Definition of several control elements relevant to the stereodefined serial elaboration of belted poly(spirotetrahydrofurans) fitted with a cyclohexane core

7492

J . Org. Chem. 1996, 61, 7492-7507

Defin ition of Sever a l Con tr ol Elem en ts Releva n t to th e

Ster eod efin ed Ser ia l Ela bor a tion of Belted

P oly(sp ir otetr a h yd r ofu r a n s) F itted w ith a Cycloh exa n e Cor e

Leo A. Paquette,* Marshall Stepanian, Uppuluri V. Mallavadhani,^†Timothy D. Cutarelli,^‡

Timothy B. Lowinger,^§and Horst J an Klemeyer

Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210

Received May 24, 1996^X

The stereochemistry of the condensations of 2-cyclohexenones, R-arylidenecyclohexanones, and

R-(tert-butyldimethylsiloxy)cyclohexanones carrying one or two (both syn and anti) spirotetra-

hydrofuran units adjacent to the carbonyl with allyl organometallics (especially indium) and with

the Normant reagent (ClMgO(CH₂)₃MgCl) is described. Good levels of anti stereoselection are

observed in the R-arylidene series. Subsequent cyclization generates a second (or third) tetra-

hydrofuran ring possessing trans vicinal oxygens. Useful levels of matched and mismatched

diastereoselection are also attainable by prior R-oxygenation. The intrinsic differences in

diastereomer production between indium and magnesium organometallics are highlighted. A clear

distinction regarding the anticipated direction of stereoselectivity is made on the grounds of chelation

capabilities and the intra- or intermolecularity of carbon-carbon bond formation. Finally, the two

protocols that are described in detail are shown to be iterative, a feature that augurs well for

ultimately accessing the eight possible hexaspirocyclohexanes in an efficient and stereocontrolled

manner.

The synthesis of structurally organized polyethers that

have a preexisting disposition for strong metal ion

binding continues to be the focus of much research.^1,2

Through reduction in the level of conformational freedom

and proper spatial orientation of the several heteroatomic

centers, efficient multipoint binding interactions can be

gained. The better structurally disposed the ligand is

for adopting the conformation favored for binding (both

entropically and enthalpically), the better a receptor it

will be.^1,3,4Despite the vigor with which research in this

area has been pursued, we are unaware of any report

dealing with the question of possible bifacial complex-

ation. This term is intended to encompass any ligand

that finds it possible because of its unique structural

features to bind a metal ion (either the same or different)

on both of its faces.

These considerations have led us to accord attention

to the elaboration of belted spirocyclic tetrahydrofurans.⁵

The eight isomers possible when the central belt is six-

^†BOYSCAST (District Government of India) Visiting Fellow, 1994-

1995. Present address: Regional Research Laboratory, Bhubaneswar

751013, India.

^‡Undergraduate research participant, 1995.

^§Merck Postdoctoral Fellow, 1992. Present address: Bayer Corpora-

tion, Pharmaceutical Division, 400 Morgan Lane, West Haven, CT

06516-4175.

F igu r e 1. The eight possible stereoisomeric poly(spiro-

tetrahydrofuranyl)cyclohexanes. The first (bold face) numerical

designation specifies the unique locus of the â-oxygen atoms;

the last digit delineates the number of ¹³C signals each

polyether will exhibit. The symmetry designations are for

structures averaged over two chair conformations, equivalent

to planar six-membered rings, having flexible spirocyclic side

chains.

^XAbstract published in Advance ACS Abstracts, October 1, 1996.

(1) (a) Iimori, T.; Still, W. C.; Rheingold, A. L.; Staley, D. L. J . Am.

Chem. Soc. 1989, 111, 3439. (b) Erickson, S. D.; Still, W. C. Tetrahedron

Lett. 1990, 31, 4253. (c) Wang, X.; Erickson, S. D.; Iimori, T.; Still, W.

C. J . Am. Chem. Soc. 1992, 114, 4128. (d) Iimori, T.; Erickson, S. D.;

Rheingold, A. L.; Still, W. C. Tetrahedron Lett. 1989, 30, 6947. (e) Li,

G.; Still, W. C. J . Am. Chem. Soc. 1993, 115, 3804; J . Org. Chem. 1991,

56, 6964; Tetrahedron Lett. 1992, 33, 5929. (f) Burger, M. T.; Arm-

strong, A.; Guarnieri, F.; McDonald, D. Q.; Still, W. C. J . Am. Chem.

Soc. 1994, 116, 3593.

(2) (a) Novak, B. M.; Grubbs, R. H. J . Am. Chem. Soc. 1988, 110,

960. (b) Gokel, G. Crown Ethers and Cryptands; The Royal Society of

Chemistry: Cambridge, England, 1991. (c) Cooper, S. R., Ed. Crown

Compounds. Toward Future Applications; VCH Publishers, Inc.: New

York, 1992.

membered are shown in Figure 1. To simplify reference

to the individual isomers, they have been assigned simple

numerical descriptors indicative of the locus of the

(3) Cram, D. J . Angew. Chem., Int. Ed. Engl. 1988, 27, 1009.

(4) (a) Hilgenfeld, R.; Saenger, W. Top. Curr. Chem. 1982, 101, 1.

(b) Weber, E.; Vogtle, F. Top. Curr. Chem. 1981, 98, 1. (c) Inoue, Y.;

Gokel, G. W. Cation Binding by Macrocycles; Marcel Dekker: New

York, 1990.

(5) (a) Negri, J . T.; Rogers, R. D.; Paquette, L. A. J . Am. Chem. Soc.

1991, 113, 5073. (b) Paquette, L. A.; Negri, J . T.; Rogers, R. D. J . Org.

Chem. 1992, 30, 3947.

Elements of Belted Poly(spirotetrahydrofurans)

J . Org. Chem., Vol. 61, No. 21, 1996 7493

â-oriented C-O bonds.⁶The inherent time-averaged

symmetry of each isomer is provided along with the

number of ¹³C NMR signals each will display. The all-

anti and all-syn diastereomers, 7 and 8, respectively, hold

particular fascination since the degrees to which they

exhibit cation coordination would likely constitute key

points of reference for the others.

Sch em e 1

Retrosynthetic analysis associated with the prepara-

tion of 1-8 has been designed around the ready avail-

ability of the dispirocyclohexanones 9 and 10, which are

conveniently produced⁵by 2-fold ring expansion of cy-

clobutanone via oxonium ion-activated pinacol rear-

rangement.⁷Although 9 and 10 are produced in nearly

equivalent amounts, each undergoes equilibration with

the other when heated in chloroform solution containing

a catalytic quantity of p-toluenesulfonic acid. At equi-

librium, anti isomer 10 is slightly favored (K_eq) 0.56).⁸

Since the remaining spirotetrahydrofuran subunits are

to be introduced in turn around the perimeter of the

cyclohexane core, protocols are needed that accomplish

such transformations efficiently and with acceptably high

levels of stereocontrol. This paper describes experiments

addressed to these issues. These protocols have been

developed to the point where their application in more

advanced contexts has already proven feasible.^9-11

Lobben demonstrated earlier with 15 that these two

processes are not without their distinctive stereochemical

nuances.¹⁵In tetrahydrofuran solution at 0 °C, allyl-

magnesium chloride gives little indication of being sensi-

tive to chelation control. Quite strikingly, the Normant

reagent elicits a very respectable chelate-controlled

response from 15 (Scheme 2). Since 15 is conformation-

ally flexible, it is legitimate to inquire whether this

contrasting diastereoselectivity pattern will extend to less

structurally dynamic cyclohexanones. Indeed, the 4-tert-

Discu ssion of Resu lts

The reiterative capping model alluded to above must

deal suitably not only with the diastereofacial control of

nucleophilic 1,2-addition to the carbonyl group but also

with substrate variations that will allow the condensation

to be applied repetitively. Past experience has shown

that two three-carbon organometallic reagents are utili-

tarian in elaborating spirotetrahydrofuran rings from

carbonyl groups. The first utilizes allylmagnesium bro-

mide and proceeds via 11 to diol 12 upon hydroboration-

oxidation (Scheme 1).^5,12The conversion of 12 to 14 can

be accomplished under either basic or acidic conditions.¹³

As will be shown herein, the Normant reagent, ClMgO-

(CH₂)₃MgCl,¹⁴simplifies matters considerably by skirting

the need for anti-Markovnikov hydration.

(6) This nomenclature was suggested to us by Dr. B. M. Branan.

(7) Paquette, L. A.; Lawhorn, D. E.; Teleha, C. A. Heterocycles 1990,

30, 765.

(8) Paquette, L. A.; Branan, B. M.; Friedrich, D.; Edmondson, S.

D.; Rogers, R. D. J . Am. Chem. Soc. 1994, 116, 506.

(9) Paquette, L. A.; Lowinger, T. B.; Bolin, D. G.; Branan, B. M. J .

Org. Chem. 1996, 61, 7486.

(10) Paquette, L. A.; Stepanian, M.; Branan, B. M.; Edmondson, S.

D.; Bauer, C. R.; Rogers, R. D. J . Am. Chem. Soc. 1996, 118, 4504.

(11) Paquette, L. A.; Branan, B. M.; Stepanian, M. Tetrahedron Lett.

1996, 37, 1721.

(12) (a) Trost, B. M.; Bogdanowicz, M. J . J . Am. Chem. Soc. 1973,

95, 5321. (b) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J .

Chem. Soc., Perkin Trans. 1 1988, 1669.

(13) (a) Paquette, L. A.; Negri, J . T. J . Am. Chem. Soc. 1991, 113,

5072. (b) Negri, J . T.; Paquette, L. A. J . Am. Chem. Soc. 1992, 114,

8835. (c) Paquette, L. A.; Andrews, J . F. P.; Vanucci, C.; Lawhorn, D.

E.; Negri, J . T.; Rogers, R. D. J . Org. Chem. 1992, 57, 3956.

(14) Cahiez, G.; Alexakis, A.; Normant, J . F. Tetrahedron Lett. 1978,

3013.

butyl systems 16 and 17 have revealed the relevance of

the conformational predisposition of the spirocyclic ether

oxygen.¹⁵When chelation operates in 16 (equatorial oxy

substituent), nucleophilic attack by the organomagne-

sium will be guided into addition from the axial surface.

Indeed, both reagents favor kinetically controlled axial

attack, the Normant reagent significantly more so. These

results could reflect the overriding of steric effects by

chelation. In the response of 17, allylmagnesium bro-

mide continues to undergo addition with a modest

preference for anti attack while the Normant reagent

(15) Paquette, L. A.; Lobben, P. C. J . Am. Chem. Soc. 1996, 118,

1917.

7494 J . Org. Chem., Vol. 61, No. 21, 1996

Paquette et al.

Sch em e 2

to be better served by the presence of other control

elements. We reasoned that introduction of a double

bond either internal to the cyclohexane ring as in A or

external as in arylidene derivatives B would flatten the

ring somewhat and render the carbonyl group more

sterically accessible. Alternatively, an additional oxygen

atom could be introduced at the R′-position (see C and

D). Its role could be designed to induce enhanced

chelation or, contrastingly, to contribute added steric bulk

on that molecular surface toward which it is projected.

While the A and B options could open up the possibility

for competing 1,4-addition,¹⁶all four motifs were pre-

sumed to provide the necessary latitude to continue

spirocycle construction around the complete cyclohexane

periphery. All four types of structural modification have

been examined.

Un sa tu r a tion In ter n a l to th e Rin g. The early

precedent set by Klemeyer was not particularly encour-

aging.¹⁶Although the addition of allyllithium to 18

proceeded chemoselectively to deliver only 1,2-adducts,

the ratio of 19 to 20 was 1:1 (56% yield). For allylmag-

prefers again to approach syn to the ether oxygen.

Neither 16 nor 17 fares particularly well in competition

experiments with its 2-methoxy analogue, thereby indi-

cating that neither spirocyclic ketone engages in nucleo-

philic addition with maximal complexing capacity.

nesium bromide, 19 (14%) and 20 (16%) were again

formed, but the two stereoisomeric 1,4-adducts predomi-

nated (46% combined).

Consequently, when our attention became directed at

enone 22, it was already clear that alternative allylating

reagents should also be examined (Scheme 2). The

R-bromination of 9, readily achieved with pyridinium

hydrobromide perbromide in CH₂Cl₂solution, furnished

a 10:1 mixture of diastereomers 21 in a combined 88%

yield. Upon heating this mixture with anhydrous lithium

bromide and lithium carbonate in N,N-dimethylaceta-

mide at 170 °C, dehydrobromination was complete in 2

1

h. Resulting enone 22 (98%) exhibited high-field H and

¹³C NMR spectra which were quite broad at 303 K as a

result of slow conformational isomerizaton. Substantial

improvement in resolution was observed at 373 K.

The response of 22 to the action of allylmagnesium

bromide was closely comparable to that exhibited by 18.

Addition of anhydrous cerium trichloride did not signifi-

cantly affect the syn/anti diastereoselectivity ratio of 1:2.

Strikingly, however, treatment of 22 with allyl bromide

and indium metal in THF afforded only alcohol 23, the

product of syn addition. The exclusive formation of 23

is consistent with superb chelation control in that

Consequently, application of this chemistry to the

stereocontrolled synthesis of 1-8 appeared at the outset

(16) Klemeyer, H. J .; Paquette, L. A. J . Org. Chem. 1994, 59, 7924.

Elements of Belted Poly(spirotetrahydrofurans)

J . Org. Chem., Vol. 61, No. 21, 1996 7495

Sch em e 3

conformation of the ketone having the R-oxygen equato-

rially disposed.¹⁵

The next step toward the trispiro ethers involved

hydroboration of the less sterically congested double

bond. When either 23 or 24 was brought into reaction

with 2 equiv of 9-BBN, complex product mixtures re-

sulted. These undesirable reactions could, however, be

suitably suppressed by deprotonating either alcohol with

1 equiv of n-butyllithium, followed by introduction of an

equimolar quantity of 9-BBN. Subsequent oxidation with

alkaline hydrogen peroxide or sodium perborate conve-

niently gave rise to the expected diols 25 (80%) and 26

(73%).

These advanced intermediates were individually cy-

clized via their primary tosylates to give 27 and 28,

respectively. The stereochemical assignments to these

products were confirmed by catalytic hydrogenation to

the dihydro derivatives. The plane of symmetry resident

in the all-syn isomer 30 but not in the anti, syn product

29 was revealed by the anticipated simplification of the

¹H and ¹³C NMR spectra of the former and by X-ray

crystallographic analysis.^5b

alcohol revealed that both C-O bonds are projected

equatorially in the solid state. Thus, incorporation of the

benzylidene group in this fashion would appear to

facilitate axial attack without promoting detectable levels

of 1,4-addition.

When 33 was hydroborated with 9-BBN, a 71% yield

of diol 34 was realized. In keeping with previous

observations, 34 underwent ring closure to 35 in the

presence of tosyl chloride, thereby permitting firm ster-

eochemical assignment to this dispiro olefin. In further

agreement with the trans arrangement of oxygenated

centers, ozonolytic cleavage of 35 gave rise to the well-

known ketone 10.

Since the cis dispiro series was earlier shown to be

somewhat problematical in the extent and direction of

diastereofacial selectivity, it was of interest to examine

the discrimination that benzylidene derivative 36a would

exhibit. Our expectation of a dropoff in chelation control

during reaction with the allylindium reagent was quickly

dispelled by the isolation of 37 in 92% yield (Scheme 4).

On the other hand, when 36a was subjected to the

bifunctional Grignard according to Normant, a three-

component mixture was produced. The major and minor

constituents were ultimately shown to be the diols 38a

(50%) and 39a (3%), respectively. The third product 40a

was recognized to arise from competing conjugate addi-

tion. Substitution of o-tolualdehyde and mesitaldehyde

for benzaldehyde afforded 36b and 36c. Neither of these

ketones exhibited any evidence for entering into conju-

gate addition. Consequently, a single o-methyl group on

the aryl ring provides adequate steric shielding to deter

the unwanted formation of 40.

Although the allylation/hydroboration sequence pro-

ceeded adequately well, it was desirable to examine a

more direct route to the 1,4-diols. Such a procedure, if

adequately stereocontrolled, would reduce the number of

steps and diminish the need for chromatographic puri-

fication. In his study of bifunctional Grignard reagents,

Normant described the generation of ClMgO(CH₂)₃-

MgCl,¹⁴stock solutions of which can be stored for ap-

preciable periods of time. When 22 was treated with a

modest excess of this nucleophile in THF and the result-

ing products were directly tosylated, there was obtained

a mixture of 27 (6%), 28 (13%), and 31 (22%). Although

this finding was initially disconcerting, we soon came to

realize that the response of 22 to the Normant reagent

is aberrant. For example, the trans spiro enones E and

F are attacked predominantly in syn-chelate 1,2-fashion

to give adducts related to 25 in g75% yield.⁹

Five of the six diols 38 and 39 were brought into ring

closure. As usual, they were admirable precursors to

41a -c, 42a , and 42c. Ozonolysis of trispiro olefins

41a -c in methanol followed by treatment with dimethyl

sulfide resulted in degradation to 43 in only two in-

stances. The mesityl derivative 41c was recovered

unchanged, presumably as a result of substantive steric

shielding in the area of the double bond. The subsequent

conversion of 43 to 44 illustrates the reiterative potential

of this sequence. The stereochemical assignments made

to the more advanced intermediates in Scheme 4 are

securely founded on the independent conversion of 43 to

tetraspiro ketone G of established structure.¹⁸

Notwithstanding, more extensive exploitation of the

cyclohexenone approach to 1-8 was curtailed when

regiocontrolled monooxygenation of the double bond in

27 and 28 could not be accomplished efficiently.¹⁷

Th e Rep etitive Ar ylid en e Op tion . The route fol-

lowed in this instance began with the Claisen-Schmidt

condensation of benzaldehyde with 15 (Scheme 3). In-

dium-promoted allylation of 32 proved to be a highly

stereocontrolled syn-selective process, giving rise to 33

in 87% yield. X-ray crystallographic analysis of this

(17) Lowinger, T. B. Unpublished observations in this laboratory.

(18) Paquette, L. A.; Stepanian, M. Manuscript in preparation.

7496 J . Org. Chem., Vol. 61, No. 21, 1996

Paquette et al.

Sch em e 4

In view of the high selectivity encountered in the

conversion of 36a to 37, the inefficient and uncontrolled

response of 45 toward the allylindium reagent elicited

spectroscopically distinctive from 43, was confirmed by

an independent synthesis to be described (vide infra).

The findings summarized in Schemes 3-5 provide

convincing evidence that introduction of a spirotetra-

hydrofuran ring immediately adjacent to a preexisting

spirocyclic center of the same type is synthetically viable

and suitably efficient when the disposition of the oxygen

atoms is anti. In an attempt to redirect the facial

selectivity of nucleophilic attack on those ketones pres-

ently of interest, the capability of the bulky methyl-

aluminum bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD)

reagent to function as an external controller was briefly

examined. Yamamoto has demonstrated that prior for-

mation of a complex between a 2-alkoxycyclohexanone

and MAD so sterically encumbers the less congested

equatorial surface of the carbonyl carbon that nucleo-

philic attack occurs from the axial direction.¹⁹In the

considerable consternation (Scheme 5). However, con-

siderable improvement in stereocontrol and in concise-

ness was observed with the Normant reagent. In this

instance, direct cyclization of the resulting diol furnished

48 in 83% yield. The efficiency of this transformation

was parlayed into the preparation of ketone 49 and its

benzylidene derivative 50. The anti, anti arrangement

of the spiro rings in 49, which caused this ketone to be

Elements of Belted Poly(spirotetrahydrofurans)

J . Org. Chem., Vol. 61, No. 21, 1996 7497

Sch em e 5

Sch em e 7

Sch em e 6

present context, 36a was found to produce a mixture of

51 (62%) and 40a (22%) following appropriate treatment

with MAD and allylmagnesium bromide (Scheme 6).

Thus, although the allyl substituent was indeed intro-

duced from the face opposite that used by the allylindium

reagent which delivers 37, a significant level of competing

1,4-addition also materializes.

zoic acid²¹were especially suitable. Submission of 9 to

this two-step sequence afforded a 4:1 mixture of 52 and

53 in 96% overall yield (Scheme 7). Without exception,

separation of the stereoisomeric R-hydroxy ketones is

readily accomplished via chromatography on silica gel.

The stereochemistry of the individual epimers follows

from the chemical shift of their carbinol proton. As

illustrated in H and I, the appearance of the CHOH

signal in 53 at a position significantly downfield of that

in 52 convincingly points to its 1,3-diaxial relationship

relative to the proximal ethereal oxygen.

Individual silylation of 52 and 53 gave 54 and 55,

respectively, and led to an analysis of the stereochemical

course of the addition of ClMgO(CH₂)₃MgCl. To facilitate

product analysis, the resulting diols were directly cyclized

as before. When the OTBS substituent was configured

â as in 54, the only product observed was 58 (89% for

the two steps). Clearly, syn orientation of the R- and R′-

The advantages and disadvantages associated with the

arylidene functionalization option were now quite ap-

parent. Although certain facets of this chemistry are

highly adaptable to selected synthetic goals, limitations

do persist. Our quest for an enhanced range of options

proved decisive in prompting examination of the conse-

quences of preliminary R-oxygenation.

Th e Con seq u en ces of P r elim in a r y r-Oxygen -

a tion . At the outset, the various means for the R-oxy-

genation of 9 and/or 10 were screened for their overall

efficiency. On the strength of these experiments, it was

determined that initial conversion to the silyl enol

ethers²⁰and subsequent oxidation with m-chloroperben-

(19) (a) Maruoka, K.; Oishi, M.; Yamamoto, H. Synlett 1993, 683.

(b) Maruoka, K.; Oishi, M.; Shiohara, K.; Yamamoto, H. Tetrahedron

1994, 50, 8983.

(20) Garst, M. E.; Bonfiglio, J . N.; Grudoski, D. A.; Marks, J . J . Org.

Chem. 1980, 45, 2307.

(21) (a) Colvin, E. K. Silicon in Organic Synthesis; Butterworths:

London, 1981; p 236 ff. (b) Rubottom, G. M.; Vazquez, M. A.; Pelegrina,

D. R. Tetrahedron Lett. 1974, 4319.

7498 J . Org. Chem., Vol. 61, No. 21, 1996

Paquette et al.

Sch em e 8

oxygen centers fosters exceptional levels of anti attack

by the Normant reagent. When the same flanking

oxygen substituents are disposed anti as in 55, the

combination is not equally synergistic. Despite the

mismatch, anti attack continues to be favored, but 59 is

formed only about 5 times faster than 57. Unambiguous

proof of the R-orientation of the third spiro oxygen atom

in 57 followed from its conversion to 43. Once this

correlation was made, the assignment of stereochemistry

to all of the intermediates in Scheme 7 was made

possible. Thus, 60 became the third trispirocyclohex-

anone to be characterized in preparation for its utilization

in more advanced functionalization protocols.

In order to establish if these results were general with

respect to the stereoselectivity of the R-oxygenation and

spiroalkylation steps, the Rubottom oxidation^21bwas

applied to 10 (Scheme 8). This procedure led to the

coformation of 61 and 62, with the R-isomer now pre-

dominating by a factor of 2.6:1. This crossover in

stereoselectivity, initially formulated by the strength of

¹H NMR chemical shift data (see J and K), was further

verified by single-crystal X-ray diffraction studies, which

demonstrated that 61 does indeed adopt in the solid state

that conformation in which the two spirotetrahydrofuran

C-O bonds are projected axially as in J .

Another significant difference between Schemes 7 and

8 is the stereochemical outcome of the Normant addi-

tions. When the oxygen atoms flanking the carbonyl

group are syn as in 64, R-attack giving rise to 68 is no

longer the exclusive reaction pathway. A 13% yield of

66 was also observed. Furthermore, 63 was converted

into a 69:27 mixture of 65 and 67. Since 54 and 55 differ

from 63 and 64 only in the manner in which the “remote”

spirotetrahydrofuran ring is attached (see H-K), it is

appropriate to question its role in these nucleophilic

additions (vide infra).

The trispiro ethers 65-68 were transformed conven-

tionally into 49 and 69. The latter ketone was R-oxygen-

ated to produce 70 and 71 in a 1:2.2 ratio. X-ray

crystallographic analysis of 70 indicated its solid state

conformation to be as shown in L. It is noteworthy in

this instance that the chemical shift of the axial R-carbinol

proton again appears appreciably downfield. For 71,

adoption of conformer M prevails since the R-carbinol

proton also finds itself shifted to below δ 4.5 and is clearly

coupled in J _ax-axand J _ax-eqfashion to the neighboring

methylene protons.

functionalized ethers, such as 1-8, might be undertaken.

These accomplishments shall be presented elsewhere.

The conversion of 69 to 70 and 71 illustrates the

readiness with which the construction of multiply spiro

Elements of Belted Poly(spirotetrahydrofurans)

J . Org. Chem., Vol. 61, No. 21, 1996 7499

Ta ble 1. F a cia l Selectivity Obser ved in Allylin d iu m

Ad d ition s^a

equately basic. The dominance of this reactivity pattern

can be cited as strong evidence for Mg(II)-controlled

conformational engineering prior to carbon-carbon bond

formation. This key difference between magnesium and

indium is considered to be one of the root causes of the

diastereoselectivity differences observed in the present

study.

The second important consideration is the fact that it

is one single allylindium species which chelates and

reacts.^15,22This is quite distinct from other chelation

control reactions where the reacting reagent is different

from the chelating agent. Grignard reagents fall into the

latter category.²⁴This distinguishing feature for indium-

mediated allylations may well be an argument that such

reactions do indeed occur on the metal surface. However,

this feature has not yet been established experimentally.

Whatever the case, the reaction order can indeed impact

impressively on the stereoselectivity of 1,2-addition to

chiral ketones.

In order to facilitate visual analysis of the data in

Tables 1 and 2, the contrasting transition states for the

indium-promoted allylations and Normant additions have

been grouped side-by-side in Table 3. The differing

stereoinduction experienced by parent ketone 15 toward

the two organometallic reagents is consistent with (a)

axial delivery of an allyl group from indium in a complex,

N, consisting of the thermodynamically more favored

O-axial conformer,^5,15,25and (b) utilization by the Grig-

nard reagent of the ring-inverted O-equatorial option in

order to allow for maximum chelation by magnesium ion

as in O. Axial attack operates because less steric

interference materializes along that trajectory.

Parallel thinking rationalizes the seemingly peculiar

behavior of the conformationally more rigidified 4-tert-

butyl substituted pair 16 and 17. The highly preferred

equatorial allylation of 16 can be envisioned as arising

within complex P , where the enforced equatorial projec-

tion of the tetrahydrofuranyl oxygen invites suitable

chelation to indium. Once this complex is formed,

intramolecular delivery can materialize only on the

equatorial face of the ketone carbonyl. The magnesium

complex Q has the same fundamental structure. How-

ever, the subsequent attack by an independent nucleo-

philic entity has the freedom to approach axially as

shown. Since 17 is so constructed as to disallow effective

chelation of both oxygens simultaneously to either metal,

R and S reflect contrasting access routes to the carbonyl

carbon.

ketone

T, °C

attack anti to O:syn to O

15^b

16^b

17^b

22

32

36a

45

25

0

5.6:1

11.8:1

14.0:1

<3:>97

1:1.1

0

a

b

Solvent: THF. Data derived from ref 15.

Ta ble 2. F a cia l Selectivity Obser ved in Ad d ition s of th e

Nor m a n t Rea gen t^a

ketone

T, °C

attack anti to O:syn to O

15^b

16^b

17^b

22

32

36a

45

54

55

63

64

0

1:8.8

1:14.2

7.6:1

-78 f rt

2:1

<3:>97

1:16.7

<3:>97

>97:<3

4.8:1

1:2.6

6.5:1

a

b

Solvent: THF. Data derived from ref 15.

Eva lu a tion of th e Ster eoch em ica l Even ts

A compilation of the facial selectivity exhibited for

capture of the allylindium reagent is provided in Table

1. The analogous results for the Normant reagent are

summarized in Table 2. At first glance, these data give

the appearance of being very disparate. However, it is

clear that different factors must play an important role

in controlling the outcome of these sets of reactions.

Indeed, our results show that indium and magnesium

reagents exert rather different effects in a significant and

previously unappreciated manner during addition to

R-oxygenated cyclic ketones. The dissimilar roles played

by these metals prove central to the ultimate determi-

nation of diastereofacial selection.

Consider first the properties of allylindium reagents

that have been uncovered to the present time. One

provocative aspect of their chemistry is a strong coordi-

nating capability to neighboring free hydroxyl groups.²²

Comparably good attractive interactions persist when

methoxyl substituents are in close proximity,¹⁵but a

significant dropoff is seen when larger groups are present

on the flanking oxygen (e.g., benzyl, trimethylsilyl) or

when it is incorporated in a heterocyclic ring as in the

present circumstances.¹⁵This is not to say that internal

chelation will not materialize at all in the latter contexts.

Rather, geometric considerations need to be properly

preestablished for such to be operative. Added steric bulk

sufficiently deters the ability of the indium to anchor onto

the heteroatom so that conformational readjustments are

not likely to be observed under these circumstances.

In contrast, Grignard reagents enter more vigorously

into formation of preorganized complexes with R- and

â-alkoxy carbonyl compounds.²³For such reactions,

adherence to Cram’s chelate model is a consistent

phenomenon provided that the chelating oxygen is ad-

The advantages that can accrue to the intramolecular

allylative option is clearly accentuated in those examples

involving 22. The placement of a double bond within the

six-membered ring facilitates conformational flexing²⁶to

a degree such that the indium reagent can become

coordinated as in T. This complex bears some similarity

to P and can therefore be expected to proceed along a

closely related trajectory to position the allyl substituent

syn to the flanking oxygen atom. The magnesium

complex U experiences a more equitable level of syn and

anti nucleophile capture because the independent at-

tacking Grignard reagent encounters steric congestion

(24) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.

(25) (a) Fraser, R. R.; Faibish, N. C. Can. J . Chem. 1995, 73, 88. (b)

Cantacuzene, D.; Tordeux, M. Can. J . Chem. 1976, 54, 2759. (c)

Robinson, M. J . T. Tetrahedron 1974, 30, 1971.

(26) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of

Carbon Compounds; J ohn Wiley and Sons, Inc.: New York, 1994; p

726 ff.

(22) (a) Paquette, L. A.; Mitzel, T. M. J . Am. Chem. Soc. 1996, 118,

1931. (b) Paquette, L. A.; Mitzel, T. M. Tetrahedron Lett. 1995, 36,

6863.

(23) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.

(b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462.

7500 J . Org. Chem., Vol. 61, No. 21, 1996

Paquette et al.

Ta ble 3. Com p ila tion of th e Assu m ed Rea ctive Tr a n sition Sta tes

which is presumed to be coordinated to magnesium ion

as well, exerts sufficiently large spatial demands to deter

axial attack by the Normant reagent, even when this

nucleophile has to contend with a large neighboring axial

OTBS group as in AD. The inversion of stereochemistry

that positions the distal ether oxygen equatorially in AE

is accompanied by sufficient relief of nonbonded interac-

tion that a modest level of axial entry by the Grignard

species is operational.

of near comparable magnitude along both available

approaches to the carbonyl group.

The structural distortion and added flexibility resident

in benzylidene derivative 32 allows for the intervention

of complexes V and W. In this instance, axial delivery

is more feasible irrespective of the reaction order. This

state of affairs is not altered upon syn attachment of a

second spiro ring as in 36a . Of greater interest is the

fact that the anti dispiro ketone 45 responds comparably

to the Normant reagent, as clearly seen in AB. On the

other hand, the considerably weaker chelating power of

indium(III) is not capable of proceeding to product totally

via AA. As a consequence, anti attack via Z competes

effectively to give a 1:1.1 distribution of products.

In summary, recourse either to R-arylidenation or to

R-oxygenation offers an experimentally simple, highly

attractive approach to repetitive introduction of spirotet-

rahydrofuran units around the perimeter of cyclohexane

rings. Initial Claisen-Schmidt condensation with an

aromatic aldehyde lends itself especially well to the

introduction of the new C-O bond anti to a preexisiting

one. Recourse to allylmagnesium bromide in the pres-

ence of the MAD reagent, a process not extensively

screened here, merits further attention as a direct means

for dictating a predominant syn-selective outcome. The

presence of a stereodefined R′-OTBS substituent is also

enabling of stereoselectivity control and constitutes a very

competitive alternative approach to the same synthetic

goals. Since the origins of asymmetry in the examples

Finally, the stereochemical outcome of Normant addi-

tions to 54, 55, 63, and 64 can be concisely rationalized

in terms of strongly chelated intermediates (see AC-AF ).

Once the intervention of these intermediates is accepted,

their partitioning to the observed products is impacted

directly by prevailing steric factors. All of the four

R-oxygenated ketones undergo equatorial attack as ex-

pected from the model, although to quite differing

degrees. In AC and AD, the remote axial ether oxygen,

Elements of Belted Poly(spirotetrahydrofurans)

J . Org. Chem., Vol. 61, No. 21, 1996 7501

bromide (1.73 mL of 1.0 M in ether, 1.73 mmol), stirred for 1

h, diluted with ether, and quenched by the addition of

saturated NH₄Cl solution. The separated organic phase was

dried and freed of solvent. Flash chromatography of the

residue on silica gel (elution with 40% ether in petroleum

ether) gave 97 mg of 23 and 165 mg of 24 (73% combined yield).

For 23: colorless oil; IR (neat, cm^-1) 3600, 1205, 1050, 730;

¹H NMR (300 MHz, CDCl₃) δ 6.05-5.91 (m, 1 H), 5.79-5.57

(m, 2 H), 5.19-5.11 (m, 2 H), 4.10-3.65 (m, 4 H), 2.75-1.34

(series of m, 13 H); ¹³C NMR (300 MHz, toluene-d₈, 353 K)

ppm 135.8, 132.2, 126.4, 117.0, 91.2, 87.8, 76.5, 70.3, 67.8, 41.9,

37.1, 33.8, 29.0, 27.3, 26.1; MS m/ z (M⁺) calcd 250.1569, obsd

250.1574.

surveyed appear to be primarily of steric origin, an

important future consideration will be the impact of ever-

increasing conventional nonbonded interactions on over-

all stereocontrol as the intermediates become increas-

ingly functionalized. Extensions of these strategies to

more extensively elaborated members of this class,

including the development of efficient routes to 1-8, are

in progress and shall be reported in due course.

Exp er im en ta l Section

Melting points are uncorrected. ¹H and ¹³C NMR spectra

were recorded at the indicated field strengths. High-resolution

mass spectra were measured at The Ohio State University

Chemical Instrumentation Center. Elemental analyses were

performed at the Scandinavian Microanalytical Laboratory,

Herlev, Denmark. All reactions were carried out under a

nitrogen atmosphere, and the ensuing separations were ef-

fected either with Merck Lobar columns (Lichroprep Si-60)

fitted to a Fluid Metering INC pump (MPLC) or on Merck silica

gel HF₂₅₄(flash chromatography). The organic extracts were

dried over anhydrous magnesium sulfate or sodium sulfate.

Solvents were reagent grade and in many cases dried prior to

use.

(5R*,6R*)-1,7-Dioxa d isp ir o[4.0.4.4]t et r a d ec-12-en -11-

on e (22). To a magnetically stirred solution of 9 (400 mg, 1.89

mmol) in THF (5 mL) cooled to 0 °C was added dropwise a

solution of pyridinium hydrobromide perbromide (612 mg, 2.0

mmol) in THF (7 mL). The reaction mixture was allowed to

warm to rt for 15 min, diluted with ether, and washed

sequentially with 10% sodium thiosulfate solution, water, and

brine prior to drying and concentration. The residue was

subjected to MPLC on silica gel (elution with 50% ether in

petroleum ether) to give 433 mg (80%) of the major diastere-

omer, accompanied by 45 mg (8%) of the minor diastereomer.

The spectral data which follow reveal these products to be i

and ii, respectively.

For 24: colorless oil; IR (neat, cm^-1) 3640, 3440, 1520, 1430,

1230, 1060, 940, 770; ¹H NMR (300 MHz, toluene-d₈, 353 K) δ

6.27 (m, 1 H), 5.73 (dt, J ) 10.2, 2.0 Hz, 1 H), 5.38 (dt, J )

10.2, 3.6 Hz, 1 H), 5.09 (m, 2 H), 3.85 (m, 3 H), 3.52 (m, 2 H),

2.49 (m, 1 H), 2.34 (d, J ) 7.4 Hz, 1 H), 2.14 (m, 2 H), 1.92-

1.50 (series of m, 7 H), 1.38 (m, 1 H); ¹³C NMR (75 MHz,

toluene-d₈, 353 K) ppm 135.7, 133.7, 124.2, 116.1, 91.0, 89.0,

75.5, 70.4, 67.9, 42.1, 37.2, 34.3, 28.7, 27.1, 25.9; MS m/ z (M⁺)

calcd 250.1569, obsd 250.1559.

B. Or ga n ocer a te Ad d ition . A slurry of anhydrous ce-

rium trichloride²⁷(184 mg, 0.75 mmol) in dry THF (1 mL)

cooled to 0 °C was treated dropwise with allylmagnesium

bromide (0.75 mL of 1.0 M in ether, 0.75 mmol) via syringe.

The resulting deep-orange-colored solution was stirred at 0

°C for 1.5 h, at which point 22 (104 mg, 0.50 mmol) dissolved

in dry THF (1 mL) was introduced via cannula. An immediate

color change from orange to white was noted. After 1 h of

stirring, the reaction mixture was quenched with saturated

NH₄Cl solution and filtered through a small pad of Celite. The

organic phase was washed with saturated NH₄Cl solution and

brine, dried, and evaporated. Chromatography as above gave

22 mg of 23 and 49 mg of 24 (57% combined yield).

C. In d iu m -P r om oted Cou p lin g. To a solution of 22 (500

mg, 2.4 mmol) in THF (5 mL) were added indium powder (820

mg, 7.2 mmol) and allyl bromide (0.62 mL, 7.2 mmol). The

reaction mixture was stirred at rt overnight, quenched with 1

N HCl, diluted with ether, and filtered. The organic phase of

the filtrate was washed with 1 N HCl and brine prior to drying.

Purification of the residue by MPLC on silica gel (elution with

35% ether in petroleum ether) gave 306 mg (50%) of 23 as the

only product.

(5R*,6S*,11R*)-11-H yd r oxy-1,7-d ioxa d isp ir o[4.0.4.4]-

tetr a d ec-12-en e-11-p r op a n ol (25). To a cold (0 °C) solution

of 23 (126 mg, 0.50 mmol) in anhydrous THF (2 mL) was added

n-butyllithium (0.39 mL of 1.3 M, 0.50 mmol) followed by

9-BBN (1.50 mL of 0.5 M in THF, 0.75 mmol). The reaction

mixture was allowed to warm slowly to rt. After 10 h, sodium

hydroxide (225 µL of 3.0 M, 0.675 mmol) was introduced,

followed by 230 µL of 30% hydrogen peroxide. The resulting

solution was stirred for 45 min and diluted with ether. The

organic phase was washed with brine, dried, and evaporated.

Purification of the residue by MPLC on silica gel (elution with

10% methanol in CH₂Cl₂) afforded 83 mg of 25 and 27 mg of

recovered 23. The corrected yield of diol is 80%: colorless oil;

IR (neat, cm^-1) 3610, 3450, 1220, 1050, 870, 750; ¹H NMR (300

MHz, toluene-d₈, 353 K) δ 5.53 (m, 1 H), 5.47 (m, 1 H), 3.95

(m, 1 H), 3.86 (m, 1 H), 3.66 (m, 2 H), 3.41 (m, 2 H), 2.38 (br

d, 1 H), 2.09 (m, 3 H), 2.00-1.26 (series of m, 12 H); ¹³C NMR

(75 MHz, toluene-d₈, 353 K) ppm 131.9, 126.5, 91.7, 87.8, 77.0,

70.3, 67.7, 63.7, 37.0, 33.9, 33.6, 29.2, 27.3, 26.1 (one C signal

not observed); MS m/ z (M⁺) calcd 268.1675, obsd 268.1675.

(5R*,6S*,11S*)-11-H yd r oxy-1,7-d ioxa d isp ir o[4.0.4.4]-

tetr a d ec-12-en e-11-p r op a n ol (26). By means of the proce-

dure detailed above, 261 mg (1.04 mmol) of 24 was transformed

into 109 mg of 26 and 121 mg of unchanged starting material.

For i: colorless oil; IR (film, cm^-1) 1730, 1440, 1290, 1075;

¹H NMR (300 MHz, CDCl₃) δ 5.21 (dd, J ) 11.3, 6.7 Hz, 1 H),

3.87 (m, 3 H), 3.78 (m, 1 H), 2.52 (m, 2 H), 2.26 (m, 1 H), 1.91

(m, 3 H), 1.85-1.55 (series of m, 6 H); ¹³C NMR (75 MHz,

CDCl₃) ppm 201.3, 94.5, 87.6, 69.4, 69.0, 52.7, 33.1, 32.3, 31.2,

26.1, 26.0, 25.9; MS m/ z (M⁺) calcd 290.0340, obsd 290.0370.

For ii: colorless oil; IR (film, cm^-1) 1730, 1700, 1440, 1300,

1

1220, 1100, 1050; H NMR (300 MHz, CDCl₃) δ 4.72 (dd, J )

11.3, 7.5 Hz, 1 H), 3.98-3.75 (m, 4 H), 2.53-2.31 (m, 2 H),

2.19-1.70 (series of m, 9 H), 1.54-1.41 (m, 1 H); MS m/ z (M⁺

- Br) calcd 209.1177, obsd 209.1174.

To a solution of the above mixture (830 mg, 2.87 mmol) in

N,N-dimethylacetamide (17 mL) were added lithium carbonate

(650 mg, 8.58 mmol) and anhydrous lithium bromide (640 mg,

7.33 mmol). The reaction temperature was maintained at 170

°C for 1.5 h. After cooling, the solvent was removed in vacuo

at 30-40 °C and the residue was taken up in ether, filtered

through a short pad of Celite, concentrated, and purified by

flash chromatography on silica gel (elution with 40% ether in

petroleum ether). There was isolated 585 mg (98%) of 22 as

a colorless liquid: IR (neat, cm^-1) 1690, 1380, 1220, 1090, 1060;

¹H NMR (300 MHz, CCl₃) δ 6.74 (m, 1 H), 5.91 (m, 1 H), 4.04

(m, 1 H), 3.90-3.65 (m, 3 H), 2.57 (m, 1 H), 2.48-2.26 (m, 2

H), 2.13 (m, 1 H), 2.05-1.66 (series of m, 5 H), 1.54 (m, 1 H);

MS m/ z (M⁺) calcd 208.1099, obsd 208.1105.

The adjusted yield of 26 is 73%: colorless oil; IR (neat, cm^-1

)

1

3400 (br), 1300, 1050, 930; H NMR (300 MHz, toluene-d₈) δ

5.72 (dt, J ) 10.3, 1.9 Hz, 1 H), 5.39 (dt, J ) 7.4, 3.3 Hz, 1 H),

3.90 (m, 1 H), 3.78 (m, 1 H), 3.65-3.49 (m, 4 H), 2.32 (br s, 1

H), 2.19 (m, 1 H), 1.95-1.20 (series of m, 14 H); ¹³C NMR (62.5

Anal. Calcd for C₁₂H₁₆O₃: C, 69.21; H, 7.74. Found: C,

68.97; H, 7.88.

Allyla t ion s of 22. A. Allylm a gn esiu m Br om id e.

A

solution of 22 (300 mg, 1.44 mmol) in anhydrous ether (3 mL)

was cooled to 0 °C and treated dropwise with allylmagnesium

(27) Encyclopedia of Reagents for Organic Synthesis; Paquette, L.

A., Ed.; J ohn Wiley and Sons: Chichester, 1995; pp 1031-4.

7502 J . Org. Chem., Vol. 61, No. 21, 1996

Paquette et al.

MHz, toluene-d₈, 373 K) ppm 133.4, 124.9, 91.7, 89.1, 75.8,

70.6, 67.9, 63.8, 37.3, 34.6, 34.2, 27.9, 27.4, 26.2 (1 C not

observed); MS m/ z (M⁺) calcd 268.1675, obsd 268.1674.

(5R*,6R*,11R*)-1,7,12-Tr ioxatr ispir o[4.0.4.0.4.3]octadec-

16-en e (27). A solution of 25 (163 mg, 0.61 mmol) in CH₂Cl₂

(4 mL) was treated with triethylamine (1 mL), p-toluenesulfo-

nyl chloride (139 mg, 0.73 mmol), and 4-(dimethylamino)-

pyridine (4 mg). The reaction mixture was stirred at 25 °C

for 8 h, diluted with ether, washed with 1 N HCl and brine,

dried, and concentrated. Purification of the residue by MPLC

(silica gel, elution with 30% ether in petroleum ether) fur-

nished 110 mg (72%) of 27 as a clear, colorless oil: ¹H NMR

(250 MHz, toluene-d₈, 373 K) δ 5.53 (dt, J ) 8.1, 1.8 Hz, 1 H),

5.34 (dt, J ) 8.1, 3.1 Hz, 1 H), 3.91-3.55 (m, 6 H), 2.64 (m, 1

H), 2.26-1.51 (series of m, 13 H); ¹³C NMR (62.5 MHz, toluene-

d₈, 373 K) ppm 134.7, 123.3, 91.1, 88.4, 88.3, 70.5, 68.5, 67.7,

38.7, 34.3, 33.4, 31.8, 27.4, 27.3, 26.5; MS m/ z (M⁺) calcd

250.1569, obsd 250.1533.

powder (1.15 g, 10.0 mmol), and allyl bromide (0.9 mL, 10.0

mmol) in water (20 mL) and THF (50 mL) was stirred for 2 h,

poured into 10% HCl, and extracted five times with ethyl

acetate. The combined organic layers were washed with brine

(2×), dried, and concentrated. Chromatography of the residue

on silica gel (elution with 30% ether in petroleum ether)

afforded 1.47 g (87%) of 33 as a colorless solid: mp 84-86 °C;

IR (film, cm^-1

) 3546, 1638, 1600, 1493, 1444, 1310, 1220, 1068;

¹H NMR (300 MHz, CDCl₃) δ 7.36-7.30 (m, 2 H), 7.31-7.20

(m, 3 H), 6.73 (s, 1 H), 5.90-5.77 (m, 1 H), 5.20-5.13 (m, 2

H), 4.05-3.98 (m, 1 H), 3.89-3.82 (m, 1 H), 2.89-2.83 (m, 1

H), 2.67-2.59 (m, 1 H), 2.34-2.25 (m, 1 H), 2.04 (br s, 1 H),

2.00-1.65 (series of m, 7 H), 1.56-1.47 (m, 1 H), 1.40-1.20

(m, 1 H); ¹³C NMR (75 MHz, CDCl₃) ppm 141.8, 138.3, 133.3,

128.8, 127.9, 125.9, 123.5, 117.7, 88.5, 79.0, 68.5, 38.8, 34.5,

30.9, 26.9, 25.6, 23.21; MS m/ z (M⁺) calcd 284.1776, obsd

284.1775.

Anal. Calcd for C₁₉H₂₄O₂: C, 80.24; H, 8.51. Found: C,

80.01; H, 8.42.

This compound was subjected to X-ray crystallographic

analysis.²⁸

Anal. Calcd for C₁₅H₂₂O₃: C, 71.97; H, 8.86. Found: C,

72.05; H, 8.90.

(5R*,6R*,11S*)-1,7,12-Tr ioxatr ispir o[4.0.4.0.4.3]octadec-

16-en e (28). By means of the procedure detailed above, 185

mg (0.69 mmol) of 26 was transformed into 28 (94 mg, 55%),

a colorless, crystalline solid: mp 75-77 °C; ¹H NMR (250 MHz,

toluene-d₈, 373 K) δ 5.52 (m, 1 H), 5.33 (m, 1 H), 4.02 (m, 2

H), 3.75-3.45 (m, 4 H), 2.73 (s, 1 H), 2.64 (s, 1 H), 2.20-1.37

(series of m, 12 H); ¹³C NMR (62.5 MHz, toluene-d₈, 373 K)

ppm 132.8, 123.7, 91.2, 88.2, 87.8, 70.0, 67.4, 67.0, 36.9, 36.6,

34.5, 28.2, 27.2, 27.0, 26.3; MS m/ z (M⁺) calcd 250.1569, obsd

250.1572.

(5R*,6S*)-7-[(E)-Ben zylid en e]-6-h yd r oxy-1-oxa sp ir o-

[4.5]d eca n e-6-p r op a n ol (34). A cold (0 °C), magnetically

stirred solution of 33 (1.14 g, 4.0 mmol) in anhydrous THF

(12 mL) was treated sequentially with n-butyllithium (5.1 mL

of 1.6 M, 8.1 mmol) and 9-BBN (17 mL of 0.5 M, 8.5 mmol),

stirred overnight at 25 °C, and quenched with a solution of

sodium hydroxide (200 mg) in 15% hydrogen peroxide (3 mL).

After the predescribed workup and purification procedure,

there was isolated 861 mg (71%) of 34 as a white solid: mp

114-116 °C; IR (film, cm^-1) 3358, 1446, 1374, 1301, 1057,

Anal. Calcd for C₁₅H₂₂O₃: C, 71.97; H, 8.86. Found: C,

71.86; H, 9.06.

1

1006; H NMR (300 MHz, CDCl₃) δ 7.32-7.14 (m, 5 H), 6.70

Hyd r ogen a tion of 27. To a solution of 27 (13 mg) in ethyl

acetate (3 mL) was added 10 mg of 5% palladium on charcoal.

This mixture was blanketed with hydrogen, stirred overnight,

filtered through Celite, and evaporated to give 13 mg of 29 as

a colorless oil spectroscopically identical to an authentic

sample.^5b

(s, 1 H), 4.05-3.93 (m, 1 H), 3.90-3.77 (m, 1 H), 3.75-3.50

(m, 2 H), 2.86-2.78 (m, 1 H), 2.40-2.05 (m, 2 H), 2.00-1.15

(m, 13 H); ¹³C NMR (75 MHz, CDCl₃) ppm 141.6, 138.3, 128.8,

127.9, 125.9, 123.5, 89.3, 79.5, 68.4, 62.9, 34.3, 31.0, 30.6, 26.9,

26.0, 25.6, 23.2; MS m/ z (M⁺) calcd 302.1882, obsd 302.1888.

Anal. Calcd for C₁₉H₂₆O₃: C, 75.46; H, 8.67. Found: C,

75.28; H, 8.90.

Nor m a n t Ad d ition to 22. A cold (-78 °C), magnetically

stirred solution of 22 (720 mg, 3.45 mmol) in dry THF (35 mL)

was treated dropwise via syringe with a solution of the

Normant reagent (8.68 mL of 0.40 N in THF, 3.45 mmol). The

reaction mixture was allowed to warm to rt, where it was

agitated for 5 h before being quenched with saturated NH₄Cl

solution and diluted with ether. The separated aqueous layer

was extracted with ether (3 × 25 mL), and the combined

organic layers were washed with brine, dried, and evaporated.

Flash chromatography of the residue on silica gel (elution with

6% methanol in CH₂Cl₂) provided diols 25 (470 mg, 51%) and

26 (55 mg, 6%) alongside 1,4-adduct 31 (120 mg, 13%).

For 31: colorless oil; IR (neat, cm^-1) 3417, 1715, 1453, 1308,

(5R*,6S*)-11-[(E)-Ben zyliden e]-1,7-dioxadispir o[4.0.4.4]-

tetr a d eca n e (35). A. Via Cycliza tion of 34. A solution

containing 34 (302 mg, 1.0 mmol), p-toluenesulfonyl chloride

(343 g, 1.8 mmol), triethylamine (1 mL), and DMAP (5 mg) in

CH₂Cl₂(7 mL) was stirred overnight at 25 °C and processed

in the usual manner to give 220 mg (78%) of 35 as a colorless

oil: IR (film, cm^-1) 1495, 1445, 1309, 1188, 1070, 1032; ¹H

NMR (300 MHz, CDCl₃) δ 7.35 (m, 2 H), 7.20 (m, 3 H), 6.67 (s,

1 H), 3.80 (m, 4 H), 2.90-1.40 (series of m, 14 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 144.3, 138.5, 129.0, 128.0, 126.0, 121.5,

91.2, 88.0, 68.8, 68.3, 37.2, 31.8, 31.0, 27.0, 16.7, 26.4, 23.6;

MS m/ z (M⁺) calcd 284.1776, obsd 284.1772.

1

1055, 732; H NMR (300 MHz, CDCl₃) δ 3.87-3.79 (m, 3 H),

Anal. Calcd for C₁₉H₂₄O₂: C, 80.24; H, 8.51. Found: C,

80.55; H, 8.32.

3.66-3.53 (m, 3 H), 2.70-2.62 (m, 1 H), 2.38-2.30 (m, 1 H),

2.20-2.09 (m, 3 H), 1.99-1.35 (series of m, 13 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 210.0, 93.1, 86.8, 68.6, 68.5, 62.5, 42.8,

39.4, 32.7, 32.5, 31.6, 29.8, 26.2, 25.9, 23.3; MS m/ z (M⁺) calcd

268.1674, obsd 268.1674.

B. Nor m a n t Ad d ition to 32 a n d Dir ect Cycliza tion . A

242 mg (1.0 mmol) sample of 32 dissolved in dry THF (10 mL)

was treated dropwise with the Normant reagent (3.00 mL of

0.42 M in THF, 1.26 mmol) at -78 °C, allowed to warm slowly

to 0 °C, and stirred for 1 h at this temperature prior to being

quenched with saturated NH₄Cl solution. The normal workup

afforded crude diol 34, which was directly cyclized in the

predescribed manner. There was obtained 272 mg (78%) of

35, identical in all respects to the material obtained in part

A.

Ozon olysis of 35. A solution of 35 (284 mg, 1.0 mmol) in

methanol (10 mL) was ozonolyzed at -78 °C until a blue color

appeared. Dimethyl sulfide (2 mL) was added, and the

reaction mixture was allowed to warm to rt. After solvent

evaporation, the residue was purified by chromatography on

silica gel (elution with 30-40% ether in petroleum ether) to

7-[(E)-Ben zylid en e]-1-oxa sp ir o[4.5]d eca n -6-on e (32). A

solution of 15 (3.08 g, 20.0 mmol) and sodium hydroxide (800

mg, 20.0 mmol) in methanol (80 mL) was stirred at 25 °C for

1 week, poured into 200 mL of iced 1 N H₂SO₄, extracted with

ether (2×), dried, and concentrated. The residue was purified

by column chromatography on silica gel (elution with 20%

ether in petroleum ether) to give 3.01 g (70%) of 32 as colorless

crystals: mp 56-58 °C; IR (film, cm^-1) 1688, 1601, 1572, 1490,

1

1442, 1139, 1091, 1043; H NMR (300 MHz, CDCl₃) δ 7.38-

7.26 (m, 6 H), 4.04-3.94 (m, 2 H), 2.91-2.84 (m, 1 H), 2.76-

2.71 (m, 1 H), 2.29-2.21 (m, 1 H), 2.14-1.75 (m, 5 H), 1.73-

1.55 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃) ppm 202.5, 136.8,

135.7, 135.6, 130.0 (2 C), 128.3, 128.1 (2 C), 86.4, 69.0, 36.4,

34.6, 28.6, 25.5, 21.1; MS m/ z (M⁺) calcd 242.1307, obsd

242.1303.

(28) The authors have deposited the atomic coordinates for the X-ray

structures with the Cambridge Crystallographic Data Centre. The

coordinates can be obtained, on request, from the Director, Cambridge

Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,

U.K.

Anal. Calcd for C₁₅H₁₈O₂: C, 79.31; H, 7.49. Found: C,

79.17; H, 7.49.

(5R*,6S*)-6-Allyl-7-[(E)-b en zylid en e]-1-oxa sp ir o[4.5]-

d eca n -6-ol (33). A mixture of 32 (1.47 g, 6.0 mmol), indium

Elements of Belted Poly(spirotetrahydrofurans)

J . Org. Chem., Vol. 61, No. 21, 1996 7503

afford 170 mg (80%) of 10, spectroscopically identical in all

respects with authentic material.^5b

Anal. Calcd for C₂₂H₂₈O₃: C, 77.60; H, 8.29. Found: C,

77.46, H, 8.32.

(5R*,6S*)-12-[(E)-Ben zyliden e]-1,7-dioxadispir o[4.0.4.4]-

tetr a d eca n -11-on e (36a ). A mixture of 9 (4.27 g, 22.7 mmol),

benzaldehyde (6.91 mL, 68.1 mmol), and sodium hydroxide

(2.72 g, 68.1 mmol) in methanol (125 mL) was refluxed for 3

h under N₂. After cooling and the addition of cold 6 N HCl,

the product was extracted into ethyl acetate (3 × 100 mL) and

the organic phase was washed with base and brine prior to

drying and solvent evaporation. Flash chromatography of the

residue over silica gel (elution with 10% ether in petroleum

ether) followed by recrystallization from petroleum ether-CH₂-

Cl₂gave 36a (5.08 g, 75%) as colorless crystals: mp 125-126

°C; IR (KBr, cm^-1) 1691, 1602, 1491, 1448, 1272, 1120, 1090,

1062, 911, 762; ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.27 (m, 6

H), 4.28-4.20 (m, 1 H), 4.00-3.92 (m, 2 H), 3.89-3.81 (m, 1

H), 2.93-2.80 (m, 2 H), 2.09-1.57 (series of m, 10 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 202.5, 136.0, 135.7, 135.0, 130.1, 128.2,

128.1, 92.4, 87.7, 70.3, 68.9, 32.9, 32.8, 31.5, 25.9, 24.8, 24.0;

MS m/ z (M⁺) calcd 298.1569, obsd 298.1565.

Nor m a n t Ad d ition to 36a . To a solution of 36a (500 mg,

1.67 mmol) in dry THF (25 mL) cooled to -78 °C was added a

solution of the Normant reagent (4.21 mL of 0.40 M in THF,

1.68 mmol) dropwise during 10 min. The reaction mixture was

allowed to warm to 25 °C and was stirred for 5 h at that

temperature before being quenched with saturated NH₄Cl

solution. The separated aqueous layers were extracted with

ether (3 × 50 mL), and the combined organic layers were

washed with brine, dried, and concentrated. Flash chroma-

tography of the residue on silica gel (elution with 10% hexanes

in ethyl acetate) gave 39a (18.5 mg, 3%), 38a (300 mg, 50%),

and 40 (130 mg, 22%).

For 38a : white solid: mp 49-50 °C; IR (KBr, cm^-1) 3414,

1

1654, 1598, 1492, 1443, 1069, 1003, 934, 750; H NMR (300

MHz, CDCl₃) δ 7.31-7.14 (m, 5 H), 6.71 (s, 1 H), 4.17-4.07

(m, 1 H), 4.02-3.93 (m, 2 H), 3.84-3.72 (m, 1 H), 3.70-3.56

(m, 2 H), 2.86-2.76 (m, 1 H), 2.70-2.63 (m, 1 H), 2.45-2.25

(m, 3 H), 2.15-1.44 (series of m, 11 H), 1.34-1.21 (m, 2 H);

¹³C NMR (75 MHz, CDCl₃) ppm 142.6, 138.5, 128.9, 128.0,

126.0, 123.6, 93.1, 88.7, 81.8, 71.8, 68.1, 63.4, 35.0, 33.8, 32.7,

31.5, 27.0, 26.5, 24.7, 22.4; MS m/ z (M⁺) calcd 358.2144, obsd

358.2166.

Anal. Calcd for C₁₉H₂₂O₃: C, 76.46; H, 7.43. Found: C,

76.52; H, 7.48.

(5R *,6S *)-12-[(E )-(o-Me t h ylb e n zylid e n e )]-1,7-d ioxa -

d isp ir o[4.0.4.4]tetr a d eca n -11-on e (36b). A mixture of 9

(14.86 g, 70.76 mmol), o-tolualdehyde (24.56 mL, 212.28 mmol),

and sodium hydroxide (8.49 g, 212 mmol) in methanol (300

mL) was refluxed for 3 h under N₂and stirred at 25 °C

overnight. Application of the predescribed workup followed

by flash chromatography on silica gel (elution with 20% ethyl

acetate in hexanes) and crystallization from hexane-CH₂Cl₂

gave pure 36b (16.49 g, 75%) as shiny colorless crystals: mp

98-100 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.32 (s, 1 H), 7.20-

7.12 (m, 4 H), 4.28-4.21 (m, 1 H), 4.01-3.92 (m, 2 H), 3.88-

3.81 (m, 1 H), 2.85-2.75 (m, 1 H), 2.74-2.60 (m, 1 H), 2.25 (s,

3 H), 2.14 (s, 1 H), 2.10-1.57 (series of m, 9 H); ¹³C NMR (75

MHz, CDCl₃) ppm 203.3, 137.3, 136.8, 134.7, 133.2, 129.9,

129.1, 128.2, 125.2, 92.7, 88.0, 70.3, 68.9, 33.3, 33.2, 31.6, 25.9,

24.8, 23.9, 19.9; MS m/ z (M⁺) calcd 312.1725, obsd 312.1708.

Anal. Calcd for C₂₀H₂₄O₃: C, 76.88; H, 7.74. Found: C,

76.85; H, 7.82.

(5R*,6S*)-12-[(E )-(2,4,6-Tr im e t h ylb e n zylid e n e )]-1,7-

d ioxa d isp ir o[4.0.4.4]tetr a d eca n -11-on e (36c). A mixture

of 9 (500 mg, 2.5 mmol), mesitaldehyde (1.84 mL, 12.5 mmol),

and sodium hydroxide (1.2 g, 30 mmol) in methanol (25 mL)

was refluxed for 12 h and stirred overnight at 25 °C. After

the usual workup, flash chromatography (elution with 40%

ethyl acetate in hexanes), and recrystallization from hexanes-

CH₂Cl₂, there was obtained 555 mg (68%) of 36c as fluffy white

crystals: mp 122-123 °C; IR (KBr, cm^-1) 1691, 1617, 1092,

1060; ¹H NMR (300 MHz, CDCl₃) δ 7.16 (s, 1 H), 6.86 (s, 2 H),

4.29-4.22 (m, 1 H), 4.03-3.93 (m, 2 H), 3.87-3.81 (m, 1 H),

2.55-2.43 (m, 1 H), 2.27 (s, 3 H), 2.13 (s, 6 H), 2.11-2.00 (m,

3 H), 1.98-1.86 (m, 3 H), 1.84-1.81 (m, 2 H), 1.80-1.56 (m, 3

H); ¹³C NMR (75 MHz CDCl₃) ppm 202.6, 138.9, 136.9, 133.8,

132.1, 128.0, 99.7, 99.0, 92.8, 88.1, 70.3, 69.0, 33.2, 31.7, 25.9,

24.9, 23.5, 20.9, 20.0; MS m/ z (M⁺) calcd 340.2038, obsd

340.2035.

Diol 39a was characterized as the trispiro ether 42a (see

below).

Hydroxy ketone 40a was characterized as its tosylate:

colorless oil; IR (neat, cm^-1) 1715, 1598, 1494, 1453, 1359,

1188, 1175, 1097, 1058, 927; ¹H NMR (300 MHz, CDCl₃) δ 7.70

(d, J ) 8.3 Hz, 2 H), 7.28 (d, J ) 8.4 Hz, 2 H), 7.25-7.06 (m,

5 H), 3.93-3.77 (m, 4 H), 3.47-3.36 (m, 2 H), 2.90-2.83 (m, 1

H), 2.40 (s, 3 H), 2.33-2.00 (m, 2 H), 1.99-1.33 (m, 14 H),

1.06-1.00 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃) ppm 210.7,

144.6, 143.6, 133.2, 129.8, 128.2, 128.0, 127.8, 126.1, 94.4, 87.9,

70.7, 68.9, 68.4, 49.8, 43.1, 32.7, 31.0, 30.3, 27.3, 26.8, 26.1,

25.6, 24.0, 23.6, 21.6; MS m/ z (M⁺) calcd 512.2232, obsd

512.2245.

Nor m a n t Ad d ition to 36b. Treatment of 36b (774 mg,

2.3 mmol) in dry THF (30 mL) at -78 °C with the Normant

reagent (6.06 mL of 0.33 M in THF, 2.0 mmol) was carried

out as described above to give 614 mg (70%) of 38b and 44 mg

(5%) of 39b.

For 38b: colorless solid; mp 60-63 °C; IR (film, cm^-1) 3400,

1450, 1310, 1200, 1075, 945, 915; ¹H NMR (300 MHz, CDCl₃)

δ 7.26-7.03 (m, 4 H), 6.66 (s, 1 H), 4.19-4.12 (m, 1 H), 4.10-

3.96 (m, 2 H), 3.87-3.58 (m, 3 H), 2.85 (ddd, J ) 7.5, 7.5, 14.8

Hz, 1 H), 2.45-1.40 (series of m, 19 H), 1.31-1.20 (m, 1 H);

¹³C NMR (75 MHz, CDCl₃) ppm 142.1, 137.9, 136.5, 129.6,

129.1, 126.4, 125.3, 123.1, 93.0, 88.7, 81.8, 71.9, 68.0, 63.5, 34.9,

33.8, 32.6, 31.5, 27.0, 26.6, 24.7, 22.7, 20.2; MS m/ z (M⁺) calcd

372.2292, obsd 372.2300.

Anal. Calcd for C₂₃H₃₂O₄: C, 74.16; H, 8.66. Found: C,

73.80; H, 8.41.

For 39b: colorless solid; mp 56-58 °C; IR (CHCl₃, cm^-1

)

3450 (br), 1470, 1380, 1040, 915, 740; ¹H NMR (300 MHz,

CDCl₃) δ 7.26-7.04 (m, 4 H), 6.49 (s, 1 H), 4.15-3.40 (m, 6

H), 2.65-1.25 (series of m, 21 H); ¹³C NMR (75 MHz, CDCl₃)

ppm 144.7, 142.2, 137.5, 136.4, 130.4, 129.6, 129.1, 126.5,

125.3, 123.6, 71.0, 63.4, 33.4, 29.6, 27.2, 26.7, 24.03, 24.01, 20.1

(broadened signals not specified); MS m/ z (M⁺) calcd 372.2292,

obsd 372.2293.

Anal. Calcd for C₂₂H₂₈O₃: C, 77.60; H, 8.29. Found: C,

77.44; H, 8.26.

(5R *,6S *,11S *)-11-Ally l-12-[(E )-b e n z y lid e n e ]-1,7-

d ioxa d isp ir o[4.0.4.4]tetr a d eca n -11-ol (37). A magnetically

stirred mixture of allyl bromide (0.42 mL, 5.0 mmol) and

indium powder (574 mg, 5.0 mmol) in dry THF (5 mL) was

refluxed for 30 min, cooled to 25 °C, treated with 36a (500

mg, 1.67 mmol), and agitated for 48 h. The predescribed

workup was followed by flash chromatography on silica gel

(elution with 10% ether in petroleum ether) to afford 520 mg

(92%) of 37 as a colorless viscous oil: IR (neat, cm^-1) 3570,

1450, 1070, 1035, 1005, 910, 700; ¹H NMR (300 MHz, CDCl₃)

δ 7.34-7.17 (m, 5 H), 6.66 (s, 1 H), 5.87-5.73 (m, 1 H), 5.28-

5.09 (m, 2 H), 4.18-4.11 (m, 1 H), 4.06-3.96 (m, 2 H), 3.88-

3.80 (m, 1 H), 3.45-3.38 (m, 1 H), 2.74-2.63 (m, 2 H), 2.36-

1.26 (series of m, 12 H); ¹³C NMR (75 MHz, CDCl₃) ppm 143.1,

138.4, 135.2, 128.9, 128.0, 126.0, 123.5, 118.2, 92.3, 88.6, 80.8,

71.6, 68.2, 40.3, 35.0, 33.5, 32.3, 26.9, 24.8, 22.5; MS m/ z (M⁺)

calcd 340.2038, obsd 340.2047.

Nor m a n t Ad d ition to 36c. Treatment of 36c (340 mg, 1.0

mmol) in dry THF (15 mL) at -78 °C with the Normant

reagent (2.51 mL of 0.40 M in THF, 1.0 mmol) was carried

out as described above to give 360 mg (90%) of 38c and 27 mg

(7%) of 39c.

For 38c: colorless solid; mp 71-73 °C; IR (KBr, cm^-1) 3447,

1

1438, 1067; H NMR (300 MHz, CDCl₃) δ 6.85 (s, 2 H), 6.46

(s, 1 H), 4.19-4.11 (m, 1 H), 4.04-3.96 (m, 2 H), 3.82-3.63

(m, 3 H), 2.82-2.74 (m, 1 H), 2.49-2.40 (m, 3 H), 2.27 (s, 3

H), 2.17 (s, 3 H), 2.13 (s, 3 H), 2.10-2.02 (m, 2 H), 1.99-1.64

(m, 7 H), 1.62-1.41 (m, 4 H), 1.28-1.21 (m, 1 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 142.4, 136.3, 136.1, 135.5, 134.6, 127.8,

122.3, 93.3, 88.7, 81.9, 71.7, 68.0, 63.6, 34.5, 33.7, 32.7, 31.6,

27.0, 26.6, 24.7, 23.0, 20.91, 20.77; MS m/ z (M⁺) calcd

400.2613, obsd 400.2611.

7504 J . Org. Chem., Vol. 61, No. 21, 1996

Paquette et al.

Anal. Calcd for C₂₅H₃₆O₄: C, 74.95; H, 9.06. Found: C,

74.40; H, 9.22.

(5R *,6R *,11S *)-1,7,12-T r io x a t r is p ir o [4.0.4.0.4.3]-

octa d eca n -16-on e (43). A. Ozon olysis of 41a . Ozonolysis

of a solution of 41a (248 mg, 0.72 mmol) in methanol (15 mL)

at -78 °C as described above provided 130 mg (70%) of 43 as

a colorless oil: IR (neat, cm^-1) 1720, 1445, 1117, 1068; ¹H NMR

(300 MHz, CDCl₃) δ 3.97-3.80 (m, 4 H), 3.74-3.69 (m, 1 H),

2.89-2.77 (m, 1 H), 2.69-2.58 (m, 1 H), 2.24-1.45 (series of

m, 15 H); ¹³C NMR (75 MHz, CDCl₃) ppm 211.0, 94.9, 91.4,

87.4, 70.8, 68.4, 68.2, 34.7, 32.6, 32.3, 31.8, 26.6, 26.0, 25.3;

MS m/ z (M⁺) calcd 266.1518, obsd 266.1524.

Anal. Calcd for C₁₅H₂₂O₄: C, 67.63; H, 8.33. Found: C,

67.51; H, 8.42.

B. Ozon olysis of 41b. Analogous exposure of 41b (10.46

g, 29.5 mmol) dissolved in methanol (500 mL) at -78 °C to

ozone gave 5.80 g (73%) of 43.

(5R*,6R*,11S*)-[(E)-Ben zylid en e]-1,7,12-tr ioxa tr isp ir o-

[4.0.4.0.4.3]octa d eca n -16-on e (44). A mixture of 43 (5.80

g, 21.8 mmol), benzaldehyde (13.27 mL, 130.8 mmol), and

sodium hydroxide (5.232 g, 130.8 mmol) in methanol (300 mL)

was refluxed for 3 h under N₂and stirred at 25 °C overnight.

After the usual workup and chromatography on silica gel

(elution with 10% ethyl acetate in hexanes), there was obtained

5.89 g (76%) of 44 as a faint yellow oil: ¹H NMR (300 MHz,

CDCl₃) δ 7.43-7.24 (m, 6 H), 4.12-3.72 (m, 6 H), 3.08 (dd, J

) 16.1, 1.2 Hz, 1 H), 2.59 (dd, J ) 16.1, 2.8 Hz, 1 H), 2.52-

2.41 (m, 1 H), 2.25-1.62 (series of m, 11 H); ¹³C NMR (75 MHz,

CDCl₃) ppm 204.0, 137.1, 135.6, 133.7, 130.1, 128.5, 128.3,

93.5, 90.0, 86.9, 70.7, 69.4, 68.7, 37.3, 32.4, 32.73, 32.67, 26.9,

26.1, 25.6; MS m/ z (M⁺) calcd 354.1831, obsd 354.1817.

(5R*,6R*)-12-[(E)-Ben zyliden e]-1,7-dioxadispir o[4.0.4.4]-

tetr a d eca n -11-on e (45). A mixture of 10 (10.94 g, 52.0

mmol), benzaldehyde (15.87 mL, 1.56 mmol), and sodium

hydroxide (6.25 g, 156 mmol) was refluxed under N₂for 3 h

and stirred overnight at 25 °C. The reaction mixture was

cooled to 0 °C, and cold 6 N HCl was added dropwise until the

pH was equal to 6. The product was extracted into ethyl

acetate (3 × 250 mL) and processed as previously described

to give, after chromatography on silica gel (elution with 10%

ether in hexanes) and recrystallization from hexanes-CH₂-

Cl₂, 11.48 g (74%) of 45 as a colorless solid: mp 115-116 °C;

IR (KBr, cm^-1) 1693, 1618, 1508, 1491, 1445, 1127, 1100, 1066;

¹H NMR (300 MHz, CDCl₃) δ 7.38-7.27 (m, 6 H), 4.11-4.02

(m, 1 H), 3.94-3.77 (m, 3 H), 3.03-2.94 (m, 1 H), 2.60-2.48

(m, 1 H), 2.30-2.17 (m, 1 H), 2.14-2.00 (m, 2H), 1.99-1.76

(m, 6H), 1.73-1.62 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃) ppm

202.8, 135.9, 135.5, 135.2, 130.1, 128.5, 120.2, 93.3, 85.8, 69.9,

68.6, 33.3, 31.8, 30.9, 26.6, 25.9, 24.1; MS m/ z (M⁺) calcd

298.1569, obsd 298.1562.

For 39c: colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 6.86 (s,

1 H), 6.83 (s, 1 H), 6.28 (s, 1 H), 4.07-4.02 (m, 2 H), 3.89-

3.82 (m, 2 H), 3.70-3.65 (m, 2 H), 2.26 (s, 3H), 2.18 (s, 3 H),

2.12 (s, 3 H), 2.10-1.67 (series of m, 16 H), 1.35-1.25 (m, 2

H); ¹³C NMR (75 MHz, CDCl₃) ppm 142.4, 136.6, 135.8, 135.7,

128.0, 127.8, 127.6, 122.7, 70.9, 63.5, 33.3, 29.8, 27.2, 26.8, 26.0,

23.0, 20.9, 20.8, 20.3; MS m/ z (M⁺) calcd 400.2613, obsd

400.2625.

(5 R *,6 S *,1 1 S *)-1 6 -[(E )-B e n z y l i d e n e ]-1 ,7 ,1 2 -t r i -

oxa tr isp ir o[4.0.4.0.4.3]octa d eca n e (41a ). Diol 38a (275 mg,

0.768 mmol) was cyclized in the manner described above and

purified by chromatography on silica gel (elution with 10%

ethyl acetate in hexanes). There was obtained 145 mg (70%)

of 41a ; colorless oil; IR (neat, cm^-1) 1444, 1099, 1062; ¹H NMR

(300 MHz, CDCl₃) δ 7.32-7.21 (m, 2 H), 7.18-7.12 (m, 3 H),

6.56 (s, 1 H), 3.99-3.86 (m, 4 H), 3.83-3.72 (m, 1H), 3.70-

3.64 (m, 1 H), 2.70-2.55 (m, 2 H), 2.31-1.22 (series of m, 14

H); ¹³C NMR (75 MHz, CDCl₃) ppm 138.6, 129.0, 128.0, 125.9,

122.0, 99.7, 92.3, 91.2, 88.4, 70.7, 68.2, 67.5, 35.2, 32.7, 32.3,

32.1, 26.9, 26.1, 25.3, 22.8; MS m/ z (M⁺) calcd 340.2038, obsd

340.2040.

(5R*,6S*,11S*)-16-[(E)-(o-Met h ylb en zylid en e]-1,7,12-

tr ioxa tr isp ir o[4.0.4.0.4.3]octa d eca n e (41b). Diol 38b (500

mg, 1.34 mmol) was cyclized as before and purified by

chromatography on silica gel (elution with 6% ethyl acetate

in hexanes) to give 375 mg (79%) of 41b as a colorless oil: IR

(neat, cm^-1) 1482, 1453, 1099, 1061; ¹H NMR (300 MHz,

CDCl₃) δ 7.18-7.11 (m, 3 H), 7.06-7.02 (m, 1 H), 6.53 (s, 1

H), 4.02-3.90 (m, 4 H), 3.84-3.68 (m, 2 H), 2.66-2.55 (m, 1

H), 2.39-2.28 (m, 2 H), 2.23 (s, 3 H), 2.19-1.75 (m, 9H), 1.69-

1.60 (m, 1 H), 1.59-1.45 (m, 2 H), 1.33-1.22 (m, 1 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 144.2, 138.0, 136.4, 129.1, 126.3, 125.2,

121.5, 92.2, 91.1, 88.4, 70.7, 68.1, 67.4, 35.2, 32.0, 26.9, 26.2,

25.2, 23.0, 20.0; MS m/ z (M⁺) calcd 354.2195, obsd 354.2194.

Anal. Calcd for C₂₃H₃₀O₃: C, 77.91; H, 8.53. Found: C,

77.78; H, 8.65.

(5R*,6S*,11S*)-16-[(E)-(2,4,6-Tr im et h ylb en zylid en e]-

1,7,12-tr ioxa tr isp ir o[4.0.4.0.4.3]octa d eca n e (41c). Cycliza-

tion of 38c (342 mg, 0.85 mmol) in the usual way provided

295 mg (90%) of 41c as a colorless oil: IR (neat, cm^-1) 1480,

1

1453, 1099, 1063; H NMR (300 MHz, CDCl₃) δ 6.85 (s, 2 H),

6.32 (s, 1 H), 4.03-3.91 (m, 4 H), 3.83-3.68 (m, 2 H), 2.61-

2.34 (m, 2 H), 2.27 (s, 3 H), 2.16 (s, 3 H), 2.08 (s, 3 H), 2.06-

1.77 (series of m, 10 H), 1.59-1.44 (m, 3 H), 1.30-1.19 (m, 1

H); ¹³C NMR (75 MHz, CDCl₃) ppm 144.2, 136.2, 135.4, 134.8,

127.7, 120.6, 92.2, 91.2, 88.5, 70.7, 68.2, 67.5, 34.8, 32.7, 32.1,

27.0, 26.2, 25.3, 23.3, 20.9, 20.6, 20.1; MS m/ z (M⁺) calcd

382.2508, obsd 382.2505.

Anal. Calcd for C₁₉H₂₂O₃: C, 76.46; H, 7.43. Found: C,

76.44; H, 7.48.

(5R*,6S*,11R*)-11-Allyl-12-[(E)-ben zylid en e]-1,7-d ioxa -

d isp ir o-[4.0.4.4]tetr a d eca n -11-ol (46) a n d (5R*,6S*,11S*)-

11-Allyl-12-[(E)-b en zylid en e]-1,7-d ioxa d isp ir o[4.0.4.4]-

tetr a d eca n -11-ol (47). A mixture of 45 (300 mg, 1.46 mmol),

allyl bromide (0.37 mL, 4.3 mmol), and indium powder (490

mg, 4.32 mmol) in dry THF (30 mL) was stirred at 25 °C for

48 h, treated with another 2.5 mmol of each reagent, and

agitated for a final 2 h. The customary workup was followed

by flash chromatography on silica gel (elution with 10% ether

in petroleum ether). There were isolated 97 mg (28%) of 46

and 86 mg of 47 as viscous oils.

(5R *,6S *,11R *)-16-[(E )-Be n zylid e n e ]-1,7,12-t r ioxa -

tr isp ir o[4.0.4.0.4.3]octa d eca n e (42a ). Cyclization of 39a

(740 mg, 2.07 mmol) in the usual way gave rise to 42a (370

mg, 53%) as a white foam: mp 81-84 °C; IR (film, cm^-1) 1598,

1444, 1094, 1058; ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.14 (m,

5 H), 6.55 (s, 1 H), 4.14-3.69 (m, 6 H), 2.90-2.85 (m, 1 H),

2.02-1.74 (series of m, 14 H), 1.50-1.43 (m, 1 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 142.0, 138.5, 129.2, 127.8 (2 C), 125.9

(2 C), 123.1, 93.2, 91.0, 88.4, 70.0, 68.4, 67.1, 33.5, 33.1, 31.7,

27.5, 27.4, 26.4, 25.2, 23.7; MS m/ z (M⁺) calcd 340.2038, obsd

340.2045.

For 46: IR (neat, cm^-1) 3570, 1450, 1070, 1035, 1005, 910;

¹H NMR (300 MHz, CDCl₃) δ 7.34-7.17 (m, 5 H), 6.66 (s, 1

H), 5.87-5.73 (m, 1 H), 5.28-5.09 (m, 2 H), 4.18-4.11 (m, 1

H), 4.06-3.96 (m, 2 H), 3.88-3.80 (m, 1 H), 3.45-3.38 (m, 1

H), 2.74-2.63 (m, 2 H), 2.36-1.26 (series of m, 12 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 143.1, 138.4, 135.2, 128.9, 128.0, 126.0,

123.5, 118.2, 92.3, 88.6, 80.8, 71.6, 68.2, 40.3, 33.5, 32.3, 26.9,

24.8, 22.7; MS m/ z (M⁺) calcd 340.2038, obsd 340.2048.

Anal. Calcd for C₂₂H₂₈O₃: C, 77.60; H, 8.29. Found: C,

77.46; H, 8.32.

(5R*,6S*,11R*)-16-[(E)-(2,4,6-Tr im et h ylb en zylid en e]-

1,7,12-tr ioxa tr isp ir o[4.0.4.0.4.3]octa d eca n e (42c). Cycliza-

tion of 39c (25 mg, 0.06 mmol) in the manner described above

afforded 21 mg (90%) of 42c: colorless oil; IR (neat, cm^-1) 1485,

1

1440, 1100, 1050; H NMR (300 MHz, CDCl₃) δ 8.62 (s, 2 H),

6.35 (s, 1 H), 4.08-3.94 (m, 4 H), 3.85-3.71 (m, 2 H), 2.67-

2.57 (m, 1 H), 2.50-2.37 (m, 1 H), 2.29-1.70 (series of m, 19

H), 1.65-1.40 (m, 3 H), 1.27 (ddd, J ) 4.5, 13.7, 13.7 Hz, 1 H);

¹³H NMR (75 MHz, CDCl₃) ppm 144.1, 136.1, 135.3, 134.7,

127.8, 127.6, 120.5, 92.1, 91.0, 88.3, 70.6, 68.1, 67.4, 34.7, 32.6,

32.1, 26.9, 26.2, 25.2, 23.2, 20.9, 20.0; MS m/ z (M⁺) calcd

382.2499, obsd 382.2517.

For 47: colorless oil; IR (neat, cm^-1) 3570, 1635, 1600, 1495,

1450, 1330, 1200, 1070, 910; ¹H NMR (300 MHz, CDCl₃) δ

7.34-7.17 (m, 5 H), 6.60 (s, 1 H), 5.91-5.77 (m, 1 H), 5.09-

4.99 (m, 2 H), 4.06-3.82 (m, 4 H), 3.15-3.08 (m, 2 H), 2.68

(ddd, J ) 3.9, 3.9, 13.9 Hz, 2 H), 2.38-1.57 (series of m, 11

Anal. Calcd for C₂₅H₃₄O₃: C, 78.49; H, 8.96. Found: C,

78.34; H, 9.03.

Elements of Belted Poly(spirotetrahydrofurans)

J . Org. Chem., Vol. 61, No. 21, 1996 7505

H); ¹³C NMR (75 MHz, CDCl₃) ppm 143.8, 138.3, 134.7, 129.0,

127.9, 125.9, 122.8, 114.0, 93.3, 87.4, 79.8, 70.5, 67.9, 38.7, 34.3,

33.9, 27.4, 27.1, 25.2, 22.4; MS m/ z (M⁺) calcd 340.2031, obsd

340.2040.

Anal. Calcd for C₂₂H₂₈O₃: C, 77.61; H, 8.29. Found: C,

77.59; H, 8.37.

(5R*,6R*,12R*)-12-H yd r oxy-1,7-d ioxa d isp ir o[4.0.4.4]-

tetr a d eca n -11-on e (52) a n d (5R*,6R*,12S*)-12-Hyd r oxy-

1,7-d ioxa d isp ir o[4.0.4.4]tetr a d eca n -11-on e (53). To a cold

(-78 °C) magnetically stirred solution of 9 (3.15 g, 15.0 mmol)

in dry THF (150 mL) was added potassium hexamethyldi-

silazide (33.0 mL of 0.5 M in toluene, 16.5 mmol) followed by

chlorotrimethylsilane (2.82 g, 26.0 mmol) 1 h later. The

reaction mixture was allowed to warm slowly to rt, stirred

overnight, and partitioned between saturated NaHCO₃solu-

tion (100 mL) and ether (100 mL). The layers were separated,

and the aqueous phase was extracted with ether (3 × 100 mL).

The combined organic solutions were dried, filtered, and

concentrated.

(5R *,6R *,11R *)-16-[(E )-Be n zylid e n e ]-1,7,12-t r ioxa -

tr isp ir o[4.0.4.0.4.3]octa d eca n e (48). Dropwise treatment

of a solution of 45 (11.0 g, 37 mmol) in THF (550 mL) at -78

°C with the Normant reagent (115.3 mL of 0.32 M in THF)

during 30 min, followed by stirring at 25 °C for 5 h, afforded

a diol (16.76 g), which was immediately cyclized. Flash

chromatography of the product on silica gel (elution with 6%

ethyl acetate in hexanes) delivered 10.47 g (83%) of 48 as a

An analytically pure sample of the silyl enol ether was

obtained by chromatography on neutral alumina (elution with

10% ethyl acetate in petroleum ether) as a faint yellow oil:

IR (neat, cm^-1) 1720, 1460, 1350, 1310, 1260, 1240, 1145, 1070,

1

colorless oil: IR (neat, cm^-1) 1650, 1088, 1057; H NMR (300

MHz, CDCl₃) δ 7.34-7.17 (m, 5 H), 6.62 (s, 1 H), 4.01-3.60

(m, 6 H), 2.86-2.79 (m, 1 H), 2.45-2.34 (m, 2 H), 2.12-1.27

(series of m, 13 H); ¹³C NMR (75 MHz, CDCl₃) ppm 142.9,

138.3, 129.0, 128.0, 126.1, 123.1, 91.3, 91.2, 88.0, 70.1, 67.6,

67.5, 35.9, 31.2, 30.1, 29.8, 27.7, 27.2, 26.0, 23.8; MS m/ z (M⁺)

calcd 340.2038, obsd 340.2041.

1

970, 935, 920, 870; H NMR (300 MHz, CDCl₃) δ 4.75 (t, J )

3.5 Hz, 1 H), 3.99-3.77 (m, 4 H), 2.23-2.11 (m, 1 H), 2.03-

1.48 (series of m, 11 H), 0.18 (s, 9 H); ¹³C NMR (75 MHz,

CDCl₃) ppm 152.4, 103.6, 86.7, 86.6, 69.6, 67.9, 30.6, 29.39,

29.37, 28.0, 26.2, 21.1, 0.1; MS m/ z (M⁺+ H) calcd 283.1729,

obsd 283.1724.

Anal. Calcd for C₂₂H₂₈O₃: C, 77.60; H, 8.29. Found: C,

77.23; H, 8.30.

(5R *,6S *,11R *)-1,7,12-T r io x a t r is p ir o [4.0.4.0.4.3]-

octa d eca n -16-on e (49). A solution of 48 (10.39 g, 30.5 mmol)

in cold (-78 °C) methanol was ozonolyzed in the predescribed

manner to give, after chromatography on silica gel (elution

with 30% ethyl acetate in hexanes), 7.08 (87%) of 49 as a

colorless oil; IR (neat, cm^-1) 1722, 1096, 1075, 1054, 1018, 997;

¹H NMR (300 MHz, CDCl₃) δ 3.96-3.90 (m, 1 H), 3.85-3.75

(m, 3 H), 3.74-3.57 (m, 2 H), 2.49-2.27 (m, 4 H), 2.15-2.01

(m, 2 H), 2.04-1.53 (series of m, 10 H); ¹³C NMR (75 MHz,

CDCl₃) ppm 209.7, 93.6, 90.7, 86.8, 70.1, 68.2, 67.6, 35.1, 32.3,

30.9, 30.8, 30.2, 27.7, 26.8, 25.7; MS m/ z (M⁺) calcd 266.1518,

obsd 266.1521.

Anal. Calcd for C₁₅H₂₆O₃Si: C, 63.57; H, 9.61. Found: C,

63.19; H, 9.35.

The crude product from above was dissolved in CH₂Cl₂(150

mL), then treated with NaHCO₃(10.00 g, 11.90 mmol) and

m-CPBA (5.0 g of 90% purity, 29.1 mmol) in several portions.

The mixture was stirred for 20 h and quenched with Na₂SO₃

solution (50 mL). After 30 min, the separated aqueous phase

was extracted with CH₂Cl₂(3 × 75 mL) and the combined

organic layers were washed with saturated NaHCO₃solution

(50 mL), dried, and concentrated. The resulting residue was

dissolved in methanolic citric acid (100 mL, 0.1 M), stirred for

1 h, and concentrated. Chromatography of the residue on

silica gel (gradient elution, 50-95% ethyl acetate in petroleum

ether) gave 630 mg (19%) of 53 and 2.57 g (76%) of 52.

Anal. Calcd for C₁₅H₂₂O₄: C, 67.65; H, 8.33. Found: C,

67.63; H, 8.32.

(5R *,6S *,11R *)-17-[(E )-Be n zylid e n e ]-1,7,12-t r ioxa -

tr isp ir o[4.0.4.0.4.3]octa d eca n -16-on e (50). A mixture of 49

(7.08 g, 26.6 mmol), benzaldehyde (10.8 mL, 106.4 mmol), and

sodium hydroxide (4.256 g, 106.4 mmol) in methanol (300 mL)

was refluxed under N₂for 3 h, processed as before, and

ultimately subjected to chromatography on silica gel (elution

with 10% ethyl acetate in hexanes). There was obtained 8.85

1

For 52: white powder; mp 137.5-138.5 °C; H NMR (300

MHz, CDCl₃) δ 4.30 (dd, J ) 11.3, 7.5 Hz, 1 H), 4.10-3.75 (m,

4 H), 3.35 (br s, 1 H), 2.21-2.13 (m, 1 H), 2.07-1.73 (series of

m, 10 H), 1.68-1.60 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃) ppm

210.4, 92.3, 89.9, 72.4, 69.2, 69.1, 33.8, 31.8, 31.5, 30.1, 25.8,

25.4; MS m/ z (M⁺) calcd 226.1205, obsd 226.1203.

Anal. Calcd for C₁₂H₁₈O₄: C, 63.70; H, 8.02. Found: C,

63.82; H, 8.12.

g (93%) of 50 as an off-white solid: mp 99 °C; IR (neat, cm^-1

)

1685, 1654, 1097, 1075, 1062, 1040; ¹H NMR (300 MHz, CDCl₃)

δ 7.40-7.26 (m, 6 H), 4.20-4.14 (m, 2 H), 3.95-3.74 (m, 4 H),

3.65-3.57 (m, 2 H), 2.95 (d, J ) 15.8 Hz, 1 H), 2.54 (dd, J )

15.7, 1.5 Hz, 1 H), 2.45-2.25 (m, 3 H), 2.15 (s, 1 H), 2.12-

1.68 (m, 6 H), 1.69-1.47 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃)

ppm 203.7, 136.8, 135.2, 133.7, 130.0, 128.7, 128.4, 93.2, 89.1,

86.1, 70.1, 69.3, 68.0, 37.9, 32.0, 31.3, 30.5, 27.8, 26.9, 25.9;

MS m/ z (M⁺) calcd 354.1831, obsd 354.1835.

For 53: waxy white solid; mp 77-80 °C; IR (CCl₄, cm^-1

)

3700, 3520, 1740, 1530, 1435, 1220, 1125, 1050, 930; ¹H NMR

(300 MHz, CDCl₃) δ 4.78 (dd, J ) 7.7, 11.8 Hz, 1 H), 3.98-

3.80 (m, 3 H), 3.72-3.65 (m, 1 H), 3.10 (br s, 1 H), 2.52-2.41

(m, 1 H), 2.35-2.20 (m, 2 H), 2.07-1.85 (m, 3 H), 1.83-1.70

(m, 2 H), 1.68-1.40 (m, 3 H), 1.19-1.04 (m, 1 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 210.3, 93.3, 87.8, 71.8, 69.1, 68.8, 31.1,

30.4, 30.0, 26.1, 26.0, 24.0; MS m/ z (M⁺) calcd 226.1205, obsd

226.1220.

MAD-P r om oted Ad d ition of Allylm a gn esiu m Br om id e

to 36a . To a stirred solution of 2,6-di-tert-butyl-4-methylphe-

nol (4.40 g, 19.96 mmol) in toluene (10 mL) was added

trimethylaluminum (6.0 mL of 2.0 M in hexane, 10.0 mmol).

After 1 h, the mixture was cooled to -78 °C and 36a (2.0 g,

6.71 mmol) dissolved in toluene (15 mL) was added followed

by allylmagnesium bromide (20 mL of 1.0 M in ether, 20

mmol). After 3 h, the mixture was poured into 1 M HCl (100

mL) and CH₂Cl₂(50 mL). The separated aqueous layer was

extracted with CH₂Cl₂(3 × 100 mL), and the combined organic

phases were dried and concentrated. The residue was purified

by chromatography on silica gel (elution with 20-50% ether

in petroleum ether) to give 51 (1.41 g, 62%) as a clear foam in

addition to a diastereomeric mixture of 1,4-addition products

40a (0.56 g, 25%) as a waxy solid, mp 108-110 °C.

Anal. Calcd for C₁₂H₁₈O₄: C, 63.70; H, 8.02. Found: C,

63.59; H, 7.94.

(5R*,6R*,12S*)-12-(ter t-Bu t yld im et h ylsiloxy)-1,7-d i-

oxa d isp ir o[4.0.4.4]tetr a d eca n -11-on e (54). To a magneti-

cally stirred solution of 52 (2.75 g, 12.17 mmol), imidazole (1.66

g, 24.4 mmol), and DMAP (420 mg, 3.44 mmol) in CH₂Cl₂(250

mL) was added tert-butyldimethylsilyl chloride (2.75 g, 18.24

mmol). The reaction mixture was stirred for 24 h, and

saturated NaHCO₃solution (75 mL) was added. The aqueous

layer was extracted with CH₂Cl₂(3 × 50 mL), and the

combined organic phases were dried, filtered, and concen-

trated. Chromatography of the residue on silica gel (elution

with 50% ether in petroleum ether) gave 54 (3.41 g, 82%) as a

white powder: mp 93-95 °C; IR (CHCl₃, cm^-1) 1745, 1530,

1480, 1430, 1220, 1060, 1035, 935; ¹H NMR (300 MHz, CDCl₃)

δ 4.39 (dd, J ) 11.4, 7.7 Hz, 1 H), 4.08-4.06 (m, 1 H), 3.97-

3.85 (m, 2 H), 3.81-3.74 (m, 1 H), 2.10-1.58 (series of m, 12

H), 0.88 (s, 9 H), 0.13 (s, 3 H), 0.02 (s, 3 H); ¹³C NMR (75 MHz,

CDCl₃) ppm 207.7, 92.6, 89.3, 74.4, 69.1, 68.9, 34.1, 32.3, 31.4,

20.5, 15.8, 15.4, 18.5, -4.3, -5.3; MS m/ z (M⁺) calcd 340.2070,

obsd 340.2052.

For 51: IR (neat, cm^-1) 3534, 3421, 1636, 1600, 1492, 1445,

1337, 1301, 1058; ¹H NMR (300 Mz, CDCl₃) δ 7.37-7.14 (m, 5

H), 6.62 (s, 1 H), 6.04-5.91 (m, 1 H), 5.09-5.03 (m, 2 H), 4.18-

3.80 (m, 4 H), 2.80-2.71 (m, 1 H), 2.49 (d, J ) 6.7 Hz, 2 H),

2.21-1.75 (m, 9 H), 1.59 (s, 1 H), 1.49-1.41 (m, 2 H); ¹³C NMR

(75 MHz, CDCl₃) ppm 142.6, 138.1, 134.4, 128.2, 128.1, 126.1,

125.9, 92.8, 89.5, 79.9, 70.9, 68.2, 38.0, 34.6, 33.2, 29.1, 27.1,

26.1, 22.6; MS m/ z (M⁺) calcd 340.2031, obsd 340.2041.

7506 J . Org. Chem., Vol. 61, No. 21, 1996

Paquette et al.

Anal. Calcd for C₁₈H₃₂O₄Si: C, 63.48; H, 9.48. Found: C,

63.45; H, 9.39.

by chromatography on silica gel. Elution with 50% ether in

petroleum ether afforded 43 (2.40 g, 96%), identical in all

respects with the material obtained above.

(5R*,6R*,12R*)-12-(ter t-Bu t yld im et h ylsiloxy)-1,7-d i-

oxa d isp ir o[4.0.4.4]tetr a d eca n -11-on e (55). Entirely paral-

lel silylation of 53 (770 mg, 3.40 mmol) with tert-butyldi-

methylsilyl chloride (1.0 g, 6.63 mmol) afforded 1.18 g (100%)

of 55 as a clear oil: IR (neat, cm^-1) 1745, 1465, 1450, 1260,

1155, 1085, 1065, 1040, 950; ¹H NMR (300 MHz, CDCl₃) δ 4.87

(dd, J ) 11.2, 7.3 Hz, 1 H), 3.92-3.83 (m, 3 H), 3.70-3.63 (m,

1 H), 2.52-2.45 (m, 1 H), 2.23 (ddd, J ) 13.4, 13,4, 4.5 Hz, 1

H), 2.11-2.01 (m, 1 H), 1.94-1.46 (series of m, 8 H), 1.40-

1.26 (m, 1 H), 0.87 (s, 9 H), 0.08 (s, 3 H), -0.1 (s, 3 H); ¹³C

NMR (75 MHz, CDCl₃) ppm 208.2, 94.2, 87.6, 73.6, 68.9, 68.8,

31.3, 30.9, 30.1, 26.1, 25.8, 25.7, 24.5, 18.4, -4.8, -5.4; MS

m/ z (M⁺) calcd 340.2070, obsd 340.2073.

(5R *,6R *,11R *)-1,7,12-T r io x a t r is p ir o [4.0.4.0.4.3]-

octa d eca n -16-on e (60). A. F r om 58. A 2.85 g (6.72 mmol)

sample of 58 was deprotected as described above to give 1.72

g (96%) of the alcohol, which was dissolved in CH₂Cl₂(150 mL)

and treated with pyridinium dichromate (10.2 g, 20.5 mmol)

and powdered 3 Å molecular sieves (12.3 g). The mixture was

stirred for 48 h, filtered through a pad of Celite, and concen-

trated. Chromatography of the residue on silica gel (elution

with ethyl acetate) gave 60 (1.16 g, 68%) as a colorless solid:

mp 68-70 °C; IR (film, cm^-1) 1730, 1455, 1310, 1100, 1000,

1

995; H NMR (300 MHz, CDCl₃) δ 4.11-3.73 (m, 4 H), 2.49-

2.21 (m, 3 H), 2.08-1.64 (series of m, 15 H); ¹³C NMR (75 MHz,

CDCl₃) ppm 209.6, 93.9, 93.2, 87.1, 77.4, 70.5, 68.3, 67.5, 34.5,

32.2, 31.7, 27.4, 27.3, 26.1, 25.1; MS m/ z (M⁺) calcd 266.1518,

obsd 266.1521.

Anal. Calcd for C₁₈H₃₂O₄: C, 63.48, H, 9.48. Found: C,

63.53; H, 9.38.

Ca p p in g of 54 w ith th e Nor m a n t Rea gen t. A cold (-78

°C), magnetically stirred solution of 54 (3.02 g, 8.88 mmol) in

THF (150 mL) was treated with the Normant reagent (85.0

mL of 0.15 M, 12.75 mmol) and processed in the usual way to

give 3.80 g (97%) of diol. Without purification, this diol was

cyclized in the presence of p-toluenesulfonyl chloride (2.82 g,

14.8 mmol) as previously detailed. Chromatography of the

resulting material on silica gel (elution with 50-95% ethyl

acetate in petroleum ether) afforded 2.85 g (78%) of 58 as the

only product: colorless crystals; mp 84 °C; IR (film, cm^-1) 1465,

Anal. Calcd for C₁₅H₂₂O₄: C, 67.63; H, 8.33. Found: C,

67.20; H, 8.34.

B. F r om 59. Deprotection of 59 (650 mg, 1.53 mmol) as

before afforded 350 mg (85%) of the alcohol, which was oxidized

with pyridinium dichromate in the manner detailed above.

Chromatographic purification gave 240 mg (69%) of 60, which

was spectroscopically identical to the ketone obtained in part

A.

(5R*,6S*,12S*)-12-H yd r oxy-1,7-d ioxa d isp ir o[4.0.4.4]-

tetr a d eca n -11-on e (61) a n d (5R*,6S*,12R*)-12-Hyd r oxy-

1,7-d ioxa d isp ir o[4.0.4.4]tetr a d eca n -11-on e (62). To a cold

(-78 °C), magnetically stirred solution of 10 (7.48 g, 35.6

mmol) in dry THF (250 mL) was added potassium hexameth-

yldisilazide (80.0 mL of 0.5 M in toluene, 40.0 mmol), followed

by trimethylsilyl chloride (7.28 g, 67.0 mmol) 1 h later.

Adaptation of the earlier procedure for purification of the silyl

enol ether and for oxidation with m-CPBA (11.22 g of 90%

purity, 58.7 mmol) delivered 5.54 g (69%) of 61 and 2.14 g

(27%) of 62.

1

1240, 1165, 1110, 1080, 1010; H NMR (300 MHz, CDCl₃) δ

4.11-3.84 (m, 5 H), 3.82-3.65 (m, 1 H), 3.48-3.30 (m, 1 H),

2.14-1.55 (series of m, 15 H), 1.47-1.07 (m, 1 H), 0.82-0.78

(m, 9 H), 0.00 to -0.04 (m, 6 H); ¹³H NMR (75 MHz, CDCl₃)

ppm 91.8, 90.1, 87.5, 76.5, 70.8, 70.6, 67.4, 34.4, 33.1, 30.7,

30.3, 27.0, 26.2, 25.8, 25.6, 24.1, 17.8, -4.2, -5.1; MS m/ z (M⁺)

calcd 382.2539, obsd 382.2537.

Ca p p in g of 55 w ith th e Nor m a n t Rea gen t. Addition of

the Normant reagent (10.0 mL of 0.60 M, 6.0 mmol) to a cold

(-78 °C) solution of 55 (970 mg, 2.85 mmol) in anhydrous THF

(75 mL) in the manner previously described gave rise to two

diols following chromatography on silica gel (elution with ether

followed by ethyl acetate). The minor diol (150 mg, 12%) was

less polar than the major diol (740 mg, 59%).

For the silyl enol ether: colorless oil; IR (neat, cm^-1) 1660,

1245, 1195, 1170, 960, 850; ¹H NMR (300 MHz, CDCl₃) δ 4.72

(dd, J ) 3.8, 3.8 Hz, 1 H), 3.89-3.74 (m, 4 H), 2.41-2.15 (m,

2 H), 2.06-1.71 (series of m, 8 H), 1.63-1.53 (m, 2 H), 0.19 (s,

9 H); ¹³C NMR (75 MHz, CDCl₃) ppm 153.4, 102.9, 87.2, 86.4,

70.0, 68.5, 32.9, 32.8, 31.2, 27.5, 26.5, 21.1, 0.4; MS m/ z (M⁺)

calcd 283.1729, obsd 283.1741.

Cyclization of the minor component (150 mg, 0.34 mmol) in

conventional fashion furnished 90 mg (62%) of 57 as a clear

oil: IR (neat, cm^-1) 1450, 1360, 1300, 1250, 1150, 1050, 950;

¹H NMR (300 MHz, CDCl₃) δ 4.14-4.01 (m, 1 H), 3.95-3.81

(m, 4 H), 3.70-3.54 (m, 2 H), 2.72-2.56 (m, 1 H), 2.24-1.29

For 61: colorless crystals; mp 90-91 °C; IR (CCl₄, cm^-1

)

3710, 3520, 1730, 1525, 1435, 1220, 1130, 1050, 930; ¹H NMR

(300 MHz, CDCl₃) δ 4.65-4.57 (m, 1 H), 3.83-3.75 (m, 2 H),

3.68 (ddd, J ) 8.6, 6.8, 6.7 Hz, 1 H), 3.54 (ddd, J ) 8.3, 7.1,

7.0 Hz, 1 H), 3.32 (br s, 1 H), 2.60 (dt, J ) 13.3, 6.8 Hz, 1 H),

2.13-1.48 (series of m, 11 H); ¹³C NMR (75 MHz, CDCl₃) ppm

210.1, 90.6, 89.1, 71.6, 68.8, 68.0, 32.8, 30.9, 30.8, 26.1, 25.7,

24.3; MS m/ z (M⁺) calcd 226.1205, obsd 226.1202.

Anal. Calcd For C₁₂H₁₈O₄: C, 63.70; H, 8.02. Found: C,

63.78; H, 8.02.

(series of m, 15 H), 0.88 (s, 9 H), 0.08 (s, 6 H); MS m/ z (M⁺

t-BuMe₂SiO) calcd 251.1651, obsd 251.1642.

-

Analogous cyclization of the major diol (740 mg, 1.67 mmol)

provided 59 as a white powder (650 mg, 92%): mp 45 °C; IR

(CHCl₃, cm^-1) 1530, 1480, 1440, 1400, 1370, 1345, 1310, 1230,

1120, 1075, 990, 970, 930; ¹H NMR (300 MHz, CDCl₃) δ 4.07-

3.80 (m, 4 H), 3.69-3.58 (m, 2 H), 2.20-1.45 (series of m, 15

H), 1.32 (ddd, J ) 13.0, 3.6, 3.6 Hz, 1 H), 1.22-1.05 (m, 1 H),

0.83 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3 H); ¹³C NMR (75 MHz,

CDCl₃) ppm 93.3, 91.9, 88.0, 74.3, 69.8, 68.8, 66.9, 31.6, 30.4,

30.1, 28.0, 27.7, 27.0, 25.9, 25.8, 17.9, -4.7, -4.9; MS m/ z (M⁺)

calcd 382.2539, obsd 382.2539.

This compound was subjected to X-ray crystallographic

analysis.²⁸

For 62: white solid; mp 91-93 °C; IR (film, cm^-1) 3400,

1

1840, 1500, 1400, 1320, 1250, 1070, 990, 900; H NMR (300

Anal. Calcd for C₂₁H₃₈O₄Si: C, 65.92; H, 10.02. Found: C,

65.93; H, 9.97.

MHz, CDCl₃) δ 4.25 (dd, J ) 12.1, 7.5 Hz, 1 H), 3.94-3.75 (m,

4 H), 3.50 (br s, 1 H), 2.55-2.42 (m, 1 H), 2.26 (dddd, J )

13.1, 7.4, 3.7, 3.7 Hz, 1 H), 2.11-1.65 (series of m, 8 H), 1.49-

1.39 (m, 1 H), 1.32-1.18 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃)

ppm 210.1, 93.8, 88.6, 72.6, 69.1, 69.0, 32.6, 31.8, 31.7, 29.5,

26.7, 26.2; MS m/ z (M⁺) calcd 226.1205, obsd 226.1208.

Anal. Calcd for C₁₂H₁₈O₄: C, 63.70; H, 8.02. Found: C,

63.69; H, 8.00.

(5R*,6S*,12S*)-12-(ter t-Bu t yld im e t h ylsiloxy)-1,7-d i-

oxa d isp ir o[4.0.4.4]tetr a d eca n -11-on e (63). O-Silylation of

61 (5.54 g, 24.5 mmol) with tert-butyldimethylsilyl chloride

(4.43 g, 2.05 mmol) in the predescribed manner afforded 7.13

g (86%) of 63 as a clear oil that solidified on standing: mp 65

°C; IR (CHCl₃, cm^-1) 1750, 1535, 1485, 1440, 1165, 1070, 1030,

940; ¹H NMR (300 MHz, CDCl₃) δ 4.72 (dd, J ) 9.8, 7.3 Hz, 1

H), 3.88-3.80 (m, 2H), 3.79-3.70 (m, 2 H), 3.58 (dd, J ) 15.4,

7.2 Hz, 1 H), 2.68-2.59 (m, 1 H), 2.01-1.56 (series of m, 10

H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.01 (s, 3 H); ¹³C NMR (75 MHz,

Dep r otection -Oxid a tion of 57. To a magnetically stirred

solution of 57 (9.17 g, 24.0 mmol) in acetonitrile (50 mL) was

added a solution of 5% hydrofluoric acid in acetonitrile (100

mL). After 4 h, the mixture was treated with saturated

NaHCO₃solution (150 mL) and diluted with CH₂Cl₂(150 mL).

The separated aqueous phase was extracted with CH₂Cl₂(3

× 75 mL), and the combined organic layers were dried and

concentrated to give 6.57 g (100%) of the alcohol as a clear oil

that solidified on standing.

To a stirred solution of this alcohol (2.54 g, 9.48 mmol) in

CH₂Cl₂(150 mL) was added the Dess-Martin periodinane

reagent (10.35 g, 24.4 mmol). The mixture was stirred

overnight, diluted with ether (400 mL), and poured into

saturated Na₂S₂O₃solution (150 mL). The separated organic

phase was washed with saturated NaHCO₃solution (150 mL),

dried, and concentrated to leave a residue, which was purified

Elements of Belted Poly(spirotetrahydrofurans)

J . Org. Chem., Vol. 61, No. 21, 1996 7507

CDCl₃) ppm 207.8, 92.1, 88.7, 73.7, 68.7, 68.1, 32.8, 31.7, 31.0,

26.3, 26.1, 25.8, 25.2, 18.4, -4.7, -5.4; MS m/ z (M⁺) calcd

340.2070, obsd 340.2086.

Anal. Calcd for C₁₈H₃₂O₄Si: C, 63.48; H, 9.48. Found: C,

63.75; H, 9.53.

(5R *,6S *,12R *)-12-(t er t -B u t y ld im e t h y ls ilo x y )-1,7-

d ioxa d isp ir o[4.0.4.4]tetr a d eca n -11-on e (64). From reac-

tion of 62 (2.70 g, 12.0 mmol) with tert-butyldimethylsilyl

chloride (4.0 g, 24.5 mmol) under the conditions detailed above,

there was obtained 3.75 g (92%) of 64 as a white solid: mp 68

°C; IR (CHCl₃, cm^-1) 1750, 1480, 1400, 1265, 1155, 1110, 1000;

¹H NMR (300 MHz, CDCl₃) δ 4.34 (dd, J ) 12.2, 7.1 Hz, 1 H),

3.93-3.75 (m, 4 H), 2.55-2.41 (m, 1 H), 2.15-1.65 (m, 9 H),

1.60-1.38 (m, 2 H), 0.87 (s, 9 H), 0.13 (s, 3 H), 0.00 (s, 3 H);

¹³C NMR (75 MHz, CDCl₃) ppm 207.6, 94.0, 88.3, 74.7, 69.0,

68.9, 33.1, 31.9, 31.6, 29.9, 26.7, 26.3, 25.7, 18.5, -4.5, -5.5;

MS m/ z (M⁺) calcd 340.2070, obsd 340.2081.

in petroleum ether) and provided 180 mg (13%) of 49 and 1.12

g (84%) of 69.

(5R*,6S*,11S*,17S*)-17-Hyd r oxy-1,7,12-tr ioxa tr isp ir o-

[4.0.4.0.4.3]oct a d eca n -16-on e (70) a n d (5R*,6S*,11S*,-

17R *)-17-H y d r o x y -1,7,12-t r io x a t r is p ir o [4.0.4.0.4.3]-

octa d eca n -16-on e (71). To a cold (-78 °C), magnetically

stirred solution of 69 (550 mg, 2.07 mmol) in dry THF (50 mL)

was added potassium hexamethyldisilazide (4.8 mL of 0.5 M

in toluene, 2.4 mmol) followed by trimethylsilyl chloride (4.30

g, 3.91 mmol) 3 h later. Adaptation of the earlier procedure

and chromatographic separation afforded 160 mg (27%) of 70

and 350 mg (60%) of 71.

For 70: colorless solid; mp 98-100 °C; IR (CHCl₃, cm^-1

)

3610, 3540, 1735, 1530, 1485, 1435, 1220, 1095, 1065, 940; ¹H

NMR (300 MHz, CDCl₃) δ 4.73 (dd, J ) 12.7, 7.5 Hz, 1 H),

4.20-3.45 (series of m, 6 H), 3.08 (br s, 1 H), 2.80-2.60 (m, 1

H), 2.57-2.40 (m, 1 H), 2.35-1.55 (series of m, 9 H), 1.50-

1.25 (m, 3 H); ¹³C NMR (75 MHz, CDCl₃) ppm 209.1, 92.3, 90.3,

86.7, 70.9, 70.2, 69.3, 67.3, 42.6, 32.2, 30.3, 27.2, 27.0, 25.1,

25.0; MS m/ z (M⁺) calcd 282.1467, obsd 282.1468.

Anal. Calcd for C₁₅H₂₂O₅: C, 63.81; H, 7.86. Found: C,

63.79; H, 7.82.

Anal. Calcd for C₁₈H₃₂O₄Si: C, 63.48; H, 9.48. Found: C,

63.60; H, 9.45.

Ca p p in g of 63 w ith th e Nor m a n t Rea gen t. Addition of

the Normant reagent (78.0 mL of 0.60 M, 46.8 mmol) to a cold

(-78 °C) solution of 63 (9.39 g, 27.6 mmol) in dry THF (200

mL) in the manner earlier described afforded 10.23 g (93%) of

a mixture of diastereomeric diols, which was directly cyclized

in the presence of p-toluenesulfonyl chloride (5.95 g, 31 mmol).

After workup, the residue was subjected to chromatography

on silica gel (elution with 20% ether in petroleum ether) to

give 9.17 g (93%) of a diastereomeric mixture of 65 and 67.

This material was desilylated (6.57 g, 100%), and a portion of

this alcohol (2.54 g, 9.48 mmol) was oxidized (Dess-Martin)

as before to give, after chromatographic separation (silica gel,

elution with 50% ether in petroleum ether), 670 mg (27%) of

69 and 1.73 g (69%) of 49. The latter ketone proved spectro-

scopically identical to material prepared earlier.

This compound was subjected to X-ray crystallographic

analysis.²⁸

For 71: colorless oil; IR (neat, cm^-1) 3510, 1735, 1440, 1400,

1

1300, 1275, 1250, 1210, 1185, 1125, 1070, 985, 960, 935; H

NMR (300 MHz, CDCl₃) δ 4.54 (dd, J ) 12.4, 7.1 Hz, 1 H),

4.10-3.75 (m, 6 H), 3.11 (br s, 1 H), 2.20 (dd, J ) 13.0, 7.1 Hz,

1 H), 2.20-1.50 (series of m, 13 H); ¹³C NMR (75 MHz, CDCl₃)

ppm 211.2, 94.0, 93.7, 85.4, 70.3, 69.3, 68.6, 68.4, 42.3, 33.7,

33.3, 27.42, 27.38, 25.4, 25.2; MS m/ z (M⁺) calcd 282.1467,

obsd 282.1465.

Anal. Calcd for C₁₅H₂₂O₅: C, 63.81; H, 7.86. Found: C,

63.72; H, 7.96.

For 69: colorless oil; IR (neat, cm^-1) 1735, 1460, 1315, 1040,

1

970, 935, 905; H NMR (300 MHz, CDCl₃) δ 3.98-3.71 (m, 6

Ack n ow led gm en t. We thank the National Science

Foundation for financial support, the Department of

Science and Technology, Government of India, for the

award of a BOYSCAST Visiting Fellowship to U.V.M.,

Prof. Robin Rogers (Northern Illinois University) for the

X-ray crystallographic analyses, and Dr. Kurt Loening

for assistance with nomenclature.

H), 2.53-2.40 (m, 2 H), 2.29-2.14 (m, 2 H), 2.02-1.57 (series

of m, 12 H); ¹³C NMR (75 MHz, CDCl₃) ppm 209.7, 93.8, 92.0,

87.0, 70.3, 68.5, 67.7, 34.5, 32.9, 32.3, 29.1, 28.6, 27.1, 26.0,

25.0; MS m/ z (M⁺) calcd 266.1518, obsd 266.1516.

Anal. Calcd for C₁₅H₂₂O₄: C, 67.63; H, 8.33. Found: C,

67.45; H, 8.43.

Ca p p in g of 64 w ith th e Nor m a n t Rea gen t. Addition of

the Normant reagent (30.0 mL of 0.60 M, 18.0 mmol) to a cold

(-78 °C) solution of 64 (2.59 g, 7.62 mmol) in dry THF (200

mL) in the manner earlier described furnished 2.90 g (86%)

of a mixture of diastereomeric diols. This mixture was cyclized

as usual with p-toluenesulfonyl chloride (1.69 g, 8.86 mmol)

to give after chromatography on silica gel (elution with 50%

ether in petroleum ether) 2.60 g (93%) of a diastereomeric

mixture of 66 and 68. This material was sequentially de-

silylated (82%) and oxidized (PDC, 3 Å MS). Chromatographic

separation was effected on silica gel (elution with 50% ether

Su p p or tin g In for m a tion Ava ila ble: Computer-gener-

ated perspective drawings of 33, 61, and 70, as determined

by X-ray crystallography (3 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.

J O960962H

Article Doi

Definition of several control elements relevant to the stereodefined serial elaboration of belted poly(spirotetrahydrofurans) fitted with a cyclohexane core

DOI: 10.1021/jo960962h

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Article abstract of DOI:10.1021/jo960962h

Full text of DOI:10.1021/jo960962h

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