TETRAHEDRONREPORT

A REVIEW OF ANNULATION:

MICHAEL E. JUG Department of Chemistry. C’niversity of California at Los Angeles. Los Angeles, CA 90024, U.S.A.

(Receivedfor pubficalirtn 30 .~e~ie~ber 19753

INTRODULTION The methods of annulation have proved themselves to AnnulationS, derived from the Latin work annulatus be invaluable aids to the synthetic organic chemist in the (ringed) means “the formation of rings”.’ In organic syntheses of such complex natural products as steroids. chemistry this term is used to describe the process of terpenes, and alkaloids. This is especially true of the use building a ring onto a preexisting system. cyclic or of the cyclohexenone system. Several factors justify the non-cyclic. The added ring may be of any size, although importance of this ring system. and these include ease of 5- and ~membered rings are most commonly formed. formation. control of ring-juncture and side-chain This broad de~nition includes in a general sense many stereochemistry, introduction of functionality, and attach- reactions that are not normally thought of as annulation ment of additional rings. reactions, such as Diels-Alder reactions.’ acid-catalyzed In general, annulation reactions can be divided into polyolefinic cyclizations,’ photochemical,’ radical,‘ and three basic categories depending on the method of thermal’ cyclizations. This discussion will be concerned attachment of 3-ketoalkyl chain: Michael reactions,’ mainly with those processes of annulation which involve nucleophilic additions (Crignards, ylides, etc.). and construction of a cyclohexenone ring onto a me-existing alkylations. Furthermore, annulation reagents can be ketone; e.g. 1 -+t. These processes normally involve the subdivided into those designed to add one ring at a time (mon~annulation reagents) and those which result in several ring segments being added at once, the so-called his- or tris-annulation reagents. L-D I. WCHAEI. REACTION A, L (I) Mono-UnnukJfion (a) Robinson annulufion. The first example of this type attachment of an actual or potential 3-ketoalkyl chain to a of annulation reaction is the classical “Robinson annula- carbon adjacent to a carbonyl function (e.g. 344). tion”, which involves the base-catalyzed Michael addition although other methods (e.g. enol lactone-Grignard) will of a ketone to methyl vinyl ketone 6, followed by base- or also be discussed. acid-catalyzed aldol condensation.~ The method is useful only in a very few simple cases, such as Z- methylcyclohexanone 5 where the availability of starting Kontribution No. 3503. t’f’here has been some discrepancy in the spelling of this word materials compensates for the low yield of octalone 9 with IWO forms. annulation and annplation. being used. the latter produced. By proper adjustment of conditions, the somewhat more often than the former. In this review, however, reaction can be used to produce any one of the three the correct spelling (cf. Wehsrer’s Third NW lnremarionul possible products: the diketone 7, the ketolg, or the enone Dicfionory Unohid~ed) nnnuhtion will be employed. 9. Both intermediate products 7 and 3 can be converted to 4 MICHAEL E. JU?IG the enone 9 by treatment with either acid or base. With inferred that the anion at C-l may be the more stable of relatively acidic carbonyl compounds such as p- the two anions.” dicarbonyl compounds, e.g. 10: or ptetralones, e.g. 13,“’ Marshall was unable to improve the yields of the the Robinson annulation gives good yields. With ordinary Robinson annulation with a simple cyclohexanone system carbonyl substances the Robinson annulation is poor by varying the solvent, ratio of reagent, temperature or mainly because of polymerization of the vinyl ketone, base.” However, a Japanese group has reported a method initiated by strongly basic enolates, and also because of which sometimes results in high yields for unactivated the inability of controlling the site of anion formation. ketones. Treatment of the amine 24 and the ketone 5 with Furthermore, unusual products are sometimes ob- a trace of metallic sodium at 135°C gives a 70% yield of tainedYn.“~‘*which result from the base- or acid-catalyzed octalone 9.18 cleavage of the pdiketone to a diketo acid which then The problem of unusual cyclization products mentioned cyclizes to an enone acid, e.g. IS+ 17” and lo+ l&90 earlier (cf. 15 --) 17) also occurs when the Mannich base 24 (b) Munnich base and methiodide. The problem of is used. For example, the dienone acid 27 is formed via the polymerization was overcome in part by the use of the intermediates shown in 45-50% yield when one equivalent Mannich base 19.” Treatment of the methiodide of the of compound 24 is employed and in 90-95% yield when Mannich base with strong base converts it to methyl vinyl two equivalents of 24 are used.” ketone in situ. This method can improve the yields of The choice of solvent for the reaction can have a direct cyclohexenone formed; however, unexpected products bearing on the stereochemistry of the products.” Scanio are sometimes formed. The reaction of the methiodide 19 has recently shown that a change of solvents causes a with cis-IO-methyl-2-decalone 22 gives only the unex- dramatic shift in the stereochemical course of the pected anthracene-type product 23 resulting from attack annulation reaction between methyl propenyl ketone Zs at C-3 rather than attack at C-l, although it has been and 2-methylcyclohexanone 5.“’

n A review of annuhtion 5

ketones in those cases where reaction with the corres- ponding carbonyl compound fails, due either to self- condensation of the carbonyl compound or to the polymerization of the vinyl ketone by the very basic enolates. The enamine of cyclohexanone, 45, adds to methyl vinyl ketone to give directly the enamine of An intriguing, though unproved, mechanism has been octalone as a mixture of double bond isomers, 46 and 47, proposed to explain the unusual result in dimethylsulfox- in 67% yield. This enamine mixture can be hydrolyzed to a ide. This involves an initial aldol reaction in the inverse mixture of the octalones 48 and 49, or can be used directly sense with the enone anion attacking the ketone carbonyl. in the alkylation or further Michael reactions. Moreover, A thermally allowed disrotatory cyclization of the derived the use of an enamine can alter the course of annulation enolate ion 31 would then lead to the observed product 30. by causing the addition to occur at the onsubstituted Homologues of methyl vinyl ketone or their Mannich position of an a-substituted cyclic ketone, e.g. S-51?’ base methiodides have been prepared and used in the There is a recent report that the Robinson annulation annulation sequence, e.g. ethyl vinyl ketone 32” and l- gives improved yields of octalones and cyclohexenones bis(diethylaminomethyl)-acetone 33.” under catalysis by sulfuric acid rather than base.” (c) /~-H&Iketone. The use of /?-halo ketones, e.g. 40 Also it has been observed that the vapor-phase and 41, as alternatives to the above methods has also been introduction of the vinyl ketone into the solution of the investigated.*’ The reagents release the vinyl ketones ketone and base can often help improve the procedure, slowly under base treatment as do the ~annich base e.g. 52-,53.‘6 methi~ides and give comparable yields. (e) ~~nc~i~n~~~ze~p~~~uc~.~. All of the examples given (d) Enamine. The use of enamineP with their rela- thus far have resulted in the production of cyclohex- tively low basicity and high nucleophilicity often pro- anones with no other functionality in the 6-membered duces good yields in annulation reactions with vinyl ring. Several reagents have been developed to synthesize MICHAEL E. JUNG

NEf2 ti8t2

muMe + --iz--- Y0 722 u u

0 Hz 2) KOH “@OH _ 662

e 1 + 6 A reviewof annulation

more functiona~ized rings. W~dw~dz7 has introduced methyl ethynyl ketone 55 as a reagent for the construction of cycfohexadienones although in rather low yields. This is possibly due to the fact that the enedione intermediate may be largely the E-isomer 57 (which cannot cyclize to 59) rather than the desired Z-isomer 58. Oxygen functionality can also be introduced into the cyclohexenone ring. The enol ether of an *diketone 61 is produced directly by the use of methoxymethyl vinyl ketone 60.**The a-epoxide of the enedione 63 is the major product when 1,4~ich~oro-~-butanone 62 is used as an annulation reagent.”

The Michael sequence can also be used with n,& allows for the first time the general use of the Michael unsaturated ketones, but again the relatively low acidity addition with vinyl ketones under aprotic conditions. of the enones (compared to @-diketones or @-tetralones) The major drawback of the Michael sequence in genera1 causes the yields to be low. Another problem is that the is that the reactions are usually not compatible with jntermediate 1,5-diketone produced may cyclize in an specifically generated enolate ions under aprotic, non- abnormal manner to give undesired products, e.g. equilibrating conditions. The reagents are generally not 65-+66.M In the proposed mechanism, the anion of the reactive enough to trap the enolates generated by enone system, e.g. 67, acts as the nu~leophili~ component reduction of enones by lithium in liquid ammonia3’ or in the aldot reaction with the saturated ketone to yield an those generated by attack of methyllithium on an enof unexpected cyclization product, e.g. 68, which then acetate or silyl enol ether.” For example, reduction of the aromatizes giving 66. tricyclic enedione 72 with lithium in liquid ammonia (f) a-Silyl enone. In order to allow the use of vinyl followed by addition of methyl vinyl ketone, cyclization, ketones with regiospecifically formed ketone enolates, and final chromic acid oxidation (to reconvert the alcohol cr-silyl enones such as 69 were introduced by Stork.” The in ring D in steroid nomenclature to the saturated ketone) silyl group in 70 stabilizes somewhat the initial negative gave the tetracyclic product 73 in very poor yield (less charge formed by addition of the enolate ion to the enone, than 5%).” and, most im~rtantly, provides strong steric hindrance The problem in this case is probably polymerization of which slows down anionic polymerization. Once annula- the enone by the strongly basic enolate, a result also tion is complete, the sibyl group is removed from the observed in the attempted reduction-annulation of the n’-sibyl enone 71 with base. This method gives improved octalone 9. The spec~~cally-formed enolate 74 cannot be yields (70-E%) in a number of cases and most important, annufated directly in the ammonia solution. but must first MICHAEL E. JUNG

be converted via a proton source into the decalone 75. (g) a-Methylene cyclanone. Annulation sequences have Reaction of this ketone with base in a protic medium gives also been reported in which the cyclic ketone functions as rise to a mixture of the two equilibrating enolates, 74 and the Michael acceptor. In some cases a Mannich base 76, which on treatment with 6 gives the enone 78 as the methiodide 82 is the precursor of the a-methylene ketone major product with the desired isomer 77 being the minor 84, which then acts as a Michael acceptor for a pketo product. ester 83.” However, Boeckman” and Storkj6 have recently shown Hajos has recently reported sequences designed for that the use of stronger Michael acceptors, namely a-silyl steroid synthesis” which utilize an a-methylene ketone. vinyl ketones such as 79, circumvents these problems In the first sequence the hydrindanone ester 88, produced since now Michael addition is faster than polymerization quantitatively from 87 by catalytic reduction, could be and, provided that precautions are taken to insure that the converted to the keto mesylate 89 in good yield. Addition medium is truly aprotic, it is also faster than equilibration of the Pketo ester 98 followed by cyclization, saponifica- of the enolates. For example, the reductive trapping- tion, and decarboxylation yielded the tricyclic compound cyclization sequence using the silyl derivative 79 fur- 91, via the a-methylene ketone 92 as an intermediate nishes cleanly the tricyclic compound 77 in 6895 yield, produced in sifu. This compound could be isolated in the uncontaminated by isomer 78. Again base treatment second reported procedure by treatment of the keto acid removes the silyl group from the intermediate silyl ketone 93 with formaldehyde and piperidine hydrochloride. 80 during cyclization. As indicated in the figure, the initial Addition of the pketo ester 98 followed by acid-catalyzed enolate 74 can be trapped as the silyl enol ether 81 and cyclization and decarboxylation gave the tricyclic 91 in later regenerated in ethereal solution, thus allowing one to higher yield. Tetracyclic products, e.g. 94, can also be examine the purified intermediate spectrally before produced. continuing, if need be. A method of forming an a-methylene ketone by a This is the first instance of the successful trapping of a reductive trapping process has recently been developed regiospecifically generated, less stable enolate ion without by Stork.19 Reduction of an enone with lithium in liquid equilibration by an appropriate Michael acceptor and thus ammonia leads to a specific enolate which can then be this result greatly increases the potential usefulness of the trapped as the hydroxymethyl compound 96 by the Michael reaction annulation sequence. introduction of gaseous formaldehyde. Tosylation and treatment with the @-keto ester 97 in a basic medium produces in situ the cY-methyleneketone 98 which then cyclizes in a normal fashion to the tricyclic enone 77. Other examples of this type fcf compounds 135 and 156) will be given later. (h) Asymmetric induction, A very interesting synthesis of optically active steroid precursors has been recently developed by a group of chemists at Hoffman-LaRoche.“O The conditions for the condensation between methyl vinyl ketone 6 and 2-methyl-1,3-cyclopen~nedione 100 have been optimized so that the triketone 101 is now available in 87% yield. Treatment of 101 with a trace of (S)-(-)-proline in dimethyiformamide gives the cyclized aldol product 102 in 100% chemical yield and 93.4% optical purity. This is one of the highest optical yields ever reported for non-enzymatic synthesis. The proposed mechanism involves the addition of proline to one of the two possible ketones on the cyclopentane ring from the side of the alkyl chain to give an intermediate 103 which is held in its pictured conformation by hydrogen bonding. It is then suggested that C-C bond formation occurs from the side opposite the angular methyl group to give the &-fused optically active ketol 104, which then loses water to form 102.t This mechanism has the advantage of having the asymmetric carbon atom of proline only three carbons removed from the center of asymmetric induc- tThe reaction 103-rlO4 is formally a substitution reaction tion, whereas other possible mechanisms involving the proceeding with refention which can occur only if there is a large enamine of the acyclic ketone 105 would have the amount of S,l character in the reaction. Perhaps a better asymmetric C atom much farther removed. However, we mechanism of this type (via a carbinolamine such as 103) would be will see later (compounds 138 and 139) other examples of the following: attack of the bulky proline molecule trans lo the alkyl chain fcis to the smaller methyl group) to give an asymmetric induction in which the asymmetric carbon is intermediate 103’ which is then displaced by the enol function in indeed far from the reaction site. an SN2 type reaction with inversion of configuration to give the (i) Do&/e Michael unnulation. In an ingenious synth- ketol 104, esis of the antibiotic ~iseofuivin 109, Stork used a novei double Michaei reaction between the ketone 106 and the acetylenic enone 107 to construct the desired Spiro system in one step, albeit in very low yield.“’ However, the low yield is more than compensated by the stereoselectivity (only the desired isomer with the methyl group syn to the IO MICHAEI. E. JUNG

carbonyl is obtained) and the simplicity of the synthesis. exist largely in the opposite geometric isomer, thus The procedure has since been improved by Mulholland so precluding further cyclization. that the yield of griseofulvin and its analogues can be raised to 20%.‘* The initial Michael addition to the (2) Bis- and tris-annulation cross-conjugated acetylenic enone 107 occurred at the (a) Vinyl ketone. Thus far, all the examples cited have triple bond. This is due to the inductive effect of the involved the construction of only one ring onto the methoxyl group which increases the electrophilicity of the existing system. There are also numerous instances of the acetylenic carbon /? to the ketone function. In other addition of several rings at once via Michael reactions. cross-conjugated acetylenic enones only simple Michael The steroid literature is full of examples of additions of addition to the double bond was observed, e.g. llO+ carbonyl compounds (usually pdiketones) to enones (I ,4 111.” The reason for the low yield in the griseofulvin addition) dienones (I.6 addition), and trienones (I,8 annulation may be related to the reason for the low yields addition). An excellent survey of these methods has of cyclohexadienone formation mentioned earlier (55+ recently been published”’ and a few examples are 59), that is, that the product of initial addition, 108, may appropriate. A review of annulation

1.4 Addition

I ,6 Addition

An interesting example of I.6 addition followed by I ,4 steroids using an optically active enone, Mannich base, or addition and eventual Dieckmann cyclization has been &alkoxy ketone in the key annulation step.S2A series of reported recently.” The reaction of the diketo ester 130 optically active compounds, 138(a-d) and 139, was with methyl Bvinylacrylate 131 produced the tricyclic synthesized and reacted with methylcyclopentanedione compound 132 in 41% yield via a multi-step sequence 100 as shown. The stereochemistry of the C-13 methyl involving an internal proton transfer. group (steroid numbering) is determined by the absolute Danishefsky has introduced the method shown below, configuration of the hydroxyl group in the vinyl ketone. which involves the Michael addition of the Eketo ester The intermediate optically active dienol ether 140 was 136 to the enone 135 followed by acid treatment to then usually converted to the reduced and further construct the tetracyclic compound 129 containing the cyclized enone 141 via several high-yield steps.““ In one steroid backbone.” The over-all yield from methylcyc- case the mono-annulated product was prepared in high lopentanedione to the tetracyclic compound 129 is 34%. yield, 140+ 142. A modified sequence was utilized for the The hydrolysis of the vinyl chloride will be treated later. production of optically active estrone, 139+ 143.53b (b) Asymmetric induction. Saucy et al. at Hoffman- The mechanism of this annulation sequence, which LaRoche have developed a synthesis of optically active proceeds with high asymmetric induction (as high as 90% MICHAEL E. JUNG

in some cases), is not known in detail. One suggested method.“b The enone 149 was converted to the cross- mechanism involves initial Michael addition to give the conjugated dienone 156, which was then reacted with uncyclized hydroxytrione 144 which is in equilibrium cyclohexanedione 15 to give trione 157. Base catalyzed with several hemiacetal forms (one of which, 145, has ring opening and subsequent cyclization led to the been isolated from partial reaction mixtures). This intermediate 153. A similar type of operation has been mixture is converted to the cyclic enol ether 147 which mentioned previously, i.e. 92 t 95 + 94. then cyclizes as shown via ketol 148 to produce only (d) Vinyl ketone ketol. Other similar bis-annulation compound 139 with the C-13 methyl group /? (cf. reagents are the ketal enones lS&? and 1S8b.sThe major compound 105). advantage with these is that the ketal can be converted to (c) Vinyl ketone ester. Other functionalized enones a ketone in one high-yield step. The yields are comparable have been used in annulation. The methyl (or ethyl) ester to those obtained with the other enones mentioned in this 151 has been reacted with B_keto aldehydes:’ e.g. 150, or section. /3-diketones,” e.g. 10, and subsequently cyclized. In both (e) Silyluinyl ketone ketal. Again in an attempt to make cases, further elaboration of the next ring was accom- the enone a better Michael acceptor, the silyl derivative plished by the enol lactone-Grignard method, which will 160 was synthesized.‘” This reagent is also able to trap be discussed later. The tricyclic intermediate 153 was also regiospecifically generated enolates under non- synthesized from 149 by an interesting but less efficient equilibrating aprotic conditions, as was its lower analogue A review of annulation 13

79. The silyl group allows the use of kinetically generated 166, which is hydrolyzed and cyclized in acid to the keto enolate ions under aprotic conditions and is removed later enone 167. Acid-catalyzed cyclization affords the tricyclic by base. The overall yields, e.g. 161+ 163, are quite good. dienone 168. This procedure has been used to synthesize (f) Vinylpyridine. An interesting bis-annulation reagent Dhomo estrone from 169 in 15% overall yield. This has been developed by Danishefsky in which a 2- method suffers from the somewhat cumbersome, multi- vinylpyridine derivative 164 serves as the Michael step elaboration of the diketone function from the acceptor.” After Michael addition and protection of the pyridine moiety and can lead to mixtures of products in ketone, the pyridine ring in compound 165 is subjected to varying overall yields, ranging from high (e.g. 169-t 170) a Birch reduction to give the intermediate dihydropyridine to fair (e.g. 45+ 167). MICHAEL E. JUNG

(3) Conclusion In general, then, one can see that the annulation sequence based on the Michael reaction has been used quite extensively and has achieved a moderate degree of success. In a number of cases the yields are relatively low but can be improved by several modifications. Considera- ble success has been obtained in the use of the method for adding more than one ring at a time. A major drawback of the sequence-that the vinyl ketones were not reactive enough to trap specifically generated enolate ions-seems to have now been surmounted with the advent of the silyl derivatives 79 and 160. proceeds via the intermediates 175 and 176 as shown in the mechanism to give the bicyclic ketol salt 177. The 2.NUCLEOPHILIC ADDITION Grignard reaction stops at this stage since the normally The second basic category of annulation reactions can reactive carbonyl function is now so sterically hindered be grouped under the rather broad heading of nucleophilic that the Grignard reagent no longer adds to it. The ketol additions. This title is meant to encompass essentially all 178 obtained upon hydrolysis undergoes a base-catalyzed annulation sequences which involve the addition of an reverse aldol condensation to the 15diketone 179, which organometallic reagent or ylide to a carbonyl derivative at then cyclizes to the final enone product 18tk5“ some step. The enol lactone 173 is nearly always formed by the Nucleophilic reagents can be used to form the same addition of basic acetic anhydride to the keto acid 172, cyclohexanone system from a ketone or its derivative as which is itself synthesized in a variety of waysM The is formed in a Michael reaction (e.g. 1+2), that is, to give Michael addition of a ketone enolate to acrylic esters can normal annulation. However several methods have lead to the acid directly,M e.g. Ml+ 182, or to the ester recently been published which convert a ketone system which can be hydrolyzed to the acid in base.6’ Michael into a different cyclohexanone system (e.g. l-*2’), or into addition to acrylonitrile followed by base hydrolysis also a saturated ketone of a different structural type altogether yields the keto acid, ‘* e.g. 184+ 185. The ozonolysis of a (e.g. l-+2”). These types of conversions will be grouped cyclohexenone system, one of the first methods de- under the heading of “Modified Annulation.” veloped,““’ has been used frequently.“’ A variant on this method employs ruthenium tetroxide as the oxidizing (1) Normal annulation agent.W The keto acid can also be formed via the addition (a) Enol lactone-Grignard. The most common of the of a bis-annulation reagent such as 151. Finally a nucleophilic addition processes is the enol lactone- multi-step but high-yield procedure has been developed Grignard method developed by Turner and Fujimoto to involving alkylation with ally1 bromide followed by introduce a labelled carbon at the Cposition of steroidal hydroboration and oxidation, ” e.g. 188-+ 189. enones5’ This method involves the addition of a Grignard Several Grignard reagents have been used in this reagent 174 to a 6-membered enol lactone 173 which sequence with methylmagnesium bromide being the most A review of annulation

x Ref.626

common.“9,“’ Ethylmagnesium bromide was used to give a methyl-I-pentene 191 which reacted with the enol lactone methyl-substituted enone.‘4c.“’ Several different Grignard 192 to give a diketone.“” After base-catalyzed cyclization reagents have been used to add the elements of an and methylation, ozonolysis of compound 193 yielded a additional ring all at once. The first use of a functionalized second diketone which was cyclized by base to yield Grignard reagent was that derived from 5-chloro-2- enone 194 and complete the sequence. 16 MICHAEL E. JUX

A simpler Grignard reagent 195, utilizing a ketal this method has been reported by Woodward, involving protecting group, was used successfully by French the use of an enol lactam rather than an enol lactone.6’” workers in the following sequence.* In this manner, the The enol lactam 207, formed in excellent yield from the enol lactone 1% could be converted to the tetracyclic keto acid 187a, is reacted with methylmagnesium iodide dienone 1% in moderate yield. and the resulting diketone cyclized to give cholestenone Aromatic A-ring steroids have been prepared by 186a in 50’S yield. reacting the Grignard reagent 199 with the enol lactone The yields for the enol lactone-Grignard method range 200 to give the bicyclic ketol201 which is then cyclized to from poor to good. It is a multistep process that can be the bicyclic enone 202.” When the optically active enol somewhat limited by other functionality in the molecule lactone 200 is employed, optically active steroids are which may be unstable to the Grignard reaction. obtained. (c) Enol ~~Cfo~e-p~o~~~orQne. Fried ez al., have An application of this sequence to triterpene synthesis recently introduced a modification of this sequence which has been described.M The addition of the Grignard reagent employs a phosphonium ylide 208 or phosphonate anion 203 to the enol lactone 244 followed by base-catalyzed 209 rather than a Grignard reagent.@ The carbanion adds cyclization yields the enone 206, which was then to the enol lactone 210 to yield a keto phosphorane or keto converted to oleandiene in very low yield. phosphonate anion 212 formed via the initial enolate 211 (b) Enol luctam-Grignard. An interesting variant on by proton transfer. Cyclization then occurs by a normai A review of annulation 17

intramolecular Wittig or Wadsworth-Emmons reaction to (2) Modified unnuiation give the enone 213. This expands the scope of this (a) Sulfur ylide. The first of the methods to convert a annulation process since phosphoranes or phosphonate ketone into a cyclohexenone of modified structure was anions can be prepared with functional groups in other developed by Trost and involves initial attack of a sulfur parts of the molecule whereas the corresponding Grignard ylide 226 on an ~,~epoxyketone 221 to give the diepoxide reagents either cannot be formed or self-condense once 222 in good yield.‘” A four-step sequence follows utilizing formed. The yields are generally good, e.g. 214-+216 and epoxide-ketone rearrangements at two key steps leading to a bis-annulation reagent of this type 217 has been used the acetoxy ketone 225, which upon treatment with base is successfully, e.g. 218-,220. In the case of enol lactone cleaved and cyclized to the enone 227 via the diketone 214 the intermediate keto phosphorane 215 can be isolated 226. Although the yield of each step is good, the fact that and then converted to testosterone 216 either thermally or it is a multi-step process forces the overall yield to be only by treatment with base. 38%.

il THP y4 + cii-Pmd, F 216 5oz -78’

&

TFX’RA Vd. 32. No. I-B 18 MCHAE~_ E. JUNG

(bf Ketal ~r~gn~rd. A simpler procedure for accomp- hydrindanone 242. Due to ail-addition of the borane lishing the same general transformation (i.e. l-+2’) has across the double bond and oxidation with retention to the been recently developed by Stork.” Refluxing a solution carbonyl, only products with the truns-ring juncture are of 2-benzoyloxycyclohexanone 228 and the bromo-ketal obtained in ah cases. However, the application of this Grignard reagent 229 in tetrahydrofuran affords directly method to the construction of angularly substituted the ketal ketone 238 in 50% yield. Hydrolysis and systems has not been reported. cyclization give the enone 48 in 45% overall yield. The mechanism of this conversion is apparently similar to (3) Conclusion that of the Serini reaction” and probably involves a In general the nucleophilic reagents give fair yields in a hydride shift as was shown for 3-methyl-2- multi-step process. They are useful, however, for adding benzoyloxycyclohexanone 231. the elements of a second ring all at once. In addition, they The initial Crignard adduct 232 undergoes a modified introduce the possibility of converting a ketone into a Serini reaction via the tetrahedral intermediate 233 to give cyclic ketone of a different structure than that possible by the opposite benzoyloxy magnesium salt 234. This Michael reaction or alkylation. compound then collapses with hydride transfer and loss of benzoate ion to the ketal ketone 235, which could be 3. ALKYLATION cyclized to the enone 51. None of the isomer resulting The third category of annulation reactions comprises all from alkyl migration from compound 232 was detected. those reagents which are attached to the carbonyl However, the sluggish reactivity of the Grignard reagent compound by means of alkylation. These reagents have 229 limits the applicability of this sequence to unhindered the greatest potential since they may be capable of carbonyl compounds. trapping regiospecitically generated enolate ions under (c) Orgunoborune. A general method for the transfor- aprotic, non-equilibrating conditions. They may be mation of a cyclic ketone to a bicychc ketone of totally subdivided into alkyl halides (and sulfonates) and allylic different structure (cf 1+2”) has been developed by (or benzylic) halides. A minor drawback of any reagent Brown.” Conversion of a simple cyclic ketone, e.g. intr~uced by alkylation rather than by a Michael reaction cyclohexanone 234. to the l+diene 237 is easily is that some of the selectivity in the site of attachment accomplished by addition of ally1 Grignard reagent may be lost. For example, the Michael addition of followed by acid-catalyzed dehydration. Treatment of the 2-methylcyclohexanone 5 to acrylonitrile affords only the diene with thexyl borane 238 affords the borane 239, 2,2-disubstituted product 243, whereas an 82: 18 mixture which can be carbonylated and oxidized to the bicyclic of the 2,2- and 2,bdisubstituted products, 244 and 245 ketone 248 in 66% yield from the diene 237. Substitution respectively, is produced in the alkylation of 5 with of the 1,3-diene 241 (prepared from cyclohexanone by methyl iodide. acetylide ion addition, partial hydrogenation, and dehyd- However, this problem can generally be overcome by ration) into this sequence allows for the preparation of the the use of highly reactive alkylating agents and the

+ 1) tI,o+ C 2) I(OH/)(sOH

90%

$3 & 3LQ s A review of annuiation t9

regiospecific enolate ions generated from either enol catalyzed cyclization of the diketone 254 smoothly acetates or enol silyl ethers.” For example, treatment of afforded the tetracyclic enone 255. This method suffers the enol acetate 246 or the enol silyl ether 247 with from two drawbacks. First, the alkylation step introduces methyllithium generates the specific lithium enolate 248 a temporary asymmetric center into the molecule, e.g. (and an equivalent of lithium t-butoxide or tetramethyl- 253, and a mixture of diastereomers will be produced, silane, respectively). This enolate can be trapped with adding complexity to the sequence. The asymmetry is benzyl bromide to give only the 2,2-disubstituted product eliminated in the following steps, so that this is more of a 249 with none of the 2,tGisomer 250 being formed. It nuisance than a real problem: The second disadvantage is should be stressed again, however, that this process that the means by which the carbonyl function is unmasked works well only when very reactive alkylating agents is multi-step and somewhat cumbersome. (methyl iodide, allylic halides, benzyhc halides, etc.) are (b) Huio ketaf. Perhaps the most desirable and the employed. simplest reagent would be the ethylene ketal of I-bromo- 3-butanone 256 first introduced by Stork.7J.‘BbThis compound has been used a few times but only with moderate success. The ease with which the ketal can be (a) Halo etfrer. Many alkyl halides have been tried in removed and its stability in highly basic media recom- annulation reactions, with only a moderate degree of mend its use. However, the yields of alkylation using 256 success. The first to be successfully employed was I- are only fair, e.g. 257-+258. Once alkylation is complete, bromo-3-benzyloxybutane 251,6’” which was used to hydrolysis and cyclization proceed quite well to furnish convert the tricyclic enone 252 with subsequent methyla- the enone 259. The homologue of 256, I-bromo-3- tion into the dialkylated ketone 253. The protected pentanone ethylene ketal 260, has also been employed carbonyl function was then unmasked to the diketone 254 with somewhat similar resutts.7” Under optimum condi- via several steps, namely, ketalization of the carbonyl, tions, the enone MI gave a 50% yield of the desired removal of the benzyl protecting group with sodium in alkylated product 262, with the O-alkylated product 263 liquid ammonia, oxidation, and deketalization. Base- accounting for 23% of the total product mixture. The 20 MICHAEL E. June major disadvantages of both reagents 256 and 260 are the alkylating saturated ketones and enones in moderate relatively low reactivity of the halides and their tendency yield.‘9 It, too, suffers from the problem of asymmetry to dehydrohalogenate (both presumably due to the strong previously discussed, in that upon alkylation a second electron withdrawing effect of the ketal oxygens) and the center of asymmetry is produced, leading to a mixture of high proportion of 0-alkylation in polar aprotic solvents. diastereomers. The reagent is useful primarily for The reactivity of two other similar alkylating agents has a,@msaturated ketones having no a-hydrogens (so that also been investigated. The ketal iodide 264, although the problems of dialkylation do not arise) such as 273, more difficult to prepare, is more reactive than the where the overall yield of enone 275 is only about 35%. bromide. Its use in the alkylation of the unsaturated Other analogous sulfonates, e.g. brosylate and nosylate, ketone 265 to afford enone 266 in fair yield has been gave somewhat poorer resuIts.8’ described by Fried ef al.” The thioketal brosylate 276 gives somewhat better The corresponding tosylate 267 could also be pre- results.N Alkylation of testosterone benzoate Mb fur- pared,” but initial results showed that it alkylated only nishes in good yield enone 277, which is then converted to acidic carbonyl compounds, e.g. 26&3+4&in high yield.n diketone 278 by mercuric ion catalyzed hydrolysis, again However, recently Valenta has shown that alkylation of in good yield. Compounds analogous to 276, e.g. the the tricyclic enone 270 with the tosylate 267 affords the bromide, tosylate, and mesylate, give similar results.8’ ketal 271 in good yield along with a small amount of (d) Unsaturated alkyl halides. Several other alkyl dialkylated material.” halides which might seem to be obvious choices proved to (c) Hemithiokeral and thioketal sulfonate. If the elec- be unsuitable. 2-MethyWhalo-I-butene 279 and QhaIo-l- tron withdrawing inductive effect of the ketal oxygens is butyne 280 are both deliydrohalogenated under basic the cause of the low reactivity of these reagents, then conditions.n The former could have been converted to a substitution of a less electronegative sulfur atom for one 3-keto-alkyl chain after alkylation by ozonolysis, the or more 0 atoms should render the resulting latter via mercuric ion catalyzed hydration. Caine has hemithioketal and thioketal more reactive. This is in fact developed a clever scheme which circumvents the the case. The hemithioketal tosylate 272 is capable of problem of direct use of reagent 2&18*Alkylation of 2,6- A review of annulation 21

Stork has shown,‘2.X3this reductive alkylation process A.---. accomplishes several difficult tasks: (1) formation of a trans-decalone system, from the starting octalone, e.g. 287; (2) specific production, if need be, of the ther- di-methylcyclohexanone._ 245 with I ,3dichloro-tbutene modynamically less stable enolate ion, e.g. 288 and 289; 281 proceeds in good yield (as will be discussed later) to and (3) monoalkylation of this enolate ion without afford the ketone 282. Base-catalyzed elimination to the accompanying dialkylation, giving only 299. In addition to internal acetylene 283 followed by base-catalyzed methyl iodide only allylic or benzylic halides have the isomerization to the terminal acetylene leads to the reactivity required for this type of alkylation to proceed in intermediate 2&l which would have been produced if high yields, and thus they have the greatest possibility of alkylation with the halide 280 had been successful. being successful, general annulation reagents. Mercuric ion catalyzed hydration leads to the diketone (a) Wichterle reagent. The most commonly used allylic 285 which is then cychzed as usual to the enone 2% in an halide is 1,3-dichloro-2-butene281, the Wichterle reag- overall yield of 29%. Internal acetylenes, such as u13, entU Alkylation of acidic ketones, e.g. @-keto ester 268, which might have been expected to afford IJ-diketones, with 281 proceeds in high yield? whereas alkylation of e.g. 285, directly upon hydration, have been shown to simple ketones, e.g. cyclohexanone 236. affords the yield only l+diketones under mercuric ion catalyzed alkylated product 292 in onty moderate yield.% The hydration conditions.” product from pketo ester alkylation, 291, can be hydrolyzed and decarboxylated to furnish a second route (2) Allylic halides to compound 292. Problems with this sequence arise at One important quality of any truly general annulation the stage of conversion of the intermediate vinyl chloride reagent is that it be capable of trapping the regiospecific- 292 to the diketone 293 and ultimately to the enone 48, ally produced enolate ion formed by reduction of an which requires concentrated sulfuric acid. The initial enone with lithium in liquid ammonia. As the work of work on this system by Prelog” indicated the octalone 48 22 MICHAEL E. JUNG as the product, whereas Julia later found that under any The major drawback of this sequence is that the similar conditions a mixture of the two enones 48 and 294 conditions necessary for hydrolysis of the vinyl chloride were formed, with the bicyclononene product 294 slightly are often too drastic for other functional groups in the predominating.“” This implies that in strong acid the enol molecule and often result in undesired cyclization of the cyclic ketone adds to the acyclic carbonyl function products. However, the method has been used quite leading. via bicyclic ketol 2%, to the enone 294. The successfully in certain cases, e.g. 137+ 129,” and espe- alternate procedure, attack of the enol of the acyclic cially in total steroid synthesis.” For example, the group ketone on the cyclic carbonyl function (analogous to the at Roussel-UCLAF has reported a high yield in the predominate mode of cyclization under basic catalysis), reaction of the Wichterle reagent 281 with the dienamine also occurs in the strongly acidic medium to yield the 302 in dimethylformamide cont~ning an equivalent of enone 48 via the ketol 295. The early workers had also potassium iodide.R9 The alkylating agent is the allylic seen evidence of this unusual type of cyclization, since iodide formed in situ. The intermediate vinyl chloride 303 the vinyl chloride 291 yielded only bicyclononene is hydrolyzed by a sulfuric acid-acetic acid mixture to products 297. Marshall later confirmed that under some produce the diketone 304 in excellent overall yield. conditions the unusual cyclization products predominate, Reduction of the enone followed by acid-catalyzed although by careful control of conditions one can force cyclization yields nor-progesterone 305. The use of vinyl the reaction to yield the octalone as the major product.” chloride intermediates for the construction of annulated For example, the methyl-substituted com~unds, 29&b, ketones of totally different structures will be described at afforded approx. 50% of the octalones 9 and 51 with only the end of this section. 10% bicyclic compounds 299a-b being formed. However, (b) Halo ether and thioether. Several possible reagents the dimethyl compound 29& afforded only the bicyc- are too unstable to be of any use. Two such halides are I- lononenone 299e under all conditions in high yield. The chloro-3-methoxy-2-butene 3% and I-chloro-3-phenoxy- Wichterle reagent 281 has been used to alkylate an 2-butene 397, both of which undergo extremely facile El enolate ion in liquid ammonia solution in fair yield, elimination of hydrochloric acid with subsequent 300-+298a.‘” It also has been shown to trap a regios- pecifically generated, less stable enolate ion in fair yield, 9-+301.“b

3% 2%

polymerization.” The enol ether 308 is more stable and proved to be a good reagent for a-substituted enones.“’ For example, the di-methyloctalone 273 was converted to the tricyclic dienone 275 via the intermediate enol ether 309 in good overall yield. However, when the use of enol A review of annu~tion 23 ether 308 was attempted in the reduction alkylation possible mechanism involves formation of the enol ether sequence, the reaction was unsuccessful, as the alkylating derivative of the @-diketone 317 followed by a Claisen agent was converted to the corresponding diene. The rearrangement to compound 316. Treatment of the alcohol somewhat more stable thio enol 310 was capable of 315 with thiourea in acetic acid leads essentially reductive alkylation, trapping the enolate ion in fair yield. quantitatively to the rearranged thiouronium salt 318, e.g. 9-+311.* The cleavage of the thio ether is sometimes which reacts with the @diketone 100 in aqueous solution unsatisfactory, however. The related halo enol deriva- to furnish the product 316 in excellent yield. Acid tives, 312-+314, all give very poor yields in the alkylation catalyzed cyclization completes the sequence affording in step.” high yield the tetracyclic compound 114, which can also (c) Aicohoi and thiouronium salt. Although alcohols be obtained directly in one step in 65% yield from the are not normally regarded as alkylating agents, certain reaction of the alcohol 315 with the @-diketone 100 in very reactive alcohols have found use in several refluxing acetic acid-xylene solution.9’ The isomeric annulation methods designed for steroid total synthesis. allylic alcohol 319 has also been used in the sequence The allylic benzylic alcohol 315 was condensed with 2- although the yields are much lower.” methylcyclopentane-l,3-dione 100 to afford the endione The following three annulation sequences-isoxazole, 316 in good yields.W,9’Although this reaction was first tiglate, and vinylsilane-are probably the most general yet reported to proceed in a basic medium,91 it was later developed. Each possesses to a greater or lesser extent shown that the reaction was acid-catalyzed with the dione most of the properties of an ideal annulation reagent, itself (pK, =4.5) acting as catalyst.” Two mechanisms namely: (1) high reactivity so that normal alkylation can be offered for the reaction, the first involving anionic occurs in high yield and enolate trapping in the reductive allylic displacement of the hydroxyl function in which the alkylation scheme is successful; (2) moderate stability and proton is delivered by the acidic diketone.% A second an efficient method of preparation; (3) the ability of 24 MICHAEL E. JUKG

modifying the preparative scheme so that homologues compound 322 in 70% yield) with triethyloxonium (including bis-annulation reagents) can be readily pro- fluoroborate followed by treatment of the salt 333 with duced and (4) an easily unmasked carbonyl function so dilute aqueous base, which gives the desired enone 335 in that the conditions necessary for generating the ketone yields of about 3.5%.% are neither too drastic nor too acidic (e.g. concentrated sulfuric acid which leads to undesired bicyclic products with the Wichterle reagent). (d) Isoxazole. Some of the most successful annulation reagents are the 4-halomethylisoxazole reagents 320 and 321 introduced by Stork.% They alkylate saturated and a&unsaturated ketones well, e.g. 12+ 322, and also can be used successfully in the enolate trapping required by the reductive alkylation process, affording the alkylated product, e.g. 257-+3X3, in low yield?’ The carbonyl Cl function is unmasked by the following procedure: HaoH _ hydrogenolysis of the isoxazole 324 over Raney nickel -/ 4O - PH &

The carbonyl can also be generated in somewhat higher yield by an improved sequence as is shown for the isoxazole XML9’Ketalization atfords the ketal337 which is hydrogenated to the stable enamide 338 which can no longer form a vinylogous carbinolamide such as 326. The enamide 338 is not isolated but is converted with aqueous base directly to the ketone 339 which is cyclized in acid to the enone 48 in an overall yield of 65%:’ a moderate improvement on the 50% yield obtained by the simple hydrogenation-base catalyzed cyciization sequence.%’ The improved yields can probably be attributed to the suppression of the formation of the carbinolamines, e.g. leads to the vinylogous carbinolamide 326, which is 326, which upon treatment with base, rapidly dehydrate to cleaved by hot me&oxide to the enimine 329; this in turn dihydropyridines. e.g. 327, compounds which are known is hydrolyzed by aqueous base to the 15diketone 330 to be susceptible to oxidation and/or disproportionation to which then cyclizes to the enone 331 in the basic medium. give undesired byproducts and lower yields. The overall yield for this process is about M-60%. With respect to carbonyl unmasking, the best isoxazole Two other methods of generating the carbonyl function reagent is 3~methyl4chloromethylisoxazole, 340.%“ For have been reported. The first involves reaction of the example, the alkylated octalone derivative 341 is con- isoxazole 332 (prepared by catalytic hydrogenation of verted to the tricyclic enone 335 in 70% yield by the A reviewof anRu~ation 25

La J hydrogenation to the crystalline intermediate 342 fol- yields of up to 90% by sequential alkylation and lowed by basic cyclization. The very serious drawback hydrolysis without isolation of any intermediates. The here is that monomethylisoxazoles such as 340 give very conversion of the a&unsaturated acid function in 349 to poor yields in the alkylation step for reasons not yet fully the ketone requires several steps and utilizes the understood, and this poor reaction in the first step causes Weinstock modification of the Curtius reaction. Addition the overall yields to be only fair.% of triethylamine to the acid 349 followed by ethyl Examination of the mechanism of the conversion of the chloroformate gives the mixed anhydride 350, which was isoxazole to the 3-ketoalkyl chain leads to the observation converted directly to the acyl azide 351 by addition of that it is the alkyl group next to nitrogen which is retained aqueous sodium azide. Heating of 351 in anhydrous in the final 3-ketoalkyl chain. This led to the use of the methanol affords the vinyl urethane 352, a readily isoxazole 343 as a bis-annulation reagent, as in the hydrolyzable enamine derivative. Hydrolysis to the synthesis of progesterone 346.Y’h Alkylation of the diketone 7 and cyclization to the octalone 9 occur upon octalone 12 with 343 gave in moderate yield the isoxazole refluxing the vinyl urethane 352 with potassium carbonate 344 which was converted by the usual method to the in methanol. Although this conversion is a multi-step crystalline tricyclic enone 345 in 60% yield. A multi-step process, the procedure is simple and the yields are sequence was then employed to produce progesterone 346 generally good (70-80%). from 345. Other alkylations can also be conducted?‘.% For (e) Tiglate. The tiglate sequence, developed by Stotter. example, the conversion of 2-methylcyclohexanone 5 to employs t-butyl riodotiglate 347 as the annulation the 2.6-dialkyl compound 353 can be accomplished in reagent.n.pa The general scheme is outlined for the several ways: via the enamine 50 (560/o), by direct annulation of 2-methylcyclohexanone. Alkylation of the alkylation (89%). and via the enol silyl ether 354a(90%) or enolate ion 248 derived from the enol acetate 246 by enol acetate 3541,(>95% crude). Hydrolysis of the ester treatment with methyllithium gives a 90-95% yield of the 353 gives in excellent yield the acid 355 which is then alkylated product 348. Refluxing the t-butyl ester jqs in converted to the octalone 51 by the modified Curtius benzene with p-toluenesulfonic acid gives the free acid sequence in good yield. 349 in 9@-95%yield. This acid can be obtained directly in The reagent 347 can be used in the reductive alkylation 26 MICHAEL E. JUNG

aa AL process although it is necessary to remove the ammonia general annulation sequence, the vinylsilane method.‘“.“’ and to replace it with tetrahydrofuran before adding the This procedure employs halomethyl vinylsilanes, and in alkylating agent.” For example the ketal enone 169 could particular E-3-trimethylsilyl-Zbutenyl iodide 358. as be converted in good yield to the ketone 356, which was reactive alkylating agents. The general reaction scheme is hydrolyzed in two steps to the diketo acid 357. The illustrated for the annulation of 2-methyl-cyclohexanone 5 tricyclic enone 335 was then produced from this via its enol acetate 246. Addition of the silylbutenyi iodide compound in 73% yield by the usual process described 358 to a solution of the lithium enofate of 2- earlier. The reagent is easy to prepare and homologues methylcyclohexanone 248 in tetrahydrofuran (formed have been made although attempts to prepare a bis- from the enol acetate 246 by addition of two equivalents annulation reagent have so far proved unsuccessful.* of methyl lithium) affords the alkylated product 359 in (f) VinyMane. We have recently developed a third 9 1% yield after purification by chromatography. Epoxida-

2) Clap 3) NeN3 4) n#~lA s> Kp3 HeO” A reviewof annuiation 27 tion and opening to the diketone 7 is effected in 89% 364 in dimethylformamide iontaining an equivalent of purified yield (94% based on recovered starting material) potassium iodide gave after hydrolysis the alkylated by treatment of the vinylsilane 359 with m- octalone 365 in 85% crude yield. The iodide 358 is most chloroperbenzoic acid in methylene chloride. Base- probably the alkylating agent. formed in situ. The catalyzed cyclization completes the sequence, producing reductive alkylation sequence with testosterone 216 was the octalone 9 in 90% yield, so that the overall yield of quite successful. Simple addition of the iodide 358 to the annu~ation is 73%. A possible mechanism of carbonyl ammonia soiution of the fithium enolate formed by enone formation involves ~rotonation of the jntermediate reduction furnished after work-us and ~hromato~a~hy epoxysilane 360 by the meta~hjorobenzoi~ acid formed in the crystalline viny&lane 366 in 58% yield. Epoxidation the initial epoxidation to give 361 and then anchimeric and final treatment with formic acid gave the dione 367 in assistance of the carbonyt group in opening the proto- 71% yield. nated epoxide function /? to the silyl group. Finally, the Addition of the iodide 358 to a solution of the enolate meta-chlorobenzoate ion in solution then eliminates the ion 369 formed from the addition of lithium dimethylcup- silyl group in compound 362 via an SN2-type of attack to rate to cyclohexenone 368 afforded the 2,3mdialkylproduct yield the enol 363 of the diketone 7. 370 in 75% yield after chromatography. Treatment of the Several other types of alkylations were performed with vinylsilane 370 with m-chloroperbenzoic acid effected iodide 3.58and the analogous chloride 364, The reaction of epoxidation and rearrangement to the dione 371 which has the pyrrolidine enamine of octalone 46 with the chloride been cyclized to the enone 372.“’ 28

The vinylsilane reagents are easy to prepare and are tanones and acetylcyclopentanes starting from ketones.“‘* quite stable, perhaps due to the inductive effect of the silyl Alkylation of cyclohexanone 236 with 2,3-dichloro-l- group on the double bond which should decrease the propene 377 alfords the chloro ketone 378 which is tendency toward E 1 1,4-dehydrohalogenation. Also a converted to the tertiary alcohol 379 on reaction with a bis-annulation vinylsilane reagent 373 has been prepared Grignard reagent. Acid-catalyzed cyclization then pro- and used in annulation sequences.“’ duces the cis-hydrindanone 380 in poor yield.“‘” Some- what higher yields are obtained from acyclic ketones, e.g. 1 381-, 382.‘O)bThe conversion of the cyclic enone 48 into Me,si

d

An important advantage of the vinylsilane reagents is the stability of the vinylsilane moiety to dissolving metal reductions. For example, addition of the vinylsilane octalone 365 to two equivalents of lithium in liquid ammonia affords the vinylsilane decalone 374 in quantita- tive yield. The similar system 375 (formed via the alkylation of the enone 169 with the bis-annulation reagent 373 in 52% yield) gives under the same conditions the analogous decalone 376 in quantitative yield. It should be pointed out that this type of reduction, which is quite often necessary for the synthesis of polycyclic com- pounds of the steroid or triterpenoid type, is not possible 65% II H H3

%L &3 3ki the cyclopentyl methyl ketones 387 and 388 proceeds in much higher yield. Alkylation of 48 with 2,5-dichloro-2- pentene 384 followed by reduction furnishes the ketone 385 which reacts with methyllithium to produce the tertiary alcohol 386 in good overall yield. Treatment of n 386 with formic acid affords in 90% yield a 65: 35 mixture of two sets of isomers with the trans-hydrindane ketones 387 being formed in preference to the cis-ketones 388. This is not a general result since the simple series derived from cyclohexanone yields the cis-hydrindane ketones 390 as the major isomers.“” Recently, this procedure has ?22 w been extended to allow for the synthesis of 7-membered ketones.““’ For example, cyclopentanone 392 was con- in the isoxazole or the tiglate sequences, since the masked verted in good yield to the hydrazulenone 3% via the carbonyl function in each contains easily reducible groups intermediates 393 and 394 as shown. (namely, isoxazole and a&unsaturated ester). However, (b) a,a’-Annulation. The synthesis of bicyclic keto catalytic hydrogenation of an Q-unsaturated ketone in esters can be easily effected via a,a’-annulation by the use the presence of the carbonyl protecting group can be of a-bromomethylacrylates, 397a-b, reagents which com- successfully accomplished only in the isoxazole sequ- bine the properties of both allylic halides and a,@ ence,(ub since the vinylsilane moiety is reduced catalyti- unsaturated esters. Reaction of the ethyl ester 397a with cally in competition with the enone functionality.“” the cyclic enamines 398 and 45 affords the bicyclic keto esters 399 and 400 in high yield.‘MY”The methyl ester 397b (3) Modified annulation gives the Spiro-annulated product 403 when reacted with (a) Chloro o&in cyclization. Lansbury et al. have the enamine of acetylcyclopentane 401.‘MhThe mechan- developed a scheme for the construction of cyclopen- ism involves initial alkylation, either by a direct SN2 A review of annulatioo 29

65 : 35

I mzEC -(CHZ)” Yield a02 87% 2 E reaction or via Michael addition-elimination (a formal halide reagents have been shown to be quite general SJ’ process), which is then followed by Michael addition affording very high yields of annulation from several and hydroiysis. The product from simple alky~ation, e.g. different carbonyl derivatives (ketones, enones, 484, can sometimes be isolated. The keto diester 405 enamines, enol esters, enol ethers, diketones, etc.). A furnishes the cyclohexanone 406 when reacted with one major advantage of the allylic halides is their ability to equivalent of acrylate 3978 and the bicyclic ketone 407 trap, in high yield, regiospecifically generated, ther- when two equivalents of 3Wa are used.‘oS4Reaction of modynamically less stable enolate ions formed by several the enamine 4(#1with 3Wa affords the adamantanedione different methods (e.g. enone reduction, enol ester or enol 409 directly in high yield.““” ether cleavage, alkyl copper addition to enones). A disadvantage is that the annulation methods based on (4) Conclusion alkylation have not yet been shown to be as generally Thus, alkylation annulation sequences have been used applicable to bis- or tris-annulation as have the Michael extensively with a high degree of success. The allytic reaction or nucleophilic addition sequences. However, it 30 WCHAEL E. JUNG

+

is possible to convert a ketone via an alkylation ‘W. S. Rapson and R. Robinson, J. Chem. Sot. 1285 (1935). annulation method into a cyclic ketone of a structure ‘“I. N. Nazarov and S. I. Zav’yalov, fzoesf. Akad. Nauk SSSR, unobtainable via the other two annulation sequences. Otd. Xhim. Nauk 300 (1952); bN. L. Wendler and H. L. Slates, U.S. pat. 2S42.223; [Chem. Abstr. 45, 7599 (19Sl)l; ‘Org. 4. CONCLUSION Syntheses, Coil. 5, 486 (1973). ‘%. Stork, Bulf. SOC.Chim. Fr. 256 (1955). Thus, one can see that there exists today a broad range “K. Baiasubramanian, J. P. John and S. Swaminathan, Synthesis of possible annulation methods which permit the con- 51 (1974). struction of a large number of different cyclic enones and ‘*“J. W. Patterson, Jr. and W. Reusch, Ibid. lSS (1971); bA. M. ketones from a wide variety of starting structures. The Chalmers and A. 1. Baker, Ibid. 539 (1974). Michael reaction annulation sequence is employed suc- ““E. C. du Feu, F. J. McQuillin and R. Robinson, 1. Chem. Sot. cessfully manly for acidic carbonyl compounds f/3- 53 (t937); *A review of the use of ~aunich base me~hi~ides diketones, &keto esters, etc.) and for the addition of more has been published: J. H. Brewster and E. L. Eliel, Organic than one ring at a time (his- and his-annulation~. Reactions, Vol. VII, pp. 99-197. Annulation via nucleophilic addition is somewhat less “1. W. Cornforth and R. Robinson, .I. Chem. Sot. 1855 (1949). ““D. A. H. Taylor, Chem. Ind. 250 (1954); ‘t. Velluz, G. NominC useful in general, ~though in some cases it can proceed in and 3, Mathieu, Angew. Chem. 72, 725 (1960); ‘L. Velluz, J. fairly high yield. The annulation sequences involving Valls and G. Nomine, Angew. Gem. intf. Ed. 4, l8l (196s). alkylation, especially with allylic halides (e.g., isoxazole, laF. J. McQuillin and R. Robinson, J. Chem. Sac. 1097 (1938). tiglate, vinylsilane), are probably the most generally “J. A. Marshall and W. 1. Fanta, 1. Org. Chem. 29,250l (1964). useful ones. They are particularly good for use in the IRaM. Yanagitaand K. Yamakaw, [bid. 22,291(195?); *P. Rosen, trapping of regiospe~i~cally generated, thermodynami- Ph.D. Thesis, Columbia University, New York, New York cally less stable enolate ions under aprotic conditions. (l%2). However, in general, these reagents have not yet been “1. A. Marshall and T. H. Warne, Jr., 1. Org. &em. 36.178 (1971). successfully utilized for bis- and tris-annulation. “C. J. V. Scanio and R. M. Starrett. 1. Am. C/rem. Sot. 93. 1539 (1971). “P. S. Adamson, F. J. McQuillin, R. Robinson and J. L. Simonsen, L Chem. Sot. 1576 ( 1937). “A. L. Wilds and C. H. Shunk, I, Am, Chem. Sot. 65,469 (1943). ‘Recently a very short review of annulation methods has been *‘“D. A. H. Taylor, J. Chem. Sot. 3319 (I%& ‘A. R. Pinder and published: B. P. Mundy, +r Chem. Edn. 50, 110 (1973). R. A. Williams, Ibid. 2773(19633; “T. G. Halsall. D. W. Theobald ‘For the exhaustive review of the Diels-Alder reactions, see and K. B. Walshaw, Ibid. 1029 (1964); dD. W. Theobald, Houben-Weyi, Mef~oden der U~unisc~e~ Chemie. 997-l 139. Tefrahed~n 22, 2869 (1966). Kohlenwasserstoff-Verbindungen III. 14G. Stork. A. Brizzolara. H. Landesman, J. Szmuszkovicz and R. ‘“Acid-catalyzed polyolefinic cyclizations: see W. S. Johnson, Terrell, 1. Am. Gem. Sot. 8.5, 207 (1963). Accounfs Chem. Res. I, 1 (1948);‘Qlefinic-acid cyclizations: *T. H. Heathcock, J. E. Ellis, J, E. McMurry and A. Coppolino, see M. F. Ansell and M. H. Palmer, Quart. Rer;. 18,211 (1964); Tetr~hed~n Letters 4995 (1971). ‘Oleiin-cyclopropane cvclizations: G. Stork, M. Gregson and P. *6C. D. DeBoer, J. Org. Chem. 39. 2426 (1974). Grieco, ~erra~e~~onLetfers, 1391, 1393 (1969). _ “R. B. Woodward andi’. Singh, 1. Am. Chem. Sot. 72,494 (1950). ‘“G. S. Hammond and N. J. Turro. Science 142.154111963):bG. zx’R. E. Ireland. D. R. Marshall and J. W. Tillev, Ibid. 92,4754 L. Chapman, A&an. ~~oroc~em. 1,359 (1963); ’ W.‘L. Dilling, (1970); bD. Caine and F. N. Tuller. J. Org. &em. 38, 3663 Chem. Ren. 66, 373 (1966);69, 845 (1%9); ‘P. E. Eaton, (1973). Accounts Chem. Res. 1, 50 (1968); “P. de Mayo, Ibid. 4, 41 “S. Danishefsky and G. A. Koppel, Chem. Cammaa, 367 (1971). (1971). “L. 1. Chinn and H. L. Dryden. I. 0~. Chem. 26.3904 (1961). ‘M. Julia, Rec. Chem. Prog, 25, 3 (1964). “G. Stork and 8. Ganem. J. Am. Chem. Sot. 95, 6152 (1973). “Ene Reaction: ‘H. M. R. Hoffmann, Angew. Chem. l&f. Ed. 8, ‘fG. Stork, P. Rosen and N. L. Goldman. f&d. 83.2965 U%l). 556 (1%9); ‘P. Be& and J. M. Conia, Bull. S’oc.C&m. Fr. 959 ‘“H. 0. House, M. Gall and H. D. Glmstead. J. Org. Chem. 36, (1970): “W. Oppolzer, E. Pfenninger and K. Keller, Heh. Chin. 2361 (1971); ‘For enol acetates see: H. 0. House and T. M. A&I 56.1807 (3973); dJ. ht. Coma and P. La Percbec, Synr~es~~ Bare, ibid. 33,943 f 1968):and refs therein; ‘For enol silyl ethers I (l975). Oxy-Cope Rearrangement:‘J. A. Berson and M. Jones, see: G. Stork and P. Hudrlik. 1. Am. Chem. Sot. 90,4462,4464 Jr., 1. Am. Chem. Sot. 86.5017, SO19(1964); ‘J. A. Berson and (1968); H. 0. House, L. J. Czuba, M. Gall and H. D. Olmstead,J. E. J. Walsh, Jr., l&id. 90,4729,4730,4732 (1968); *D. A. Evans. Org. Chem. 34.2324 (1969). W. L. Scott and L. K. Truesdale. Te~rabedraa Letters $37 ‘*J. Schreiber, Dissertation No 2292, EidgenijssischeTechnische (1972l. Hochschule. Zurich, Switzerland (1953). ‘AR extensive review of the Michael reaction has been “*R. K. Boeckman, Jr., .I. Am. Chem Sot. 95.6867 (1973); bR. K. published. E. D. Bergmann, D. Ginsburg and R. Pappo, Organic Boeckman, Jr., Ibid. 96. 6179 (1974). Reactions, Vol. X, pp. 179-555. ‘bG. Stork and J. Singh, Ibid. 96, 6181 (1974). A review of annulation 31

“A. V. Logan, E. N. Marvel], R. LaPore and D. C. Bush, Ibid. 76, @E. 1. Corey, H.-J. Hess and S. Proskow, J. Am. Cbem. Sot. 85, 4127 (1954). 3979 (1%3). ‘*Z. Cf. Hajos and D. R. Parrish, J. Org. C/tern. 38. 3239, 3244 “C. A. Henrick, E. Bohme, J. A. Edwards and J. H, Fried, ibid. (1973). 90, 5926 (f%8). 39G. Stork and J. D’Angefo, J. Am. Chem. Sot. 96.7114 (1974). ‘“8. M. Trost and M, J. Bogdanowicz, Ibid. 944777 (1972). “2. G. Haios and D. R. Parrish. J. Onr. Chem. 39. 1612, 1615 “6. Stork, A. A. Ponaras and G. A. Garcia, private communica- (1974). - tion. “‘G. Stork and M. Tomasz, f. Am. Chem. Sot. 86.471 (1964). “‘A. Serini. W. Logemann and W. Hifdebrand, Chem. Ber. 72. “T. P. C. Mufhoffand, R. I. W. Honeywood, H. D. Preston and D, 391 f 1939): ‘For a discussion of the mechanism. see L. F. Fieser T. Rosevear, J. Chem. Sot. 4939 (I%!). and M. Fieser, Steroids, p. 628ff. Reinhold, New York (1959) ‘“G. Stork and J. Hill, private communication, “E. Negishi and H. C. Brown, Synthesis 77 (1974). “A. A. Akhrem and Y. A. Titov, Total Steroid Synthesir. Plenum “H. 0. House and V. Kramer. J. Ore. Chem. 28. 3362 (19631. Press, New York (1970). “G. Stork and R. Borch, J. Am Chem. Sue. 86, 935 (f%4). “‘“C. H. Douglas. J. M. H. Graves, D. Hartley, G. A. Hughes, 8. “‘2. G. Hajos. R. A. Yicheli, D. R. Parrish and E. P. Oliveto. J J. McLoughfin, J. Siddall and H. Smith. J. Chem. Sot. 5072 Org. Chem. 32, 3008 (1%7). (1963): bC. A. Hughes and H. Smith, Chem. d Ind. 1022 (1960). “Ml. J. Green, N. A. Abraham, E. B. Fleischer, J. Case and J. “S. I. Zav’yalov, G. V. Kondrat’eva and L. F. Kudryavtseva, Fried, Chem. Commun. 234 (1970). Izvest. Akad. Nauk SSSR. Otd. Khim. Nauk 529 (I%]). 7HG. Stork, E.rcerpta Medica. Iniernationui Congress Series No. “J. J. Panouse and C. Sannie, Bull. Sot. Chim. Fr. 1429 (1956). 219, IO1 (1970). *“T. D. Windhofz. J. H. Fried. H. Schwam and A. A. Patchett. J. “‘S. Stoumas, Ph.D. Thesis, Columbia University, New York, Am. Chem. Sot. 85, f707 (1963); “N. N. Gaidamovich and I. V New York (1970). Torgov. Steroids 4, 729 (1964). -2. Valenta and R. A. Dickinson, private communication. “*A. Eschenmoser. J. Schreiber and S. A. Julia, He/c. Cbim. Acta “T. C. McKenzie, Ph.D. Thesis, Columbia University, New 36, 482 (1953). York, New York (1973). ‘“S. Danishefsky, W. E. Hatch. M. Sax, E. Abofa and J. Pfetcher, X2D. Caine and F. N. Tulfer, J. Oa. Cbem. 34, 222 (1969). J. Am. Chem. Sac. 95, 2410 (1973). R’“G. Stork and S. D. Darling, J. Am. Chem. Sot. 82, 1512 (l%O); ““S. Danishefsky. L. S. Crawley, D. M. Solomon and P. Heggs, Ibid. 86, 1761 (1964): bG. Stork and J. Tsuii. Ibid. 83. 2783 Ibid. 93.2356(1971); ‘S. Danishefsky and B. H. Migdalof, ibid. (I%!): ‘G. Stork, P.‘Rosen, N. L. Goldman, R. V. Coombs and 91, 2806 (1969). J. Tsuji, Ibid. 87, 275 (f%5). ““N. Cohen, B. Banner. R. Borer, R. Mueller. R. Yang, M. “0. Wichterle, 1. Prochaska and J. Hoffman, CON. Czech. Chem. Rosenberger and Cf. Saucy, 1. 0~. Chem. 37, 3385 (1972); and Commun. 13, 300 (1948); and refs therein. refs therein: ‘N. Cohen. B. Banner. J. F. Bfount. M. Tasi and G. ‘IV Prelog, P. Barman and M. Zimmermann, Hefu. Chim. Acta Saucy, Ibid. 38, 3229 (1973). 32, 1284 (1949). “‘L. B. Barkefy. W. S. Knowles. H. RafTelson and Q. E. ?S. Julia, Bull. Sot. Chim. Fr. 21,780 (1954). Thompson, 1. Am. Chem. Sot. 78, 41 If (1956); “U.S. Patent “‘J. A. Yarshalfand D. J. Schaeffer. J. Org. C/rem. 30,3642 (1965). 2,786.836; [Chem. Absfr. 51, I2163 (1957)l. MFor examofes, see Ref. ISc and also Ref. 44, Schemes 72-74. “‘See ref. $J ; * 1.N. Nazarov and S. I. Zav’yafov, Zh. Obshch. mR. BUCO&, J. Tessier andC. Nomine, Bull. Sot. Chim. Fr. 1923 Khim. 25, 508 (1955): ‘N. K. Chaudhuri and P. C. Mukharii. t 1963). J. Indian Chem. So;. 33, 81 (1956). Yi. N. Ananchenko and 1. V. Toraov, Tetrahedron Letters 1553 ‘“G. Saucy, W. Koch, ?.4. Mifller and A. Fiirst, He/v. Chim. Acta (1%3). 53.964 (1970). “C. H. Kuo, D. Taub and N. L. Wendier, J. 0~. Chem. 33.3126 s6R. E. frefand and C. Heng~tner, 1. Am. Chem. Sot. 94, 3652 (1968); Chem. & lad. 1340(1966); Annew. Chem.77,1142(3%5). (1972). =D. P. Strike, T. Y. Jen. G.‘H. Doug]& and H. Smith, Steroid; 8, ““S. Danishefsky and R. Cavanaugh, fbid. 90, 520 (1968); “S. 309 (1966). Danishefsky and A. Nagef, Chem. C~~rnrnaa. 373 (1972): “S. “A. V. Zakharychev, S. N. Ananchenko and I. V. Torgov, Iroes?. Danishefsky, A. Nagel and D. Peterson, Ibid. 374 (1972); “S. Akod. Nartk SSSR, Ser. Khim. 2056 (1%3). Danishefsky, P. Cain and A. Nagef, J. Am. Chem. Sot. 97.380 “*G. Stork, S. Danishefsky and Y. Ohashi, J. Am. C&m. Sot. t 1975). 89, 5459 (1967): “G. Stork and J. E. YcMurrv. . &id. 89. 5463. ‘*“R. B. Turner. Ibid. 72.579 (1950); “G. Fujimoto, ibid. 73, I856 5464 (1%7). (1951). “J. W. Scott, B. L. Banner and G. Saucy, I. Org. Chem. 37,1664 ‘9A review of the enol IactoneGrignard annufation sequence (1972). has been recently published: J. Weiff-Raynaf, Synthesis 1, 49 “G. Stork, Pure A&. C’hem. 9, I31 (1964). (f%9). 97P. L. Stotter and K. A. Hill, J. Am. Chem. Sot. 96.6524 ( 1974). -A recent review of the methods of enol factone formation has “K. A. Hill, Ph.D. Thesis, University of Texas, Austin, Texas appeared: N. P. Shusherina and R. Y. Levina, Russ. Chem. (1972). Revs, 37, I98 (I%@. “K. A. Hill, private communication. “‘“H. J. Schneider, T. W. Riener and H. A. Bruson, 1. Am. Cbem. rmaG. Stork and hi. E. Jung, J. Am. Chem. Sac. 94,3682 (1974); Sot. 72, 1486 (1950); “D. S~uffacher and H. Schinz, Helv. “G. Stork, M. E. Jung, E. Cofvin and Y. Noel, &id. 94, 3684 Chim. Acta 37, 1223 (1954). (19741. n2sR. L. Frankand R. C. Pierfe, J. Am. Chem. Sot. 73,724(195f); ““M. E. Jung, Ph.D. Thesis, Columbia University, New York, “R. B. Woodward, F. Sondheimer. D. Taub, K. Heusfer and W. New York (1973). M. McLamore, Ibid. 74,4223 (1952); ‘ G. Stork, S. D. Darling, I. “‘*P. T. Lansbu~, Accts. Chem. Res. 5, 311 (1972): and refs T. Harrison and P. S. Wharton, Ibid. 84, 2018 (1962). therein. 63aG. Stork, H. J. E. Loewenthal and P. C. Mukh~ii, Bid. 78,501 ““‘P. T. f_.anSbUry and E. J. Nienhouse, J. Am. Cbem. Sot. 88, tf956): “J. A. Hartman, A. J. Tomasewski and A. S. Dreiding, 4290 (1966); “P. T. Lansbury, E. J. Nienhouse, D. J. Scharf and Ibid. 78, 5662 (1956); ‘S. Kushinsky. J. Biol. Chem. 230, 31 F. R. Hilfiker, i&d. 92, 5649 (1970); ‘P. T. Lansbury, P. C. (1958); ‘M. Uskokovic and M. Gut,J. 0%. Chem. 22,996(1957). Brimts, T. R. Demmin and G. E. Dubois. ibid. 93. 1311 (1971t: b*D. M. Piatak, H. B. Bhat and E. Caspi. Ibid. 34. If2 (1%9). dP.-‘T. Lansbury, P. M. Workufich and P. E. Gallagher: “‘G. Stork, S. Uyeo, T. Wakamatsu. P. Grieco and J. fabovitz. J: Tetrahedron Letters 65 (1973). Am. Chem. Sot. 93, 4945 (1971). jMU”R. P. Nelson, J. M. McEwen and R. G. Lawton, J. Org. Chem. ML. Veffuz, G. Nomine, G. Amiard, V. Torefli and J. Cerede, 34, 1225 (1%9); 35, 690 (1970); ‘D. J. Dunham and R. G. C.R. Acod Sci.. Pan’s 257, 3086 (1963). Lawton. J. Am. Chem. Sot. 93, 2074 (Igl). “R. Bucourt, M. Vignau and J. Weill-Raynaf, Ibid. 265, 834 ““,H. Stetter and K. Elfert, Synthesis 36 (1974); “H. Stetter and (I%?). H. G. Thomas, Chem. Ber. 101, IIIS (1968).