7492
J. Org. Chem. 1996, 61, 7492-7507
Definition of Several Control Elements Relevant to the Stereodefined Serial Elaboration of Belted Poly(spirotetrahydrofurans) Fitted with a Cyclohexane Core Leo A. Paquette,* Marshall Stepanian, Uppuluri V. Mallavadhani,† Timothy D. Cutarelli,‡ Timothy B. Lowinger,§ and Horst Jan Klemeyer Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210 Received May 24, 1996X
The stereochemistry of the condensations of 2-cyclohexenones, R-arylidenecyclohexanones, and R-(tert-butyldimethylsiloxy)cyclohexanones carrying one or two (both syn and anti) spirotetrahydrofuran 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) tetrahydrofuran 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.1,3,4 Despite the vigor with which research in this area has been pursued, we are unaware of any report dealing with the question of possible bifacial complexation. 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, 19941995. Present address: Regional Research Laboratory, Bhubaneswar 751013, India. ‡ Undergraduate research participant, 1995. § Merck Postdoctoral Fellow, 1992. Present address: Bayer Corporation, Pharmaceutical Division, 400 Morgan Lane, West Haven, CT 06516-4175. X Abstract 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.; Armstrong, 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. (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.
S0022-3263(96)00962-0 CCC: $12.00
Figure 1. The eight possible stereoisomeric poly(spirotetrahydrofuranyl)cyclohexanes. The first (bold face) numerical designation specifies the unique locus of the β-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.
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 (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.
© 1996 American Chemical Society
Elements of Belted Poly(spirotetrahydrofurans)
β-oriented C-O bonds.6 The inherent time-averaged symmetry of each isomer is provided along with the number of 13C NMR signals each will display. The allanti 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. Retrosynthetic analysis associated with the preparation of 1-8 has been designed around the ready availability of the dispirocyclohexanones 9 and 10, which are conveniently produced5 by 2-fold ring expansion of cyclobutanone via oxonium ion-activated pinacol rearrangement.7 Although 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 equilibrium, anti isomer 10 is slightly favored (Keq ) 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
J. Org. Chem., Vol. 61, No. 21, 1996 7493 Scheme 1
Lobben demonstrated earlier with 15 that these two processes are not without their distinctive stereochemical nuances.15 In tetrahydrofuran solution at 0 °C, allylmagnesium chloride gives little indication of being sensitive to chelation control. Quite strikingly, the Normant reagent elicits a very respectable chelate-controlled response from 15 (Scheme 2). Since 15 is conformationally flexible, it is legitimate to inquire whether this contrasting diastereoselectivity pattern will extend to less structurally dynamic cyclohexanones. Indeed, the 4-tert-
Discussion of Results 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 utilitarian in elaborating spirotetrahydrofuran rings from carbonyl groups. The first utilizes allylmagnesium bromide and proceeds via 11 to diol 12 upon hydroborationoxidation (Scheme 1).5,12 The 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,14 simplifies 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.15 When chelation operates in 16 (equatorial oxy substituent), nucleophilic attack by the organomagnesium 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 bromide 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 Scheme 2
Paquette et al.
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,16 all four motifs were presumed to provide the necessary latitude to continue spirocycle construction around the complete cyclohexane periphery. All four types of structural modification have been examined. Unsaturation Internal to the Ring. The early precedent set by Klemeyer was not particularly encouraging.16 Although 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 indicating that neither spirocyclic ketone engages in nucleophilic addition with maximal complexing capacity.
Consequently, application of this chemistry to the stereocontrolled synthesis of 1-8 appeared at the outset
nesium bromide, 19 (14%) and 20 (16%) were again formed, but the two stereoisomeric 1,4-adducts predominated (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 CH2Cl2 solution, 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-dimethylacetamide at 170 °C, dehydrobromination was complete in 2 h. Resulting enone 22 (98%) exhibited high-field 1H 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 significantly 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 (16) Klemeyer, H. J.; Paquette, L. A. J. Org. Chem. 1994, 59, 7924.
Elements of Belted Poly(spirotetrahydrofurans)
conformation of the ketone having the R-oxygen equatorially 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 resulted. 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 conveniently gave rise to the expected diols 25 (80%) and 26 (73%). These advanced intermediates were individually cyclized 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
Although the allylation/hydroboration sequence proceeded 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 purification. In his study of bifunctional Grignard reagents, Normant described the generation of ClMgO(CH2)3MgCl,14 stock solutions of which can be stored for appreciable periods of time. When 22 was treated with a modest excess of this nucleophile in THF and the resulting 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
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 The Repetitive Arylidene Option. The route followed in this instance began with the Claisen-Schmidt condensation of benzaldehyde with 15 (Scheme 3). Indium-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.
J. Org. Chem., Vol. 61, No. 21, 1996 7495 Scheme 3
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 stereochemical assignment to this dispiro olefin. In further agreement with the trans arrangement of oxygenated centers, ozonolytic cleavage of 35 gave rise to the wellknown 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 threecomponent 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 addition. Substitution of o-tolualdehyde and mesitaldehyde for benzaldehyde afforded 36b and 36c. Neither of these ketones exhibited any evidence for entering into conjugate addition. Consequently, a single o-methyl group on the aryl ring provides adequate steric shielding to deter the unwanted formation of 40. 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 instances. 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 (18) Paquette, L. A.; Stepanian, M. Manuscript in preparation.
7496 J. Org. Chem., Vol. 61, No. 21, 1996
Paquette et al. Scheme 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
considerable consternation (Scheme 5). However, considerable improvement in stereocontrol and in conciseness 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
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 spirotetrahydrofuran 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 presently of interest, the capability of the bulky methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) reagent to function as an external controller was briefly examined. Yamamoto has demonstrated that prior formation of a complex between a 2-alkoxycyclohexanone and MAD so sterically encumbers the less congested equatorial surface of the carbonyl carbon that nucleophilic attack occurs from the axial direction.19 In the
Elements of Belted Poly(spirotetrahydrofurans) Scheme 5
J. Org. Chem., Vol. 61, No. 21, 1996 7497 Scheme 7
Scheme 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 introduced from the face opposite that used by the allylindium reagent which delivers 37, a significant level of competing 1,4-addition also materializes. The advantages and disadvantages associated with the arylidene functionalization option were now quite apparent. 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 consequences of preliminary R-oxygenation. The Consequences of Preliminary r-Oxygenation. At the outset, the various means for the R-oxygenation 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 ethers20 and 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.
zoic acid21 were 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 β as in 54, the only product observed was 58 (89% for the two steps). Clearly, syn orientation of the R- and R′(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. Scheme 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 trispirocyclohexanone 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 oxidation21b was applied to 10 (Scheme 8). This procedure led to the coformation of 61 and 62, with the R-isomer now predominating by a factor of 2.6:1. This crossover in stereoselectivity, initially formulated by the strength of 1 H 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 additions. 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 conventionally into 49 and 69. The latter ketone was R-oxygenated 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 Jax-ax and Jax-eq fashion to the neighboring methylene protons. The conversion of 69 to 70 and 71 illustrates the readiness with which the construction of multiply spiro
functionalized ethers, such as 1-8, might be undertaken. These accomplishments shall be presented elsewhere.
Elements of Belted Poly(spirotetrahydrofurans) Table 1. Facial Selectivity Observed in Allylindium Additionsa
a
ketone
T, °C
15b 16b 17b 22 32 36a 45
25 25 25 0 0 0 0
attack anti to O:syn to O 5.6:1 11.8:1 14.0:1 97 97 97 1:1.1
Solvent: THF. b Data derived from ref 15.
Table 2. Facial Selectivity Observed in Additions of the Normant Reagenta ketone
T, °C
attack anti to O:syn to O
15b
0 0 0 -78 f rt -78 f rt -78 f rt -78 f rt -78 f rt -78 f rt -78 f rt -78 f rt
1:8.8 1:14.2 7.6:1 2:1 97 1:16.7 97 >97:
