Scholarly article on topic 'Cobalt-Mediated [2 + 2 + 2]-Cycloadditions: A Maturing Synthetic Strategy [New Synthetic Methods (43)]'

Cobalt-Mediated [2 + 2 + 2]-Cycloadditions: A Maturing Synthetic Strategy [New Synthetic Methods (43)] Academic research paper on "Chemical sciences"

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Academic research paper on topic "Cobalt-Mediated [2 + 2 + 2]-Cycloadditions: A Maturing Synthetic Strategy [New Synthetic Methods (43)]"



International Edition in English

Volume 23 ■ Number 8 August 1984 Pages 539-644

Cobalt-Mediated [2 + 2 + 2]-CycIoadditions : A Maturing Synthetic Strategy

By K. Peter C. VoIIhardt*

New Synthetic Methods (43)

Dicarbonyl(r|5-cyclopentadienyl)cobalt functions as a matrix on which a variety of unsaturated organic substrates undergo mutual bond formation. In this way a,co-diynes cocyclize with monoalkynes to give annelated benzenes, while o-diethynylbenzenes furnish biphenyl-enes, and a,co-enynes lead to the formation of complexed bi- and tricyclic dienes. Nitriles cocyclize with two alkynyl groups to give pyridines and other heterocycles, isocyanates allow access to annelated 2-pyridones, and incorporation of carbon monoxide provides complexed cyclopentadienones. In many cases remarkable chemo-, regio-, and stereoselectivity are observed, partially facilitated by use of the trimethylsilyl substituent as a controlling group. The scope and level of maturity of the method are demonstrated by the synthesis of a series of hitherto inaccessible, novel, and theoretically interesting molecules, and by its utilization in several unique approaches to a variety of natural products, e.g. protoberber-ines, steroids, vitamin B6, and camptothecin.

1. Introduction

The discovery and control of new bond formations are two of the primary tasks of the synthetic organic chemist. The arsenal of current synthetic methods has already allowed the construction of even the most complex natural products and most remarkable, "unnatural" molecular assemblies. Nevertheless, despite these advances, there remains much room for improving and particularly simplifying synthetic strategies. This can be done by either cleverly manipulating existing methodology or, probably more successfully, by finding new methods through which simple materials are converted into structures of greater complexity. In this connection we deem it especially important to design new reactions in which a maximum change of topological complexity'11 can be effected with the highest de-

gree of efficiency and selectivity. Many cycloaddition reactions fall into this category, because at least two bonds may be formed in one step while steric and electronic factors reduce the number of options available to the substrates en route to the products. A striking example is the cyclization reaction of Johnson et al.'21 in which a stereo-specifically constructed polyene undergoes acid-catalyzed multiple ring closure to the steroid nucleus (Scheme 1).


q y ho

Scheme 1. Polyene cyclization according to Johnson et al. [2].

[»5 Prof. Dr. K. P. C. VoIIhardt

Department of Chemistry, University of California, Berkeley, and The Materials and Molecular Research Division, Lawrence Berkeley Laboratory Berkeley, CA 94720 (USA)

Perhaps the most widely used cycloaddition reactions are the Diels-Alder cyclizations (Scheme 2) and their various modifications'31. Typically, six-membered rings are generated by two CC bond formations with the potential

to construct four chiral centers. More complex topological changes may ensue on application of its intramolecular version (Scheme 2)'41. The power of this method lies in its extraordinary specificity: it is chemoselective, in other words the dienophile prefers to react with the diene, and neither of the starting materials react competitively with themselves; it is regioselective, unsymmetrical dienes choosing only one sense of cycloaddition to unsymmetrical dienophiles; and it is stereoselective, mostly following the endo-rule.

Scheme 2. Inter- and intramolecular Diels-Alder reactions.

A simple analysis shows that a potentially more powerful strategy would be one based upon the [2 + 2 + 2]-cy-cloaddition of three unsaturated moieties (Scheme 3). Now three new bonds would be constructed in one step, constituting a considerably larger change in molecular complexity, and up to six chiral centers could be generated from completely achiral starting materials.

R R R R'

R/=\ R" R"

/ \ '// %

R"- = -R"

age the use of heteroatomic units furnishing various heterocyclic systems151 and a plethora of partially or completely intramolecular versions.

It is surprising that, although symmetry-allowed'61, and in most cases strongly exothermic'71, there is a paucity of examples of purely thermal [2 + 2 + 2]-cycloadditions. It is possible that entropie and, in some cases, enthalpic'81 activation energy contributions account for the relative rarity of these transformations. This report will describe how the use of a transition metal, particularly cobalt in the form of the dicarbonyl(r|5-cyclopentadienyl) derivative CpCo(CO)2 as a catalyst or reagent may lead to the successful execution of a variety of [2 + 2 + 2]-cycloadditions of the type depicted in Scheme 3. The many previously unattainable molecules generated in this way have been used as starting materials for the preparation of several unnatural and natural products of theoretical and/or medicinal-synthetic interest.

2. a,ra-Diyne Cyclizations in the Preparation of Annelated Benzene Derivatives: Control of the Substitution Pattern

2.1. Background

Berthelot reported in 1866 on the thermal cyclization of acetylene to benzene'101. High temperatures (ca. 400 °C) are required and a mixture of products is formed'111. In 1949, Reppe et al. described the first transition metal catalyzed version of this transformation, in which nickel was employed, and which under certain conditions leads to the predominant formation of cyclooctatetraene'121. Subsequently, it was found that a large number of transition metal systems catalyze the cyclotrimerization of substituted, frequently functionalized alkynes to benzene derivatives'131. At the outset of the work described in this account, comparatively little was known about the utilization of these reactions in organic synthesis, particularly when employing oligoynes, even though such reactions would hold considerable potential in complex molecule construction. The validity of this premise was indeed demonstrated earlier when it was shown that a variety of oligocycles were obtainable by cyclization of a,co-diynes'141. Furthermore, in a series of over 40 papers, Mtiller et al. showed that stoichiometric amounts of rhodium complexes could be used in the "diyne reaction" to generate a multitude of rhodacy-cles capable of varied reactivity to furnish quinones, car-bocycles, and heterocycles'151. Although the method has its limitations with respect to scope, generality, and expense, it clearly pointed out some of the possibilities in store. Very recently, other groups have become interested in this problem'161.

Scheme 3. Prototypical [2 + 2 + 2]-cycloadditions.

Employment of varying proportions of cycloaddends containing double and triple bonds would provide access to six-membered, partially or completely unsaturated rings. As in the Diels-Alder reaction, one could also envis-

2.2. General Mechanistic Considerations

Based on the results of several investigators, the general Scheme 4 may be formulated for the mechanism of cyclotrimerization of acetylene to benzene catalyzed by low valent transition metal complexes'171. Initially, one and then two alkyne moieties sequentially displace two ligands on

the metal to form alkyne complexes 1 and 2. Oxidative coupling may occur to give the coordinatively unsaturated metallacyclopentadiene 3, in which the metal has adopted a formal oxidation state two units higher than in its precursor 2. This change appears to facilitate chemoselectivity in

+ 111 I

•Ill I


(Qlx-2-- 0*LX-2

Scheme 4. Mechanism of cyclotrimerization of acetylene.

certain cases. Complex 3 may then coordinate a third molecule of alkyne to give 4. On the other hand, calculations show that the direct conversion of 2 into 4 should be kine-tically more advantageous'181, since coordinative unsaturation is avoided. Species 4 appear to be very reactive, since, in contrast to 2, 3, 5, and 6, derivatives of which have been characterized, it has so far eluded isolation. This is unfortunate, because its preparation could provide crucial information with respect to the next step in the catalytic cycle: either an alkyne-insertion to form the metallacyclo-heptatriene 5 or a Diels-Alder type addition to furnish the benzene complex 6. Precedence exists for the conversion of either species into the free arene'171, and perhaps both options are viable.

addition processes'171. On the other hand, chlorophenylal-kynes are readily cyclized according to Scheme 5'201.


CpCo(CO)2 7 30-95%


Scheme 5. CpCo(CO)2-catalyzed cocyclotrimerization of a,ro-diynes with al-kynes.

In order to circumvent the aforementioned problems of chemoselectivity, bulky alkynes may be employed, particularly trimethylsilylalkynes which are too sterically hindered to autocyclize but not so encumbered not to cocy-clize. Their application (usually in excess) frequently results in excellent yields of the corresponding annelated ar-enes'19-211. The trimethylsilyl group in the products functions as an excellent leaving group in electrophilic aromatic substitution reactions'22'. This is particularly advantageous when employing bis(trimethylsilyl)acetylene (BTMSA) in the cyclization reaction, since the resulting o-bis(trimethylsilyl)benzene derivatives 9 can be substituted selectively and in high yield in a step-wise manner (Scheme 6)'19-201. Even in the case of deuteriodesilylation the first silyl group is more reactive than the second by a factor of about 40'19cl. Another interesting feature of com-


Scheme 6. Selective electrophilic aromatic substitution of o-bis(trimethylsi-lyl)arenes.

2.3. Cobalt-Catalyzed Cocyclizations to Benzocycloalkenes

Approximately 10 years ago, it was found that CpCo(CO)2 7 catalyzes a variety of [2 + 2 -I- 2]-cycloaddi-tions involving a,co-diynes to give annelated benzenes 8 as shown in Scheme 5'191. The reaction works best for n = 3 and 4 and tolerates a wide variety of substituents, such as R= H, alkyl, aryl, vinyl, C02R', CH2OH, CH2OR', COR', C=NOR', NR2, SR', and Si(CH3)3. In some cases there is a problem of chemoselectivity in as much as alkynes of comparable bulk or electronic make-up tend to undergo random cyclizations. The presence of substituents at the terminal position of the diyne may also lead to diminished yields when bulky groups such as Si(CH3)3 are involved'201. Although the reaction is poor for the preparation of benzo-cycloheptenes 8, n = 5, it is capable of generating strained four-membered rings, thus providing a fairly general synthetic entry to the 1,2-dihydrocyclobutabenzenes (benzocy-clobutenes) 8, n = 2, which are useful synthetic intermediates (see Section 3.1). Functional groups such as N02, alkyl halides, and reactive vinyl and aryl halides are detrimental to the catalyst, presumably due to facile oxidative

pounds 9 is their ability to rearrange to the m-bis(trime-thylsilyl) derivatives 10 when exposed to dilute electro-philes (Scheme 7)n»c,23]_ jj^ phenomenon appears to be caused by the slow rate of desilylation of the cationic intermediate formed during electrophilic aromatic substitution relative to 1,2-silyl migration, relieving steric strain, followed by rapid deprotonation.


diluted electrophiles 9 -y-_ (CH2)n ^


Scheme 7. Rearrangement of o-bis(trimethylsilyl)arenes (E = H, Br).

An example of the use of the cobalt-catalyzed cocycliza-tion reaction, incorporating a silicon-directed intramolecular regioselective Friedel-Crafts acylation'211, is illustrated for the synthesis of a linear annelated tricycle in Scheme



2. BF3 )

Scheme 8. Formation of a linear annelated tricycle by CpCo(CO)2-catalyzed cyclization and silicon-directed intramolecular Friedel-Crafts acylation.

2.4. Specific Mechanistic Considerations

If we recall the discussion in Section 2.2 and apply its conclusions to the case of CpCo(CO)2, there are two co-baltacyclopentadiene intermediates of the type 4 to be considered, namely 11 and 12 (Scheme 9). The mechanism of the reaction of CpCo(CO)2 with alkynes to give cobalta-cyclopentadienes and ultimately benzene derivatives has been well investigated117,24,251. Intermediates such as those of the type 11 (but not 12) have been isolated1261, except for n = 2, although a related iron compound is known1271. Cyclobutadiene complexes derived from both 11 and 12 are obtained as by-products in catalytic reactions employing a,(o-diynes119,20,281 and are responsible for some of the catalyst depletion, since they appear to be unsuitable as precursors for any catalytic intermediates129,301. On the basis of previous findings, neither of the two possible intermediates 11 or 12 can be ruled out; indeed, either one or both may be formed depending on the reaction conditions and substrate structures.

The trimethylsilyl group, which is used extensively for controlling the chemo- and regioselectivity, has a pronounced tendency to a-selectivity in the metallacycle (vide infra), as can be concluded from product isolation studies. An example of how this effect may be synthetically exploited in the formation of 17 as the sole isomer on cocy-clization of 1-trimethylsilyl-1,5-hexadiyne 13 and trime-thylsilylacetylene 14 is shown in Scheme 10[19c]. On steric grounds the kinetically favored metallacycle is expected to be 15, which, after insertion of the complexed alkyne to give 16, can only lead to 17.





Si (CH3)3

Scheme 10. Exclusive formation of the regioisomer 17 in the cyclization of 13 with 14.


Cp# / R2 R'

Scheme 9. Proposed cobaltacyclopentadiene intermediates in the cocycliza-tion of a,w-diynes with alkynes.

A mechanistically curious and synthetically unexploited result was obtained when attempts were made to catalyze cocyclizations of the type shown in Scheme 5 with polystyrene-supported CpCo(CO)2'321 (Scheme 11). The monosub-stituted acetylenes were not incorporated into the aromatic products, and only diyne dimers, such as 19 (major product), and trimers, such as 20, were isolated. Since homogeneous CpCo(CO)2 converts 18 exclusively into 20, indicat-

The structure of 12, with the alkynyl group in the a-position, is in accord with expectations based on steric arguments'24"1. These arguments also predict that R1 should be larger than R2. Electronic factors, in particular the polarization of the alkyne n* orbital, are, however, thought to favor the preferential emergence of alkyl substituents in the Imposition, whereas the trimethylsilyl group should, according to both theories, occupy the a-position'311. The inconsistency of some of the predictions with the experimental results'24"1 may simply be due to thermodynamic factors. Since the oxidative coupling of two complexed alkynes to a cobaltacyclopentadiene proceeds endothermi-cally (by an estimated 14 kcal/mol), this step may well be reversible; hence, the observed regioselectivity of the cyclization may not in any way reflect the initial course of the reaction. In the specific case of systems of the type 12, it may also be that additional involvement of the appendant alkyne group in the transition state for oxidative coupling (modelled by 2->4 in Scheme 4) controls the outcome of the process.

_ Si(CH3)3

= ^ ®-CpCo(CO)2 S R


Scheme 11. Catalytic cyclization of 1,6-heptadiyne by polystyrene-supported CpCo(CO)2. ® = polystyrene.

ing that the catalyst is transferred intramolecularly from the benzene ring in 19 to the appendant alkyne unit, which is next to be cyclized, and since CpCo(CO)2 also cocyclizes trimethylsilylalkynes, the polystyrene-supported or similar catalysts may offer an opportunity for interesting shape-selectivity in some of these transformations.

2.5. Synthetic Applications:

Anthracycline Antibiotics and Protoberberine Alkaloids

The CpCo(CO)2-catalyzed [2 + 2 + 2]-cycloaddition of three alkyne units could in principle be applied to the total synthesis of a variety of natural products containing anne-lated benzene rings. Two target molecules which require 1,7-octadiyne structures as cooligomerization precursors

The protoberberines 29 are readily accessible by the sequence of reactions shown in Scheme 13[361. For example, 29, R1 = R2 = Si(CH3)3, is formed in 96% isolated yield by cocyclization of 28 with bis(trimethylsilyl)aceylene (BTMSA). Unfortunately, but perhaps not unexpectedly, unsymmetrical alkynes [R' = CH30, R2 = Si(CH3)3] cyclize non-regioselectively. However, such selectivity is attainable starting from 28, again the sterically more demanding

1. (CH3)3SiC= CCH2MgBr

2. HC = CCHgBr_

Scheme 13. CpCo(CO)rcatalyzed protoberberine syntheses.

R1 , R2 = CH30, Si(CH3)3

are the antitumor anthracycline aglycones 211331 and the protoberberine alkaloids 22'34'. Both systems have already been synthesized via a multitude of approaches, none, however, involving the retrosynthetic disconnection made possible by the "cobalt-way". Two strategies are currently being employed en route to anthraquinone type antibiotics

CH30 0 HO OH

(Scheme 12), one involving the cyclization of aromatic bis(alkynylketones) 23 to furnish directly the desired framework 24, albeit in only moderate yields'190', the other utilizing dipropargylbenzenes of the type 25 to assemble initially a dihydroanthracene nucleus as in 26'35'.

R1= H, Si(CH3)3

r2,r3 = H, olkyl, Si(CH3)3


0CH3 25

Si(CH3)3 iii


Scheme 12. Two cyclization strategies for the preparation of anthraqui-nones.

arene, e.g. 30, being generated exclusively (Scheme 14)'361. Finally, the trimethylsilyl substituents in the compounds 24 , 26, 29, and 30 can function as leaving groups in elec-trophilic aromatic substitution reactions.


(CH3)3Si' f "0CH3 (CH3)3Si

Scheme 14. Regioselective protoberberine synthesis.

3. Theoretically Interesting Molecules

3.1. 1,2-Dihydrocyclobutabenzenes (Benzocyclobutenes)

The ready access to functionalized 1,2-dihydrocyclobu-tabenzenes according to Scheme 5 has enabled their use in the construction of a host of theoretically interesting, strained ring activated, benzenoid hydrocarbons'37'. Thus, 4-bromo-5-iodo-l,2-dihydrocyclobutabenzene 31 (Scjieme 15) functions as a precursor of 331381 and 341391 via the in-termediacy of l,2-dihydro-4,5-didehydrocyclobutabenzene





Scheme 15. Generation and oligomerization of l,2-dihydro-4,5-didehydrocy-clobutabenzene.

32. The activating effect of the four-membered ring is reflected in the physical and chemical properties of the products. Thus, e.g., both 33 and 34 are rapidly hydrogenated over platinum at ambient pressures. In a similar sequence, compound 17 afforded l,2-dihydro-3,4-didehydrocyclobu-tabenzene, predicted by bond fixation arguments to be more reactive than 32140'.

Hydrocarbon 35, readily prepared in one step by trimer-ization of 1,5-hexadiyne, undergoes oxidative photocycli-zation to give the two isomeric dicyclobutaphenanthrenes 36 and 37 (Scheme 16)1411. In contrast to 36 and phenan-

ogy to the multiphenyls (biphenyl, terphenyl, etc.). Curiously, the series is alternating with respect to the 7t-elec-tron count of the individual members between formally an-tiaromatic and formally aromatic. Theory predicts1501 a rapidly narrowing HOMO-LUMO gap with increasing n. Therefore, these compounds might have potential as novel materials with conductive behavior1511.

threne itself, the more reactive 37 is mutagenic in the Ames test, and thus constitutes the first substance in which such physiological activity is increased by ring strain. Flash vacuum pyrolysis1421 of 35 results1431 in diastereosel-ective cycloaddition to give cyclophane 38; the conceivable alternative isomer (±)-[2.2.2](l,2,4)(1,2,5)cyclo-phane1441 could not be detected. This preparation of 38 is clearly the method of choice1451.

The currently most severely strained simple annelated benzene derivative is probably1461 39, which can be prepared rapidly as in Scheme 17[471. This sequence is comparable in effectiveness with an alternative route1481 because of its speed, even though the last cyclization step is poor («5% yield).


I = + ill

1—s I


Si(CH3)3 OCH,

1. Br2

2. n-BuLi

Scheme 17. CpCo(CO)2-catalyzed synthesis of 3,4-dihydro-l//-cyclobu-ta[a]cyclopropa[d]benzene 39.

3.2. Multiphenylenes and Related Hydrocarbons

The synthetic strategy is based on the palladium-catalyzed ethynylation of halobenzenes1521, on the cobalt-catalyzed cotrimerization of o-diethynylarenes with alkynes to give biphenylenes (Scheme 18)[531, and on the ability of the


R'.R2 = H.alKyl, aryl.C02CH3, Si(CH3)3

Scheme 18. A CpCo(CO)2-catalyzed biphenylene synthesis.

trimethylsilyl group to function as a masked halogen. Scheme 19 depicts the rapid construction of terphenylene 42, the first new member in the series1541.


2. KOH, CH30H

BTMSA. 7 71%

(CH3)3Si (CH3)3Si

Í5- —

'Si(CH3>3 (CH^CQSK®


^-rr ^

Scheme 19. Synthesis of terphenylene.

Cobalt-catalysis has opened up an iterative synthetic approach to the preparation of a novel series of cyclobuta-dienoid1491 aromatic polycyclic hydrocarbons 40, termed multiphenylenes (biphenylene, terphenylene, etc.), in anal-

The cyclization of 1,2,4,5-tetraethynylbenzene to 41 is the first reaction to form four rings in one step. Even though terphenylene has 18 7i-electrons, the system does not behave like an [18]annulene, either physically or chem-

ically. Although the two outer benzene rings show considerably more bond alternation than the central ring, as revealed by an X-ray crystallographic investigation1551, it is the central "cyclohexatriene" which exhibits unusual reactivity : it hydrogenates (all-m) faster than a normal alkene and it adds both electrophiles and alkyllithium reagents. The dianion is surprisingly diatropic1551, suggesting that the system avoids antiaromatic circuits1561.

cocyclization of 1,5-hexadiynes with alkynes can be utilized in the construction of more complex assemblies by exploiting their ability to ring-open thermally to the reactive o-quinodimethanes, which subsequently undergo Diels-Alder cycloadditions119-201. A particularly interesting example is shown in Scheme 21; five of the carbon-carbon bonds of the naphthalene 45 are made in one step1581. The product 45 not only enables a facile synthesis of otherwise

1. (CH3)3SiC"CH pd2©


3. BTMSA , 7

1. (CH3)3SiC»CH pd2®

2. K0H,CH30H

3. BTMSA , 7

(CH3)3Si. (CH3)3Si







Scheme 20. A novel synthesis of hydrocarbons containing biphenylene units.

The methodology for the preparation of 42 is of general utility, as shown by the additional examples in Scheme 20t57l Its effectiveness becomes apparent when one reflects that eleven (!) of the bonds present in 43 are formed by cobalt catalysis; the precursor of 43, 2,3,6,7-tetraiodonaph-

inaccessible 2,3,6,7-tetrasubstituted naphthalene derivatives157'591, but its preparation also demonstrates the feasi-

0Si(CH3)3 E—j/ 3 BTMSA, 7 |

(CH3)3Si (CH3)3Si




(CH3)3Si V Si(CH3)3

(CH3)3Si <CH3)3Si

(CH3)3Si (CH3)3Si

Scheme 21. A one-pot synthesis of naphthalenes according to the "tandem principle"




thalene, is prepared by iodination of 45 (Scheme 21). The cyclization furnishing 44 constructs a record number of, e.g., six rings in one step.

4. Coupling of Alkyne Cooligomerizations and o-Quinodimethane Cycloadditions: The "Tandem Principle"

4.1. A One-Pot Synthesis of Polycycles

Aside from their use in the synthesis of strained ring systems, the 1,2-dihydrocyclobutabenzenes generated by the

BTMSA, 7 80%

BTMSA. 7 45%

Scheme 22. One-pot syntheses of polycyclic compounds according to the "tandem principle".

bility of executing tandem cyclization-cycloaddition reactions. When the latter are carried out intramolecular-ly[58b>601, polycyclic systems are assembled chemo-, regio-and stereoselectively with remarkable ease. Two of several examples are shown in Scheme 22. The observed stereoselectivity appears to be controlled by the intermediacy of an o-quinodimethane formed by conrotatory outward opening of the initially generated 1,2-dihydrocyclobutabenzene, followed by an exo-Diels-Alder closure'58b,60!. Control experiments demonstrate that the metal is not involved in the latter.

4.2. The Cobalt-Way to (±)-Estrone: the D-.-ABCD Approach

5. |2 + 2 + 2]-Cycloadditions of Enediynes: Stereospecific One-Pot Synthesis of Tri- and Tetracyclic Diene Complexes

5.1. Intramolecular Cyclizations of Enediynes with a Terminal Double Bond

Entry 3 in Scheme 3 indicates the potential utility of a cocyclization in which an alkene is employed. The synthetic versatility of such a transformation becomes apparent when one realizes that stereochemical consequences, e. g., ensue upon transformation of a stereochemically defined double bond. There are indeed various organometal-lic compounds which catalyze such reactions'291, one of which is based on the stoichiometric reaction of CpCo(CO)2 leading to cyclohexadiene complexes1621. In order to establish the utility of such a method, purely intra-

Based on the above model systems, a CpCo(CO)2-cata-lyzed steroid synthesis may be designed as in Scheme 23[611, in which in the crucial step the ABC portion of the steroid nucleus is fused onto the D-ring already present. The salient features of this synthesis are:

1. the regiospecific alkylation of 1,5-hexadiyne to furnish 46 and ultimately 47,

2. the stereoselective alkylation of the lithium enolate derived from 48 with 47 to give 49 (two diastereomers),

3. the stereoconvergent cocyclization of 49 to construct steroid 50 stereospecifically,

4. the regiospecific protodesilylation at C-2 of 50, and

5. the oxidation of ring A to furnish racemic estrone. The target molecule 51 is formed in five steps from 2-me-thylcyclopentenone (21% overall yield), and in six steps from 1,5-hexadiyne (14%). The ketal derived from 49 gives even better cyclization yields. Unfortunately, a more direct approach to the A-ring phenol present in estrone by cocyclization of 49 with alkoxyalkynes was not regioselective and suffered from catalyst depletion by cyclobutadiene formation'611.

=-Si(CH3)3 52

=—Si(CH j)j 54

Si (CH3)3

Si(CH3)3 56

Scheme 24. Intramolecular cyclizations of enediynes with terminal double bonds.

molecular cyclization reactions were chosen involving terminal alkenes. Scheme 24 shows examples of the success-

1. n-BuLi.TMEDA

1. TsCL, pyridine

2. NoX, acetone


LiNH2.NH3l 47 4 3%


1. CF3C02H

2. Pb(00CCF3)4

Scheme 23. A CpCo(CO)2-catalyzed synthesis of (±)-estrone.

ful outcome of these attempts129-631. Interestingly, complete stereoselectivity is observed in some cases, its utter absence in others. Thus, 52 leads only to diastereomer 53, whereas the homologue 54 gives an equimolar mixture of 55 and 56. Why this is so remains a mystery. It is attractive to invoke an exo-Diels-Alder type mechanism involving a me-tallacycle of the type 57 leading to 53 (Scheme 25). However, insertion pathways and kinetic metallacyclopen-tene1641 formation cannot be ruled out as alternatives, and it is not clear why merely extending the appendant side-chain by one carbon should completely eradicate any selectivity. More puzzling, the desilylated analogue of 52 is equally unselective in its reactions.

5.2. Intramolecular Cyclizations of Enediynes with Internal Double Bonds: Stereochemistry of the Double Bond

With the demonstration of the successful cyclization of terminal enediynes, it became necessary to establish the scope of the reaction by testing more highly substituted systems, particularly those in which the stereochemical fate of the double bond could be determined. For this purpose a series of internal enediynes was subjected to the cyclization conditions, altered to include photochemical acceleration of CO dissociation (Scheme 27)[67]. It can be seen that

7, A, h»

Scheme 25. Diels-Alder-like mechanism for the reaction 52 ^ 53.

Regardless of this mechanistic question, the method provides an efficient preparation of hitherto inaccessible poly-cyclic dienes, liberated almost quantitatively from their complexes by oxidative demetalation1631. Some preliminary indication has been gathered that dienylsilane moieties such as those present in the cyclization products 53, 55, and 56 may be useful masked functional groups, for example a,p-unsaturated enones1631.

7 ,A, h* 74%

CoCp H3C I H



CpCo Si(CH3)3

cpc° Si(CH3)3


Co^ "SKCH3)3

CPC° Si(CH3)3

Scheme 26. Attack by nucleophiles on CpCo-cyclohexadienyl cations.

The presence of the metal may be beneficial. It protects the diene from rearrangements, polymerization, and (when applicable) protodesilylation. As observed for the analogous isoelectronic tricarbonyliron systems1651, hydride abstraction can be effected with trityl hexafluorophosphate to give cations which are subjectable to nucleophilic attack (Scheme 26). However, the regioselectivity1661 appears unpredictable.

3-1 endo-l e*o-CH3

Scheme 27. Intramolecular cyclizations of enediynes with internal double bonds.

these transformations proceed relatively efficiently and with remarkable stereoselectivity, both with respect to the stereochemistry of the original double bond and the stereochemistry at cobalt. For example, of the four possible diastereomers, the enediyne 58 forms only one, namely 59. The observed selectivity is consistent with mechanisms in which either an enyne unit or the two ethynyl groups undergo initial coupling. Subsequent incorporation of the third unsaturated moiety may then occur by Diels-Alder or insertion pathways. Some possible crucial intermediates arising from the reaction of 58 are depicted in Scheme 28, illustrating the variety of options. It appears in all cases that steric arguments can be invoked to explain the observed stereochemical results. It also transpires that, unlike

Scheme 28. Possible intermediates in the cyclization of 58.

the Diels-Alder and numerous other cycloaddition reactions, the steric encumbrance of the double bond has little influence on the successful outcome of the reaction. The cyclization can therefore be used to accomplish a traditionally very difficult synthetic task: the introduction of quaternary carbon atoms into polycyclic frameworks, particularly those bearing angular methyl groups1681. Currently, the most impressive demonstration of this potential is the conversion of the substrate 60, which contains a tetra-substituted double bond and, under standard conditions (see Scheme 29), affords the tricyclic diene 61 bearing two adjacent quaternary carbon atoms1691. Surprisingly, and perhaps attesting to the (sterically induced?) relatively greater sensitivity of complex 61, filtration through silica gel gave the free ligand in high yield.

7,A,hv 60%

Scheme 29. Cyclization of 60 to 61 with two adjacent quaternary centers.

5.3. Intermolecular Cyclizations of Enynes

Intramolecular [2 + 2 + 2]-cycloadditions of enediynes have found a fair amount of applications, whereas their intermolecular variants have so far been little exploited. Part of the problem appears to be the occurrence of a competing rapid valence tautomerization of the intermediate me-tallacyclopentadiene to give cyclobutadiene complexes. For example, cooligomerization of the a,©-enynes 62 with BTMSA gave mainly 65 and only moderate amounts of the desired bicycle 64[29'701 (Scheme 30). Moreover, only

tivity is observed when 1-trimethylsilyl-l-heptyne is cocy-clized with 62 (n = 3, 4), suggesting that the trimethylsilyi group, as expected, prefers the a-position to the metal upon oxidative coupling to the metallacycle 63. Improvement of the yields awaits the outcome of experiments designed to probe further the stereoelectronic aspects of the reactions.

5.4. The Cobalt-Way to (±)-Estrone: the A-+ABCD Approach

The effectiveness of the cycloadditions depicted in Scheme 24 suggested further application to the total synthesis of steroids in which the BCD portion of their framework would be fused to a pre-existing aromatic A-ring. This approach also provided the opportunity to test the [2 + 2 + 2]-cycloadditions of a 1,1-dialkylated olefin. With this aim in mind, the crucial enediyne precursor 66 was synthesized (Scheme 31)[711, utilizing in the key step a dihy-drothiazole-mediated coupling of benzyl and propargyl halides1721. Reaction of 66 with 7 gave the steroid complex

67 completely stereospecifically, the methyl group at C-13 being positioned exo to the metal. It was surprising to find that the steroidal pentaene ligand 68 had not been described in the literature prior to the present synthesis. There appear to be two reasons for this: firstly, the ligand

68 obtained on oxidative demetalation of 67 is very sensitive, turning into colorless, flocculent, insoluble material on exposure to air; secondly, the position of the diene moiety in 68 is thermodynamically disfavored over that present in 69, into which it can be converted by acid treatment. Compound 69 is the Torgov intermediate in the synthesis of estrone1731; its novel preparation as in Scheme 31



n = 2-4



R Si(CH3)3

R = Si(CH3)3,(CH2)4CH3 ]®[ 65


Scheme 30. Cocyclizations of a,to-enynes with alkynes.

in the case of 64 (n = 2) was stereoselectivity observed in the product. The cyclobutadienes 65 cannot, unfortunately, be induced to re-enter the cyclization manifold, regardless of the application of photochemical, thermal, or oxidative degradation methods. It appears that 63 undergoes relatively slow alkene incorporation. Complete regioselec-

constitutes another formal total synthesis of the racemic natural product. Mechanistically, one could again invoke a Diels-Alder cycloaddition of the type depicted in 57 to account for the stereoselectivity observed. The added bulky ketal group would ensure that the chain connecting diene to dienophile would be placed exo.

FeCI3 78%

H*. H20 95%

Scheme 31. Steroid synthesis by enediyne cyclization.

Similar arguments could be advanced to explain the changes in selectivity encountered in the transformations of 70 into the 7-oxa-5-homosteroid complexes 71 and 72 (Scheme 32)[711. For example, when R=(CH3)3Si, the ke-

R= H, Si (CH3>3 X = 0, O

Scheme 32. A 7-oxa-B-homosteroid synthesis.

talized system 70 (X = 0CH2CH20) produces only 71 (analogous to the conversion of 66 into 67), whereas the ketone 70 (X = 0) leads to a mixture of 71 and 72 in which the latter predominates. This finding is possibly a consequence of the preferred endo-arrangement of the car-bonyl group in the transition state for addition.

5.5. Diastereoselective Cyclizations of Chiral Substrates

Since the [2 + 2 + 2]-cycloaddition of achiral enediynes leads to the formation of ligands containing new chiral centers, it was of interest to investigate the potential diaste-reoselectivity of such a process with chiral substrates. In particular, it was hoped that a mechanistic insight might be gleaned from the reaction of 73, for, if a Diels-Alder-like process involving 74 was operating, steric arguments would have to place the substituent OR2 exo (as shown and as seen in general in intramolecular reactions of this type), ultimately furnishing only 75 (Scheme 33) at the ex-

CpCo r! 75

Scheme 33. Diastereoselective cyclizations of enediynes.

pense of the other three possible diastereomers 76 — 78. However, as the results in Table 1 show'74'751, the outcome

Table 1. Yields of Complexes 75-78.

R1 R2 Relative yields [%] Isolated t

75 76 77 78 yields [%] [h]

Si(CH3)3 CH3 71 26 _ 3 88 4

Si(CH3)3 C6H5CH2 73 23 — 4 85 4

Si(CH3), CH3OCH2 69 24 — 7 91 4

Si(CH3)3 <BuSi(CH3)2 36 52 — 12 94 6

Si(CH3)3 Si(/Pr)3 37 39 6[b] 18 [b] 88 24

Si(CH3)3 fBuSi(C6H5)2 33 [b] 47 [b] — 20 [b] [a] [a]

(BuSi(CH3)2 (BuSi(CH3)2 35 50 — 15 91 6

[a] 44% conversion after 24 h. [b] Not isolated; presence ascertained by NMR spectra.

of this experiment appears to confuse the issue rather than to clarify it. Thus, although the first three entries appear to bear out the premise of Scheme 33, introduction of bulkier OR2-groups, expected to maximize the intermediacy of a species of the type 74 and hence the yield of 75, has exactly the opposite effect. Whether this phenomenon is general for non-silicon-containing groups has yet to be ascertained. The observed results, at odds with the simple Diels-Alder picture, might be more readily explained by invoking 79 as an intermediate formed by initial enyne coupling. Models show that 79 adopts a pseudo-chair config-

R20 ha Cp

uration, placing the OR2 substituent in an initially favorable equatorial position. Upon oxidative coupling, this group emerges severely eclipsed with HA- This effect would lead to the OR2-moieties increasingly preferring to be positioned axially with increasing bulkiness, or to the formation of a boat-shaped transition state in which the prochiral vinyl hydrogen points towards the metal (giving appreciable amounts of 77 and 78, in addition to 75 and 76, as observed).

C —Cl


7,A.hy 72%



FeCl3, HCl

Scheme 34. Diastereoselective steroid synthesis.

of complex 81 (but not observed in the free ligand) is the presence of hindered rotation of the trimethylsilyl group (AH* = 18.8 kcal/mol) on the NMR time scale, the first such impaired mobility observed for a vinyltrimethylsi-lane'771, obviously caused by the bay-region hydrogen at C-l.

6. The Cobalt-Way to Heterocyclic Systems

6.1. Cocyclization of a,oj-Diynes with Nitriles: Synthesis of Cycloalka[l,2-c]pyridines and a Total Synthesis of Vitamin B6

In the early 1970s, several groups independently discovered that cobalt complexes could cocyclize alkynes with nitriles to furnish pyridines in stoichiometric and catalytic reactions (Scheme 35)'78'. Bonnetnann et al. have carried

R1C = N + 2R2CSCH

5.6. A Diastereoselective Steroid Synthesis

The fairly selective outcome of at least some of the examples in Table 1 can be exploited in a diastereoselective steroid construction as shown in Scheme 34'751. The required precursor 80 is readily prepared in good overall yield starting from />-methoxybenzoyl chloride. Cyclization gives mainly 81 (72%) in addition to its 17a-isomer (20%). Oxidative demetalation under acidic conditions converts 81 directly into the known estrapentaenol 82[761, by (presumably in this sequence) loss of metal, diene isomeriza-tion, protodesilylation, and removal of the alcohol protecting group. The free ligand is also obtainable from 81 (81%), and in contrast to 68, is air stable. A curious feature

Scheme 35. Cobalt-catalyzed pyridine synthesis.

out a comprehensive study of the scope and limitations of this reaction'791. Although good control of chemoselectivity is obtained in the preparation of 2-substituted pyridines, product mixtures are formed in the cocyclization of un-symmetrical alkynes (Scheme 35)'791. This potential prob-

lern can be avoided by the use of a,co-diynes (Scheme 36),

n = 3-5 , R = alky I, aryl, CH20CH3, CH2C02C2H5

Scheme 36. Cocyclization of a,<o-diynes with nitriles.

28 + C6H5CN

(CH3)3Si N C6H5

with benzonitrile to give 86[361, an example of the rare iso-quino[2,l-i>]-2,6-naphthyridine nucleus. Similarly, the 2-azaanthracene framework 87 is accessible from 25[351.

in which regioselectivity is controlled by the chelating nature of the1 ajkyne component and by steric effects, whereas chemoselectivity is apparently controlled by electronic interactions1801. Unsymmetrical diynes lead to predominant generation of the sterically less encumbered substitution pattern (Scheme 37). With electron-deficient ni-

Scheme 37. Regioselective cocyclization of unsymmetrical diynes with nitriles.


Employment of excess ethylcyanoacetate in the cocyclization with diynes can lead to further condensation of the intermediate 2-pyridylacetic esters1821. This facilitates the one-pot synthesis of annelated quinolizinones such as 88[35-801.

+ ncch2co2c2h5 excess

C02C2H5 NH2

triles, the reaction fails to give satisfactory yields of pyridines, furnishing instead diyne oligomers. On the other hand, with other nitriles it is remarkably chemospecific, requiring only equimolar amounts of starting materials1801.

Mechanistically, the above results are readily accommodated by invoking initial formation of the metallacycle 83 (Scheme 38). The Co(in) center may now be postulated to

Scheme 38. Mechanism postulated for the formation of annelated pyridines.

Dipropargylamines1831 and dipropargyl sulfides183"1 have been successfully cocyclized to give the corresponding 1,3-dihydropyrrolo- and thieno[3,4-c]pyridines. Based on this principle, but using dipropargyl ether 89 as starting material, a regioselective synthesis of vitamin B6 90 has been

select for nitrile by ligation through its lone pair1811, as in 84, an interaction which becomes noncompetitive with al-kyne complexation in the case of electron-deficient nitriles. Insertion into the less hindered cobalt-carbon bond, placing the nitrogen next to cobalt (85), eventually furnishes the observed products. This mechanism is consistent with the finding that isolated cobaltacyclopentadienes react like 83[78al and lead to substituent patterns similar to those observed in normal pyridine formation1791. However, there is no conclusive evidence ruling out other pathways.

Irrespective of the mechanistic questions, the cocyclization depicted in Scheme 36 is potentially synthetically useful. For example, the diyne 28 cotrimerizes regioselectively

accomplished (Scheme 39)'841. The cyclizations of 89 are the first to employ stannylalkynes, necessary in this case to ensure the successful outcome of electrophilic aromatic substitution on the resulting stannylpyridine.

6.2. Cocyclization of w-AIkynyl Nitriles with Alkynes: Synthesis of Cycloalka[l,2-A]pyridines

Scheme 40 shows a complementary cyclization strategy which enables the preparation of [¿>]annelated pyridines1851. Regioselectivity is again attained in the case of unsymmetrical alkynes, the bulky substituent emerging next to the nitrogen. The successful outcome of this reaction appears

/-= — Sn (CH3>3

S-= -Sn(CH3)3

C 1' 7

I 2. Si 02

CH3 45%

Sn(CH3)3 CH3

2. NaOCH3,CuI 37%

1. HBr

2. AgCl HO 68% HO

Scheme 39. A cobalt-catalyzed synthesis of vitamin B6.

to depend on the efficiency of oxidative coupling to 91, the larger group on either of the original alkynes being lo-


+ ill -C = N R2

7, A, hi/ 25-95%




n = 3-5 R1 and R2 = H, alkyl, aryl, Si(CH3)3, CH20CH3

Scheme 40. Cocyclization of ro-alkynyl nitriles with alkynes.

cated in the a-position to the metal. The trimethylsilyated pyridine derivatives can be further functionalized by elec-trophilic aromatic substitution. A recent extension of Scheme 40 has involved the cyclodimerization of two co-al-kynyl nitrile molecules to give the corresponding cyanoal-kyl-substituted cycloalka[6]pyridines1861. Finally, it should be pointed out that cyclopentadienylcobalt does not appear to be capable of coupling more than one nitrile group in these transformations. This contrasts with Fe2(CO)9, which facilitates the cocyclization of adiponitrile with nitriles to give 1,2,4-triazines1871.

6.3. Cocyclizations of co-Alkynyl Isocyanates: a Total Synthesis of Camptothecin

In analogy to the topological change occurring when going from alkynes to alkenes in [2 + 2 + 2]-cycloadditions, the employment of an imine unit instead of a nitrile in cocyclizations with alkynes could provide a ready synthetic entry to dihydropyridines. Moreover, if the C=N-substruc-ture were to be incorporated into an a,«-doubly unsaturated chain, its cyclization could lead to the rapid construction of polyheterocyclic systems incorporating bridge-

head nitrogen atoms. Although this goal remains to be realized with simple imines'881, isocyanates appear to be suitable substrates in such an endeavor179,89'. In simple cocyclizations leading to substituted pyridones (Scheme 41)[881

+ C6H5'

,N = C = 0 7

Scheme 41. Product distribution in the cocyclization of P-phenethyl isocya-nate with 1-phenyl-1-butyne.

there is a potential problem of regioselectivity179'88,891. However, it may be circumvented by the use of co-alkynyl isocyanates (Scheme 42)'90). Good chemo- and regioselectivity are observed, the latter favoring the bulky substituent (particularly trimethylsilyl) taking up the a-position to the carbonyl group. An intermediate of the type 91 is indicated, but bearing an appendant complexed isocyanato rather than a nitrile group. Unexpectedly, based on steric

? 7 ,A , hv + III -•

0 0 X= 0, (Qb R1 and R2 = o^y'. Ketal, Si(CH3)3 , CH20R

Scheme 42. Cocyclization of <o-alkynylisocyanates with alkynes.

considerations, the trimethylsilyl group always wins out and takes over the a-position, even when in competition with a íerí-butyl group. This finding clearly indicates the operation of both steric and electronic effects with the silyl substituent (see Section 2.4). The silyl moieties in the product allow for selective halodesilylations at C-6'901. In contrast, the halogenation of ordinary 2-pyridones leads to mixtures'9'1. Finally, carbon-carbon bond formation is possible at C-6 by employing palladium-catalyzed coupling reactions of the corresponding 6-iodides'52,92).

Application of the above methodology has led (Scheme 43)'90! to two formal syntheses of the antitumor alkaloid camptothecin 931931 ; one proceeds via the intermediate 921941, the other via 94'95).


-N^ ^ 54%


JLH 2.


nh2 58.5%


1. Os O4 , Na IO4

2. NH2OH HCt,SeQ2 70%


bait system in the presence of terminal alkynes'88'. Evidently, a different mechanism is operating in this system.

7. [2 + 2 + 2]~Cycloadditions Involving

Carbon Monoxide: Cyclopentadienone Formation

7.1. Synthesis of Cyclopentadienones

An alternative to the mode of cyclization depicted in Scheme 3 is provided by cyclization partners with "carbe-noid" atoms, such as isocyanides'971 and carbon monox-ide'13c-981. If multiple insertion pathways could be avoided and product selectivity were controlled, the CpCo moiety should enable a [2 + 2 + 2]-cycloaddition to give five-mem-bered ring systems in the presence of either substrate'136"1. Although isocyanides have not yet proven successful'1001, it has been found that trimethylsilylalkynes undergo such reactions under low-temperature photolytic conditions in the presence of stoichiometric amounts of CpCo(CO)2 7 to furnish complexed cyclopentadienones regioselectively (Scheme 44)'1011.

(CH3)3SiC = CH

7 , hy, - 20°C 70%

Si(CH3)3 0

CpCo Si(CH3)3

major product 95

= — Si ( CH 3 )3

(CH3)3Si /

minor product

7 , h»

Scheme 43. Two total syntheses of camptothecin.

Scheme 44. Formation of cyclopentadienone complexes.

The utility of these complexes lies in their ready decom-plexation (Ce4®) to give the free monomeric cyclopentadienones, which function as extraordinarily reactive substrates in further transformations (Scheme 45)"°'].

Ce4® (CH3)3Si^>V^Si<CH3)3 SCH(C02C2HS)2

95 -► \J -•

It is interesting to note that bis(t|4-cyclooctadiene)nickel, another catalyst reported to catalyze the formation of pyri-dones from alkynes and isocyanates1961, gives not only a different product distribution in the case depicted in Scheme 41, but is also a much poorer catalyst than the co-


<CH3)3 CH(C02C2H5)2

Scheme 45. Nucleophilic addition to 2,5-bis(trimethylsilyl)cyclopentadi-enone.

Metallacyclopentadienes117-261, metallacyclobuteno-nes198-1031, and more complex intermediates11031 have been invoked in the formation of cyclopentadienones from al-kynes and carbonylmetal compounds. All are consistent with the observed product regioselectivity. For example, 95 is the major product in the cyclization of trimethylsilyl-acetylene with 7 (Scheme 44). On the other hand, when (CH3)5C5Co(CO)2 was employed, the corresponding 2,4-disilylated product predominated1'011.



7,hi>,-30°C 20%


Cocyclization of 1-hexyne with BTMSA results in 97 as the exclusive cotrimer11021, indicating further synthetic potential, although the yield is, as yet, unsatisfactory.


100 FeCI3,CH3CN.-40°C

(R= n - C6H,3C=C) 87%

1. FeCI3

2. (C00H)2





1. FeCI3 P

2. H*, H20 (CH3)3Si_

(R = CH30C = C) 75%

Scheme 47. Oxidative decompiexation of the substituted ligands in 100.

7.2. Cobaltocenium Salts as Precursors of Substituted Cyclopentadienes and Cyclopentadienones

Cyclopentadienone complexes of the type 95 can be exploited synthetically if they are activated by methylation to give cobaltocenium salts'1041. In the case of 95, the resulting cation 98 can be ring-selectively and regioselectively attacked by organolithium reagents to give predominantly either 99 (R=bulky substituent, alkyl) or 100 (R = small substituent, alkynyl) (Scheme 46)11051. It is the latter which

zations in conjunction with the use of auxiliary groups, such as for example silicon- or tin-based substituents, allow for the rapid build-up of polycyclic ring systems with extensive control of ring-substitution. However, much remains to be done. The synthetic potential of such [2 + 2 + 2]-cycloadditions, as outlined in Scheme 3, has only barely begun to be explored. Many additional unsaturated organic (and organometallic?) substrates could be envisaged to participate in such a reaction. The possible stereochemical complexity of cyclizations involving in-





\cx5p— 3

lXSi(CH3)3 Co

H--i Si(CH3)3


Co Si(CH3)3

Scheme 46. Nucleophilic additions to cobaltocenium salts.

commands synthetic attention, because highly substituted and functionalized cyclopentadienes or cyclopentenones may be liberated from these species under mild oxidizing conditions (Scheme 47)[1051. Five-membered ring compounds of this type should be useful in the construction of cyclopentanoid natural products11061.

8. Conclusions and the Future

It is clear that the present methodology has not only provided some powerful simplifications in approaches to the construction of natural and medicinal products, but has also given access to novel structures of theoretical and synthetic interest. Chemo-, regio-, and stereospecific cycli-

creasing numbers of double-bonded partners should be elucidated. There must be a host of other catalysts, waiting to be discovered, which might exhibit specific selectivities. The use of optically active ligands in enantioselective transformations should be explored. Novel structures incorporating unusual strain-related and electronic features will become available, and their chemistry should provide further insight into the theories of bonding, derealization, and aromaticity. Finally, why stop at [2 + 2 + 2]? There are many other combinations of one, two, and higher atomic synthons which might be induced to undergo multiple bond-formations in the presence of the appropriate catalyst to supply structures of increasingly higher complexity. Such will be the task of future investigators and collaborators.

I wish to thank my devoted, enthusiastic, and readily stimulated collaborators mentioned in the references. This work was supported by the National Institutes of Health (GM 22479 and in part CA 20 713) and in part by the National Science Foundation (CHE 76-01783, 79-03954, and 8200049).

Received: April 25, 1983 [A 499 IE] German version: Angew. Chem. 96 (1984) 525

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[53] a) B. C. Berris, Y.-H. Lai, K. P. C. Vollhardt, J. Chem. Soc. Chem. Commun. 1982, 953; see also: b) E. R. F. Gesing, J. Org. Chem. 47 (1982) 3192; c) V. Bakthavachalam, M. d'Alarcao, N. J. Leonard, ibid. 49

(1984) 289.

[54] a) B. C. Berris, G. H. Hovakeemian, K. P. C. Vollhardt, J. Chem. Soc. Chem. Commun. 1983, 502; b) J. W. Barton, D. J. Rowe, Tetrahedron Lett. 24 (1983) 299.

[55] G. H. Hovakeemian, K. P. C. Vollhardt, Angew. Chem. 95 (1983) 1001; Angew. Chem. Int. Ed. Engl. 22 (1983) 994.

[56] M. Rabinovitz, I. Willner, A. Minsky, Acc. Chem. Res. 16 (1983) 298.

[57] H. E. Helson, D. J. Pernich, K. P. C. Vollhardt, Z.-Y. Yang, unpublished.

[58] a) R. L. Funk, K. P. C. Vollhardt, J. Chem. Soc. Chem. Commun. 1976, 833; b) J. Am. Chem. Soc. 98 (1976) 6755; 102 (1980) 5245.

[59] J. McKinney, P. Singh, L. Levy, M. Walker, R. Cox, M. Bobenrieth, J. Bordner, J. Agric. Food Chem. 29 (1981) 183.

[60] For reviews see a) G. Quinkert, H. Stark, Angew. Chem. 95 (1983) 651; Angew. Chem. Int. Ed. Engl. 22 (1983) 637; b) R. L. Funk, K. P. C. Vollhardt, Chem. Soc. Rev. 9 (1980) 41; c) T. Kametani, Pure Appl. Chem. 51 (1979) 747; d) W. Oppolzer, Angew. Chem. 89 (1977) 10; Angew. Chem. Int. Ed. Engl. 16 (1977) 10; Synthesis 1978, 793; e) T. Kametani, K. Fukumoto, Heterocycles 8 (1977) 519; f) T. Kametani, H. Nemoto, Tetrahedron 37 (1981) 3.

[61] a) R. L. Funk, K. P. C. Vollhardt, J. Am. Chem. Soc. 99 (1977) 5483; 101 (1979)215; 102 (1980) 5253; b) K. P. C. Vollhardt, Ann. N. Y. Acad. Sci. 333 (1980) 241.

[62] a) Y. Wakatsuki, T. Kuramitsu, H. Yamazaki, Tetrahedron Lett. 1974, 4549; b) Y. Wakatsuki, H. Yamazaki, J. Organomet. Chem. 139 v1977) 169.

[63] E. D. Sternberg, K. P. C. Vollhardt, J. Am. Chem. Soc. 102 (1980) 4839; J. Org. Chem. 49 (1984) 1564.

[64] Y. Wakatsuki, K. Aoki, H. Yamazaki, J. Am. Chem. Soc. 101 (1979) 1123.

[65] a) A. J. Birch, Ann. N. Y. Acad. Sci. 333 (1980) 101; b) A. J. Pearson, Acc. Chem. Res. 13 (1980) 463; Transition Met. Chem. 6 (1981) 67.

[66] a) S. G. Davies, M. L. H. Green, D. M. P. Mingos, Tetrahedron 36 (1978) 3047; b) S. G. Davies: Organotransition Metal Chemistry: Applications to Organic Synthesis, Pergamon Press, New York 1982.

[67] T. R. Gadek, K. P. C. Vollhardt, Angew. Chem. 93 (1981) 801; Angew. Chem. Int. Ed. Engl. 20 (1981) 802.

[68] S. F. Martin, Tetrahedron 36 (1980) 419.

[69] M. Malacria, K. P. C. Vollhardt, unpublished.

[70] C.-A. Chang, J. A. King, Jr., K. P. C. Vollhardt, J. Chem. Soc. Chem. Commun. 1981, 53.

[71] E. D. Sternberg, K. P. C. Vollhardt, J. Org. Chem. 47 (1982) 3447; 49 (1984) 1574.

[72] KL. Hirai, Y. Kishida, Tetrahedron Lett. 1972, 2117.

[73] a) S. N. Ananchenko, I. V. Torgov, Tetrahedron Lett. 1963, 1553; b) A. V. Zakharychev, S. N. Ananchenko, I. V. Torgov, Steroids 4 (1964) 31 ; c) G. H. Douglas, J. M. Graves, G. A. Hughes, B. J. McLoughlin, J. Siddall, H. Smith, J. Chem. Soc. 1963, 5073.

[74] J.-C. Clinet, K. P. C. Vollhardt, unpublished.

[75] J.-C. Clinet, E. Dunach, K. P. C. Vollhardt, J. Am. Chem. Soc. 105 (1983) 6710.

[76] C. Rufer, E. Schroder, H. Gibian, Justus Liebigs Ann. Chem. 701 (1967) 206.

[77] For hindered rotation around silicium-carbon bonds in saturated systems: N. Nakamura, M. Kohno, M. Oki, Chem. Lett. 1982, 1809.

[78] a) H. Yamazaki, Y. Wakatsuki, Tetrahedron Lett. 1973, 3383; J. Chem. Soc. Chem. Commun. 1973, 280; b) H. Bijnnemann, R. Brinkmann, H. Schenkluhn, Synthesis 1974, 575; c) R. A. Clement, US-Pat. 3829429 (1974), duPont; d) K. P. C. Vollhardt, R. G. Bergman, J. Am. Chem. Soc. 96 (1974) 4996.

[79] H. Bijnnemann, Angew. Chem. 90 (1978) 517; Angew. Chem. Int. Ed. Engl. 17 ( 1978) 505.

[80] A. Naiman, K. P. C. Vollhardt, Angew. Chem. 89 (1977) 758; Angew. Chem. Int. Ed. Engl. 16 (1977) 708.

[81] M. Kilner, Adv. Organomet. Chem. 70(1972) 115.

[82] M. E. Neubert in R. A. Abramovitch: The Chemistry of Heterocyclic Compounds, Vol. 14, Part 3, Chapter XI, Wiley, New York 1974, p. 331.

[83] a) A. Naiman, PhD thesis, University of California, Berkeley 1979; b) G. P. Chiusoli, L. Pallini, G. Terenghi, Transition Met. Chem. 8 (1983) 250.

[84] C. A. Parnell, K. P. C. Vollhardt, unpublished.

[85] D. J. Brien, A. Naiman, K. P. C. Vollhardt, J. Chem. Soc. Chem. Commun. 1982, 133.

[86] F. A. Selimov, U. R. Khafizov, U. M. Dzhemilev, lzv. Akad. Nauk Ser. Khim. 1983, 1885.

[87] E. R. F. Gesing, U. Groth, K. P. C. Vollhardt, Synthesis 1984, 351.

[88] R. A. Earl, K. P. C. Vollhardt, unpublished and PhD thesis, University of California, Berkeley 1983.

[89] P. Hong, H. Yamazaki, Tetrahedron Lett. 1977, 1333; Synthesis 1977, 50.

[90] R. A. Earl, K. P. C. Vollhardt, J. Am. Chem. Soc. 105 (1983) 6991.

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[92] R. F. Heck, Org. React. 27 (1982) 345.

[93] A. G. Schulz, Chem. Rev. 73 (1973) 385; b) C. R. Hutchinson, Tetrahedron 37 (1981) 1047.

[94] R. Volkmann, S. Danishefsky, J. Eggler, D. M. Solomon, J. Am. Chem. Soc. 93 (1971) 5576.

[95] a) M. C. Wani, P. E. Rowman, J. T. Lindley, M. E. Wall, J. Med. Chem. 23 (1980) 554; b) Shanghai No. 5 Pharm. Plant, Sei. Sin. (Engl. Transl.) 21 (1978) 87.

[96] a) H. Hoberg, B. W. Oster, J. Organomet. Chem. 234 (1982) C35; 252 (1983) 359; b) Synthesis 1982, 324.

[97] a) Y. Yamamoto, H. Yamazaki, Coord. Chem. Rev. 8 (1972) 225; b) Y. Yamamoto, ibid. 32 (1980) 193.

[98] P. Pino, G. Braca in I. Wender, P. Pino: Organic Synthesis via Metal Carbonyls, Vol. 2, Wiley, New York 1977, p. 419.

[99] a) H. Yamazaki, K. Aoki, Y. Yamamoto, Y. Wakatsuki, J. Am. Chem. Soc. 97 (1975) 3546; b) H. Yamazaki, Y. Wakatsuki, Bull. Chem. Soc. Jpn. 52 (1979) 1239.

[100] R. L. Brainard, K. P. C. Vollhardt, unpublished.

[101] E. R. F. Gesing, J. P. Tane, K. P. C. Vollhardt, Angew. Chem. 92 (1980) 1057; Angew. Chem. Int. Ed. Engl. 19 (1980) 1023.

[102] H. Kaulen, K. P. C. Vollhardt, unpublished.

[103] a) R. Burt, M. Cooke, M. Green, J. Chem. Soc. A 1970, 2981; b) P. A. Corrigan, R. S. Dickson, G. D. Fallon, L. J. Michel, C. Mok, Ausl. J. Chem. 31 (1978) 1937; c) P. A. Corrigan, R. S. Dickson, ibid. 32 (1979) 2147; d) P. A. Corrigan, R. S. Dickson, S. H. Johnson, G. N. Pain, M. Yeoh, ibid. 35 (1982) 2203.

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[105] J. P. Tane, K. P. C. Vollhardt, Angew. Chem. 94 (1982) 642; Angew. Chem. Int. Ed. Engl. 21 (1982) 617; Angew. Chem. Suppl. 1982, 1360.

[106] For reviews and recent studies see a) A. E. Greene, M.-J. Luche, J.-P. Depres, J. Am. Chem. Soc. 105 (1983) 2435; b) M. Demuth, K. Schaffner, Angew. Chem. 94 (1982) 809; Angew. Chem. Int. Ed. Engl. 21 (1982) 820; c) B. M. Trost, Chem. Soc. Rev. 11 (1982) 141; a) L. A. Pa-quette, Top. Curr. Chem. 119 (1984) 1.

Chelation or Non-Chelation Control in Addition Reactions of Chiral a- and p-Alkoxy Carbonyl Compounds

By Manfred T. Reetz*

The addition of C-nucleophiles such as Grignard reagents or enolates to chiral a- or p-al-koxy aldehydes or ketones creates a new center of chirality and is therefore diastereogenic. In order to control stereoselectivity, two strategies have been developed: 1) Use of Lewis-acidic reagents which form intermediate chelates, these being attacked stereoselectively from the less hindered side (chelation control)', 2) use of reagents incapable of chelation, stereoselective attack being governed by electronic and/or steric factors (non-chelation control). Generally, the two methods lead to the opposite sense of diastereoselectivity. It is possible to predict the outcome by careful choice of organometallic reagents containing elements such as Li, Mg, B, Si, Sn, Cu, Zn, or Ti.

New Synthetic Methods (44)

1. Introduction

The two n-faces of a carbonyl compound having at least one chiral center are diastereotopic. Addition of C-nucleophiles such as Grignard reagents or enolates can therefore lead to unequal amounts of diastereomers. Reactions involving such l,n-asymmetric induction'lbcl have been

[*] Prof. Dr. M. T. Reetz

Fachbereich Chemie der Universität Hans-Meerwein-Strasse, D-3500 Marburg (FRG)

termed "diastereofacially selective"'21. Although this phenomenon was observed as early as 1894'11, it was not until the work of Cram et al. that some degree of systematiza-tion was attempted'31. In what is now known as Cram's rule'11, an a-chiral aldehyde (or ketone) such as I1*1 is assumed to adopt a conformation in which the largest of the three a-substituents is antiperiplanar to the carbonyl function, nucleophilic attack then occurring from the less hin-

[*] Only one enantiomer is shown, although a racemate was used leading to racemic products.