Methods of Reactivity Umpolung

Volume 18 - Number 4 April 1979 Pages 239 - 336 International Edition in English

By Dieter SeebachL"]

Dedicated to Professor Horst Pommer on the occasion of his 60th birthday

The past decade of organic chemistry may be characterized as a period of violent development of new synthetic methods. This was accompanied by a systematization of the analysis of synthetic problems (synthetic strategy). The planning of the synthesis of an organic target molecule is greatly facilitated by distinguishing between reagents X(C),, . . . with normal reactivity (acceptor properties at C'*3,5-, donor properties at X, C2,4-.)and with reactivity umpolung (acceptor properties at X, C2,"...,donorproperties at C',3,5-.).In this context, reactivity umpolung turned out to be useful as a heuristic principle, as a classification scheme, and as an aid for locating so-called strategic bonds (synthon, transform, and antithesis according to E. J. Corey). There are six principal methods of umpolung: 1,2n-oxidation, heteroatom exchange and modification, homologation and its reversal, the cyclopropane "trick", use of acetylenes, and redox reactions; under certain circumstances none of these techniques is necessary in cases where direct umpolung is possible. Throughout the article, normal reactivity is indicated by green print; reactivity umpolung by red print.

1. Postulates and Nomenclature 3. These heteroatoms impose an alternating acceptor and donor reactivity pattern (I upon the carbon skeleton, i.e. Before describing and systematizing the methods of reactiv- acceptor properties or attack by donors at carbons C'.3.5-, ity umpolung, the scope of the discussion, the nomenclature and donor properties or attack by acceptors at carbons of synthetic methodology and the synthetic problem behind C2.4.6.-;the heteroatom Xo itself is a donor center tl"['al. reactivity umpolung must be defined. 1. The reactions most frequently used in organic synthesis are polar in nature, i. e. nucleophilic or donor (d) and electrophilic or acceptor (a) sites are used to make and break bonds (I). x = 0, N A XO (1 I (Lewis acid base combinations)['". lbl. 0 W+&e\6 A A A (la) 2. The large majority of target molecules of organic syn- In order to clearly distinguish donor and acceptor reactivity from partial thesis contain the heteroatoms nitrogen and oxygen as func- charge separation (8or ti@ and 0 or se) we use the letters d and a tional groups (amino, imino, hydroxy, ether, carbonyl)['"! throughout this article [see /I 1 [I c]]. The signs A for d and o for a [see ii may also he employed and avoid additional letters to be written in more complex formulas. Green print indicates normal reactivity, red print [*I Prof. Dr. D. Seebach reactivity umpolung (see definition 1.8). Laboratorium fur Organische Cbemie der Eidgenossischen Technischen Hochschule, ETH-Zentrum 4. A consequence and synthetic limitation is the fact that Universitatstrasse 16, CH-8092 Zurich (Switzerland) combination of components with reactivity (1 J leads only

Ailyew. Clwm. Int. Ed. Engl. 18, 239-258 (1979)

0 Verlag Chemie, GmbH, 6940 Weinheim, 1979 0570-0833.179'0404-0239 1.5- ... to 1.3-, I.f I t-disubstitutedroducts (odd number R4,N,R3 R4,"R3 0 0 01 cxbon aioms between the functional groups) [see (2) and (3)]""1. x,u- x' XLJ'

..'/,id or :L'/&I' a'/synthons are 8. A reagent has normal reacti\ii) if it corresponds to a "structural units within a molecule which are related to pos- synthon of general type ( / J. sible synthetic operations"r3a].Thus, the molecule (4) is related Rcacti\itj umpolung is present in a reagent in which a- and d-centers are reversed as compared to f I ) [see general representation ~1~~~;cf. (7b), (8b), (9a)l. Thus, x~'''- or (4) (5) (61

with the substrate synthon (5) and the formyl synthon (6). This is irrespective of the type of reaction employed (polar, I0 , x = 0,N radical" 'I, pericyclic, transition-metal mediated, pho tochemi- cal, electrochemical). d "I-synthons correspond to reagents of normal reactivity, cjlli k 1 - 6. An an- or d"-synthon (nrl) is, respectively, a synthon or a'"-synthons to those with reactivity umpolung with an 0- or N-heteroatom at C' and an acceptor or donor (see Table 1). center at Cn[3b341.Six such synthons are shown in (7)-(9). Unipolung is also present if the alternuiioii of rcacti\ ii! An a"- or d"-synthon is an acceptor or donor heteroatom is violated [see also query 4 in Section 2, and Section 3.5). (0 or N), respectively. Finally umpolung is any process by which donor and acccp- 7. A reagent is the compound or intermediate actually used tor reacti\ity of an atom are interchanged (see Sections 3.2 to carry out the synthetic operation. Synthetically equivalent and 3.6). reagents or series of reactions perform identical transforma- 9. When discussing particular transformations, the names tions (see Table 1 and definition 1.9)[3c]. of the structural units under consideration are used with the

Table 1. Preparations of an aldehyde R-CH2-CH2-CHO (target molecule).

Transformations and Reagents Ref. synthons leading to target - CH20 [a1 synthetically HC(OCH3)3 [b] equiualent reagents PI R-CHZ-CHI d + .I CHO R-CH2-CHl-MgX + HCO[N(CH,),] (four of many possible (the 1 formyl ,I ' -reagents) formyl .I' -synthon) r4g. 91

R-CHI-CH2 r + rCHO

synrhrticuiij equivalent reugeiits d' R-CH2-CHZ a R-CH2-CH2-OTos + NaCN [d] (formy1 -reagents) R-CH2-CHO + CHjOCH=P(CeHs)3 [b] I rORIb1 R-CH2 a + 11 CH2-CHO R-CHIX + L1 synrhetirull~~ I' '1 (

R-CH2 d n + Br-CH2-CH(OC2Hs)2 [e, b] (acetaldehyde reagent) fi (fbl Ra RBr + 20 s (propionaldehyde ~31

Rd R2CuLi + [dl (propionaldehyde AcOOC2H, ,I '-reagent) - [a] Oxidation of the product. [b] Hydrolysis of the product. [c] Radical chain initiator. [d] Reduction of the product. [el Raney-Ni desulfurization. [fl S- methylation of the primary alkylation product.

240 Aiipw. Ckem. Iiit. Ed. Engl. IH, 239-258 (1979) corresponding reactivity symbols; newly formed bonds are 10. A reaction or reagent which differentiates between sites indicated in bold type [see eqs (a)[61and (b)[’J and Table of identical reactivity in a conjugate system of type i I I or 113~.51. ( I 1 is called ambidoselective (see selectivity nomenclature and examples in Table 2). I I

2. The Synthetic Problem

Four Views of Synthetic Situations Requiring Reactivity Umpo- ethox\~alhvl acetone lung I -synthon ’ -synthon 1. As stated in Section 1, the normal reactivity I i does not enable us to construct I .I/!-disubstituted products (C\CII i1iiiiiIw ofcarhoii atom\ between the functional groups). How are compounds of type (11) and (12) synthesized? osif X X R-C H(OC zH,) 2 +A ethoxyalkyl reagent acetone u’-reagent (. ~reactivity) (~i’-reactivity)

0 HO

2. We can rephrase this question in the following way: propionaldehyde lsopropanol how do wecc)tiple ti\<) ccnltI\ 01 IJCII~ILAIpol,i~it\ OI ~\IlIi1i1\ ’ ’ I ’- reagent r? - reagent [see eqs (c) and (d), X/X = 0, N].

Table 2. Structural definition of selectivities.-Three principal selectivities are distinguished [a]: 1. type selectivity (nort-Isomericproducts, mostly different types of reactions, i.e. substitution, addition, elimination, ... A/B); 2. con- stirurional selectivity (same kind of reaction, products are constitutional isomers; CiD, E/F, IiK); 3. stereo- selectivity (products are stereoisomers; diastereoselectivity L/M or enantioselectivity G/H [b, c]).-Constitutional selectivity is subdivided into site selectivity (differentiates unrelated functional groups in a molecule which can undergo the same type of reaction, IiK), regio-selectivity [d] CiD and ambido-selectivity E/F (see definition 1.10 [el).

...... ’

Base i C H,X

......

[a] The term diumoselectivity [B. M. Trort, Th. N. Salmunn, K. Hiroi, J. Am. Chem. SOC.98, 4887 (1976)] is not structurally dehed, stereospecificity is an often criticized term [H. E. Zimmerrnann, L. Singer, B. S. Thyagarajan, ihid 81, 108 (1959); E. Ruch, I. Ugi, Theoret. Chim. Acta 4, 287 (1966)l; “specificity” should be dropped altogether. [b] See Y. Izumi, A. Tair Stereodifferentiating Reactions, Academic Press, New York, 1977. [c] Of course, (G) and (HI are only enantioselective routes if the hydrogens of the a-keto CH,-group are enantiotopic in the starting molecule of the present example; in LiM they must be didstereotopic. [d] See A. Nassner, J. Org. Chem. 33, 2684 (1968). [el This was part of the original definition of regioselectivity (see [d]), However, the term was rarely used to distinguish between 1,2- us. 1,4-addition to an enone or 0- us. C-alkylation of an enolate [reviews: J. (I‘Angelo, Tetrahedron 32,2979 (1976); R. Gompper, N.-U. Wugner, Angew. Chem. 88, 389 (1976); Angew. Chem. Int. Ed. Engl. 15, 321 (1976); L. M. Jackman, B. C. Lange, Tetrahedron 33, 2737 (1977)l. As evident from the louer part of Table 2, the a/d-nomenclature is very convenient in this connection.

Aii~qew.Cherrr. lilt. Ed. Engl. 18. 239-258 (1979) 241 COX ROOC I (y2" ROOC 0 cox

R' R' R R'R H pinacols ,

R' R R;

Examples of molecules from the "black magic box".

RA.4. + :x' and (22) (from fumarate and ~yanide['~*~~]),furan and its derivatives, amino acids (23), highly functionalized molecules 3. How can we sqstcmatically achievc a reactivity urnpolling such as tartaric acid (24) and carbohydrates (25j12''. These or construct reagents which correspond to synthons such may or may not arise along the lines described below. We as (13)-(15)? [cf. postulates 1.6 and 1.8, (10) and Table might call these sources the "black magic box" of the synthetic 11. organic chemist which should never be forgotten when plan- YR" ning the synthesis of a (chiral) molecule with complex func- '*I. R-O., R2Nd R';C d R J5 tionaIity[2'' R (13) (14) (15) 3.1. 1.2n-Oxidation (electrophilic (~Y~~oxY-or (amiiiopropyl- d3, oxygen or alkoxyalkyl- d') "homoenamine't) nitrogen, 39 A process creating a 1 .?u-oxygen and/or -nitrogen functionalized carbon skeleton without formation of a C-C bond is 4. A fourth way of putting the question is: How do we an oxidation (conservative conversion, non-connective). Some generate equal rcitctivity in 1 ,(%I)- or opposite reactivity in common transformations of this sort are listed in Table 3. 1 .(7n + 1 )-positions of a carbon framework? [see (16)-(28)]. As can be seen, many classical reactions and their recent improvements are among the examples: epoxidation (No. 1, 2), hydroxylation (No. 3, 4, 6, 7), oxygenation (No. 5, 8, 10, 11, 16), amination (No. 4), oximation and imination (No. 9), ozonolysis (No. 18), hydroboration /oxidation (No. 12), the Neber (No. 13), Bayer-Villiger (No. 17), and Criegee-Hock rearrangements (No. 19), the Hofmann-Lomer-Freytag (No. 14), and the Barton reaction (No. 15). We are dealing with cases in which the heteroatoms oxygen and nitrogen have become acceptor (sextet or septet) sites (10) rather than acting as donors I I [umpolung of heteroatom reactivity;

242 Angew. Chem. Inr. Ed. Engl. 18,239-258 (1979) Table 3. Some reactions creating I .?ri-doubly functionaliaed carbon skeletons without C-C-formation [23]. No. Starting Reagent [ref.] Product material

R-COaH t-Bu-OOHiMo 4 V-derivative 1241 Os04/R3N0 [25] OsO,/chloramine-T [26] TR)OH(NHR)

6 02[2Sl I MoOPH [29]

9 ArNy, NO’ [31,32]

10 11 12

13 NHzOH/TosCl/base 121 0 RY2

RONO/hv [2, 371

base/02 1381

18 o3or OSO~/IO?; Pb(OAc), [40]

19 TosCl 12, 411

6 (5OR

3.2. Exchange and Modification of the Heteroatom Furthermore, nitrogen, unlike oxygen, has so many oxidation states and occurs in a multitute of bonding situations Fortunately, organic chemistry is not restricted to the that it can be “modified” to allow for jumping back and elements C, H, N, O! We can utilize all the elements of forth between the two reactivity patterns ( 1 i and [ 10 J the periodic chart to achieve the goal of synthesizing C, H, N, 0-containing products (see postulate 1.2) and to break out of the reactivity pattern ( I j (see 1.3). The most common 3.2.1. Heteroatom Exchange and best established systematic way of reactivity umpolung of As stated above, there is a lack of methods which cleanly N- or 0-functionalized molecules is the temporary exchange introduce nitrogen and oxygen at donor sites. The use of of these heteroatoms by others which convey opposite re- BrQ as an electrophilic substitute heteroatom is a classical activity to the carbon moiety. Thus, we use derivatives of solution to this problem [see eq. (e)]. When the desired C-N other heteroatoms like a boat to cross a river. bond is formed, the nitrogen acts as a nucleophile, the a-car-

Angrw. Chem. lnt. Ed. Engl. 18, 239-258 (1979) 243 3.2.2. Heteroatom Modification In sharp contrast to oxygen, which can hardly be modified

to allow ~1'-and ii'-reactivity as in I //J I[~~-~~](see Section 4.1) without the help of heteroatom exchange, nitrogen is a very rich heteroatom in this respect. There are two fundamen- tal reasons for this: nitrogen can 1) make one more bond with carbon and thus be incorporated "in the middle" of bony1 carbon as an electrophile; therefore the corresponding conjugated systems, and 2) it has many more oxidation states; synthons are d" and :I' (see also the I 4-oxidation, entry it can stabilize M-C@in the lower ones and x-CO in the 1 in Table 4). The use of a-chloronitrones (Table 4, entry higher ones. Thus, modification of the nitrogen of methylamine 2) and of sr-hetev .ubstituted oxime~'~~]and hydra zone^[^^] in the Schiff-base with benzophenone allows a-N-CH-depro- as ketone '-reagents in C-C-bond forming processes has tonation (cf. umpolung of amine reactivity with pyridoxal recently been demonstrated. The preparation of Grignard de- in Nature["]) and converts the normal aminoalkylating ;I I- rivatives, the employment of tin-containing intermediates, and the use of certain acyl-metal and acyl-phosphorus compounds 0 for reactivity umpolung are outlined in Table 4 (entries 3-5). HzC=O + H3N [H2C=N-$Phz - HZC-N-CPh Especially versatile heteroatoms Y for this purpose are phos- +Hm/-H20 1. PhzCO f 2 - Hm phorus, sulfur and seleni~m1~"~~~.They can be readily intro- 0 0 + He [H~C-NHZ ++ HzC-NHz] ---P CH3'NHz FI((k) 60 R1 R3P=CHR3 R1 )0 + H0-CH2R3 - R R 0 reactivity of iminium derivatives[s2Jinto ti ' -reactivity[53][see duced at electrophilic (+R,Ye) and at nucleophilic sites eq. (k)]. On the other hand, we can convert the amine (oxida- (+R,YX). Sulfur in particular stabilizes positive and negative tion state -3) into the nitronate (oxidation state +5) and charges in the a-position, and there are numerous ways of use this as an aminomethyl d ' -reagentI4". removing all three heteroatoms from a molecule[4g1.Conver- We need not go all the way to the nitro or diazo group sions associated with the names of Wittig, Homer, Emmons, to achieve a-N-CH acidification and a-N-C-donor proper- Wadsworth, Michaelis and Arbuzod2] allow the coupling of ties. Any amine derivative which bears an electron-withdraw- carbon atoms of the same polarity [cf. eqs. (c) and (01; recent ing group causing a partial positive charge on nitrogen appears improvements and promising developements in this general to suffice under appropriate conditions [see the isocyanides area are the so called redox condensations with pho~phanes[~~] (27)rs4J, the carbamoyllithium compounds (28 s51, the and the conversion of NH2 into the leaving group nitrosamines (29)[4d.s61,the amides (30 j with sterically pro- N(SOzR)z["".

The temporary replacement of the heteroatom oxygen by sulfur for the preparation of 1.2ii-functionalized products is (31). X = NR2, OR 1320) described in equations (9) and (h) [cf. eqs. (c) and (d); for further examples see Table 4, entries 6-8, and detailed reviews[4bs4g, h, 12. 451]. The interconvertibility of oxygen and nitrogen functions (functional group eq~ivalence'~"])renders (324 the use of N-containing reagents with reactivity umpolung (see Section 3.2.2) a heteroatom exchange method for oxygen tected but electronically effective carbonyl gro~ps'~~,~~,s71, [cf. eq. (i)]. and the vinylogous ureas, urethanes, and cyanamides (31 )['*l]. 40 R-CH20H --H R-CH2N02 -D R-CH-NO2 + R-C, (i) It is not entirely clear yet whether the dipolar anion stabiliza- I R' R' tion indicated in (32) is the decisive effect causing the ready

244 Aiigriv. Chrm. Int. Ed. Eiigl. 18. 239-258 (1979) Table 4 Exchange and modification of heteroatorns [23]

No Conversions and Reagents Synthons Ref.

68 66 R~CH~OH+ HOCH~R~ R'CH, P i ban, R'CH~OTOS+ BrMgCH2R2 - R'CHz-CHZR2 RZCHzd

RzNH + CHzO + NaHSO, -+ R2N

r641

CIizO + KjSnMgC1 - HOCHzSnR3 A ~51

K' >O + R3SnLi - R R2 SnR3 RZ R3 HOAR4

,$'/,I'

[67--691

1701 aR2 OH

)-OH

R' 0' c721 ,3: R3AR4

Aiiyiw. Chem. lilt. Ed. Eiiyl. 18, 239-258 (19791 245 Table 4 (continued).

No. Conversions and Reagents Synthons Ref.

RCOOH homologous acid, amide, ketone, .iCOOH CONHz 121 aldehyde, alcohol, amme, a-amino acid, u-hydroxyamide, -acid, 1231 RCHO -ketone, -aldehyde, -=mine CHO .iCOR 173-761 CHzOH I CH,NH,

R'-COOH + HO-CH~

1781

hydrolyns c411

formation and unexpected stability of these sys- (C') can be specifically introduced (homologation) for the tem~[~~,~~,~~*571. An almost complete list of N-derivatives purpose of reactivity umpolung. with nucleophilic a-carbons is found in a previous review A d'-reagent of this type has the general formula (33) (Table 3 in Ref. 14d1).The use of cyanide (Kolbe and Strecker where X and X' may be oxygen and/or nitrogen, or other syntheses['], cyanohydrin formation), a recent example of heteroatoms, and must fulfil three conditions: the C=X group incorporation of nitrogen into a conjugated system (cf. Section is essential for anion stabilization, attack of the electrophile 3.9, and novel derivatives with "dipole stabilization" are listed must occur on carbon, and the product must be amenable in Table 4 (entries 9-1 3). and Examples of simultaneous heteroatom exchange modifi- X cation for the purpose of reactivity umpolung are the versatile R reagent TosCH2NC: (Tosmi~~~~,~~~)and the thiocarbamoyl- - c - )=o (1) lithium derivatives LiCSNR'RZ[601. R' (33) 3.3. Homologation and Its Reversal

As stated in Section 3.1, any compound with a 1.31-func- tionalization has the normal reactivity pattern ( I ) with respect to one of the two functional groups and reactivity umpolung ( 10) of the other one [cf. Section 3.1, (26)]. After a reaction with an acceptor at C2, which in this case is at the same time a d'- and a d'" ~ '-center, the C-C bond leading to C' can be cleaved (reversal of homologation, degradation). This procedure then provides a reagent which corresponds to cleavage to a carbonyl compound [see eq. (1) and Table to a d'"' I -synthon. The extra functionalized carbon atom 51. Especially attractive are catalytic processes, the best known

246 Anyew. Chem. Int. Ed. Enyl. IN, 239-258 (1979) example of which is the benzoin condensation [eq. (m)]. The carbon framework. It is equally possible to use this method Stork method["] is conceived along these lines; it uses lithium to supply ti2- and <{'-reagents [see eqs (p)-(r)]. In the first derivatives of protected cyanohydrins (see Table 5) and is ingeniously applied to a prostaglandin synthesis as indicated in eq. (n)[811.The method by which Nature performs nucleophilic acylations again involves a catalytic homologation, with

process a glycine derivative (34a) is used as a 1.2-bifunctional molecule'841. Condensation with cyclohexanone gives a Michael acceptor (21~)(34b), which also is an enamine derivative (normal reactivity d2, here it2); the product obtained from the Gilman reaction[85]is hydrolyzed to the corresponding a-amino acid which is cleaved by lead tetraacetate (retroho- mologation; the carbonyl carbon has "done its job"!) to give the final aldehyde product. If we consider the synthesis from (reversal of cyclohexanone, the oxazolidone (34u) is a d '-reagent (in the homologation ) Dakin-West reaction['] it is clCH2NH2); comparing (340) with the aldehyde, we see that it is an a'-reagent. thiamine pyropho~phate[~~,*~],and was adopted by Stetter The reversible homologation of equation (q)'861is vinylo- et a1.[831for laboratory scale preparations [eq. (o)]. gous to the above mentioned use of cyanide for nucleophilic Further examples of devising d'-reagents by the homolo- acylation and brings about a P-alkylation of an enone (cf. gative approach are listed in Table 5. entries 7 and 9 of Table 4). The reaction sequence in equation So far, we have discussed only cases in which d '-reactions (9) employs a I .l-bifunctional intermediate (35)--like the were performed with homologues of the actually required classical Stobbe condensation"] (and its many recent modifica-

OH Table 5. Reactivity urnpolung by homologative methods [?3]. Reagents (or conversions) corresponding to the d'-synthons ,f, A"

Reagent (or conversion) Ref. Reagent (or ConLcrsion) Ref

No 51' + electrophiles

C H3 0-tetrahydropyranyl X2= metal or alkyl. X = SR [981 OSi(CH3J3 N -CR 184. 991 OCOC6H5 H(+OOH, see above) r 1 ooi OCOOR' C OOH SCSN(CH3J2 C1 (Ijarrrns reaction) ?iR'COC& (Heisserr compounds) NR'Z

OOH, R. R-CH&\ - R-CH-CX - R-C-CN - [ 1021 I I R' R'

(cf. Darzens reaction [ZIJ

Angew. Chrm. Inr. Ed. Engl. 18, 239-258 (1979) 241 0 0 0 3.4. Use of Cyclopropanes

Opening of a cycloalkane with an odd number of carbon atoms and with substituents as indicated in (36a) and (36b) (351 by donors and acceptors, respectively, constitutes yet another lol

a!”- reactivity c~~~’+’-reactivity (360) (36 b) (37a) (37b) tions[”]; see also Section 3.4). As indicated in equation (r), the enolate derived from succinic ester corresponds to a principal method of reactivity umpolung. It is related to the d3-synthon; the cyclopentenone annelation (route B) is part homologative method of the previous section by also rendering of a three carbon ring expansion method[88]. Some further normal reactivity i I i [counting the short distance between the attacked and the functionalized carbon in (36)] identical COOR with reactivity umpolung [counting around the ring ol of (36)];the resemblance becomes even closer if we consider that this kind of process is most likely to occur with cyclopropanes (110 kJ/mol strain release), the next higher homologues of “cycloethanes” [see (37a) and (37b), and Table 61. Most of the processes of this scheme were discovered some ten

or more years ago[’041 (cj.lI105al , JI 4105bI ;,‘~[~O~cl),but only recently have they been exploited systematically for this purpose; improved methodology ofcyclopropanation[’04~ was a prerequisite. A fair coverage of the field is not possible in the present only a few illustrative examples will be mentioned. In the field of heterocyclic chemistry and natural product classical[2] reactions which can be used in homologative reac- synthesis, the construction of pyrrolines, pyrrolidines, tetra- tivity umpolung as defined here are the degradation methods hydrofurans, y-lactones and y-lactams is a problem of reac- according to Baeyer-Villiger, Beckmann, Hofmann-Curtius- tivity umpolung because in all of these five-membered rings, Lossen-Schmitt, Hunsdiecker (all RCOR or RCOOH+ROH, the chain of carbon atoms is I .A-bifunctionalized. It is therefore RNH2),and Barbier- Wieland (R2CHCOOH-tR2CO)in which not surprising that cyclopropanes have been widely applied arbon functions a\ a le,iving group and is replaced by a in this area. One example each from Danishefski’s[’081, heteroatom (N or 0). Stevens’[1og1and Wenkert’s“ approaches is given in equa-

Table 6. Umpolung of carbonyl reactivity with cyclopropanes.

Synthon Olefin or “Homoolefin” or Synthon “cycloethane” cyclopropane

D 0”

248 Angew. Chem. Int. Ed. Engl. 18, 239-258 (1979) with the methyl(vinylcyclopropy1) ketone shown in equation (w)r' ' 'l, methoxycyclopropyllithium (42) is a propionaldehyde d'-reagent[' 16], and the phosphonium salts (42)[1171and (43)'' "1 are used in cyclopentane annelations to 1,3-dicar- bony1 derivatives [cf. the synthons with (18b); see also Section 5, (77)-(82), eq. (av) and Table 91.

3.5. Acetylenes

Acetylenes are extremely versatile synthetic intermediates" ' 'I. The highly reactive, "strained" triple bond can be attacked by electrophiles or nucleophiles [see (44), and compare (18a)], terminal acetylenes are rather strong CH- acids, and the acetylides obtained by deprotonation are very good, non-hindered nucleophiles [(45)] (compare (18 a), acyl

R-CH~-C-R'F: X = 0, NCOOCH, (39) X = 0, NH R-c EC-R' 1li' R1 OH R-C-C d R2+- c-2--f,R4 R-C-C-R' f dl HO R3 DonT R-C-CH2-R' (44) (46) tions (s)-(u). In reactions of the type (s)['''1 the three-mem- :: (45) bered ring is opened stereoselectively with inversion ; they have been termed homoconjugative The general d'-reagents]. Acetylene itself is therefore a welcome moiety route outlined in equation (t) was followed in a synthesis for the synthesis of 1 .hbifunctional systems (46) [see (17u)l. uiu (38)[1'21; (u) of aspidospermine equation outlines the An advantageous stereochemical aspect is that disubstituted key step of an eburnamonine synthesis" ''3 ' 13]. Formally, alkynes can be selectively hydrogenated to (E) or (Z)-olefins. the I &relationships N-C4-N and O-C4-0 have been If acetylene is attached to a molecule of normal reactivity established by an ;?-reaction with a nitrogen or oxygen atom I I, a carbon framework with reactivity umpolung ( If))results donor in all three cases. The ring enlargements in equations [eq. (x)]. This principle is used if propiolic acid or propargyl (t) and (u) could also be classified as hetero analogues of the pericyclic vinylcyclopropane + cyclopentene rearrangement. The carbene used in equation (u) [cf. (18a)] corresponds to the ,r'-synthon drawn underneath it; in (39) a pushing (or donor) effect of X is probably also involved [cf. (36u) and (36b)l. Stobbe-type conversions are possible with the cyclopro- derivatives (aldehyde, alcohol, bromide) (d') or 4-pentynoic panone acetal (40)" 141 [eq. (v)], a"-reactivity was observed acids (d 5, are employed" 201. If one traces back the components of the synthesis of phoracantholide, one finds that the ultimate

60 ,COOR HzC=O (Y) OCH\ ~j=J0Q @C\H ,I, ( ROOC)~CHO COCH3 reagents with reactivity umpolung are oxirane (see Section 3.1) and acetylene [see eq. (Y)]~'~~!A recent muscone synthesis OH

Anyi,w. Chem. Int. Ed. Engl. 18, 239-258 (1979) 249 via (47) uses cyclododecanone, acetaldehyde and acetylene alkali metal, is readily accomplished'Iz6J, while we do not as components[1zz];these are first joined to a 1.4-diol which normally cleave pinacols and olefins by such simple methods. is cyclized by sequential Rupe-Meyer-Schuster and Nazarov The products mentioned-except for the olefin-are i .?)I- reactions[21. Acetylene corresponds to a d ',d2-synthon [cf. bifunctional and have been made by joining carbon atoms eq. (41. of the same polarity (cf. queries 1 and 3 in Section 2). We formally obtain these products, if we assume that half of 3.6. Redox Reactions the startingmolecules are converted into reagents with reactivity umpolung [see the d"'- and 2-synthons in eqs (aa)-(ac)] Conceptually, the most simple method of reactivity umpo- and then couple with the other half of normal reactivity. lung is the addition or removal of electrons in a system which In reality, of course, radical anion or cation coupling (r-reac- is electrophilic or nucleophilic, respectively. This will of course tivity""]) furnishes the products in most cases. Therefore, it reverse the reactivity of the species (cf. also the formation is difficult to prepare cross-coupling products in better than of a Grignard reagent in Table 4, entry 3). Thus, we can statistical amounts, unless we carry out intramolecular reac- reduce ketones and aldehydes to pinacols [eq. (aa)] and esters tion~['~'! Some exceptions to this statement are listed in to acyloins[' 231 by electrochemical[' 241 or photochemical1' 251 Table 7; a confirmation is the still very short and efficient methods or with metals" "1; further reduction leads to olefins synthesis of the pheromone brevicomin1'39, I4O1 [equation (ad) which can now be obtained directly from ketones with low- (Kolbe carboxylate electrolysis[21)].

-coo0 0 .2 e" oso, + __f -2cq -

(ab) exo- brevicomin

A way out of the problem of "self condensation" or scrambling, when selective cross coupling is desired, is being systematically investigated by our gr~up["',"~'~~-'~~!The principle

Table 7. Examples for cross-coupling of carbonyl derivatives to olefins, pinacols, and 1 .+dicarbonyl compounds

Coupling reaction Yield Ref. ["/.I

OA c 0

valent titanium" "~'1. Likewise, electrochemical or metal is described in the accompanying equation (ae). Instead of oxidation of enol ethers['321or enolatesr'33~ 351, respectively, adding two electrons (A), the n-system is reduced (€3) and furnishes I .l-dicarbonyl derivatives [eq. (ab)] ; electrochemical the resulting dihydro compound is doubly deprotonated (C). processes of this type have been called cathodic ~rnpolung~'~~~.The overall result is the same, and no intermediates are A coupling reaction of industrial importance is the anodic involved which could couple with each other. The derivative dimerization of acrylonitrile to adiponitrile [eq. (ac)]. The of the doubly reduced ("LUMO-filled") n-system thus obtained converse of equation (ab), the cleavage of a 1 .+diketone with can be added to a different partner to give a "crosslinked 250 Aiigew. Chem. Int. Ed. Engl. 18, 239-258 (1979) OQ R3KR4 OH R4

2. HzO

dimer”, for instance (48). Only a one electron transfer during this latter step could prevent a clean cross-coupling and would 149b) (50 b) 151 b) , lead to scrambling. In the conversion via route A, the formerly M = Li, 1/2 Mg electrophilic carbonyl carbon has become nucleophilic, an umpolung (“polar reversal”, “charge reversal”) in the literal sense of the word [see also (18a)l. With more extended n-systems, there are several possible hydrogenated precursors to the desired dianion (see Table 8).

Table 8. Doubly reduced n-systems from hydrogenated precursors [see eq. be)].

Precursors “LUM 0-filled’’ n-system

X 11 .. 20 2 atoms +H ,c, 4 electrons with a double roactiriij timpolunp if they are used to prepare normal 0, N-derivatives (see postulates 1.2-1.4): one is achieved by heteroatom exchange or modification, the other one by the redox method [see eq. (af), cf. eq. (i) and Section eyy, 4 atoms 51. Some amine derivatives with umpolung achieved by going 6 electrons 2BX to the doubly reduced state can only be referred to here[’491. /-..dx

6 atoms 8 electrons

The smallest system, the formaldehyde dianion (49b) could not be generated by double deprotonation of methanol; only tin/lithium exchange in (49a) was suc~essfu1~~~~(see also Table 4. Direct Umpolung and Substrate Umpolung 4, entry 4). The other dianion derivatives (50b)-(55 b) are 4.1. Direct Umpolung accessible from the “hydrogenated” precursors (50a)-(55 a) and strong base. They preferentially react in the o-positions There are of course exceptions to postulate 1.3. If reactivity with electrophiles. Reagents (50b) correspond to di-syn- umpolung is observed without using one of the methods de- th~ns[’~~~,’~’];the lithium compound (51 b) is attacked at scribed in Section 3, we call it direct umpolung. Carbon mon- C3(11’) by all types of ele~trophiles[~~-133 14231441, while the oxide and isocyanides are simple one-carbon reagents which magnesium derivative adds to carbonyl compounds with >95 % a-selectivity (d’);(52b) also reacts at the a-S-carbon. The doubly deprotonated nitro alkane^^^'^ are nitroolefins with reactivity umpolung: while 1 -nitro-butadiene is known to accept donors at Czor C4, its dianion (53 b) (deep-red solution in THF/HMFT, stable at room temperature for a few hours) couples with acceptors (mainly d4-reaction). Similarly, (54b) and (55 b) react with alkyl halides, ketones, and aldehydes can be attacked by a donor and an acceptor [see (56) and (57) at the ~-N02-positionexclusively. It is interesting to note and compare (f8a)l. Thus, if carbon monoxide, an olefin that the nitroolefin dianions (53 b)-(55 b)constitute reagents and water combine to give a carboxylic acid under strongly

Angen.. Chem. lilt. Ed. Eiigl. 18, 239-258 (1979) 251 acidic conditions[' "1, the CO-carbon atom formally combines and this is not possible with all the methods mentioned in with a carbenium ion (a/d') and OHe (a'/d). Isonitriles are the previous sections. Should we arrive at a certain stage used in the Passerini- and Ugi-reactions (see refs. in 14']) to of a synthesis where we need to perform the conversions prepare a-hydroxy- and a-aminocarboxylic acid derivatives, (ah)-(ak), this would be a task much more difficult than respectively; given proper substitution in R of (57), Grignard- constructing a "small" reagent molecule with reactivity umpo- and lithium-reagents can be added to the carbon atom (a') lung. We are here concerned with a more complex molecule to give an iminoacyl anion derivative; subsequent reaction whose functional groups must be compatible with all opera- (d ' ) with an electrophile and hydrolysis furnish aldehydes tions necessary to achieve the umpolung. Therefore, this may and ketones (Walborsky's method" 501). In the formose reac- be called a substrate umpolung. Of the methods in Section tion[l5'I, formaldehyde (58) oligomerizes to give carbohy- 3 which fulfill this condition, we have to choose the mildest; drates when treated with alkali. the ones which require more stringent conditions will be applic- We realize that it is arbitrary to say that CO and CNR able only for reagent umpolung or in the early stages of are reagents with direct umpolung while we put other, similar a synthesis when there is less complexity. compounds [(27)-(3I), entries 9 and 11--13 of Table 41 HO K into the section on reactivity umpolung by way of heteroatom (ah) modification; in (56) and (57), not only the carbons but ----+electrophlle nucleophile moH moR K' also 0 and N are in special bonding situations. This is also true of highly conjugated systems such as (59)['521; CI5 m aY "not care" whether it is attacked by a nucleophile or an electrophile. Some unambiguous cases ofdircct ~unpolungare the genera- tion of (60)-(68) directly from the CH-precursors and strong bases, without any of the manipulations described in Section OH ?H 3. (60) is formed by metalation of TMEDA['531and, like the other a-0- and a-N-lithium derivatives (61 ), (63), (65) (4 and (66)" 571, is surprisingly resistant towards Wittig-type rearrangements['541; (61)-(63) are also obtained by depro- The reversible homologations through cyanohydrins [eq. (n)] and thiazolium derivatives [eq. (o)], and the heteroatom OR OR OR exchange method through thioacetal would appear the most promising for the realization of process (ah). Li Li Li R' The nitrosamine method[4d][see (29)] might be applicable for (ai), and the allyl sulfoxide (entry 6 in Table 4) for (ak). " A 5. Analysis of Some Synthetic Methods

There are many possible combinations of the methods described in Sections 3 and 4.1 by which reactivity umpolung can be achieved. An interesting exercise is the analysis of the numerous ways of preparing I .A-dicarbonyl compounds (12). This has been a very active field because of the importance of jasmonoid, rethrolonoid, and prostanoid synthesis. Extensive review articles on this subject have tonation[' 551; the heterosubstituted allyllithium compounds appeared["3, 1621. In the following discussion some reactions (65) and (66) have been discussed in a recent review will be analyzed which use the six principal methods given article" 571. The ortho-Li-derivative of benzyl alcohol and a in Section 3 in a more or less 'disguised' way. variety of substituted analogues including cr-tetralol[' 581 as One such case is the use of w-functionalized terminal olefins well as (68)['591 are only two examples of a large number (see Lednicer's article on latent functionality in ref. [51)[1631. of similar reagents which are formed by direct ortho-metala- This method is based on the oxidative cleavage to a carbonyl tion['601. Equation (ag) shows a conversion in which allyl alcohol undergoes sequential a'- and d3-reactions['611.-It is important to note that in these cases the lithium is bonded to vinylic, arylic (both sp2), or allylic carbon moieties and/or is internally complexed (chelation). C Hz CHz 4.2. Substrate umpolung R~C~-H~RACm-M@ (69) (70) By definition, umpolung must be reversible: the final goal normal A,m=2n :

ity : i I with a I,2n-functionality transposition['651[a 1,(2n+ 1)- transposition will only shift reactivity within ( / I or 1/01, see below]. A simple example is outlined in equation (am): The 1,2-carbonyl transposition converts the product of the (74) (75) Friedel-Crafts acylation (.I I/&) into the product of an :i'/d- combination (acylmethylation). All transpositions of this type Bond shifts with C-C-formation are another important group of synthetic transformations. A [3,3]-shift does not 0 change the relationship (i. e. the number of carbon atoms) II s Ar-H f X-CO-CH2R -D Ar-C-CH2-R -+ Ar-CH2-C-R between functional groups (whether odd or even). The classical (am) CIaisen rearrangement''. ' 701 converts an ;I '/cI''- into an ;I '/(.I '- product [see eq. (a~)].If a precursor is synthesized with reactivity umpolung [eq. (aq)][171Jor from a compound which contains an even number of carbon atoms between the func- a

are 1,2n-oxidation-reductionprocesses (see Section 3.1). They either convert the C' carbon atom of f I ) into a donor carbon

or they transform d"or '1.'- into a" or a'-reactivity, respectively d I' (see also Table 3). Two examples are given in equation (an), "7ig:I - route B11661,and equation (ao), route B[167a1,a "weird" Robin- son-annelation [normal: eq. (an), route A]" 681 and aldol-con- xxoR densation [normal: eq. (ao) route A]11691,respectively. The first sequence of reactions necessitates twofold umpolung. The first one is achieved by heteroatom exchange to (71) (Section 3.2), the second one by a 1,2-functionality transposition tional groups [eq. (ar)'' 721], the "even relationship" is pre- (72) + (73) (carried out by dehydration, anti-Markownikoff served in the rearrangement product. The first transfor- mation is realized by the heteroatom exchange method and

A c- Rs

'COOR COOR

RGJ

a [3,3]-shift which converts the product of a d I -reaction into that of a d'-reaction. On the other hand, in equation (ar) one starts with a 12-product (see Section 3, "black magic-box'' and 1 .?n-oxidations), a mandelic acid derivative, and furnishes a 1 h-bifunctionalized compound. This is also true of the oxide- Cope rearrangement", ' 731 described in equation hydration, and oxidation) with an 3"-reagent (BH3/Hz02cor- (as)[4'.'42.'441; the reactivity umpolung proceeds via hetero- responds'to the HO-a" synthon and the H-d synthon). atom exchange (Section 3.2).

Angen,. Chem. Int. Ed. Engl. 18,239-258 (1979) 253 R' 1 .(?/I+ I )-bifunctional system-as in the reactivity pattern (1I (cf. postulate 1.4). As is evident from Table 9, Trost's cyclopropylidene sulfur- Mg2@ ane and phenylthiocyclopropyllithium (76)" 761 are true syn- (as) thetic chameleons; one can easily count ten different synthon If a molecule contains X-X'-hetero-hetero bonds [R-O- combinations if one compares the products with the starting 0-R, R-O-NR2, R-N=O, RZC=N(O)R, RO-N=CRz, carbonyl compounds; all of them make at least one bond R2N-NR2, R2C=N-NR2, RN=NR, . . . or heteroatom with reactivity umpolung [see e. g. (79)-(82)]. This plethora exchange analogues], it has a built-in I .?-oxidation (see Section 3.1 and Table 3), and thus a reactivity umpolung. Therefore, we can consider Fischer's indole synthesis['] and Gossman's recent modificationr1741as a'/d'-combinations leading to a I &disubstituted carbon framework [see eq. (at), routes A and B]. The Reimer-Tiemann-typel2] reaction in equation (au)" 751 is obviously an a2/d' -combination; both components (101, a 0 have reactivity and we must necessarily obtain q02:@ - 82, CP/2', ti:; (at)

(RZ= SR) H H .I *, t'/:i' , (1' a, tjleX',(I" (il, L!'/ct',a' ;I1, ,i'/.il, &OR' (79) 180) (81) (82) ROC 1 RS RSC H~COR' of possibilities is obtained by a combination of: 1) heteroatom exchange [Section 3.2, see oxaspiropentane formation (SO)], 2) the cyclopropane trick [Section 3.4, see (77) and (78) (02'/d2)] and 3) the I.%-oxidation [Section 3.1, see (8211. CHO One limitation of the method, the general lack of availability of substituted reagents (76), can be over~ome~~~~~~"]by start-

a2/111 ing from dibromo cyclopropanes as outlined in equation (av); (au) they are easily converted into Br/Li-carbenoids or RS-substi-

Table 9. Conversions of aldehydes and ketones with sulfur-substituted cyclopropyl nucleophiles of type f 76).

Reagents: bS(CeHsI7, kz6".

A "x"' Q

254 Angeiv. Chem. Int. Ed. Engl. 18.239-258 (1979) :,,--%,Er I thank Miss R. Pfister, and Dip/.-Chem. E. Hungerbuhler, M. Liesner,andDr. N.Meyerfor their most competent help in prepar- 0 U ing the manuscript. Many valuable discussions with a number - of colleagues, especially with Professor A. Eschenmoser are ... gratefully acknowledged. Our own work referred to in this article a- would not have been possible without the enthusiastic collabora- tion of my graduate students whose names are git’en in the list of references. We were generouslji supported financially by the Deutsche Forsclzungsgemeinschaft, the Fonds der Chemis- chen Industrie, the BASF AG (Ludwigshafen) and SANDOZ tuted . cyclopropyllithium derivatives, which may be up to AG (Basel). tetrasubstituted, and which can be used just as the unsubsti- tuted reagent (76). In the overall reaction, the final product Received: November 2, 1978 [A 264 IE] in (46) is made from cyclohexene, cyclohexanone, and German version: Angew. Chem. 9J. 259 (1979) bromoform, which illustrates that this approach constitutes a synthetic elaboration of the ketone and of the olefin [39b, 1773. [13 a) See textbooks of organic chemistry. b) Cf. k! Cutmunn, The Donor- Acceptor Approach to Molecular Interactions, Plenum Press, New The use of the Trost method for the preparation of 1.0- and York 1978; c) For radical reactivity, the sign would be r [for the I .S-bifunctionalized carbon skeletons can only be alluded to term radicophilic see L. Stella, 2. Janousek, R. Merinji, H. C. Viehe, here“ 781. Angew. Chem. 90, 741 (1978); Angew. Chem. Int. Ed. Engl. 17, 691 (1978)]. 121 H. Krauch, W Kunz: Reaktionen der organischen Chemie. Hiithig, Heidelberg 1976; see also J. E. Gowan, 7: S. Wheeler, Name Index of Organic Reactions, Longmans, London 1960. [3] a) E. J. Coreg, Pure Appl. Chem. 14, 19 (1967); b) Previously, we have used the terms N”- and E”-synthon [4], indicating the affinity oftheattackingmoiety,and + and - signsdenotingtheelectrophilicity and nucleophilicity, respectively, of the reagent related to a certain synthon. Although derived from a practical point of view, this terminol- I I I , ogy turned out to be subject to confusions; c) We do not use “synthetic equivalent” as a noun; “synthetic equivalents of acetaldehyde enoiate” are simply acetaldehyde d2-reagents. Reviews: a) D. Seebach, Angew. Chem. 81,690 (1969); Angew. Chem. Int. Ed. Engl. 8, 639 (1969); b) D. Seebuch, Synthesis I, 17 (1969); c) D. Seebach, M. Kolb, Chem. Ind. (London) 1974,687; d) D. Seebach, D. Enders, Angew. Chem. 87, 1 (1975); Angew. Chem. Int. Ed. Engl. I4,15 (1975); e) Journal of Organometallic Chemistry Library. Elsevier, f) D. Seebach, K.-H. Geiss Vol. I; As Amsterdam; in [4e], I. 1976, p. last example of a recent, useful development in the g) D. Seebuch, K:N. Geks, M. Kulb, A. K. Beck: Modern Synthetic field of aromatic substitution with reactivity umpolung, Sem- Methods 1976, Schweiz. Chemiker-Verband Zurich 1976, p. 173ff.; B. Grobel, D. Seebach. D. Serburh. Kolb. melhack’s method“ 791 is mentioned: formation of the benzene- h) Synthesis 1977. 357; i) M. Justus Liebigs Ann. Chem. 1977, 81 1; k) D. Seebach, R. Biirsrinyhaus, (tricarbonyI)chromiumcomplex (83) renders the benzene ring 8. T Gr6be1, M. Kolb, ibid. 1977, 830; I) D. Seebach, E. W. Colvin, amenable to attack by nucleophiles; instead of the Friedel- F. Lehr, Th. Weller, Chimia, 33, 1 (1979). Crafts productsI*], aryl ketones, a-arylated carbonyl deriva- We don’t use the terms “latent” [D. Lednicer, Adv. Org. Chem. 8, 179 (1972); 0. W Lever, jr., Tetrahedron 32, 1943 (1976); L. Cull, tives are formed [see eq. (aw), cf. eq. (am)]. The chromium Chern. Unserer Zeit 12, 123 (1978)], “symmetrization of reactivity” metal atom decreases the electron density of the benzene 13 a], “charge affinity inversion operation, consonant and dissonant relationships” [D.A. Evans, G. C. Andrrw.7, Acc. Chem. Res. 7, 147 ring (lowers the LUMO energy) sufficiently for nucleophilic (1974) and private communication], “control elements” [St Turner attack to take place. At least formally, we may say that this The Design of Organic Syntheses. Elsevier, Amsterdam 19761 and is an umpolung by the redox method (Section 3.6). “illogical disconnections” [St. Warren. Designing Organic Syntheses, Wiley, Chichester 19781. Reviews: a) 7: Mukaiwma, Aneew. Chem. 89, 858 (1977); Aneew. Chem. Int. Ed. Engl. 16, 817 (1977); b) J. K. Rasmussrn, Synthesis 6. Conclusion 1977. 91 ; c) E. W Colvin, Chem. Soc. Rev. 7, 15 (I 978). [7] C. Biichi, H. Wuesf, J. Org. Chem. 34, 1122 (1969); H. J. J. Loozm, The present article has tried to classify the methods by E. F. Godefroi, J. S. M. M. Besters, ibid. 40, 892 (1975); A. A. Ponuras, Tetrahedron Lett. 1976, 3105. which reactivity umpolung can be achieved. Hopefully, it will [XI a) Huuben- Weyl-Miiller: Methoden der organischen Chernie. 4th Edit. help organic chemists to recognize the necessity of umpolung Thieme, Stuttgart; b) K. Niirzel in pa], Vol. XIII/2a, 1973, p. 264. I. Degmi, R. 1 when planning a synthesis, to see new methods appearing [9] Fochi, J. Chem. Soc. Perkin Trans. I886 (1 976). [lo] J. Mathiru, J. Weil~-Ragnal:Formation of C-C Bonds. Vol. I. Thieme, in the literature in a systematic way, and to choose or even Stuttgart 1973, a) p. 168, b) p. 303. discover the best possible reagents for their synthetic problems. [ll] R. H. Wollenberg, K. F. Albizati, R. Peries, J. Am. Chem. Soc. 99, 7365 (1977); A. Alerakis, G. Cahiez, J. F. Normant, J. Wllieras, Bull. Reactivity umpolung is an essential part of synthetic strategy Soc. Chim. Fr. 1977, 693; K. S. Y Lau, M. Schlosser. J. Org. Chem. which is now also applied with the aid of 43, 1595 (1978); for the vinologous case (di) see: R. H. Wullenberg, It is still a controversial subject among synthetic Tetrahedron Lett. 1978, 71 7. 1121 a) A. 1. Meyrrs: Heterocycles in Organic Synthesis, Wiley-Interscience, but highly esteemed in many pharmaceutical and pesticidal New York 1974; b) Review: K. Hirai, Y. Kishidu, Heterocycles 2, industrial laboratories. A most important aspect of organic 185 (1974); c) Review: J. ApSimon, A. Hnlmes, ibid. 6, 731 (1977). synthesis, stereochemistry, was naturally excluded from the 1131 K.-H. Geiss. D. Seebach, B. Sewing, Chem. Ber. 110, 1833 (1977). 1141 D. Vorlaufer, Ber. Dtsch. Chern. Ges. 52, 263 (1919); A. Lapworth, present discussion, and it is appropriate to stress its importance J. Chem. Soc. 121, 416 (1922); W 0. Kermack. R. Robinmn, ibid. by quoting: “Stereochemistry rears its ugly head” and “Multi- 121. 427 (1922); cf. the calculations by J. A. Pople. M. Gordon, J. Am. Chem. Soc. 89, 4253 (1967); cf. also S. W Benson. Angew. Chem. stage synthesis: logistics and stereochemistry combine to pro- YO. 868 (1978); Angew. Chem. Int. Ed. Engl. 17, 812 (1978), and refer- duce ences cited therein.

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258 Anyew Cliem. Itif. Ed. Engl. 18. 239-258 (1979)