of vinylmagnesium bromide (1.0 M in THF) over a

5-min period. The reaction mixture was stirred at rt for a 1-h

period. Standard ethereal workup, followed by purification

by chromatography (elution with H:E, 4:1), provided 830 mg

(74%) of conjugated dienone 6 which was homogeneous by TLC

analysis (H:E, 2:1, R_f13 ) 0.37, R_f6 ) 0.68): ¹H NMR (300

MHz) δ 1.18 (d, 6 H, J ) 6.8 Hz), 1.24 (s, 3 H), 1.94 (t, 2 H, J

) 6.9 Hz), 2.55 (t, 2 H, J ) 6.8 Hz), 3.17-3.35 (m, 1 H), 3.68

(s, 2 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 5.13 (dd, 1H, J ) 17.8 Hz,

1.9 Hz), 5.35 (dd, 1 H, J ) 12.0 Hz, 1.7 Hz), 6.35 (dd, 1 H, J

) 17.8 Hz, 12.0 Hz), 6.53 (d, 1 H, J ) 8.1 Hz), 6.82 (d, 1H, J

) 8.1 Hz); ¹³C NMR (75.5 MHz) 198.5, 163.4, 150.4, 150.2,

139.9, 133.4, 132.3, 132.2, 122.6, 120.7, 119.5, 60.5, 59.7, 37.2,

ppm; IR (film) 1616, 1452, 1364, 1244 cm^-1

.

Anal. for

C₂₁H₃₀O₄. Calcd: C, 72.79%, H, 8.73%. Found: 72.95%, H,

8.90%.

2-(2,3-Dim eth oxy-4-isop r op ylp h en ylm eth yl)-1,3-cyclo-

h exa n ed ion e (14). To 2.00 g of 1,3-cyclohexanedione (13.96

mmol) dissolved in aqueous 20% K₂CO₃(3.09 mL, 5.58 mmol)

at rt were added KI (233 mg, 1.40 mmol) and bromide 10 (3.29

Use of Conjugated Dienones in Cyclialkylations

J . Org. Chem., Vol. 61, No. 23, 1996 8177

35.4, 34.4, 27.2, 26.5, 26.2, 23.5 ppm; IR (film) 1669, 1451,

1408, 1269 cm^-1. Anal. for C₂₂H₃₀O₃. Calcd: C, 77.10%, H,

8.80%. Found: 76.95%, H, 8.90%.

0.92 (s, 3 H), 1.25 (d, 6 H, J ) 6.9 Hz), 1.72-2.15 (m, 5 H),

2.60-2.90 (m, 3 H), 3.00-3.15 (m, 1 H), 3.15-3.35 (m, 2 H),

3.78 (s, 3 H), 5.52 (br s, 1 H), 5.62 (s, 0.4 H), 5.69 (s, 0.6 H),

6.52 (s, 0.6 H), 6.71 (s, 0.4 H). These data represent a mixture

of phenols 18a and 18b.

11,12-Dim e t h oxy-9(10f20)-10rH -a b e o-a b ie t a -5(10),

8,11,13-tetr aen -1-on e (7) an d 8,9-Dim eth oxy-1,1-dim eth yl-

7-isop r op yl-1,2,10,11-t et r a h yd r o-5H -d ib en zo[a ,d ]cyclo-

h ep ten -4-on e (16). To a solution of 6 (4.0 g, 11.70 mmol) in

100 mL of CH₂C1₂at -78 °C was added 4.0 mL of TiCl₄(36.60

mmol), and the reaction mixture was allowed to warm to rt

over a 1-h period. Standard ethereal workup, followed by

chromatography (elution H:E, 4:1), provided 600 mg (15%) of

8,9-dimethoxy-1,1-dimethyl-7-isopropyl-1,2,10,11-tetrahydro-

5H-dibenzo[a,d]cyclohepten-4-one (16) which was homoge-

neous by TLC analysis (H:E, 1:1, R_f6 ) 0.68, R_f16 ) 0.62):

¹H NMR (250 MHz) δ 1.15-1.25 (m, 12 H), 1.82 (t, 2 H, J )

6.9 Hz), 2.50 (t, 2 H, J ) 6.8 Hz), 2.70 (br t, 2 H, J ) 6.4 Hz),

3.00 (br t, 2 H, J ) 6.5 Hz), 3.21-3.30 (m, 1 H), 3.79 (s, 2 H),

3.83 (s, 6 H), 6.82 (s, 1 H).

Continued elution (H:E, 10:1) afforded 425 mg (65%) of

racemic barbatusol which was homogeneous by TLC analysis

(H:E, 5:1, R_f17 ) 0.94, R_f1 ) 0.22): ¹H NMR (300 MHz) δ

0.88 (s, 3 H), 0.92 (s, 3 H), 1.11-1.43 (m, 8 H), 1.81 (br d, 1 H,

J ) 12.0 Hz), 1.92-2.07 (m, 3 H), 2.74-2.82 (m, 2 H), 3.05-

3.12 (m, 2 H), 3.68 (d, 1 H, J ) 14.9 Hz), 4.94 (br s, 1 H), 5.28

(br s, 1 H), 5.51 (br t, 1 H), 6.52 (s, 1 H); ¹³C NMR (75.5 MHz)

140.3 (s), 139.0 (s), 138.0 (s), 134.6 (s), 131.0 (s), 124.4 (s), 121.2

(d), 117.6 (d), 77.2 (s), 50.8 (d), 35.3 (t), 34.5 (t), 32.1 (s), 31.2

(t), 30.5 (t), 27.5 (q), 27.2 (q), 23.2 (t), 22.8 (q), 22.5 (q) ppm;

IR (film) 3500-3100 (br), 1446, 1282, 998 cm^-1

.

Dep r otection of 17 Usin g L-Selectr id e. To 41 mg of 17

(0.125 mmol) in 4.0 mL of dry glyme was added 750 µL of

L-Selectride (1.0 M, 0.75 mmol), and the resulting mixture was

refluxed (90 °C) until TLC analysis indicated that the reaction

was complete (2 days). The reaction mixture was cooled to 0

°C and diluted with 50 mL of ether, and the resulting mixture

was quenched slowly with water. Standard ethereal workup,

followed by chromatography (elution with H:E, 10:1), gave 18

mg of phenols 18a and 18b (45%) as an inseparable mixture.

Continued elution (H:E, 5:1) provided 17 mg (45%) of

racemic-barbatusol which was identical to that described

above.

Continued elution afforded 3.0 g (75%) of 1,12-dimethoxy-

9(10f20)-10RH-abeo-abieta-5(10),8,11,13-tetraen-1-one (7)

which was homogeneous by TLC analysis (H:E, 1:1, R_f7 )

0.53): ¹H NMR (250 MHz) δ 1.17 (s, 6 H), 1.20 (d, 6 H, J )

7.0 Hz), 1.80 (t, 2 H, J ) 6.9 Hz), 2.50 (t, 2 H, J ) 6.9 Hz),

2.67 (t, 2 H, J ) 6.3 Hz), 2.99 (t, 2 H, J ) 6.3 Hz), 3.28 (heptet,

1 H, J ) 7.0 Hz), 3.82 (s, 3 H), 3.85 (s, 3 H), 3.91 (s, 2 H), 6.70

(s, 1 H); ¹³C NMR (75.5 MHz) 197.4 (s), 165.2 (s), 150.2 (s),

148.6 (s), 140.1 (s), 136.1 (s), 133.1 (s), 130.2 (s), 121.1 (d), 60.9

(q), 60.8 (q), 37.1 (t), 36.4 (s), 34.3 (t), 30.9 (t), 29.4 (t), 26.7

(d), 26.6 (q), 23.6 (q), 20.2 (t) ppm; IR (film) 1660, 1048, 727

2-(2,3-Dim eth oxy-4-isop r op ylp h en ylm eth yl)-3-vin yl-2-

cycloh exen on e (19). A solution of 1.18 g (3.28 mmol) of

enone 15 and CeCl₃(161 mg, 0.66 mmol) in 25 mL of ether at

0 °C was treated dropwise with 5.0 mL (5.0 mmol) of vinyl-

magnesium bromide (1.0 M in THF) over a 5-min period. The

reaction mixture was stirred for 3 h with slow warming to rt.

It was then diluted with ether (30 mL), and 10 mL of a solution

of aqueous 10% HCl was added. After 5 min of vigorous

stirring, the phases were separated, and the ethereal phase

was washed with saturated aqueous sodium bicarbonate,

saturated aqueous NH₄Cl, dried over anhydrous magnesium

sulfate, filtered, and then concentrated. Purification by chro-

matography (elution with H:E, 4:1) provided 830 mg (74%) of

conjugated dienone 19 which was homogeneous by TLC

analysis (H:E, 2:1, R_f15 ) 0.37, R_f19 ) 0.68): ¹H NMR (300

MHz) δ 1.18 (d, 6 H, J ) 6.6 Hz), 2.06 (heptet, 1 H, J ) 6.4

Hz), 2.50 (t, 1 H, J ) 6.4 Hz), 2.60 (t, 1 H, J ) 6.4 Hz), 3.26

(heptet, 1 H, J ) 6.6 Hz), 3.81 (s, 2 H), 3.86 (s, 3 H), 3.91 (s,

3 H), 5.44 (d, 1 H, J ) 11.2 Hz), 5.70 (d, 1 H, J ) 17.6 Hz),

6.60 (d, 1 H, J ) 8.2 Hz), 6.84 (d, 1 H, J ) 8.2 Hz), 6.96 (dd,

1 H, J ) 17.6 Hz, 11.2 Hz); ¹³C NMR (75.5 MHz) 199.4 (s),

151.0 (s), 150.5 (s), 150.2 (s), 140.3 (s), 135.1 (d), 135.1 (s) (the

preceding signals overlap), 131.4 (s), 123.3 (d), 120.8 (d), 120.6

(t), 60.5 (q), 60.0 (q), 38.0 (t), 26.6 (d), 25.5 (t), 23.5 (t), 23.5 (q)

(the preceding signals overlap), 21.5 (t) ppm.

cm^-1

.

Cycliza tion of 6 Usin g Bor on Tr iflu or id e Eth er a te. To

a solution of 6 (80 mg) in 3 mL of CH₂Cl₂at rt was added 95

µL of boron trifluoride etherate (0.58 mmol), and the reaction

mixture was stirred for 10 h. Standard ethereal workup,

followed by purification by silica gel chromatography (elution

with H:E, 4:1), afforded 59 mg (74%) of enone 16 and 15 mg

(16%) of enone 7.

11,12-Dim et h oxy-9(10f20)-10RH -a b eo-a b iet a -1(10),8,

11,13-tetr a en e (ba r ba tu sol d im eth yl eth er , 17). Enone 7

(743 mg, 2.17 mmol) was heated at reflux for 30 min with 606

mg (3.25 mmol) of tosylhydrazine in 10 mL of absolute ethanol.

Evaporation of the solvent and elution of the residue through

a plug of silica gel afforded the crude hydrazone, which was

used without further purification or characterization (H:E, 5:1,

R_fhydrazone ) 0.32, R_f7 ) 0.85).

The hydrazone was stirred under nitrogen in 9 mL of DMF

and 9 mL of sulfolane containing 50 mg of bromocresol green.

The mixture was warmed to 100 °C, and sodium cyanoboro-

hydride (1.36 g, 21.70 mmol) was added, followed by sufficient

2 N HCl to give a tan color. Heating was continued for 40

min during which time several portions of 2 N HCl were added

to maintain the proper acidity, as indicated by the tan color.

The mixture was cooled, poured into water, and extracted with

ether. The residue obtained was dried over anhydrous mag-

nesium sulfate, filtered, and concentrated. The resulting

residue was chromatographed to give 528 mg (75%) of bar-

batusol dimethyl ether (17) which was homogeneous by TLC

analysis (H:E, 1:1, R_fhydrazone ) 0.32, R_f17 ) 0.80): ¹H

NMR (250 MHz) δ 0.87 (s, 3 H), 0.89 (s, 3 H), 0.92-0.99 (m, 2

H), 1.19 (d, 6 H, J ) 8.0 Hz), 1.12-1.38 (m, 8 H), 1.79 (d, 1 H,

J ) 12.1 Hz), 1.90-2.15 (m, 3 H), 2.77-2.84 (td, 2 H, J ) 8.6

Hz, 3.0 Hz), 3.03 (d, 1 H, J ) 14.4 Hz), 3.27 (heptet, 1 H, J )

6.9 Hz), 3.83 (s, 3 H), 3.85 (s, 3 H), 5.50 (br t, 1 H), 6.72 (s, 1

H); ¹³C NMR (75.5 MHz) 149.5, 148.7, 139.2, 138.3, 137.9,

132.4, 121.6, 121.3, 60.7, 60.6, 51.4, 35.3, 35.1, 32.1, 31.3, 30.0,

27.6, 27.2, 26.6, 23.8, 23.5, 23.2 ppm.

(()-Ba r ba tu sol (1). Barbatusol dimethyl ether (17) (710

mg, 2.20 mmol) was combined with ethanethiol (3.0 mL, 36.00

mmol) and 800 mg of sodium hydride (80% dispersion in oil)

in 20 mL of freshly distilled DMF. The reaction mixture was

refluxed under nitrogen for 5 h and acidified with 2 N HCl.

Standard ethereal workup, followed by purification by chro-

matography on silica gel (elution with H:E, 10:1), gave 170

mg (25%) of phenols 18a and 18b as an inseparable mixture

which was homogenous by TLC analysis (H:E, 5:1, R_f17 )

0.95, R_f18a /b ) 0.56): ¹H NMR (300 MHz) δ 0.88 (s, 3 H),

Cycliza tion of 19 u sin g BF ₃-Et₂O. To a solution of 19

(26 mg, 0.08 mmol) in 3 mL of CH₂Cl₂at rt was added 50 µL

of BF₃-Et₂O. The resulting mixture was refluxed for 50 h.

Standard ethereal workup, followed by chromatography (elu-

tion with H:E, 2:1), gave 10 mg (38%) of 8,9-dimethoxy-7-

isopropyl-1,2,10,11-tetrahydro-5H-dibenzo[a,d]cyclohepten-4-

one (21) which was homogeneous by TLC analysis (H:E, 2:1,

R_f19 ) 0.68, R_f21 ) 0.55): ¹H NMR (250 MHz) δ 1.20 (d, 6

H, J ) 7.2 Hz), 1.50 (heptet, 2 H, J ) 6.5 Hz), 2.21 (t, 2 H, J

) 6.5 Hz), 2.43 (t, 2 H, J ) 6.2 Hz), 2.55 (t, 2 H, J ) 6.5 Hz),

3.06 (t, 2 H, J ) 6.2 Hz), 3.28 (heptet, 1 H, J ) 7.2 Hz), 3.78

(s, 2 H), 3.83 (s, 3 H), 3.84 (3 H), 6.84 (s, 1 H); ¹³C NMR (75.5

MHz) 198.4 (s), 157.7 (s), 149.8 (s), 148.8 (s), 140.1 (s), 137.4

(s), 132.6 (s), 131.8 (s), 121.6 (d), 60.8 (q), 37.8 (t), 35.9 (t),

33.0 (t), 28.2 (t), 26.6 (d), 23.6 (q), 22.5 (t), 22.0 (t) ppm.

Continued elution (H:E, 2:1) gave 8 mg (31%) of 6,7-

dimethoxy-8-isopropyl-1,2,10,11-tetrahydro-5H-dibenzo[a,d]-

cyclohepten-4-one (20) which was homogeneous by TLC analy-

sis (H:E, 2:1, R_f19 ) 0.68, R_f20 ) 0.52): ¹H NMR (250 MHz)

δ 1.22 (d, 6 H, J ) 7.2 Hz), 1.88 (heptet, 2 H, J ) 6.5 Hz), 2.20

(t, 2 H, J ) 6.5 Hz), 2.42 (t, 2 H, J ) 6.5 Hz), 2.54 (t, 2 H, J

) 6.5 Hz), 2.98 (t, 2 H, J ) 6.5 Hz), 3.30 (heptet, 1 H, J ) 7.1

Hz), 3.76 (s, 3 H), 3.84 (s, 3 H), 3.90 (s, 2 H), 6.78 (s, 1 H); ¹³

C

8178 J . Org. Chem., Vol. 61, No. 23, 1996

Majetich et al.

NMR (62.9 MHz) 197.4 (s), 158.0 (s), 157.8 (s), 149.8 (s), 148.6

(s), 140.0 (s), 137.4 (s), 132.4 (s), 132.2 (s), 120.2 (d), 60.9 (q),

60.8 (q), 37.7 (t), 36.3 (t), 33.0 (t), 29.6 (t), 26.5 (d), 23.6 (q),

22.0 (t), 19.3 (t) ppm.

Cycliza tion of 19 Usin g TiCl₄. To a solution of 19 (45

mg, 0.14 mmol) in 3 mL of CH₂Cl₂was added 90 µL of TiCl₄

(0.82 mmol) at -78 °C. The reaction mixture was warmed to

0 °C over a 90-min period, stirred at 0 °C for a 30-min period,

and then stirred at rt for 4 h. Standard ethereal workup,

followed by chromatography (elution with H:E, 2:1), afforded

2.1 mg (7%) of 21 and 25.2 mg (56%) of 20, both of which were

identical to that previously characterized.

by chromatography (elution with H:E, 2:1), gave 51 mg (66%)

of 23, which was identical to that previously prepared.

P r ep a r a tion of 23 Usin g F eCl₃. To a solution of FeCl₃

(25 mg) in 2 mL of CH₂Cl₂was added dienone 22 (49 mg, 0.15

mmol) in 1 mL of CH₂Cl₂. The resulting mixture was stirred

at rt for 12 h. Standard ethereal workup and chromatography

gave 39 mg (80%) of enone 23, which was identical to that

previously characterized.

2-(4-I s o p r o p y lp h e n y lm e t h y l)-3-v in y l-2-c y c lo h e x -

en on e (24). To sodium borohydride (2.57 g, 68.00 mmol) in

175 mL of absolute ethanol at 0 °C was added 4-isopropyl-

benzaldehyde (20.0 g, 0.135 mol, Eastman) over a 5-min period.

The reaction mixture was concentrated under reduced pres-

sure to half volume, and 100 mL of water was added.

Standard ethereal workup, followed by chromatography (elu-

tion with H:E, 10:1), gave 19.00 g (94%) of 4-isopropylphenyl-

methyl alcohol which was homogeneous by TLC analysis (H:

E, 1:1, R_faldehyde ) 0.82, R_falcohol ) 0.50): ¹H NMR (250

MHz) δ 1.28 (d, 6 H, J ) 6.9 Hz), 2.29 (br s, 1 H), 2.94 (heptet,

1 H, J ) 6.9 Hz), 4.63 (s, 2 H), 7.24 (d, 2 H, J ) 8.2 Hz), 7.30

(d, 2 H, J ) 8.2 Hz); ¹³

4-(2,3-Dim eth oxy-4-isop r op ylp h en ylm eth yl)-4-m eth yl-

3-vin yl-2-cycloh exen on e (22). To a solution of LDA, pre-

pared from diisopropylamine (700 µL, 5.0 mmol) in 15 mL of

THF and 2.0 mL (5.00 mmol) of n-butyllithium (2.5 M in

hexanes), at -78 °C was added a solution of 660 mg (4.28

mmol) of 3-ethoxy-6-methyl-2-cyclohexenone in 6 mL of THF

over a 50-min period. After an additional 1 h at -78 °C,

bromide 10 (1.27 g, 4.64 mmol) was added and the reaction

mixture was warmed to rt over a 12-h period. Standard

ethereal workup, followed by chromatograpy (elution with H:E,

1:1), afforded 490 mg (74%) of 3-ethoxy-6-(2,3-dimethoxy-4-

isopropylphenylmethyl)-6-methyl-2-cyclohexenone which was

homogeneous by TLC analysis (H:E, 1:1, R_fenone ) 0.35, R_f

alkylated adduct ) 0.43): ¹H NMR (250 MHz) δ 1.00 (s), 1.13

(d, 6 H, J ) 7.0 Hz), 1.29 (t, 3 H, J ) 7.0 Hz), 1.52-1.68 (m,

1 H), 1.71-1.86 (m, 1 H), 2.22-2.51 (m, 2 H), 2.76 (d, 1 H, J

) 11.4 Hz), 2.85 (d, 1 H, J ) 11.4 Hz), 3.21 (heptet, 1 H, J )

7.0 Hz), 3.73 (s, 3 H), 3.75 (s, 3 H), 3.83 (q, 2 H, J ) 7.0 Hz),

5.24 (s, 1 H); ¹³C NMR (62.9 MHz) 203.6 (s), 175.7 (s), 151.7

(s), 150.0 (s), 140.6 (s), 128.9 (s), 126.9 (d), 120.1 (d), 101.2 (d),

63.8 (t), 60.2 (q), 59.7 (q), 44.5 (s), 35.4 (t), 31.2 (t), 26.4 (d),

25.9 (t), 23.3 (q), 22.4 (q), 13.9 (q) ppm.

A solution of 280 mg (0.81 mmol) of the above enone in 15

mL of ether at 0 °C was treated dropwise with 2.0 mL (2.00

mmol) of vinylmagnesium bromide (1.0 M in THF) over a

5-min period. The reaction mixture was warmed to rt over a

12-h period. Standard ethereal workup, followed by chroma-

tography (elution with H:E, 2:1), provided 262 mg (98%) of

dienone 22 which was homogeneous by TLC analysis (H:E,

2:1, R_fenone ) 0.37, R_f22 ) 0.68): ¹H NMR (300 MHz) δ

1.06 (s, 3 H), 1.18 (d, 6 H, J ) 7.0 Hz), 1.61-1.72 (m, 1 H),

1.94 (dt, 1 H, J ) 17.5 Hz, 5.3 Hz), 2.54 (ddd, 1 H, J ) 17.1

Hz, 11.4 Hz, 5.3 Hz), 2.76 (d, 1 H, J ) 13.3 Hz), 2.85 (d, 1 H,

J ) 13.4 Hz), 3.27 (heptet, 1 H, J ) 7.0 Hz), 3.49 (s, 3 H), 5.36

(dd, 1 H, J ) 10.9 Hz, 1.4 Hz), 5.71 (dd, 1 H, J ) 16.7 Hz, 1.4

Hz), 6.12 (s, 1 H), 6.53 (dd, 1 H, J ) 16.7 Hz, 10.9 Hz), 6.79

(d, 1 H, J ) 8.0 Hz), 6.85 (d, 1 H, J ) 8.0 Hz); ¹³C NMR (62.9

MHz) 199.9 (s), 165.8 (s), 151.8 (s), 150.3 (s), 141.5 (s), 134.4

(d), 128.2 (s), 126.5 (d), 123.4 (d), 120.3 (d), 119.9 (t), 60.3 (q),

59.9 (q), 38.9 (s), 36.6 (t), 34.1 (t), 33.6 (t), 26.6 (d), 25.2 (q),

23.4 (q) ppm.

6,7-Dim et h oxy-8-isop r op yl-4a -m et h yl-4,4a ,10,11-t et -

r a h yd r o-5H-d iben zo[a ,d ]cycloh ep ten -2-on e (23). To a

solution of 22 (84 mg, 0.26 mmol) in 3 mL of CH₂Cl₂was added

150 µL of BF₃-Et₂O, and the resulting mixture was refluxed

for 12 h. Standard ethereal workup, followed by chromatrog-

raphy (elution with H:E, 1:1), afforded 81 mg (96%) of 23 which

was homogeneous by TLC analysis (H:E, 1:1, R_f22 ) 0.51, R_f

23 ) 0.46): ¹H NMR (250 MHz) δ 1.09 (s, 3 H), 1.21 (dd, 6 H,

J ) 7.1 Hz, 3.4 Hz), 1.89 (dt, 1 H, J ) 13.5 Hz, 5.1 Hz), 2.03

(ddd, 1 H, J ) 15.0 Hz, 12.4 Hz, 5.3 Hz), 2.35-2.58 (m, 3 H),

2.69 (d, 1 H, J ) 13.9 Hz), 2.71-2.96 (m, 2 H), 3.00 (d, 1 H, J

) 13.9 Hz), 3.28 (heptet, 1 H, J ) 7.1 Hz), 3.81 (s, 3 H), 3.83

(s, 3 H), 5.75 (s, 1 H), 6.72 (s, 1 H); ¹³C NMR (62.9 MHz) 199.8

(s), 171.4 (s), 151.2 (s), 148.6 (s), 140.6 (s), 136.6 (s), 128.6 (s),

126.6 (d), 121.2 (d), 60.5 (q), 60.3 (q), 38.9 (s), 37.3 (t), 37.2 (t),

34.3 (t), 34.3 (t) (the two preceding signals overlap), 33.5 (t),

26.6 (d), 23.5 (q), 23.0 (q) ppm.

C NMR (62.9 MHz) 148.3 (s), 138.2 (s),

127.1 (d), 126.5 (d), 65.0 (t), 33.8 (d), 23.9 (q) ppm.

To a solution of 18.71 g (0.125 mol) of the above alcohol in

200 mL of dry ether at 0 °C was added phosphorus tribromide

(5.90 mL, 62 mmol) over a 5-min period. Standard ethereal

workup, followed by chromatograpy (elution with H:E, 1:1),

afforded 22.33 g (84%) of 4-isopropylphenylmethyl bromide

which was homogeneous by TLC analysis (H:E, 5:1, R_falcohol

) 0.12, R_fbromide ) 0.85): ¹H NMR (250 MHz) δ 1.35 (d, 6

H, J ) 6.2 Hz), 2.91 (heptet, 1 H, J ) 6.2 Hz), 4.51 (s, 2 H),

7.14 (d, 2 H, J ) 7.8 Hz), 7.35 (d, 2 H, J ) 7.8 Hz); ¹³C NMR

(62.9 MHz) 149.3 (s), 135.1 (s), 129.0 (d), 126.9 (d), 33.9 (d),

33.8 (t), 23.9 (q) ppm.

1,3-Cyclohexanedione (5.25 g, 46.80 mmol) was dissolved in

10 mL of absolute methanol. To this solution was added 5.00

g of the above benzyl bromide (23.50 mmol), 1.95 g of KI (11.71

mmol), and 3.24 g of K₂CO₃(23.42 mmol). The reaction

mixture was then stirred for a 3-h period. The reaction

mixture was diluted with 50 mL of water and extracted twice

with 50 mL of a 1:1 mixture of ethyl acetate and ether. The

organic phase was extracted with saturated aqueous NaHCO₃

to remove unreacted 1,3-cyclohexanedione. The sodium salt

of the alkylated dione was extracted into aqueous 5% NaOH.

This solution was acidified by addition of aqueous 10% HCl

and extracted with 50 mL of a 1:1 mixture of ethyl acetate

and ether. The combined organic extracts were dried over

anhydrous magnesium sulfate and concentrated. The white

solid residue was recrystallized from ethanol/water (1:3) to give

3.80 g (66%) of 2-(4-isopropylphenylmethyl)-1,3-cyclohexanedi-

one which was homogeneous by TLC analysis (ether, R_fdione

1

) 0.35): mp 171-172.5 °C; H NMR (250 MHz) δ 1.22 (d, 6

H, J ) 6.9 Hz), 1.92 (tt, 2 H, J ) 6.4 Hz, 6.4 Hz), 2.43 (t, 4 H,

J ) 6.4 Hz), 2.46 (heptet, 1 H, J ) 6.9 Hz), 3.63 (s, 2 H), 7.09

(d, 2 H, J ) 8.2 Hz), 7.16 (d, 2 H, J ) 8.2 Hz); ¹³C NMR (62.9

MHz) 204.0 (s), 146.1 (s), 137.9 (s), 128.9 (d), 126.3 (d), 115.5

(s), 33.5 (d), 27.0 (t), 24.0 (q), 20.6 (t), 20.6 (t) (the two preceding

signals overlap) ppm.

To a suspension of NaH (57% dispersion in mineral oil, 690

mg, 16.43 mmol) in 10 mL of DMF at 0 °C was added the above

dione (2.50 g, 10.21 mmol) in 25 mL of DMF over a 30-min

period. Dimethyl sulfate (1.30 mL, 13.32 mmol) was then

added and the resulting mixture was stirred for 3 h. Standard

ethereal workup, followed by chromatography (elution with

H:E, 3:1), gave 2.17 g (82%) of 2-(4-isopropylphenylmethyl)-

3-methoxy-2-cyclohexenone which was homogeneous by TLC

analysis (ether, R_fdione ) 0.66, R_fenol ether ) 0.43): ¹H NMR

(300 MHz) δ 1.22 (d, 6 H, J ) 6.9 Hz) 2.00 (tt, 2 H, J ) 6.2

Hz, 6.2 Hz), 2.37 (t, 2 H, J ) 6.2 Hz), 2.59 (t, 2 H, J ) 6.2 Hz),

2.85 (heptet, 1 H, J ) 6.9 Hz), 3.59 (s, 2 H), 3.82 (s, 3 H), 7.08

(d, 2 H, J ) 8.2 Hz), 7.18 (d, 2 H, J ) 8.2 Hz); ¹³C NMR (62.9

MHz) 198.0 (s), 172.7 (s), 145.7 (s), 138.8 (s), 128.5 (d), 126.0

(d), 119.1 (s), 55.2 (q), 36.2 (t), 33.6 (d), 27.2 (t), 24.8 (t), 24.0

(q), 20.7 (t) ppm.

P r ep a r a tion of 23 Usin g TiCl₄. To a solution of dienone

22 (80 mg, 0.24 mmol) in 5 mL of CH₂Cl₂was added 150 µL of

TiCl₄(1.37 mmol) at -78 °C and the reaction mixture was

warmed to 0 °C over a 90-min period. The reaction was stirred

an additional 5 h at 0 °C before TLC analysis indicated that

reaction was complete. Standard ethereal workup, followed

A solution of 4.09 g (15.8 mmol) of the above enone and 390

mg of CeCl₃(1.58 mmol) in 53 mL of ether at rt was treated

dropwise with 31.6 mL (31.60 mmol) of vinylmagnesium

Use of Conjugated Dienones in Cyclialkylations

J . Org. Chem., Vol. 61, No. 23, 1996 8179

bromide (1.0 M in THF) over a 5-min period. The reaction

mixture was stirred for 5 min. Standard ethereal workup,

followed by chromatography (elution with H:E, 10:1), provided

3.30 g (82%) of conjugated dienone 24 which was homogeneous

by TLC analysis (H:E, 1:2, R_fenone ) 0.23, R_f24 ) 0.80): ¹H

NMR (250 MHz) δ 1.23 (d, 6 H, J ) 6.9 Hz), 1.95-2.15 (m, 2

H), 2.50 (t, 2 H, J ) 6.1 Hz), 2.59 (t, 2 H, J ) 6.1 Hz), 2.86

(heptet, 1 H, J ) 6.9 Hz), 4.81 (s, 2 H), 5.49 (d, 1 H, J ) 11.0

Hz), 5.71 (d, 1 H, J ) 17.3 Hz), 6.90-7.15 (m, 5 H); ¹³C NMR

(62.9 MHz) 199.5 (s), 150.5 (s), 146.1 (s), 137.5 (s), 135.5 (s),

135.0 (d), 128.1 (d), 126.3 (d), 120.9 (t), 38.1 (t), 33.6 (d), 29.5

(t), 25.5 (t), 24.0 (q), 21.9 (t) ppm. Anal. for C₂₂H₃₀O₃. Calcd:

C, 84.99%, H, 8.72%. Found: 84.75%, H, 8.80%.

Na₂CO₃, dried over anhydrous magnesium sulfate, concen-

trated, and chromatographed (elution with H:E, 3:1) to give

477 mg (74%) of 2-(4-isopropyl-3-methoxyphenylmethyl)-3-

methoxy-2-cyclohexenone which was homogeneous by TLC

analysis (H:E, 1:2, R_fdione ) 0.75, R_fenol ether ) 0.18): mp

94-96 °C; ¹H NMR (250 MHz) δ 1.18 (d, 6 H, J ) 6.9 Hz),

1.95-2.10 (m, 2 H), 2.38 (t, 2 H, J ) 6.2 Hz), 2.60 (t, 2 H, J )

6.2 Hz), 3.25 (heptet, 1 H, J ) 6.9 Hz), 3.59 (s, 2 H), 3.81 (s,

3 H), 3.83 (s, 3 H), 6.75-6.85 (m, 2 H), 7.05 (d, 1 H, J ) 7.7

Hz); ¹³C NMR (62.9 MHz) 197.9 (s), 172.5 (s), 156.3 (s), 140.0

(s), 133.8 (s), 125.3 (d), 120.4 (d), 119.0 (s), 111.2 (d), 55.2 (q),

55.2 (q) (the methoxyl signals overlap), 36.2 (t), 27.5 (t), 26.3

(d), 24.8 (t), 22.7 (q), 20.7 (t) ppm.

Attem p ted Cycliza tion of 24 Usin g TiCl₄. To a solution

of substrate 24 (400 mg, 1.57 mmol) dissolved in 10 mL of

CH₂Cl₂was added 520 µL (4.70 mmol) of TiCl₄at -78 °C. The

reaction mixture was warmed to 20 °C over a 7-h period. The

reaction was then stirred for an additional 5 h at 0 °C.

Standard ethereal workup, followed by chromatography (elu-

tion with H:E, 10:1), gave 65 mg (14%) of 2-(4-isopropylphen-

ylmethyl)-3-(2-chloroethyl)-2-cyclohexenone (25), which was

homogeneous by TLC analysis: ¹H NMR (250 MHz) δ 1.22 (d,

6 H, J ) 6.9 Hz), 1.90-2.10 (m, 2 H), 2.35-2.55 (m, 4 H), 2.75-

2.95 (m 3 H), 3.52 (t, 2 H, J ) 7.4 Hz), 3.70 (s, 2 H), 7.04 (d,

2 H, J ) 8.3 Hz), 7.11 (d, 2 H, J ) 8.3 Hz).

Rea ction of 24 Usin g BF ₃-Et₂O. To a solution of 24 (100

mg, 0.39 mmol) in 4 mL of CH₂Cl₂was added 145 µL (1.18

mmol) of BF₃-Et₂O. The reaction mixture was stirred for 6 h

at rt and then refluxed for a 7-h period. Standard ethereal

workup furnished only unreacted 24.

A solution 470 mg of the above enone in 15 mL of THF was

treated dropwise with 3.30 mL (3.30 mmol) of vinylmagnesium

bromide (1.0 M in THF) over a 5-min period. The reaction

mixture was stirred at rt for 5 min and then quenched with

ice and diluted with 20 mL of ether and 10 mL of 10% aqueous

HCl. Standard ethereal workup, followed by purification by

chromatography (elution with H:E, 10:1), provided 410 mg

(88%) of conjugated dienone 26 which was homogeneous by

TLC analysis (H:E, 1:2, R_f26 ) 0.79): ¹H NMR (250 MHz) δ

1.17 (d, 6 H, J ) 6.9 Hz), 1.95-2.15 (m, 4 H), 2.50 (t, 2 H, J )

6.1 Hz), 2.59 (t, 2 H, J ) 6.1 Hz), 3.20 (heptet, 1 H, J ) 6.9

Hz), 3.79 (s, 3 H), 3.80 (s, 2 H), 5.49 (d, 1 H, J ) 11.0 Hz), 5.71

(d, 1 H, J ) 16.8 Hz), 6.63-6.75 (m, 2 H), 7.04 (dd, 1 H, J

)16.8 Hz, 11.0 Hz), 7.06 (d, 1 H, J ) 7.7 Hz); ¹³C NMR (62.9

MHz) 199.5 (s), 156.6 (s), 150.6 (s), 138.7 (s), 135.5 (s), 135.1

(d), 134.3 (s), 125.7 (d), 120.9 (t), 119.9 (d), 110.7 (d), 55.2 (q),

38.1 (t), 29.8 (t), 26.4 (d), 25.6 (t), 22.7 (q), 21.9 (t) ppm.

2-(3-Met h oxy-4-isop r op ylp h en ylm et h yl)-3-vin yl-2-cy-

cloh exen on e (26). To a solution of 3.30 g (18.31 mmol) of

4-isopropyl-3-methoxybenzyl alcohol (30)³¹in 75 mL of dry

ether at 0 °C was added phosphorus tribromide (2.10 mL, 22.00

mmol) over a 5-min period. The reaction mixture was stirred

at rt for 10 h. Standard ethereal workup, followed by chro-

matography (elution with H:E, 20:1), afforded 3.50 g (79%) of

3-methoxy-4-isopropylphenylmethyl bromide (31) which was

homogeneous by TLC analysis (H:E, 9.75:0.25, R_falcohol )

0.05, R_fbromide ) 0.43): ¹H NMR (300 MHz) δ 1.18 (d, 6 H,

J ) 6.8 Hz), 3.23-3.30 (m, 1 H), 3.83 (s, 3 H), 4.48 (s, 2 H),

6.85 (s, 1 H), 6.94 (d, 1 H, J ) 7.9 Hz), 7.14 (d, 1 H, J ) 7.8

Hz).

Bromide 31 (0.50 g, 2.06 mmol) was dissolved in 0.5 mL of

water and 0.5 mL of THF. 1,3-Cyclohexanedione (0.46 g, 4.11

mmol), K₂CO₃(0.57 g, 4.11 mmol), and KI (173 mg, 1.03 mmol)

were then added and the mixture was stirred at rt for 12 h.

The reaction was quenched with 2 mL of saturated NH₄Cl.

Mixture was extracted with ether (3 × 10 mL). The organic

phase was extracted with saturated aqueous NaHCO₃to

remove unreacted 1,3-cyclohexanedione. The sodium salt of

the alkylated dione was then extracted into aqueous 5%

NaOH. This solution was acidified by the addition of aqueous

10% HCl and extracted twice with 50 mL of a 1:1 mixture of

ethyl acetate and ether. The combined organic extracts were

dried over anhydrous magnesium sulfate and concentrated.

The white solid residue was recrystallized from methanol:

water (1:1) to give 243 mg (43%) of 2-(4-isopropyl-3-methoxy-

phenylmethyl)-1,3-cyclohexanedione which was homogeneous

by TLC analysis (ether, R_fdione ) 0.35): mp 178-179 °C; ¹H

NMR (250 MHz) δ 1.15 (d, 6 H, J ) 6.8 Hz), 1.96 (quintet, 2

H, J ) 6.5 Hz), 2.42 (t, 4 H, J ) 6.5 Hz), 3.42-3.50 (m, 0.5 H),

3.15-3.25 (m, 1 H), 3.63 (s, 2 H), 3.70 (s, 3 H), 6.23 (s, 0.5 H),

6.70 (s, 1 H), 6.75 (d, 1 H, J ) 7.5 Hz), 7.07 (d, 1 H, J ) 7.7

Hz); ¹³C NMR (62.9 MHz) 188.0 (s), 156.8 (s), 138.8 (s), 134.6

(s), 125.8 (d), 120.1 (d), 115.4 (s), 110.9 (d), 55.3 (q), 32.6 (t),

32.6 (t) (the two preceding signals overlap), 27.5 (t), 26.4 (d),

22.7 (q), 20.6 (t) ppm.

7-Meth oxy-8-isop r op yl-1,2,10,11-tetr a h yd r o-5H-d iben -

zo[a ,d ]cycloh ep ten -4-on e (27). To a solution of dienone 26

(52 mg, 0.18 mmol) in 2 mL of dry CH₂Cl₂was added BF₃-

Et₂O (77 mg, 0.54 mmol). The reaction was refluxed for 12 h.

Standard ethereal workup, and purification by chromatogra-

phy (elution with H:E, 5:1), provided 52 mg (100%) of 27 which

was homogeneous by TLC analysis (H:E, 5:1, R_f26 ) 0.48, R_f

27 ) 0.40): ¹H NMR (250 MHz) δ 1.21 (d, J ) 6.9 Hz), 1.80-

2.00 (m, 2 H), 2.21 (t, 2 H, J ) 5.8 Hz), 2.43 (t, 2 H, J ) 6.2

Hz), 2.55 (t, 2 H, J ) 6.7 Hz), 2.98 (t, 2 H, J ) 6.7 Hz), 3.29

(heptet, 1 H, J ) 6.9 Hz), 3.81 (s, 5 H), 6.73 (s, 1 H), 6.99 (s,

1 H); ¹³C NMR (62.9 MHz) 198.3 (s), 157.9 (s), 154.9 (s), 138.8

(s), 134.7 (s), 132.5 (s), 125.5 (d), 111.1 (d), 55.4 (q), 37.7 (t),

36.5 (t), 33.0 (t), 30.2 (t), 28.1 (t), 26.3 (d), 22.7 (q), 21.9 (t)

(two aryl signals overlap) ppm; GC-MS (m/z) 284 (M⁺, 9%),

122 (100%).

2-(2-Met h oxy-4-isop r op ylp h en ylm et h yl)-3-vin yl-2-cy-

cloh exen on e (28). To a solution of 3-isopropylphenol (20.00

g, 0.147 mol, Aldrich) and NaOH (7.36 g, 0.184 mol) in 250

mL of absolute ethanol was added dimethyl sulfate (35.0 mL,

0.36 mol) over a 5-min period. The reaction mixture was

refluxed for 2 h. The reaction mixture was concentrated to

half volume under reduced pressure and the resulting mixture

was diluted with 100 mL of water. Standard ethereal workup

provided 21.0 g of 3-isopropylanisole (95%), which was ho-

mogenous by TLC analysis (H:E, 1:1, R_fphenol ) 0.61, R_f

anisole ) 0.87): ¹H NMR (300 MHz) δ 1.26 (d, 6 H, J ) 6.9

Hz), 2.90 (heptet, 1 H, J ) 6.9 Hz), 3.83 (s, 3 H), 6.70-6.89 (m,

3 H), 7.22 (t, 1 H, J ) 7.5 Hz).

To 3-isopropylanisole (10.00 g, 66.60 mmol) dissolved in 150

mL of dry ether was added 20.00 mL of TMEDA (0.13 mol).

The resulting mixture was cooled to -78 °C and 35.0 mL of

2.5 M n-butyllithium in hexanes (86.61 mmol) was added

slowly. The mixture was allowed to warm to rt over 2 h, after

which it was treated at rt with excess gaseous formaldehyde

(generated from 6.0 g of paraformaldehyde via pyrolysis at 135

°C). The reaction was quenched with saturated aqueous

NH₄Cl. Standard ethereal workup, followed by chromatogra-

phy (elution with H:E, 5:2), gave 10.51 g (88%) of a 1:1 mixture

of 2-methoxy-4-isopropylphenylmethyl alcohol and 2-methoxy-

6-isopropylphenylmethyl alcohol which was inseparable based

on TLC analysis (H:E, 1:1, R_fanisole ) 0.94, R_falcohols )

0.34): ¹H NMR (300 MHz) δ 1.26 (d, 3 H, J ) 6.9 Hz), 1.27 (d,

3 H, J ) 6.9), 2.46 (br s, 2 H), 2.91 (heptet, 0.5 H, J ) 6.9 Hz),

3.32 (heptet, 0.5 H, J ) 6.9 Hz), 3.86 (s, 3 H), 3.88 (s, 3 H),

To a suspension of degreased NaH (57% dispersion in

mineral oil, 151 mg, 3.60 mmol) in 5 mL of dry DMF at 0 °C

was added the above dione (617 mg, 2.25 mmol) in 5 mL of

DMF over a 5-min period. The resulting solution was stirred

at rt for 30 min. Dimethyl sulfate (369 mg, 2.93 mmol) was

then added, and the resulting mixture was stirred at rt for 1

h. The reaction mixture was diluted with ether, washed

sequentially with aqueous 10% HCl and saturated aqueous

8180 J . Org. Chem., Vol. 61, No. 23, 1996

Majetich et al.

4.65 (s, 1 H), 4.80 (s, 1 H), 6.65-6.85 (m, 1.5 H), 6.95 (d, 0.5

H, J ) 7.3 Hz), 7.15-7.30 (m, 1 H).

(d), 108.4 (d), 55.2 (q), 38.1 (t), 34.1 (d), 25.5 (t), 24.0 (q), 23.4

(t), 21.9 (t) ppm.

S p i r o [4 -i s o p r o p y l c y c l o h e x a d i e n o n e -1 ,2 ′-(1 ′H )-

1′,3′,4′,5′,6′,7′-h exa h yd r on a p th a len -8′-on e (29). To a solu-

tion of 28 (75 mg, 0.26 mmol) in 2 mL of CH₂Cl₂was added 87

µL of TiCl₄(150 mg, 79.00 mmol) at -78 °C, and the reaction

mixture was warmed to 0 °C over a 3-h period. Standard

ethereal workup, followed by chromatography (elution with

H:E, 5:1), gave 45.5 mg (65%) of 29 which was homogeneous

by TLC analysis (H:E, 1:1, R_f28 ) 0.67, R_f29 ) 0.15): mp

90.5-92.5˚C; ¹H NMR (300 MHz) δ 1.19 (d, 6 H, J ) 6.8 Hz),

1.50-1.65 (m, 1 H), 1.75-2.10 (m, 3 H), 2.25-2.65 (m, 9 H),

5.90 (br s, 1 H), 6.16 (dd, 1 H, J ) 9.8 Hz, 1.5 Hz), 6.33 (d, 1

H, J ) 9.8 Hz); ¹³C NMR (62.9 MHz) 205.1 (s), 198.4 (s), 162.0

(s), 154.6 (s), 143.2 (d), 129.5 (s), 122.8 (d), 120.1 (d), 47.8 (s),

37.9 (t), 34.1 (d), 30.9 (t), 30.3 (t), 30.2 (t), 28.8 (t), 22.3 (t),

20.7 (q) ppm; IR (Nujol mull) 1650, 1454, 1385 cm^-1; MS (m/

z): 270 (14%), 149 (100%), 136 (54%).

To a solution of 10.52 g (58.31 mmol) of the above mixture

of alcohols in 200 mL of dry ether at 0 °C was added 2.77 mL

of phosphorus tribromide (29.22 mmol) over a 5-min period.

Standard ethereal workup, followed by chromatography (elu-

tion with H:E, 1:1), provided 11.56 g (81%) of an inseparable

mixture of 2-methoxy-4-isopropylphenylmethyl bromide and

2-methoxy-6-isopropylphenylmethyl bromide (1:1) which was

homogenous by TLC analysis (H:E, 5:3, R_fbromide ) 0.82):

¹H NMR (250 MHz) δ 1.27 (d, 3 H, J ) 6.9 Hz), 1.30 (d, 3 H,

J ) 6.9 Hz), 2.91 (heptet, 0.5 H, J ) 6.9 Hz), 3.31 (heptet, 0.5

H, J ) 6.9 Hz), 3.90 (s, 1.5 H), 3.91 (s, 1.5 H), 4.59 (s, 1 H),

4.74 (s, 1 H), 6.72-6.94 (m, 2 H), 7.20-7.35 (m, 1 H).

To 2.77 g of 1,3-cyclohexanedione (24.73 mmol) was added

1.71 g of solid K₂CO₃(12.30 mmol) dissolved in 4.5 mL of

water. To the resulting solution was added 3.00 g of the above

mixture of bromides (12.34 mmol). The reaction mixture was

stirred for a period of 8 h. The aqueous solution was diluted

with 50 mL of water and extracted with 50 mL of a 1:1 mixture

of THF and ether. The organic phase was extracted with

saturated aqueous NaHCO₃to remove unreacted 1,3-cyclo-

hexanedione, then extracted again with aqueous 5% NaOH.

The resulting solution was acidified by addition of aqueous

10% HCl and extracted with 50 mL of a 1:1 mixture of THF

and ether. The combined organic extracts were dried over

anhydrous magnesium sulfate and concentrated. Titeration

of the crude residue with a 3:1 mixture of H:E separated the

alkylated product derived from 2-methoxy-6-isopropylphenyl-

methyl bromide and the desired adduct. The remaining solid

residue was recrystallized from methanol:water (1:1) to give

760 mg (22%) of 2-(2-methoxy-4-isopropylphenylmethyl)-1,3-

cyclohexanedione which was homogeneous by TLC analysis

(ether, R_fdione ) 0.64): mp 166-168 °C; ¹H NMR (300 MHz)

δ 1.24 (d, 6 H, J ) 6.9 Hz), 1.85-2.15 (m, 2 H), 2.33 (t, 2 H, J

) 6.9 Hz), 2.41 (t, 1 H, J ) 6.3 Hz), 2.87 (heptet, 1 H, J ) 6.9

Hz), 3.58 (s, 2 H), 3.97 (s, 3 H), 6.75 (d, 1 H, J ) 1.2 Hz), 6.82

(dd, 1 H, J ) 7.7 Hz, 1.2 Hz), 7.41 (d, 1 H, J ) 7.7 Hz); ¹³C

NMR (62.9 MHz) 198.2 (s), 172.0 (s), 154.6 (s), 148.5 (s), 131.6

(d), 126.0 (s), 120.0 (d), 115.1 (s), 108.7 (d), 55.7 (q), 36.6 (t),

34.1 (t), 28.7 (t), 23.9 (q), 20.5 (t), 20.4 (t) ppm.

3-Meth oxy-4-m eth ylp h en ylm eth yl Alcoh ol (33). To a

suspension of LiAlH₄(460 mg, 12.00 mmol) in 25 mL of THF

at 0 °C was added dropwise a solution of 3-methoxy-4-

methylbenzoic acid (32) (1.0 g, 6.01 mmol, Aldrich) in 15 mL

of THF. The reaction mixture was warmed to rt over a 10-h

period and standard ethereal workup afforded 934 mg of

residue. Purification using chromatography (elution with H:E,

3:1) yielded 887 mg (97%) of benzyl alcohol 33, which was

homogeneous by TLC analysis (H:E, 1:2, R_f32 ) 0.20, R_f33

) 0.43): ¹H NMR (250 MHz) δ 2.23 (s, 3 H), 3.85 (s, 3 H), 4.67

(s, 2 H), 6.84 (d, 1 H, J ) 7.6 Hz), 6.89 (s, 1 H), 7.13 (d, 1 H,

J ) 7.4 Hz); ¹³C NMR (62.9 MHz) 157.9 (s), 139.7 (s), 130.6

(d), 126.1 (s), 118.7 (d), 108.7 (d), 65.5 (t), 55.2 (q), 16.1 (q)

ppm; IR (film) 3403, 1258 cm^-1

. Anal. for C₉H₁₂O₂. Calcd:

C, 76.56, H, 6.43. Found: C, 76.90, H, 6.59.

3-Meth oxy-4-m eth ylp h en ylm eth yl Br om id e (34). Al-

cohol 33 (880 mg, 5.8 mmol) was dissolved in 25 mL of ether,

and the resulting solution was cooled to 0 °C. Phosphorus

tribromide (1.72 g, 6.4 mmol) dissolved in 10 mL of ether was

added dropwise over a 30-min period. The resulting mixture

was stirred for 8 h. Standard ethereal workup afforded 1.27

g of a pale yellow oil. Purification by chromatography (elution

with H:E, 15:1) gave 1.14 g (92%) of benzyl bromide 34 which

was homogeneous by TLC analysis (H:E, 3:1, R_f33 ) 0.03, R_f

34 ) 0.74): ¹H NMR (250 MHz) δ 2.23 (s, 3 H), 3.85 (s, 3 H),

4.67 (s, 2 H), 6.84 (d, 1 H, J ) 7.6 Hz), 6.89 (s, 1 H), 7.13 (d,

1 H, J ) 7.4 Hz); ¹³C NMR (62.9 MHz) 157.9 (s), 139.8 (s),

130.6 (d), 126.0 (s), 118.7 (d), 108.7 (d), 65.5 (t), 55.2 (q), 16.1

To a suspension of NaH (57% dispersion in mineral oil, 172

mg, 4.08 mmol) in 3 mL of DMF at 0 °C was added the above

dione (700 mg, 2.55 mmol) in a mixture of 7 mL of DMF and

3 mL of THF over a 30-min period. Dimethyl sulfate (313 µL,

3.32 mmol) was then added, and the resulting mixture was

stirred for 3 h. The reaction mixture was diluted with ether,

washed sequentially with aqueous 10% HCl and saturated

aqueous Na₂CO₃, dried over anhydrous magnesium sulfate,

concentrated, and chromatographed (elution with H:E, 1:2) to

give 564 mg of 2-(2-methoxy-4-isopropylphenylmethyl)-3-meth-

oxy-2-cyclohexenone (76%) which was homogeneous by TLC

analysis (ether, R_fdione ) 0.62, R_fenol ether ) 0.38): ¹H NMR

(250 MHz) δ 1.23 (d, 6 H, J ) 6.9 Hz), 1.95-2.15 (m, 2 H),

2.42 (t, 2 H, J ) 7.1 Hz), 2.63 (t, 2 H, J ) 6.1 Hz), 2.85 (heptet,

1 H, J ) 6.9 Hz), 3.58 (s, 2 H), 3.74 (s, 3 H), 3.85 (s, 3 H),

6.65-6.75 (m, 2 H), 6.8 (d, 2 H, J ) 8.2 Hz); ¹³C NMR (62.9

MHz) 197.9 (s), 172.9 (s), 157.1 (s), 147.1 (s), 127.3 (d), 126.1

(s), 117.7 (d), 117.3 (s), 108.5 (d), 55.2 (q), 36.3 (t), 34.9 (d),

24.9 (t), 24.0 (q), 21.1 (t), 20.8 (t) ppm.

(q) ppm; IR (film) 3401, 1258 cm^-1

.

4,4-Dim et h yl-2-(3-m et h oxy-4-m et h ylp h en ylm et h yl)-

1,3-cycloh exa n ed ion e (35). Dione 11 (1.31 g, 9.31 mmol)

was dissolved in 2.0 mL of aqueous 20% K₂CO₃solution (3.80

mmol). Bromide 34 (2.03 g, 9.31 mmol) was added to the

mixture. After 5 min solid KI (1.62 g, 4.7 mmol) was added,

and the reaction was stirred for 10 h. The reaction mixture

was diluted with 30 mL of ether and washed twice with 10

mL of aqueous 10% HCl. The solution was then washed with

saturated aqueous NaHCO₃solution to remove any unreacted

11. The ethereal phase was washed with aqueous 20% KOH

to extract the dione into the aqueous layer. The aqueous layer

was then acidified with concentrated HCl to a pH of 2.

Standard ethereal workup, followed by chromatography (elu-

tion with H:E, 2:1), yielded 1.43 g (56%) of product. TLC

analysis revealed the residue to be homogeneous (H:E, 1:1, R_f

35 ) 0.35): ¹H NMR (250 MHz) δ 1.18 (s, 6 H), 1.83 (t, 2 H, J

) 6.5 Hz), 2.16 (s, 3 H), 2.49 (t, 2 H, J ) 6.2 Hz), 3.65 (s, 2 H),

3.78 (s, 3 H), 6.63 (s, 1 H), 6.71 (d, 1 H, J ) 7.5 Hz), 7.03 (d,

1 H, J ) 7.5 Hz); ¹³C NMR (62.9 MHz) 169.8 (s), 158 (s), 130.7

(d), 120.5 (d), 119.6 (d), 113.5 (s), 111.2 (d), 110.0 (d), 55.2 (q),

36.8 (t), 34.2 (t), 32.2 (t), 27.9 (t), 27.3 (t), 25.7 (q), 24.9 (q),

A solution of 470 mg (1.63 mmol) of the above enone and 40

mg of CeCl₃(0.163 mol) in 5 mL of dry ether at rt was treated

dropwise with 3.20 mL (3.20 mmol) of vinylmagnesium

bromide (1.0 M in THF) over a 5-min period, and the resulting

mixture was stirred for 5 additional min. Standard ethereal

workup, followed by chromatography (elution with H:E, 5:1),

provided 336 mg (82%) of dienone 28 which was homogeneous

by TLC analysis (H:E, 1:2, R_fenone ) 0.13, R_f28 ) 0.77): ¹H

NMR (250 MHz) δ 1.23 (d, 6 H, J ) 6.9 Hz), 1.95-2.15 (m, 2

H), 2.52 (t, 2 H, J ) 6.2 Hz), 2.09 (t, 2 H, J ) 6.4 Hz), 2.86

(heptet, 1 H, J ) 6.9 Hz), 3.76 (s, 2 H), 3.87 (s, 3 H), 5.41 (dd,

1 H, J ) 11.1 Hz, 0.8 Hz), 5.66 (dd, 1 H, J ) 17.4 Hz, 1.0 Hz),

6.65-6.75 (m, 2 H), 6.81 (d, 1 H, 8.0 Hz), 6.94 (dd, 1 H, J )

17.4 Hz, 11.1 Hz); ¹³C NMR (62.9 MHz) 199.5 (s), 156.8 (s),

150.1 (s), 147.7 (s), 135.1 (s), 128.2 (d), 125.6 (s), 120.2 (t), 118.0

15.9 (q) ppm; IR (film) 3390, 1643, 1374 cm^-1

. Anal. for

C₁₆H₂₂O₃. Calcd: C, 73.24, H, 8.46. Found: C, 73.01, H, 8.39.

6,6-Dim eth yl-2-(3-m eth oxy-4-m eth ylp h en ylm eth yl)-3-

m eth oxy-2-cycloh exen on e (36). To NaH (125 mg, 3.78

mmol of an 80% dispersion in mineral oil) in 40 mL of DMF

at 0 °C was added a solution of dione 35 (500 mg, 1.8 mmol)

in 10 mL of DMF over a 30-min period. The resulting mixture

was stirred for 3 h, and then dimethyl sulfate (250 mg, 1.98

Use of Conjugated Dienones in Cyclialkylations

J . Org. Chem., Vol. 61, No. 23, 1996 8181

mmol) was added and the reaction was stirred overnight.

Saturated aqueous ammonium chloride (2 mL) was used to

quench the reaction. Standard ethereal workup gave 422 mg

of a crude residue which was purified by chromatography

(elution with H:E, 5:1) to yield 386 mg (75%) of a homogeneous

product by TLC analysis (H:E, 2:1, R_f35 ) 0.13, R_f36 )

0.29): ¹H NMR (250 MHz) δ 1.11 (s, 6 H), 1.83 (t, 2 H, J ) 6.2

Hz), 2.15 (s, 3 H), 2.49 (t, 2 H, J ) 6.3 Hz), 3.58 (s, 2 H), 3.78

(s, 3 H), 3.80 (s, 3 H), 6.70 (d, 1 H, J ) 7.8 Hz), 6.74 (s, 1 H),

6.96 (d, 1 H, J ) 7.5 Hz); ¹³C NMR (62.9 MHz) 202.6 (s), 169.9

(s), 157.3 (s), 140.7 (s), 129.9 (d), 123.2 (s), 120.1 (d), 117.0 (s),

110.6 (d), 55.1 (q), 54.8 (q), 39.3 (s), 34.2 (t), 28.0 (t), 24.5 (q),

21.9 (t), 15.8 (q) ppm; IR (film) 3440, 2957, 1616, 1366, 1250

R_f40 ) 0.37): ¹H NMR (250 MHz) δ 0.72 (s, 3 Η), 1.00 (s, 3

H), 1.35-1.70 (m, 8 H), 2.18 (s, 3 H), 2.20-2.35 (m, 3 H), 2.35-

2.48 (m, 1 H), 2.56-2.72 (m, 3 H), 3.82 (s, 3 H), 6.35 (s, 1 H),

6.62 (s, 1 H), 6.81 (s, 1 H); ¹³C NMR (62.9 MHz) 155.6 (s), 144.7

(s), 134.8 (s), 134.7 (s), 130.2 (d), 125.2 (d), 123.7 (s), 112.0 (d),

55.4 (q), 54.9 (d), 42.3 (t), 41.1 (t), 36.6 (s), 32.6 (t), 30.4 (t),

30.3 (q), 24.4 (t), 20.3 (q), 15.7 (q) ppm.

(()-Deoxofa velin e (3). Ethanethiol (130 mg, 2.00 mmol)

was added to 42 mg of NaH (80% dispersion in mineral oil,

1.28 mmol) in 1 mL of DMF at rt and stirred for 2 h. The

mixture was heated to 110 °C, and ether 39 (14.0 mg, 0.052

mmol) was added over a 5-min period. The mixture was

heated at 130 °C for 5 h and acidified with aqueous 10% HCl.

The reaction mixture was diluted with water (10 mL), followed

by standard ethereal workup and chromatography (elution

with H:E, 15:1), to yield 11.7 mg (88%) of (()-deoxofaveline

which was homogeneous by TLC analysis (H:E, 5:1, R_f40 )

0.46, R_f3 ) 0.34): ¹H NMR (250 MHz) δ 0.71 (s, 3 H), 1.00 (s,

3 H), 1.38-1.68 (m, 6 H), 2.20 (s, 3 H), 2.23-2.32 (m, 2 H),

2.33-2.42 (m, 1 H), 2.52-2.71 (m, 3 H), 6.24 (s, 1 H), 6.56 (s,

1 H), 6.78 (s, 1 H); ¹³C NMR (62.9 MHz) 152.2 (s), 144.9 (s),

135.8 (s), 134.7 (s), 130.2 (d), 124.6 (d), 120.5 (s), 116.4 (d),

54.8 (q), 42.2 (d), 41.0 (t), 36.6 (s), 32.5 (t), 30.2 (t), 30.2 (t)

(the two preceding signals overlap), 24.3 (t), 20.2 (q), 15.2 (q)

ppm.

cm^-1

.

4,4-Dim eth yl-2-(3-m eth oxy-4-m eth ylp h en ylm eth yl)-3-

vin yl-2-cycloh exen on e (37). To a solution of enol ether 36

(300 mg, 1.0 mmol) in 15 mL of ether were added vinyl-

magnesium bromide (2.1 mL of a 1 M solution in THF) and

cerium chloride (190 mg, 0.77 mmol). The resulting solution

was then stirred at rt for 8 h. Standard ethereal workup,

followed by chromatography (H:E, 5:1), yielded 290 mg (88%)

of product which was homogeneous by TLC analysis (H:E, 5:1,

R_f37 ) 0.29): ¹H NMR (250 MHz) δ 1.22 (s, 6 H), 1.90 (t, 2 H,

J ) 7.0 Hz), 2.14 (s, 3 H), 2.53 (t, 2 H, J ) 7.0 Hz), 3.68 (s, 2

H), 3.79 (s, 3 H), 5.18 (dd, 1 H, J ) 18.0 Hz, 1.8 Hz), 5.41 (dd,

1 H, J ) 10.9 Hz, 2.0 Hz), 6.38 (dd, 1 H, J ) 17.7 Hz, 11.8

Hz), 6.55 (d, 1 H, J ) 7.8 Hz), 6.63 (s, 1 H), 6.97 (d, 1 H, J )

7.6 Hz); ¹³C NMR (62.9 MHz) 198.7 (s), 163.3 (s), 157.5 (s),

140.3 (s), 133.6 (d), 132.9 (s), 130.2 (d), 123.6 (s), 119.8 (t), 119.4

(d), 110.2 (d), 77.2 (d), 55.1 (q), 37.3 (t), 35.5 (s), 34.5 (t), 34.5

(t), 32.1 (t), 27.2 (q), 15.1 (q) ppm. Anal. for C₁₉H₂₄O₂. Calcd:

C, 80.23, H, 8.51. Found: C, 79.87, H, 8.22.

Dem eth yla tion of 40 Usin g L-Selectr id e. To 12 mg of

36 (0.055 mmol) dissolved in 1.5 mL of dry THF was added

110 µL of L-Selectride (1.0 M, 0.11 mmol), and the resulting

mixture was refluxed (67 °C) until TLC analysis indicated that

the reaction was complete (24 h). The reaction mixture was

cooled to 0 °C and diluted with 50 mL of ether. Standard

ethereal workup, followed by chromatography (elution with

H:E, 5:1), gave 8.9 mg (79%) of (()-deoxofaveline which was

identical to that prepared previously.

7-Me t h oxy-1,1,8-t r im e t h yl-1,2,10,11-t e t r a h yd r o-5H -

d iben zo[a ,d ]cycloh ep ten -4-on e (38). To dienone 37 (200

mg, 0.70 mmol) dissolved in 50 mL of CH₂Cl₂was added BF₃-

Et₂O (120 mg, 0.85 mmol). The reaction was stirred until TLC

analysis indicated the reaction was complete (5 min). Stand-

ard ethereal workup and chromatography (H:E, 6:1) yielded

192 mg (97%) of tricycle 38 which was homogeneous by TLC

analysis (H:E, 2:1, R_f37 ) 0.42, R_f38 ) 0.35): ¹H NMR (250

MHz) δ 1.18 (s, 6 H), 1.80 (t, 2 H, J ) 6.9 Hz) 2.17 (s, 3 H),

2.50 (t, 2 H, J ) 6.8 Hz), 2.69 (t, 2 H, J ) 6.4 Hz), 2.98 (t, 2 H,

J ) 6.4 Hz), 3.80 (s, 5 H), 6.68 (s, 1 H), 6.86 (s, 1 H); ¹³C NMR

(62.9 MHz) 197.4 (s), 165.0 (s), 155.6 (s), 136.7 (s), 133.7 (s),

131.1 (d), 130.7 (s), 124.2 (s), 111.4 (d), 55.3 (q), 36.9 (t), 36.3

(s), 34.1 (t), 29.9 (t), 29.3 (t), 26.6 (q), 15.6 (q) ppm. Anal. for

C₁₉H₂₂O₂. Calcd: C, 80.23, H, 8.51. Found: C, 80.03, H, 8.24.

7-Met h oxy-1,1,8-t r im et h yl-1,2,3,10,11,11a -h exa h yd r o-

5H-d iben zo[a ,d ]cycloh ep ten e (39). Enone 38 (540 mg, 1.9

mmol) was refluxed with tosylhydrazine (530 mg, 2.85 mmol)

in 10 mL of dry ethanol for 3 h. The solvent was removed,

and the residue was passed through a silica gel column

(hexanes:ethyl acetate, 5:1) to yield a homogeneous product

by TLC analysis (H:E, 5:1, R_f38 ) 0.64, R_fhydrazone ) 0.01).

The crude tosylhydrazone was stirred in 5 mL of DMF and 5

mL of sulfolane containing 25 mg of bromocresol green. The

mixture was warmed to 110 °C, and sodium cyanoborohydride

(1.19 g, 6.4 mmol) was added followed by sufficient aqueous

10% HCl to maintain a tan color. Stirring was continued for

90 min, and the mixture was cooled to rt, diluted with water,

and extracted with ether. The residue was chromatographed

(elution with H:E, 20:1) to yield 237 mg (53%) of product which

was homogeneous by TLC analysis (H:E, 5:1, R_f39 ) 0.86):

1H NMR (250 MHz) δ 0.89 (s, 3 H), 0.92 (s, 3 H), 1.08-1.22

(m, 3 H), 1.28-1.39 (m, 2 H), 1.98-2.11(m, 2 H), 2.17 (s, 3 H),

2.78 (t, 1 H, J ) 7.0 Hz), 3.33 (s, 2 H), 3.84 (s, 3 H), 5.45 (t, 1

H, J ) 4.0 Hz), 6.62 (s, 1 H), 6.88 (s, 1 H) ppm; ¹³C NMR (62.9

MHz) 156.3 (s), 139.9 (s), 138.6 (s), 132.9 (s), 131.6 (d), 123.3

(s), 121.1 (d), 110.1 (d), 55.4 (q), 51.8 (d), 45.2 (t), 34.1 (t), 32.1

(s), 31.1 (t), 30.5 (t), 27.8 (q), 27.1 (q), 23.2 (t), 15.6 (q) ppm.

Deoxofa velin e Meth yl Eth er (40). To 28 mg of ether 39

(0.10 mmol) dissolved in 1 mL of dry CH₂Cl₂was added 35 µL

of BF₃-Et₂O (0.24 mol). The resulting mixture was stirred

overnight at rt. Standard ethereal workup and chromatog-

raphy (elution with H:E, 3:1) yielded 26 mg (90%) of a

homogeneous product by TLC analysis (hexanes, R_f39 ) 0.46,

4,4-Dim eth yl-2-(4-isop r op yl-3-m eth oxyp h en ylm eth yl)-

1,3-cycloh exa n ed ion e (41). To 1.38 g of 11 (9.84 mmol)

suspended in 1.5 mL of water was added 1.36 g of K₂CO₃(9.84

mmol), 0.41 g of KI (2.47 mmol), and 1.20 gram of bromide 31

(4.94 mmol). The reaction mixture was stirred at rt for a 24-h

period and then diluted with 90 mL of water and 3 mL of 10%

aqueous HCl. Standard ethereal workup furnished 0.81 g of

a crude residue which was chromatographed (elution with H:E

) 3:2) to give 0.70 g of 41 (75% yield based on recovered 31).

This material was homogeneous by TLC analysis (H:E ) 1:1,

R_f41 ) 0.24): mp 169.5-170.5 °C (recrystallized from EtOH)

as colorless needles; ¹H NMR δ 1.12 (s, 3 H), 1.17 (d, 6 H, J )

6.7 Hz), 1.28 (s, 3 H), 1.67 (m, 1 H), 2.05 (m, 1 H), 2.51 (m, 1

H), 2.71 (m, 1 H), 3.17 (d, 2 H, J ) 5.6 Hz), 3.24 (septet, 1 H,

J ) 7.0 Hz), 3.87 (s, 3 H), 6.66 (s, 1 H), 6.74 (d, 1 H, J ) 7.6

Hz), 7.07 (d, 1 H, J ) 7.6 Hz); ¹³C NMR (75.5 MHz) 204.4 (s),

157.2 (s), 134.7 (s), 126.3 (d), 125.8 (s), 120.8 (s), 119.8 (d),

113.3 (s), 111.6 (s), 110.3 (d), 66.7 (d), 55.3 (q), 36.9 (s), 34.4

(t), 32.3 (t), 27.8 (t), 27.1 (t), 26.4 (d), 25.7 (t), 25.0 (q), 24.0 (t),

22.7 (q) ppm; IR (film) 3424, 2952, 1639, 1558, 1372, 1253,

1194, 996 cm^-1; MS (m/z) 302 (M⁺, 64%), 287 (83%), 175

(100%), 161 (42%), 115, (23%); Anal. for C₁₉H₂₆O₃. Calcd: C,

75.46, H, 8.67. Found: C, 77.21, H, 8.54.

6,6-Dim eth yl-2-(4-isop r op yl-3-m eth oxyp h en ylm eth yl)-

3-m eth oxy-2-cycloh exen on e (42). To a suspension of NaH

(60% dispersion of mineral oil, 190 mg, 4.75 mmol) in 4 mL of

dry DMF at 0 °C was added dione 41 (893 mg, 2.95 mmol) in

7 mL of DMF over a 5-min period. The resulting solution was

stirred at rt for 3 h. Dimethyl sulfate (560 mg, 4.44 mmol)

was then added, and the resulting mixture was stirred at rt

for 15 h. The reaction mixture was diluted with 30 mL of

water and washed with saturated CuSO₄(3 × 20 mL).

Standard ethereal workup provided 0.91 g of a crude residue

which was chromatographed (elution with H:E ) 2:1) to give

880 mg of enol ether 42 (94%). The material was homogeneous

by TLC analysis (H:E ) 2:1, R_f42 ) 0.30): ¹H NMR (300 MHz)

δ 1.11 (s, 6 H), 1.18 (d, 6 H, J ) 7.0 Hz), 1.84 (t, 2 H, J ) 6.4

Hz), 2.60 (t, 2 H, J ) 6.4 Hz), 3.24 (septet, 1 H, J ) 7.0 Hz),

3.58 (s, 2 H), 3.78 (s, 3 H), 3.79 (s, 3 H), 6.70-6.75 (m, 2 H),

7.03 (d, 1 H, J ) 8.1 Hz); ¹³C NMR (75.5 MHz) 202.6 (s), 170.0

(s), 156.4 (s), 140.2 (s), 133.6 (s), 125.3 (d), 120.3 (d), 116.8 (s),

110.9 (d), 55.2 (q), 54.8 (q), 39.3 (s), 34.2 (t), 28.0 (t), 26.4 (d),

8182 J . Org. Chem., Vol. 61, No. 23, 1996

Majetich et al.

24.6 (q), 22.7 (q), 22.0 (t) ppm; IR (film) 2956, 2867, 1788, 1612,

1502, 1460, 1416, 1364, 1247, 1095, 1038 cm^-1; MS (m/z) 316

(M⁺, 61%), 301 (69%), 43 (100%); Anal. for C₂₀H₂₈O₃. Calcd:

C, 75.91, H, 8.92. Found: C, 76.21, H, 9.02.

isopisiferin (46) which was homogeneous by TLC analysis (H:

E, 5:1, R_f2/46 ) 0.28):

2: ¹H NMR (250 MHz) δ 0.89 (s, 3 H), 0.92 (s, 3 H), 1.22 (d,

3 H, J ) 6.9 Hz), 1.24 (d, 3 H, J ) 6.9 Hz), 1.75-1.85 (m, 1

H), 1.85-2.15 (m, 3 H), 2.75-2.85 (m, 2 H), 3.13 (septet, 1 H,

J ) 6.9 Hz), 3.25 (br s, 2 H), 5.42 (t, 1 H, J ) 4 Hz), 6.53 (s, 1

H), 6.89 (s, 1 H).

4,4-Dim eth yl-2-(4-isop r op yl-3-m eth oxyp h en ylm eth yl)-

3-vin yl-2-cycloh exen on e (43). A solution of 1.00 g (3.16

mmol) of enol ether 42 in 40 mL of ether was added to a flask

containing 630 mg of CeCl₃(2.56 mmol). The resulting

mixture was treated with 6.64 mL of vinylmagnesium bromide

(6.64 mmol, 1.0 M in THF) at rt over 5-min period. The

reaction mixture was stirred at rt for 10 h and quenched with

ice. Standard ethereal workup provided an oily residue which

was chromatographed (elution with H:E ) 3:1) to provide 782

mg of 43 (78%). This material was homogeneous by TLC

analysis (H:E ) 2:1, R_f43 ) 0.52): ¹H NMR (250 MHz) δ 1.16

(d, 6 H, J ) 6.7 Hz), 1.21 (s, 6 H), 1.91 (t, 2 H, J ) 6.9 Hz),

2.54 (t, 2 H, J ) 6.9 Hz), 3.20-3.25 (m, 1 H), 3.68 (s, 2 H),

3.78 (s, 3 H), 5.18 (dd, 1 H, J ) 1.78 Hz, 1.7 Hz), 5.39 (dd, 1

H, J ) 12.0 Hz, 1.7 Hz), 6.37 (dd, 1 H, J ) 17.8 Hz, 12.0 Hz),

6.58-6.63 (m, 2 H), 7.04 (d, 1 H, J ) 7.6 Hz); ¹³C NMR (62.9

MHz) 198.7 (s), 163.2 (s), 156.6 (s), 139.5 (s), 134.0 (s), 133.6

(d), 132.8 (s), 125.7 (d), 119.8 (d), 119.7 (t), 110.5 (d), 55.2 (q),

37.3 (t), 35.5 (s), 34.5 (t), 32.0 (t), 27.3 (q), 26.4 (d), 22.7 (q)

ppm; IR (film) 2959, 2867, 1668, 1609, 1502, 1461, 1415, 1250,

1094, 1040, 928, 730 cm^-1; MS, m/z 312 (M⁺, 12%), 269 (18%),

180 (54%), 135 (100%).

46: ¹H NMR (250 MHz) δ 0.70 (s, 3 H), 0.98 (s, 3 H), 1.22

(d, 3 H, J ) 6.9 Hz), 1.25 (d, 3 H, J ) 6.9 Hz), 1.35-1.75 (m,

4 H), 2.10-2.40 (m, 4 H), 2.50-2.72 (m, 3 H), 3.13 (septet, 1

H, J ) 6.9 Hz), 6.23 (s, 1 H), 6.51 (s, 1 H), 6.82 (s, 1 H).

Isom er iza tion of P isifer in to Isop isifer in . Ten milli-

grams of an inseparable mixture of pisiferin and isopisiferin

(7:1) was dissolved in 3 mL of CH₂Cl₂and cooled to 0 °C, and

150 µL (1.22 mmol) of BF₃-Et₂O was added. The reaction

mixture was stirred at rt for 2 days and then quenched with

saturated aqueous NaHCO₃(2 mL). Standard ethereal work-

up gave 11 mg of a crude residue which was chromatograhed

(elution with H:E, 9:1) to give 9.0 mg of an inseparable mixture

of pisiferin (2) and isopisiferin (46) in the ratio of 1:7,

respectively.

Con ver sion of 2/46 in to Tetr a cyclic Dien on e 50. Ten

milligrams of an inseparable mixture of pisiferin and iso-

pisiferin (7:1) was dissolved in 3 mL of CH₂Cl₂, and 150 µL

(1.22 mmol) of BF₃-Et₂O was added. The reaction mixture

was refluxed for a 20-h period, cooled to 0 °C, and quenched

by the addition of 3 mL of saturated aqueous NaHCO₃.

Standard ethereal workup gave 11 mg of a crude residue which

was chromatograhed (elution with H:E, 7:1) to give 7.1 mg of

tetracyclic dienone 50 (71%) which was homogeneous by TLC

analysis (H:E, 7:1, R_f50 ) 0.28): mp 107-108 °C [lit. mp 107-

109 °C];^{23b 1}H NMR (250 MHz) δ 0.95 (s, 3 H), 1.03 (s, 3 H),

1.05 (d, 3 H, J ) 6.9 Hz), 1.07 (d, 3 H, J ) 6.9 Hz), 1.18-1.50

(m, 5 H), 1.60-1.90 (m, 7 H), 2.01 (t, 1 H, J ) 9.9 Hz), 2.98

(septet, 1 H, J ) 6.9 Hz), 6.22 (s, 1 H), 6.39 (s, 1 H).

12-Acetoxy-9(10f20)-5rH-a beo-a bieta -5(10),8,11,13-tet-

r a en -1-on e (48). To a solution of 300 µL of ethanethiol (4.11

mmol) in 2 mL of DMF was added dropwise to a cold solution

(0 °C) of 82 mg of NaH (60% dispersion in mineral oil, 2.05

mmol) suspended in 4 mL of DMF. The resulting mixture was

then stirred at rt for 10 min, followed by the addition of a

solution of 38 mg of 44 (0.12 mmol) dissolved in 0.5 mL of

DMF. The mixture was refluxed for a 5-h period. Standard

ethereal workup gave 124 mg of the phenol product which was

homogeneous by TLC analysis (H:E ) 1:1, R_f47 ) 0.26). This

compound proved to be unstable; therefore, it was used directly

in the next reaction without further purification or character-

ization.

The above crude phenol was dissolved in 1.5 mL of acetic

anhydride and 1.5 mL of pyridine. The reaction mixture was

heated at 80 °C for 2 h, cooled to rt, and diluted with water (5

mL). Standard ethereal workup afforded 44 mg of a crude

residue which was purified by means of chromatography

(elution with H:E ) 4:1) to give 33 mg 48 (80%) which was

homogeneous by TLC analysis (H:E ) 4:1, R_f48 ) 0.20): mp

108-109 °C; ¹H NMR (250 MHz) δ 1.16 (s, 6 H), 1.17 (d, 6 H,

J ) 7.0 Hz), 1.19 (t, 2 H, J ) 7.0 Hz), 2.30 (s, 3 H), 2.47 (t, 2

H, J ) 7.0 Hz), 2.64-2.67 (m, 2 H), 2.92 (septet, 1H, J ) 7.0

Hz), 2.95-3.05 (m, 2 H), 3.77 (s, 2 H), 6.79 (s, 1 H), 6.97 (s, 1

H); ¹³C NMR (62.9 MHz) 197.3 (s), 170.0 (s), 164.8 (s), 145.8

(s), 137.9 (s), 137.6 (s), 137.0 (s), 133.3 (s), 127.0 (d), 123.1 (d),

36.9 (t), 36.4 (s), 34.1 (t), 30.6 (t), 29.1 (t), 28.9 (t), 27.1 (d),

26.6 (q), 23.0 (q), 20.9 (q) ppm; IR (film) 2957, 2868, 1757, 1662,

1501, 1459, 1364, 1212, 1088, 1056 cm^-1; MS (m/z) 340 (M⁺,

9%), 298 (62%), 43 (100%).

12-Acet oxy-9(10f20)-10rH -a b eo-a b iet a -1(10),8,11,13-

tetr a en e (49). A mixture of 24 mg of enone 48 (0.07 mmol)

and 27 mg of tosylhydrazine (0.09 mmol) dissolved in 2 mL of

absolute ethanol was stirred at rt for a 12-h period. Evapora-

tion of the solvent gave the crude hydrazone, which was then

dissolved in 1 mL of DMF and 1 mL of sulfolane. To this

solution was added 1 mg of bromocresol green and then 21

mg of sodium cyanoborohydride (0.33 mmol). The resulting

mixture was heated to 100 °C when sufficient 10% aqueous

HCl was added to obtain a tan-yellow color. The reaction

mixture was stirred at 110 °C for 2.5 h and then cooled to rt.

12-Met h oxy-9(10f20)-5rH -a b eo-a b iet a -5(10),8,11,13-

tetr a en -1-on e (44). A solution of 71 µL of BF₃-Et₂O (0.58

mmol) was added dropwise to a solution of 150 mg of 43 (0.48

mmol) in 30 mL of dry CH₂Cl₂at rt. The resulting mixture

was stirred at rt for a 90-min period and then quenched with

3 mL of saturated aqueous NaHCO₃. Standard ethereal

workup afforded 144 mg of crude residue. Purification by

means of chromatography (elution with H:E ) 4:1) gave 121

mg of 44 (83%) which was homogeneous by TLC analysis (H:E

1

) 4:1, R_f44 ) 0.23): mp 123-124 °C; H NMR (250 MHz) δ

1.17 (s, 6 H), 1.18 (d, 6 H, J ) 7.0 Hz), 1.82 (t, 2 H, J ) 6.8

Hz), 2.65-2.73 (m, 2 H), 2.95-3.03 (m, 2 H), 3.24 (septet, 1

H, J ) 7.0 Hz), 3.79 (s, 5 H), 6.67 (s, 1 H), 6.87 (s, 1 H); ¹³C

NMR (62.9 MHz) 197.5 (s), 165.2 (s), 154.7 (s), 136.3 (s), 134.8

(s), 133.7 (s), 131.0 (s), 126.7 (d), 111.9 (d), 55.5 (q), 37.0 (t),

36.4 (s), 34.2 (t), 30.3 (t), 29.4 (t), 29.3 (t), 26.6 (q), 26.4 (d),

22.8 (q) ppm; IR (film) 2957, 2926, 2865, 1661, 1611, 1504,

1462, 1362, 1268, 1247, 1180, 1110, 1068 cm^-1; MS, m/z 312

(M⁺, 100%), 297 (87%), 269 (52%), 55 (31%); Anal. for C₂₁H₂₈O₂.

Calcd: C, 80.73, H, 9.03. Found: C, 80.50, H, 8.88.

(()-P isifer in Meth yl Eth er (45). Enone 44 (486 mg, 1.56

mmol) and tosylhydrazine (350 mg, 1.88 mmol) were dissolved

in 10 mL of absolute ethanol and stirred at rt for 12 h. The

solvent was evaporated, and to the resulting residue were

added 12 mL of DMF and 12 mL of sulfolane containing 4 mg

of bromocresol green. The mixture was warmed to 105 °C,

and sodium cyanoborohydride (420 mg, 6.68 mmol) was added,

followed by sufficient 2 N HCl to give a tan color. Heating at

110 °C was continued for 7 h during which time several

portions of 2 N HCl were added to maintain the proper acidity,

as indicated by the tan color. The mixture was cooled, poured

into water, and extracted with ether. The residue obtained

was dried over anhydrous magnesium sulfate, filtered, and

concentrated. The resulting residue was chromatographed to

give 287 mg (46%) of pisiferin methyl ether (45) which was

homogeneous by TLC analysis (H:E, 4:1, R_f45 ) 0.77): ¹H

NMR (300 MHz) δ 0.89 (s, 3 H), 0.93 (s, 3 H), 1.18 (d, 3 H, J

) 7.0 Hz), 1.20 (d, 3 H, J ) 7.0 Hz), 1.75-1.85 (m, 1 H), 1.85-

2.15 (m, 3 H), 2.81 (m, 2 H), 3.25 (septet, 1 H, J ) 7.0 Hz),

3.32 (s, 2 H), 3.82 (s, 3 H), 5.45 (t, 1 H, J ) 4.0 Hz), 6.63 (s, 1

H), 6.91 (s, 1 H).

Dem eth yla tion of Eth er (45). Ethanethiol (0.35 mL, 4.39

mmol) was added to 112 mg of NaH (60% dispersion in mineral

oil, 2.81 mmol) in 3 mL of DMF at rt and stirred for 30 min.

The mixture was heated to reflux, and ether 45 (70 mg, 0.34

mmol) dissolved in 1 mL of DMF was added. The resulting

mixture was refluxed for 4 h, cooled to 0 °C, diluted with water

(10 mL), and acidified with aqueous 10% HCl. Standard

ethereal workup and chromatography (elution with H:E, 6:1),

yielded 57 mg (85%) of a 4:1 mixture of pisiferin (2) and

Use of Conjugated Dienones in Cyclialkylations

J . Org. Chem., Vol. 61, No. 23, 1996 8183

Standard ethereal workup afforded 19 mg of an oily residue

which was purified by chromatography (elution with H:E, 5:1)

to give 10 mg of 49 (43%) which was homogeneous by TLC

analysis (H:E ) 4:1, R_f49 ) 0.80): ¹H NMR (250 MHz) δ 0.88

(s, 3 H), 0.91 (s, 3 H), 1.17 (d, 3 H, J ) 7.0 Hz), 1.20 (d, 3 H,

J ) 7.0 Hz), 2.31 (s, 3 H), 2.80-2.85 (m, 2 H), 2.94 (septet, 1

H, J ) 6.9 Hz), 3.29 (s, 2 H), 5.41 (t, 1 H, J ) 4.0 Hz), 6.73 (s,

1 H), 6.99 (s, 1 H).

(()-P isifer in (2). Ten milligrams of acetate 48 was dis-

solved in 2 mL of absolute ethanol saturated with NaOH. The

reaction mixture was then gently refluxed for a 6-h period.

The reaction mixture was then cooled to 0 °C and acidified

with 10% aqueous HCl. Standard ethereal workup gave a

colorless oil. Purificaton by chromatography (elution with H:E,

5:1) gave 8.0 mg of 2 (92%) as a colorless oil which was

homogeneous by TLC analysis (H:E ) 5:1, R_f2 ) 0.28): ¹H

NMR (250 MHz) δ 0.88 (s, 3 H), 0.91 (s, 3 H), 1.22 (d, 3 H, J

) 7.0 Hz), 1.24 (d, 3 H, J ) 7.0 Hz), 1.75-1.83 (m,1 H), 1.85-

2.05 (m, 3 H), 2.75-2.81 (m, 2 H), 3.12 (septet, 1 H, J ) 7.0

Hz), 3.24 (br s, 2 H), 4.51 (br s, 1 H), 5.41 (t, 1 H, J ) 4.0 Hz),

6.53 (s,1 H), 6.88 (s, 1 H).

7-Meth oxy-1,1,8-tr im eth yl-1.10.11.11a -tetr a h yd r o-2H-

d iben zo[a ,d ]cycloh ep ten -4-on e (51). To a solution of 39

(72 mg, 0.27 mmol) in 3 mL of CH₂Cl₂were added 143 mg of

PCC (0.67 mmol) and 143 mg of Celite, and the resulting

mixture was refluxed for 8 h. Standard ethereal workup

followed by chromatography (elution with H:E, 5:1) gave 18

mg (25%) of unreacted 39 and 42 mg (55% yield or 80% yield

based on mass balance) of enone 51 which was homogeneous

by TLC analysis (H:E, 2:1, R_f51 ) 0.40): ¹H NMR (300 MHz)

δ 0.91 (s, 3 H), 1.06 (s, 3 H), 1.65-1.92 (m, 3 H), 2.21 (s, 3 H),

2.24-2.36 (m, 1 H), 2.37-2.48 (m, 1 H), 2.50-2.62 (m, 2 H),

2.65-2.75 (m, 2 H), 3.82 (s, 3 H), 6.79 (s, 1 H), 6.93 (s, 1 H),

7.56 (d, 1 H, J ) 2.1 Hz); ¹³C NMR (75.5 MHz) 202.0 (s), 155.9

(s), 139.1 (s), 138.8 (d), 135.0 (s), 133.2 (s), 131.3 (s), 127.6 (s),

113.9 (d), 55.3 (d), 50.0 (q), 35.9 (t), 35.3 (t), 32.9 (t), 32.8 (s),

31.2 (t), 29.2 (q), 22.8 (q), 16.0 (q) ppm; IR (film) 2926, 1680,

1504, 884 cm^-1; ESI-MS (m/z) 285 (MH⁺, 100%).

P r ep a r a tion of 51 Usin g SeO₂. To a stirred solution of

enone 39 (14 mg, 0.05 mmol) in 2 mL of absolute ethanol was

added selenium dioxide (8 mg, 0.074 mmol), and the mixture

was refluxed for 2 h. Standard ethereal workup, followed by

chromatography (elution with H:E, 5:1), gave 8.0 mg of dienone

51 (58%) which was identical to that previously described.

Xoch itlolon e Meth yl Eth er (53). To a stirred solution of

enone 51 (70 mg, 0.25 mmol) in 3 mL of ethyl acetate was

added phenylselenyl chloride (47 mg, 0.25 mmol), and the

resulting mixture was stirred for 5 min at 0 °C. TLC analysis

indicated the complete conversion of 51 to the phenylselen-

ylated adduct [H:E, 2:1, R_f51 ) 0.40, R_fselenylated cmpd )

0.71]. The mixture was maintained at 0 °C while a solution

of m-CPBA (42.0 mg, 0.246 mmol) dissolved in 1 mL of ethyl

acetate was added dropwise and the resulting mixture was

ethereal workup and purification via chromatography (elution

with H:E, 2:1) gave 8.1 mg of dienone 54 (55%) which was

homogeneous by TLC analysis [H:E, 2:1, R_f54 ) 0.20]: ¹H

NMR (300 MHz) δ 1.26 (s, 6 H), 2.75-2.88 (m, 2 H), 2.98-

3.08 (m, 2 H), 3.81 (s, 3 H), 3.94 (s, 2 H), 6.22 (d, 1 H, J ) 9.9

Hz), 6.71 (s, 1 H), 6.72 (d, 1 H, J ) 9.9 Hz), 6.83 (s, 1 H).

(()-Xoch itlolon e (5). To a stirred solution of dienone 53

(35 mg, 0.124 mmol) in 5 mL of dry CH₂Cl₂at -78 °C was

added boron tribromide (248 µL, 0.248 mmol of a 1.0 M

solution in CH₂Cl₂). The resulting mixture was allowed to

warm to 10 °C over a 2-h period. Standard ethereal workup

and chromatography gave 8 mg (23%) of the unreacted

substrate and 22 mg (66% yield, 88% yield based on mass

balance) of racemic 5 which was homogeneous by TLC analysis

(H:E, 1:2, R_f53 ) 0.71, R_f5 ) 0.51): mp 234-236 °C; ¹H NMR

(250 MHz) δ 0.94 (s, 3 H), 1.26 (s, 3 H), 1.65-1.85 (m, 1 H),

2.15-2.40 (m, 1 H), 2.26 (s, 3 H), 2.62-3.00 (m, 4 H), 6.13 (d,

1 H, J ) 9.6 Hz), 6.84 (d, 1 H, J ) 9.6 Hz), 6.88 (s, 1 H), 6.96

(br s, 1 H), 7.10 (s, 1 H), 7.75 (d, 1 H, J ) 2.3 Hz); ¹³C NMR

(62.9 MHz) 190.8 (s), 162.9 (d), 152.9 (s), 138.7 (d), 135.8 (s),

135.7 (s), 132.0 (s), 131.1 (d), 127.1 (d), 126.0 (s), 120.4 (d),

52.1 (d), 38.2 (s), 33.0 (t), 27.9 (q), 27.8 (t), 22.1 (q), 15.8 (q)

ppm; IR (KBr pellet) 3265, 1654, 1571, 1418, 1270, 1124, 875

cm^-1; ESI-MS (m/z) 269 (MH⁺, 100%).

11a (R*),4(S*),4a (S*)-4,4a -E p oxy-7-m et h oxy-1,1,8-t r i-

m et h yl-1,2,3,4,4a ,10,11,11a -oct a h yd r o-5H -d ib en zo[a ,d ]-

cycloh ep ten e (58). To a cold solution (0 °C) of 38 mg of olefin

39 (0.14 mmol) in 10 mL of dry CH₂Cl₂were added 56 mg of

85% mCPBA and 44 mg of Na₂CO₃. The reaction mixture was

stirred at rt for 3 h and then diluted with 30 mL of petroleum

ether. Standard ethereal workup provided 14 mg of crude

residue which was chromatographed (elution with H:E, 7:1)

to furnish 26 mg (68%) of epoxide 58 which was homogeneous

by TLC analysis (H:E, 7:1, R_f39 ) 0.90, R_f58 ) 0.65): ¹H

NMR (250 MHz) δ 0.75 (s, 3 H), 0.88 (s, 3 H), 1.15-1.95 (m, 7

H), 2.18 (s, 3 H), 2.50-2.80 (m, 4 H), 3.32 (d, 1 H, J ) 15.8

Hz), 3.79 (s, 3 H), 6.52 (s, 0.8 H), 6.56 (s, 0.2 H), 6.90 (s, 0.8

H), 6.85 (s, 0.2 H). This data represents a 4:1 mixture of

diastereomers.

11a (R*),4a (S*)-4a ,7-Dih yd r oxy-1,1,8-tr im eth yl-1,2,3,4,

4a,10,11,11a-octah ydr o-5H-diben zo[a ,d]cycloh epten e (60).

To 65 mg of a 4:1 mixture of epoxides 58 (0.21 mmol) dissolved

in 3.0 mL of dry THF was added 1.10 mL of L-Selectride (1.0

M, 1.10 mmol), and the resulting mixture was refluxed (67

°C) until TLC analysis indicated that the reaction was

complete (48 h). The reaction mixture was cooled to 0 °C and

diluted with 50 mL of ether, and the resulting mixture was

quenched slowly with water. Standard ethereal workup,

followed by chromatography (elution with H:E, 4:1), gave 5.0

mg (9%) of 11a(R*),4a(S*)-4a-hydroxy-7-methoxy-1,1,8-tri-

methyl-1,2,3,4,4a,10,11,11a-octahydro-5H-dibenzo[a,d]cyclo-

heptene (59) which was homogeneous by TLC analysis (H:E,

3:1, R_f59 ) 0.32): ¹H NMR (250 MHz) δ 0.89 (s, 3 H), 0.93 (s,

3 H), 1.18-1.65 (m, 6 H), 1.70-2.06 (m, 3 H), 2.18 (s, 3 H),

2.47-2.82 (m, 3 H), 3.03 (d, 1 H, J ) 14.1 Hz), 3.80 (s, 3 H),

6.61 (s, 1 H), 6.89 (s, 1 H); ¹³C NMR (62.9 MHz) 155.8 (s), 135.3

(s), 134.2 (s), 130.8 (d), 124.5 (s), 113.9 (d), 70.6 (s), 57.9 (q),

55.3 (q), 51.2 (t), 42.4 (t), 42.0 (t), 34.9 (t), 34.2 (s), 32.1 (d),

24.0 (t), 21.5 (q), 18.6 (t), 15.5 (q) ppm. This data represents

a single compound.

Continued elution (H:E, 4:1) provided 27 mg of alcohol-

phenol 60 (49%) which was homogenous by TLC analysis (H:

E, 3:1, R_f60 ) 0.11): ¹H NMR (250 MHz) δ 0.71 (s, 3 H), 1.00

(s, 3 H), 1.38-1.68 (m, 6 H), 2.20 (s, 3 H), 2.23-2.32 (m, 2 H),

2.33-2.42 (m, 1 H), 2.52-2.71 (m, 3 H), 6.24 (s, 1 H), 6.56 (s,

1 H), 6.78 (s, 1 H). This data represents a single compound.

11a (R*),4a (S*),5(S*)-5-H yd r oxy-7-m e t h oxy-1,1,8-t r i-

m et h yl-1,2,3,4,4a ,10,11,11a -oct a h yd r o-5H -d ib en zo[a ,d ]-

cycloh ep ten e (61) a n d 4a (R*),5(R*),11a (R*)-5-Hyd r oxy-

7-m eth oxy-1,1,8-tr im eth yl-1,2,3,4,4a ,10,11,11a -octa h yd r o-

5H-d iben zo[a ,d ]cycloh ep ten e (66). To a solution of 40 (534

mg, 1.61 mmol) in 10 mL of THF was added diborane (16.1

mL, 16.1 mmol of a 1.0 M solution in THF), and the resulting

mixture was refluxed for a 7-h period and then cooled to 0 °C.

Aqueous NaOH (16 mL, 32 mmol of a 2 M solution) and

hydrogen peroxide (12 mL, 119 mmol of 30% aqueous solution)

stirred for

a 30-min period. Standard ethereal workup,

followed by chromatography (elution with H:E, 5:1), gave 37

mg of dienone 53 (53%) which was homogeneous by TLC

analysis (H:E, 2:1, R_fselenylated cmpd ) 0.71, R_f53 ) 0.39):

¹H NMR (250 MHz) δ 0.95 (s, 3 H), 1.25 (s, 3 H), 1.65-1.85

(m, 1 H), 2.21 (s, 3 H), 2.24-2.40 (m, 1 H), 2.65-3.00 (m, 3

H), 3.82 (s, 3 H), 6.11 (d, 1 H, J ) 9.9 Hz), 6.79 (d, 1 H, J )

9.9 Hz), 6.87 (s, 1 H), 6.89 (s, 1 H), 7.66 (d, 1 H, J ) 2.3 Hz);

¹³C NMR (62.9 MHz) 190.0 (s), 161.7 (d), 155.9 (s), 137.7 (d),

136.4 (s), 135.9 (s), 132.2 (s), 131.0 (d), 127.8 (s), 127.3 (d),

115.2 (d), 55.4 (q), 52.1 (d), 38.0 (s), 32.9 (t), 28.0 (t), 28.0 (q),

22.2 (q), 16.0 (q) (the overlapping signals at 28.0 are resolved

by a DEPT experiment) ppm; IR (film) 2954, 1662, 1595, 1509,

1244, 1125, 827 cm^-1; ESI-MS (m/z) 283 (MH⁺, 100%).

7-Meth oxy-1,1,8-tr im eth yl-10,11-d ih yd r o-2H-d iben zo-

[a ,d ]cycloh ep ten -4-on e (54). To a stirred suspension of 15

mg of NaH (0.39 mmol) in 0.5 mL of dry DMF at 0 °C was

added ethanethiol (42 µL, 0.56 mmol) in 0.5 mL of DMF. The

mixture was allowed to warm to rt over a 3-h period.

A

solution of dienone 53 (16 mg, 0.056 mmol) dissolved in 0.5

mL of DMF was added in one portion to the reaction and the

resulting mixture heated at 100 °C for a 90-min period. The

reaction mixture was cooled to rt, after which standard

8184 J . Org. Chem., Vol. 61, No. 23, 1996

Majetich et al.

were added, and the mixture was warmed to rt and stirred

for a 2-h period. Standard ethereal workup, followed by

chromatography (H:E, 4:1), gave 110 mg (24%) of alcohol 66

which was homogeneous by TLC analysis (H:E, 1:1, R_f66 )

0.31): ¹H NMR (250 MHz) δ 0.72 (s, 3 H), 0.94 (s, 3 H), 1.10-

1.21 (m, 2 H), 1.23-1.40 (m, 6 H), 1.45-1.60 (m, 3 H), 2.19 (s,

3 H), 2.65-2.75 (m, 2 H), 3.85 (s, 3 H), 4.64 (d, 1 H, J ) 8.3

Hz), 6.85 (s, 1 H), 7.08 (s, 1 H).

202 (25%), 43 (100%). Anal. Calcd for C₂₁H₂₈O₄: C, 73.2; H,

8.19. Found: C, 73.14; H, 8.21.

4a (R *),5(R *),11a (R *)-5-Ace t oxy-7-m e t h oxy-1,1,8-t r i-

m et h yl-1,2,3,4,4a ,10,11,11a -oct a h yd r o-5H -d ib en zo[a ,d ]-

cycloh ep ten -10-on e (68). To a solution of acetate 67 (100

mg, 0.303 mmol) in 3 mL of CH₂Cl₂were added PCC (489 mg,

2.27 mmol) and Celite (489 mg). The mixture was refluxed

for 24 h. Standard ethereal workup, followed by chromatog-

raphy (elution with H:E, 4:1), gave 27 mg of unreacted 67

(27%) and 34 mg of ketone 68 (33% yield, 60% based on mass

balance) which was homogeneous by TLC analysis (H:E, 2:1,

R_f68 ) 0.31). An analytical sample was recrystallized

isothermally from ether: mp 124-126 °C; ¹H NMR (250 MHz)

δ 0.88 (s, 6 H), 1.00-1.75 (m, 6 H), 1.85-2.05 (m, 2 H), 1.94

(s, 3 H), 2.22 (s, 3 H), 2.62-2.86 (m, 2 H), 3.90 (s, 3 H), 5.60

(s, 1 H), 6.67 (s, 1 H), 7.49 (s, 1 H); ¹³C NMR (62.9 MHz) 206.0

(s), 169.8 (s), 160.1 (s), 135.9 (s), 131.5 (s), 129.8 (s), 127.2 (s),

110.8 (d), 81.6 (d), 55.6 (q), 46.1 (d), 43.1 (d), 41.0 (t), 40.9 (t),

33.4 (s), 31.5 (t), 30.1 (q), 22.4 (t), 21.3 (q), 19.8 (q), 15.8 (q)

ppm; IR (KBr pellet) 1735, 1669, 1606, 1236 cm^-1; GC-MS (m/

z) 344 (15%), 302 (33%), 284 (17%), 149 (22%), 43 (100%). Anal.

Calcd for C₂₁H₂₈O₄: C, 73.2; H, 8.19. Found: C, 73.15; H, 8.20.

11a (R*),4(S*),4a (S*)-5-H yd r oxy-7-m e t h oxy-1,1,8-t r i-

m et h yl-1,2,3,4,4a ,10,11,11a -oct a h yd r o-5H -d ib en zo[a ,d ]-

cycloh ep ten -10-on e (64). To a solution of acetate 63 (19 mg,

0.055 mmol) was added 3 mL of a 2% solution of KOH in

methanol, and the mixture was stirred at rt for 2 h. The

solvent was removed at reduced pressure, and the residue was

chromatographed (elution with H:E, 5:1) to give 15 mg of

alcohol 64 (90%) which was homogeneous by TLC analysis (H:

E, 1:1, R_f64 ) 0.36): ¹H NMR (250 MHz) δ 0.87 (s, 3 H), 0.92

(s, 3 H), 1.05-2.10 (m, 9 H), 2.21 (s, 3 H) 2.40-2.70 (m, 2 H),

3.93 (s, 3 H), 4.43 (d, 1 H, J ) 9.0 Hz), 7.12 (s, 1 H), 7.53 (s, 1

H).

4a (R*),5(R*),11a (R*)-5-H yd r oxy-7-m et h oxy-1,1,8-t r i-

m et h yl-1,2,3,4,4a ,10,11,11a -oct a h yd r o-5H -d ib en zo[a ,d ]-

cycloh ep ten -10-on e (69). Thirty-five milligrams of acetate

68 (0.102 mmol) were dissolved in 1 mL of a 2% solution of

KOH in methanol, and the mixture was stirred at rt for a 30-

min period. The solvent was removed at reduced pressure,

and the residue was chromatographed (elution with H:E, 1:1)

to give 29 mg of alcohol 69 (85%) which was homogeneous by

TLC analysis (H:E, 1:2, R_f69 ) 0.47): ¹H NMR (250 MHz) δ

0.85 (s, 3 H), 0.89 (s, 3 H), 0.95-2.06 (m, 8 H), 2.45-3.00 (m,

2 H), 3.88 (s, 8 H), 4.60 (s, 1 H), 6.55 (s, 1 H), 7.45 (s, 1 H).

(()-F a velin e Meth yl Eth er (57) by Deh yd r a tion of (64).

To a solution of alcohol 64 (14 mg, 0.046 mmol) and DCC (13

mg, 0.064 mmol) in 0.1 mL of THF was added CuCl (1 mg,

0.009 mmol). The solvent was removed under reduced pres-

sure, and the residue was heated to 90 °C for 4 h. Chroma-

tography of the crude residue (elution with H:E, 10:1) provided

10 mg of faveline methyl ether (57) (76%) which was homo-

geneous by TLC analysis (H:E, 1:1, R_f57 ) 0.82): mp 136-

138 °C [lit. for (()-4 is 139-140 °C;²²135-136 °C for (-)-4⁷]:

¹H NMR (250 MHz) δ 0.76 (s, 3 H), 1.13 (s, 3 H), 1.40-1.51

(m, 2 H), 1.55-1.85 (m, 2 H), 1.60 (s, 3 H), 2.19 (s, 3 H), 2.20-

2.50 (m, 3 H), 3.03 (dd, 2 H, J ) 6.1 Hz, 1.1 Hz), 3.88 (s, 3 H),

6.30 (s, 1 H), 7.63 (s, 1 H); GC-MS (m/z) 284 (69%), 215 (73%),

202 (100%), 173 (85%).

Continued elution (H:E, 1:1) provided 230 mg of alcohol 61

(50%) which was homogeneous by TLC analysis (H:E, 3:1, R_f

61 ) 0.22): ¹H NMR (300 MHz) δ 0.86 (br s, 3 H), 1.01 (br s,

3 H), 1.05-1.15 (m, 2 H), 1.16-1.40 (m, 4 H), 1.42-1.60 (m, 5

H), 1.75 (br s, 1 H), 2.18 (s, 3 H), 3.82 (s, 1 H), 4.57 (d, 1 H, J

) 6.3 Hz), 6.72 (br s, 1 H), 6.85 (s, 1 H).

11a (R *),4(S *),4a (S *)-5-Ace t oxy-7-m e t h oxy-1,1,8-t r i-

m et h yl-1,2,3,4,4a ,10,11,11a -oct a h yd r o-5H -d ib en zo[a ,d ]-

cycloh ep ten e (62). To a solution of alcohol 61 (196 mg, 0.680

mmol) in 6 mL of CH₂Cl₂were added TEA (0.2 mL), DMAP (4

mg, 0.036 mmol), and acetic anhydride (128 µL, 0.88 mmol).

The resulting mixture was stirred for 2 h. Standard ethereal

workup, followed by chromatography (H:E, 5:1), gave 209 mg

(93%) of the 62, an oil which was homogeneous by TLC

analysis (H:E, 2:1, R_f62 ) 0.72): ¹H NMR (250 MHz) δ 0.89

(s, 3 H), 1.00 (s, 3 H), 1.05-2.00 (m, 10 H), 2.09 (s, 3 H), 2.17

(s, 3 H), 3.81 (s, 3 H), 5.67 (d, 1 H, J ) 6.3 Hz), 6.67 (s, 3 H),

6.86 (s, 1 H); ¹³C NMR (62.9 MHz) 155.3 (s), 134.5 (s), 131.8

(d), 125.8 (s), 81.2 (br), 55.4 (q), 45.7 (br), 36.7 (br), 34.0 (t),

32.8 (br), 30.4 (q), 27.3 (q), 24.3 (br), 23.4 (br), 22.0 (t), 21.3

(q), 15.7 (q) ppm. Note: Six peaks observed were so broadened

by conformational interconversion that they were not detected

by DEPT for determination of the multiplicity. The four

remaining signals were not detected. IR (film) 1736, 1511,

1368, 1238, 733 cm^-1; GC-MS (m/z) 330 (0.4%), 270 (39%), 201

(37%), 43 (100%). Anal. Calcd for C₂₁H₃₀O₃: C, 76.3; H, 9.15.

Found: C, 76.26; H, 9.13.

4a (R *),5(R *),11a (R *)-5-Ace t oxy-7-m e t h oxy-1,1,8-t r i-

m et h yl-1,2,3,4,4a ,10,11,11a -oct a h yd r o-5H -d ib en zo[a ,d ]-

cycloh ep ten e (67). To a solution of alcohol 66 (127 mg, 0.44

mmol) in 3 mL of CH₂Cl₂were added TEA (0.1 mL), DMAP (4

mg, 0.034 mmol), and acetic anhydride (83 µL, 0.88 mmol).

The resulting mixture was stirred at rt for a 30-min period.

Standard ethereal workup, followed by chromatography (H:

E, 4:1), gave 112 mg (77%) of acetate 67 which was homoge-

neous by TLC analysis (H:E, 2:1, R_f67 ) 0.72). An analytical

sample was recrystallized isothermally from ether: mp 137-

138 °C; ¹H NMR (300 MHz) δ 0.73 (s, 3 H), 0.93 (s, 3 H), 0.95-

1.80 (m, 8 H), 1.95-2.15 (m, 2 H), 2.17 (s, 6 H), 2.70-2.92 (m,

2 H), 3.82 (s, 3 H), 5.79 (d, 1 H, J ) 7.6 Hz); ¹³C NMR (62.9

MHz) 169.9 (s), 155.8 (s), 137.8 (s), 132.6 (s), 131.2 (d), 124.9

(s), 107.0 (d), 77.5 (d), 55.4 (q), 52.2 (d), 43.0 (d), 42.2 (t), 34.1

(s), 32.4 (t), 30.9 (q), 30.2 (t), 27.0 (t), 21.7 (t), 21.1 (q), 20.4

(q), 15.7 (q) (the benzylic methine at 77.5 overlaps the CDCl₃

triplet, but is detected by DEPT) ppm; IR (KBr pellet) 1734,

1503, 1277, 1244, 1094 cm^-1; GC-MS (m/z) 330 (M⁺, 0.1%), 270

(27%), 201 (19%), 43 (100%). Anal. Calcd for C₂₁H₃₀O₃: C,

76.3; H, 9.15. Found: C, 76.22; H, 9.11.

11a (R *),4(S *),4a (S *)-5-Ace t oxy-7-m e t h oxy-1,1,8-t r i-

m et h yl-1,2,3,4,4a ,10,11,11a -oct a h yd r o-5H -d ib en zo[a ,d ]-

cycloh ep ten -10-on e (63). To a solution of acetate 62 (66 mg,

0.200 mmol) in 3 mL of CH₂Cl₂were added PCC (323 mg, 1.50

mmol) and Celite (323 mg). The mixture was refluxed for 48

h. Standard ethereal workup, followed by chromatography

(elution with H:E, 4:1), gave 13 mg (20%) of unreacted 62 and

25 mg (36% yield, 56% based on mass balance) of ketone 63

which was homogeneous by TLC analysis (H:E, 2:1, R_f63 )

0.31). An analytical sample was recrystallized isothermally

(()-F a velin e Meth yl Eth er (57) by Deh yd r a tion of (69).

To a solution of alcohol 69 (20 mg, 0.066 mmol) and DCC (19

mg, 0.092 mmol) in 0.1 mL of THF was added CuCl (1 mg,

0.009 mmol). The solvent was removed at reduced pressure,

and the residue was heated to 90 °C for a 14-h period.

Chromatography of the resulting residue (elution with H:E,

10:1) gave 12 mg of 57 (64%) which was identical to that

prepared from 64.

1

from ether: mp 177-179 °C; H NMR (250 MHz) δ 0.90 (s, 3

11a (R *),4(S *),4a (S *)-5,7-Dih yd r oxy-1,1,8-t r im e t h yl-

1,2,3,4,4a ,10,11,11a -octa h yd r o-5H-d iben zo[a ,d ]cycloh ep -

ten -10-on e (65). Sodium hydride (36 mg, 0.90 mmol of 60%

dispersion in mineral oil) was suspended in 1.5 mL of DMF.

Ethanethiol (111 µL, 1.50 mmol) was then added to the

H), 0.94 (s, 3 H), 1.10-1.90 (m, 6 H), 2.11-2.33 (m, 2 H), 2.19

(s, 3 H), 2.20 (s, 3 H), 2.56-2.82 (m, 2 H), 3.88 (s, 3 H), 5.74

(d, 1 H, J ) 9.4 Hz), 6.72 (s, 1 H), 7.47 (d, 1 H, J ) 0.5 Hz); ¹³

C

NMR (62.9 MHz) 204.5 (s), 169.9 (s), 161.0 (s), 137.4 (s), 130.9

(d), 128.3 (s), 126.0 (s), 104.8 (d), 77.7 (d), 55.3 (q), 41.4 (d),

38.9 (t), 38.6 (d), 34.4 (t), 33.1 (s), 29.9 (q), 26.9 (q), 24.9 (t),

21.0 (q), 20.8 (t), 15.6 (q) ppm; IR (KBr pellet) 1734, 1666, 1603,

1236, 1051 cm^-1; GC-MS (m/z) 344 (4%), 302 (14%), 284 (38%),

reaction, and the resulting mixture was stirred for 1 h.

A

solution of ether 63 (52 mg, 0.150 mmol) dissolved in 1.5 mL

of DMF was added, and the mixture was heated to 135 °C for

3 h and then acidified by addition of 10% aqueous HCl.

Use of Conjugated Dienones in Cyclialkylations

J . Org. Chem., Vol. 61, No. 23, 1996 8185

Standard ethereal workup, followed by chromatography (H:

E, 5:1 gradient elution to 1:2), gave 32 mg of keto-alcohol 65

(74%) which was homogeneous by TLC analysis (H:E, 1:2, R_f

65 ) 0.20): ¹H NMR (250 MHz) δ 0.85 (s, 3 H), 0.88 (s, 3 H),

1.08-1.40 (m, 4 H), 1.42-1.70 (m, 2 H), 1.85-2.25 (m, 2 H),

2.26 (s, 3 H), 2.30-2.68 (m, 2 H), 4.12 (d, 1 H, J ) 9.0 Hz),

7.10 (s, 1 H), 7.42 (d, 1 H, J ) 0.6 Hz).

4a (R*),5(R*),11a (R*)-5,7-Dih yd r oxy-1,1,8-t r im e t h yl-

1,2,3,4,4a ,10,11,11a -octa h yd r o-5H-d iben zo[a ,d ]cycloh ep -

ten -10-on e (70). Sodium hydride (11 mg, 0.28 mmol of 60%

dispersion in mineral oil) was suspended in 0.5 mL of DMF.

Ethanethiol (35 µL, 0.46 mmol) was then added to the reaction,

and the resulting mixture was stirred for 1 h. A solution of

ether 68 (16 mg, 0.046 mmol) dissolved in 0.5 mL of DMF was

added, and the resulting mixture was heated to 135 °C for 3

h and then acidified by addition of 10% aqueous HCl. Stand-

ard ethereal workup, followed by chromatography (H:E, 5:1

gradient elution to 1:2), gave 9 mg of 70 (67%) which was

homogeneous by TLC analysis (H:E, 1:2, R_f68 ) 0.66, R_f70

) 0.20): ¹H NMR (250 MHz) δ 0.85 (s, 3 H), 0.88 (s, 3 H),

1.00-2.05 (m, 8 H), 2.50-2.95 (m, 2 H), 4.51 (s, 1 H), 6.54 (s,

1 H), 7.45 (s, 1 H).

(s, 1 H), 7.64 (s, 1 H); ¹³C NMR (62.9 MHz) 202.0 (s), 157.8 (s),

147.7 (s), 136.6 (s), 132.0 (d), 129.9 (s), 124.9 (d), 122.0 (s),

118.0 (d), 51.2 (d), 43.0 (t), 42.4 (t), 40.1 (t), 38.4 (s), 28.9 (q),

25.0 (t), 20.7 (q), 15.1 (q) ppm; GC-MS (m/z) 159 (67%), 188

(100%), 201 (67%), 270 (69%).

(()-F a velin e fr om 70. Nine milligrams of KHSO₄(0.066

mmol) and nine milligrams of benzylic alcohol 70 (0.031 mmol)

were heated under a continous N₂stream in 140 °C oil bath

for 2 h. Chromatography (H:E, 2:1) provided 7 mg of racemic

4 (83%) which was identical to that prepared from 65.

Ack n ow led gm en t. Acknowledgment is made to the

Donors of The Petroleum Research Fund, administered

by the American Chemical Society, for support (in part)

of this research. Thanks are extended to Dr. Melvin

Gary Newton (UGA) for carrying out a single crystal

X-ray diffraction analysis on enone 16. Finally, special

appreciation is extended to Dr. Gilbert Rishton of

Tanabe Research (CA) for helpful discussions regarding

Friedel-Crafts-based rearrangements.

(()-F a velin e fr om 65. Thirty-two milligrams of KHSO₄

(0.12 mmol) and 32 milligrams of benzylic alcohol 65 (0.11

mmol) were heated under continous N₂stream in 140 °C oil

bath for 2 h. Chromatography (H:E, 2:1) gave 18 mg of racemic

faveline (60%) which was homogeneous by TLC analysis (H:

Su p p or tin g In for m a tion Ava ila ble: NMR spectra for

obtained compounds (77 pages). This material is contained

in libraries on microfiche, immediately follows this article in

the microfilm version of the journal, and can be ordered from

the ACS; see any current masthead page for ordering

information.

1

E, 1:2, R_f65 ) 0.17, R_f4 ) 0.67): mp 194-196 °C; H NMR

(250 MHz) δ 0.76 (s, 3 H), 1.12 (s, 3 H), 1.35-1.51 (m, 2 H),

1.53-1.72 (m, 4 H), 2.23 (s, 3 H), 2.25-2.45 (m, 3 H), 3.03

(dd, 2 H, J ) 5.7 Hz, 0.6 Hz), 5.44 (s, 1 H), 6.20 (s, 1 H), 6.60

J O9606968

Article Doi

Use of conjugated dienones in cyclialkylations: The total syntheses of (±)-barbatusol, (±)-pisiferin, (±)-deoxofaveline, (±)-xochitlolone, and (±)-faveline

DOI: 10.1021/jo9606968

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