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1559

REVIEW

Information Theory Description of Synthetic Strategies in the Polyquinane Series. The Holosynthon Concept

M. Chanon,*

a

R. Barone,

a

C. Baralotto,

c

M. Julliard,

a

J.B. Hendrickson

b

a

AM3 Lab. Case 561. ESA CNRS 6009. Fac. Sciences St Jérôme, 13397 Marseille Cedex 20, FranceE-mail: [email protected]

b

Department of Chemistry. Brandeis University. Waltham, MA 02254–9110. USA; E-mail: [email protected]

c

Provence Technologies. IMT-Technopôle de Château-Gombert, 13451 Marseille Cedex 20, France

Received 4 August 1998

Abstract:

Information theory makes it possible to give a semi-quantitative graphical representation of the various strategies usedto reach a given synthetic target. Skeletal complexity and similar-ity of the precursors with respect to the target structure providefigures which monitor the progress made from the starting mate-rial en route toward the target. Examples selected from thetriquinane family are used to illustrate the benefits but also thepresent limits of such an approach. Whereas for silphinene andhirsutene various synthetic strategies appear in a clear graphicalform when treated within this framework, coriolin shows that theskeleton-only approach provides graphics which can be mislead-ing. To improve this limitation, progress will have to be made inthe treatment of functional complexity from a synthetic point ofview. From a more general point of view, a practical treatment ofstereochemistry within the information theory framework is stillwaited for.The graphical treatment displays clearly the key step(s) in a givenstrategy. Such steps are often characterized by a large change incomplexity and/or similarity. This semiquantitative representationconverges with, on one hand, the interest of some rearrangementsin shorter synthesis and, on the other hand, the interest and thelimits of the class of reactions variously christened as cascades,domino, tandem. The treatment shows also the indissociable

counterpart of these reaction-centered approaches: the structuralentities which make them possible. Such structural entities (holo-synthons) call attention to synthetic strategies where a global part(holos: whole) of the target is looked at, this view complementsthe more classical bond by bond, disconnection approach.

Key words:

information theory, startegy, synthesis, triquinane,silphinene, hirsutene, coriolin, holosynthon

1 Molecular Complexity and Information Theory2 Similarity, an Indispensable Complement of Molecular Com-

plexity3 Present Limitation of Complexity and Similarity Quantification4 Semi-Quantitative Description of Synthetic Strategies Reported

for Polyquinane Natural Products4.1 Silphinene4.2 Hirsutene4.3 Coriolin5 Holosynthons5.1 Definition and Further Development5.2 Good and Less Good Holosynthons

Appendix

1 Molecular Complexity and Information Theory

Chemists have had intuitive feelings about molecularcomplexity. In 1981 Bertz

1

developed a quantitative ap-proach based on information theory

2

and graph represen-tation of molecules.

3

In this approach, the molecular com-plexity is measured as a function of the number and natureof its constitutive atoms and of the number and nature ofthe constitutive bonds. The overall complexity of the mol-ecule is calculated as being the sum of complexities asso-ciated with connectivity factors and complexities associ-ated with the presence of heteroatoms. Hendrickson andToczko

4

have developed a simple algorithm for calculat-ing this complexity for any organic compound. The resultsconverge with a chemist's intuition on many structuralfeatures: a cyclic compound is considered more complexthan its acyclic counterpart; a ramified hydrocarbon ismore complex than its linear counterpart; a molecule withseveral carbons replaced by heteroatoms is more complex.

The virtue of this approach is to provide figures allowingeasy graphical comparisons of synthetic strategies. Wehave used it here as a convenient tool for such compari-sons. Figure 1 shows on simple examples the convergenceof its results with chemical intuition. Its systematic appli-

cation will also reveal its limits in the analysis to come. Ifthese limits are clearly identified, this quantitative ap-proach has the advantage of providing a semi-quantitativeframework to express the beauty of building a complexmolecule out of simple fragments.

Figure 1.

Complexity changes in some classical reactions

1560

M. Chanon, R. Barone, C. Baralotto, M. Julliard, J. B. Hendrickson SYNTHESIS

Biographical Sketches

Michel Chanon

is Professor in the Faculté de Sciences de Saint-Jérôme. He has heldvisiting appointments at the University of London, Indiana University, Kansas State Uni-versity, Texas University, Brandeis University, Osaka University Hyderabad School ofChemistry, Universitad Autonoma de Barcelona. Besides Computer-Aided Synthesis,his research interests include experimental determination of mechanisms and reactivityconcepts, electron transfer and catalysis.

Christophe Baralotto

was born in 1968 and studied chemistry at the University ofMarseille (France) where he received his Ph.D. degree under the supervision of ProfessorMichel Chanon in 1997. His thesis subject was devoted to the study of the holosynthonconcept and its application in practical organic synthesis. In 1998 he left the academicworld to create his own company.

Michel Julliard

is research director at the CNRS. In 1973 he received his ChemicalEngineer and Ph.D. degree at the University of Marseille (France). After post-doctoralwork at the Industrial Physical and Chemistry School (Paris) he moved to ProfessorJaques Metzger’s team where he studied the photochemical behaviour of diaryl triazenes.Since 1983 he has worked on redox photochemistry, electrocatalytic processes, support-ed photosensitization and photoactivation of oxygen. In 1993 he began to apply the pho-toredox properties of phthalocyanines to the photodynamic therapy of cancer cells.

Rene Barone

has been Directeur de Recherche at CNRS since 1986. He has worked inthe field of Computer-Aided Synthesis since 1970. In 1979 he did post-doctoral study inM.L.H. Green’s group to develop the first program able to predict the products and by-products of processes catalyzed by transition metal complexes. In 1981 he began to de-sign programs working on personal computers with the aim of making available to me-dium sized laboratories tools for use in synthesis design. His recent programs HOLO-WIN, CONAN, SESAM are developed along this line.

Professor Hendrickson

took his doctoral degree from Harvard under Professor R.B.Woodward and was on the staff at UCLA before coming to Brandeis, developing re-search programs both in synthetic chemistry and in application of chemistry to the com-puter. Some 40 of his 150 research publications have been concerned with the latter area.

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Information Theory Description of Synthetic Strategies in the Polyquinane SeriesNovember 1998

In this review, we will analyze the different total synthe-ses which have been reported for some natural products ofthe triquinane family: silphinene; hirsutene and coriolin.Fortunately, Mehta’s recent review provides an in-depthcoverage of the recent synthetic achievements in the fieldof polyquinane natural products.

5

This review will allowus to lighten the weight of chemical considerations in or-der to concentrate more on the field as a kind of bench-mark to judge the strengths and weaknesses of informa-tion theory as applied to the comparison of different build-ing strategies.

2 Similarity, an Indispensable Complement of Molecular Complexity

In 1981, when Bertz

1

applied information theory to syn-thetic strategies, his approach was a breakthrough. It per-mitted the description, in a two dimensional way, of theoverall progression of a synthesis. Previously, this pro-gression was only monitored in terms of steps or yields.Bertz's graph plots the number of steps versus the increasein complexity of the target. We propose, now, that a morerealistic way of looking at synthetic strategies has to be atleast tridimensional; Figure 2 illustrates this point. It com-pares an overall synthetic approach to mountain climbing.Starting from the valley (small sized starting material) thechemist follows footpaths to reach a given summit (thetarget). Looking at Figure 2 clearly shows the necessity ofadding something more to the complexity only descrip-tion. Indeed, starting from the valley, one may progresstowards either summit A or summit B. In both cases thecomplexity is increasing. The climber having only a com-plexity measurement of his progress is “blind” with re-

spect to the question “do I aim for A or for B?”. A conve-nient way of circumventing this blindness is to define, atevery step, the distance

6

between the partially synthesizedfragment of the target and the target itself. This distance isdirectly connected to the similarity between this fragmentand the desired target. Actually, the chemist knows whichstructural target he is aiming at; the other advantage ofcompleting complexity by similarity results from an al-most material visualisation of the different strategic ap-proaches.

We have established a rough method of evaluating thesimilarity of two skeletons containing only carbon and hy-drogen atoms (Appendix). For most of the strategies thatwe will examine the progression of the synthesis will berepresented in terms of both complexity and similaritychanges.

Before leaving this mountain metaphor for strategies, letus examine its virtues and shortcomings. Virtues first.This representation clearly shows the crucial importanceof planning the strategy looking in all the directions fromthe summit. In other terms the selection of starting mate-rials is crucial. Indeed if the climber has missed the factthat, not far from the summit, a large plateau exists wherea helicopter could easily land, he may waste his effortsstarting from a far deeper valley. The large plateau obvi-ously corresponds to another natural product starting ma-terial available in suitable quantity. A recent and spectac-ular example has been provided by the synthesis of taxolfrom 10-deacetyl baccatin III.

7

Wipke's SST algorithmhas addressed this problem.

8

What would be even moreuseful is not yet available, i.e., a network-map of naturalproducts displaying the synthetic similarity of naturalcompounds.

Figure 2.

Synthetic strategies and mountain climbing

1562


Another advantage of the representation in Figure 2 is thatit demonstrates the difficulty of ranking strategies. In-deed, depending upon the walker, the selected path maydrastically change. The security-minded walker (industri-al approach) will rather follow a succession of smoothvalleys to reach, with a minimum of bad surprises, the se-lected summit. The highly competitive sportsman willcertainly select a way which challenges his technical andphysical abilities. Another one would just focus on thepleasure of exploring a given aspect of the available path-ways (e.g. exploration of a radical reaction in a new struc-tural context).

Despite its pedagogical attractiveness the shortcomings ofthis representation follow from its roughness. In the nextsection we will examine some of the limits associatedwith the present treatment of complexity and similarity.Even if these two concepts were totally satisfactory interms of quantitative treatment one would still have to an-swer the question “Is a three dimensional space sufficientto represent synthetic strategies?”

In previous work

9

we applied the multivariate statisticalapproach to explore the space of representation of a largeset of solvents. Comparing the present approach to the oneused for solvent classification shows that much remains tobe done to cleanly delineate the “space of synthetic strat-egies”. Other efforts are in progress in this direction.

10

3 Present Limitation of Complexity and Similarity Quantification

As the biological applications of information theory havealready shown,

11

this approach may be rather loose de-spite its mathematical appearance. One of the reasons forthis looseness is that the data which are dealt with are of-ten conceptual rather than material quantities. As suchthey depend critically on the context.

Let us take the example of complexity. The Bertz ap-proach could convey the misleading message “yes there isa unique way of measuring complexity.” In actuality thereare several; the content of complexity in a natural productis not the same for the pharmacologist, the material sci-ence chemist and the synthetic chemist. Even for the syn-thetic chemist the complexity defined by Bertz that we ex-tensively use in this report is rather biased. It stresses theskeletal aspects of structural complexity. As such it con-verges with Hendrickson's description of synthetic prob-lems,

12

since adopted by several groups.

13

It divergeshowever from the actual overall knowledge accumulatedfor decades in synthesis.

Indeed the synthetic aspects of complexity should be di-vided into three components. The first one, skeletal com-plexity, is predominant in polycyclic natural compounds.The second one should be “functional complexity” con-sidered from a synthetic point of view (chemo- and regio-selectivities and protecting group strategies

14

). There ispresently no satisfactory quantitative treatment of this

kind of complexity and we will see, with the coriolin case,that such considerations can play a determining role in theclever synthesis of some families of targets. The thirdcomponent is “stereochemical complexity”. No actual at-tempts has been made to evaluate this complexity.

15

Thesethree components are also reflected in computer-aidedsynthesis programs which are either only skeleton-orient-ed or deal also with functionality

16

and stereochemistry.

17

An equivalent state of imperfection characterizes “molec-ular similarity”. As the blossoming of recent reviews andmonographs

18

shows, this concept is gaining more andmore popularity in molecular sciences. The main incen-tive for this growth is molecular recognition

19

and itspharmacological applications.

20a,b

The scale of similarities for a series of natural compoundsas perceived by the active site of a given enzyme would bequite inappropriate for ranking the similarities of the sameseries from the point of view of synthetic strategy. Someof the structural features of the studied series could be rel-evant for both approaches but others would completelydiffer. The reason is again a question of context. In a pop-ulation of athletes the similarity perceived by an Ameri-can football coach and a polo team coach obviously differ.It is

expected, however, that the American football coachwould do a better job than an average spectator would atselecting the most efficient team. It is within this ratherpragmatic and limited spirit that we have built the similar-ity scale described in Appendix 1.

4 Semi-Quantitative Description of Synthetic Strategies Reported for Polyquinane Natural Products

In this section the synthetic achievements associated withthe targets silphinene, hirsutene and coriolin will be ex-amined within the semi-quantitative framework describedin Sections 1 and 2. To keep this report within a reason-able size, the publications after 1980 have been selectedand some synthetic attempts towards these natural prod-ucts were not discussed if the intermediate finally ob-tained was still too far from the actual target. Because ofthe skeleton-centered approach the syntheses designed toreach a given enantiomer are not examined here sincecomparing the strategies to racemic products with thosefor just one enantiomer of the target would be quite unfair.A more exhaustive treatment may be found in Mehta's re-cent review.

5

All the figures describing complexitychanges versus the progression of the synthesis use a skel-eton-only calculation of complexity. This means that allthe functions (multiple bonds, heteroatoms) have been ne-glected in terms of complexity change. The perspective istherefore a direct application of Hendrickson's simplify-ing approach.

12

The calculation of the overall yield is justthe multiplication of all the yields reported for each ele-mentary step in the published work.

Every synthesis examined is also chemically representedaccording to certain conventions. Only the steps associat-

1563

Information Theory Description of Synthetic Strategies in the Polyquinane SeriesNovember 1998

ed with a change in the carbon skeleton are shown in theschemes. When a transformation has several steps the firstis usually the one inducing a skeletal

change. The symbols“+” and “–” are respectively associated with steps whichare holosynthetic and steps with a yield lower than 60%.The symbol “+–” designs steps possessing both character-istics (strategically interesting but impeded by low yields).The bold numbers placed under each structural formula arethe skeletal complexities calculated by Hendrickson's pro-gram.

4

The italic number stands for a measure of similarityof the given structure with respect to the target. For the sakeof clarity we have gathered the syntheses which, at firstsight, seems to be the best. We stress the point on the arbi-trariness of this choice. In Section 2 we have specificallyexplained that reasons of context may completely upsetranking of syntheses based on simplistic considerationssuch as number of steps or overall apparent yields. Con-cerning the question of uncertainties attached to yields thereader is referred to Hudlicky's lucid discussion.

21

4.1 Silphinene

(Schemes 1–8)

Silphinene synthesis has attracted considerable attentionbecause its angular triquinane skeleton makes it a leadinto the series laurenene, coriolin, retigeranic acid.

22

Figures 3 and 5 gather the descriptions of eight reportedsynthetic strategies (Schemes 1–8). In Figure 3 the select-ed strategies share a common feature: the skeletal com-plexity of silphinene (290) is reached before the seventhstep and as soon as the fourth step a value of 250 isreached. Of the three displayed complexity curves twoshow that a precursor on the way to the target is of highercomplexity than the target itself. This corresponds to anegative situation in terms of atom economy

23

if the at-oms bringing the excedent of complexity have to be elim-inated in a further step toward the target. In both cases theintermediate is obtained by a holosynthetic transforma-tion (see definition in Section 5) so that nothing can bedone to improve further the strategy concerning this point.

Whereas all the strategies gathered in Figure 3 include atleast one step in which

∆

C (increase in complexity) ishigher than 100, Figure 5 describes only two strategies(Itô and Yamamura) which contain such a step. Thesesteps with a large change of complexity often correspondto key steps. Before jumping to the conclusion that thethree other strategies depicted in Figure 5 contain no actu-al key step one has to add two other considerations. Thefirst is that only skeletal complexities have been displayedhere. If a fair semi-quantitative treatment of functional

a) 58%. b) HClO

4

. c) NaOMe. d) Me

2

CuLi. e) LiCl, H

2

O, Me

2

SO; 89% (4 Steps). f) EtCO

2

TMS, TBAF; 89%. g)

h

ν

;

86%. h) TMSI; 89%. i)(

n-

Bu)

3

SnH; 98%. j) LDA, (EtO)

2

POCl; 64%. k) Li, CH

3

NH

2

liq.; 99%. (Overall yield : 22%).

Scheme 1.

Crimmins’ strategy for silphinene synthesis

24

a) Na

+

Cp

-

; 75%. b) Li(Me)C=CH

2

. 71%.

c

) 160˚C; d) H

2

O, PyH, OTs; 68% (2 Steps). e) O

3

. f) KOH; 75% (2 Steps). g) Jones’ reaction; 95%.h) Pb(OAc)

4

, Cu(OAc)

2

; 68%. i) Me

2

CuLi; 89%. j) N

2

H

4

, K

2

CO

3

; 93%. (Overall yield : 15%).

Scheme 2.

Sternbach’s strategy for silphinene synthesis

25

1564


a) 1. Li. 2. NH

3

. 3. NH

4

Cl; 87%.

b

)

h

ν

; 35%. c) Li, CH

3

NH

2

liq.; 66%. (Overall yield : 20%).

Scheme 3.

Wender’s strategy for silphinene synthesis

26

a) CuBr, Me

2

S. b) HCl. c) MsCl. d) DBU. e) MeLi. f) PCC; 70% (5 Steps). g) CuBr, Me

2

S. h) HCl; 100% (2 Steps). i)

p-

MPTC; 100%. j) 200˚C;84%. k) CH

3

Li. l) TsOH. m) CH

3

CO

3

H. n) BF

3

-Et

2

O. o) N

2

H

4

, K

2

CO

3

; 17% (5 Steps). (Overall yield : 10%).

Scheme 4.

Paquette’s strategy for silphinene synthesis

27

a) AlCl

3

. b) HO(CH

2

)

2

OH; 80% (2 Steps). c) NaIO

4

, OsO

4

. d) NaBH

4

. e) HCl, MeOH; 73% (3 Steps). f) Jones’ reaction. g) CH

2

N

2

; 76% (2Steps). h) LDA, MeI; 86%. i) LiAlH

4

. j) PCC. k) N

2

H

4

, KOH; 72% (3 Steps). l) TMS, NaI; 99%. m) DBU; 87%. n) CuI; 70%. o) HCl; 98%.p) POCl

3

; 81%. q) MeLi. r) SOCl

2

. s)

m-

CPBA. t) BF

3

-Et

2

O; 33% (4 Steps). u) N

2

H

4

, KOH; 90%. (Overall yield : 4%).Scheme 5. Itô’s strategy for silphinene synthesis28

a) LDA, TMSCl. b) HC≡C-CO2Et, ZrCl4; 90% (2 Steps). c) CF3SO3TMS; 94%. d) 85%. e) hν; 85%. f) TBAF; 100%. g) H2SO4; 100%. h)CF3SO3SiMe2Thexyl. i) SeO2; 76% (2 Steps). j) C6H5CH2OCNHCCl3; 80%. k) DIBAH. l) MnO2; 73% (2 Steps). m) 80%. n) MnO2; 85%. o)BF3-Et2O. p) TBAF; 50%(2 Steps). q) (COCl)2, DMSO; 89%. r) LDA., MeI; 63%. s) Me2CuLi; 78%. t) N2H4, KOH. u) N2H4, KOH; 46% (2Steps). (Overall yield : 2%).Scheme 6. Franck-Neumann’s strategy for silphinene synthesis29

1565Information Theory Description of Synthetic Strategies in the Polyquinane SeriesNovember 1998

and stereochemical complexities were available it couldwell reveal strong complexity increases for these threestrategies. The second consideration follows from Figures4 and 6. Within a given strategy, similarity is often corre-lated to complexity, as might be expected. In Figure 2,when one progresses from one valley towards the target,the normal evolution is an increase in the complexity ofthe intermediates and an increase in their similarity withrespect to the target. This trend reveals itself in Figure 4.This usual trend led Bertz to state that complexity andsimilarity are correlated.32 Figure 6, however, shows thatthis trend is not always observed.

In the plot describing Franck-Neumann's strategy there isindeed a step in which complexity decreases while simi-larity increases. This step corresponds to g, h, i, j, k, l inScheme 6. The complexity value indeed decreases from216 to 157 while the similarity with respect to silphineneincreases from 45% to 66%. One does not necessarilyneed information theory to pick out this fact. The com-plexity decreases on going from the first intermediate tothe second one because there is one ring less in the secondintermediate. A quick glance at the two intermediates andat the structure of the target convinces any chemist that thesecond intermediate is more similar to the target. This sit-

a) AlCl3; 80%. b) Anodic oxidation; 54%. c) DIBAH. d) Ac2O, Pyr.; 82% (2 Steps). e) H2O; 76%. f) MeMgBr; 72%. g) LiAlH4; 98%. h)Pb(OAc)4; 100%. i) NaClO2; 99%. j) MOMCl; 97%. k) PDC; 35%. l) HCl; 96%. m) NaOEt/EtOH; 100%. n) Me2Cu(CN)Li2; 92%. o, p) SeeCrimmins; 63% (2 Steps). (Overall yield : 6%).Scheme 7. Yamamura’s strategy for silphinene synthesis30

a) NaH; 88%. b) LDA; 90%. c) 1. Li, NH3 liq. 2. NH4Cl; 60%. d) RuCl3, NaIO4; 100%. e) CH2N2; 100%. f) HO(CH2)2OH; 60%. g)CH3P(O)(OMe)2, n-BuLi; 100%. h) HCl; 100%. i) (n-Bu)4NOH; 70%. j) NaBH4; 72%. k) p-MPTC; 70%. l) (n-Bu)3SnH; 70%. m, n) SeeCrimmins; 63% (2 Steps). (Overall yield : 7%).Scheme 8. Nagarajan’s strategy for silphinene synthesis31

1566 M. Chanon, R. Barone, C. Baralotto, M. Julliard, J. B. Hendrickson SYNTHESIS

uation, in which the main change brought by the transfor-mation is on the similarity coordinate rather than on thecomplexity one, is not exceptional. It will be met againlater in this report and is widely illustrated in theliterature33 (Equations 1–3).

Equation 133a

Equation 233b

Equation 333c

Returning to Figure 2, this would correspond to a pathwhich, for a while, seems to lead the climber further awayfrom the summit. Then this path crosses a valley whichgoes more directly towards the selected summit. This pat-tern will help us in proposing a definition of holosynthon(Section 5).

In this treatment of silphinene we have omitted Fraser-Reid's approach.34 The reason is that the selected strategyinvolves several protection-deprotection steps. We willsee with coriolin synthesis (Section 4.3) the limitations ofour approach for this kind of strategy. Taylor’s transition

Figure 3. Evolution of skeleton complexities and similarities (with re-spect of the target) in silphinene synthesis (A)

Sternbach (10 Steps, 15%)Wender (3 Steps, 20%)Crimmins (11 Steps, 22%)

300

250

200

150

100

50

0

Complexity

0 20 40 60 80 100 120

Similarity vssilphinene

Figure 4. Complexities versus similarity (with respect of the target)in silphinene synthesis (A)

Figure 5. Evolution of skeleton complexities and similarities (withrespect of the target) in silphinene synthesis (B)

Figure 6. Complexities versus similarity (with respect of the target) insilphinene synthesis (B)

300250200150100

500

Complexity

0 20 40 60 80 100 120


Franck-Neumann (21 Steps, 2%)Nagarajan (14 Steps, 7%)Yamamura (16 Steps, 6%)

Paquette (15 Steps, 10%)Itô (21 Steps, 4%)

Silphinene

Paquette (15 Steps, 10%)Yamamura (16 Steps, 6%)

Itô (21 Steps, 4%)

Franck-Neumann (21 Steps, 2%)Nagarajan (14 Steps, 7%)

300

250

200

150

100

50

021

0

20

40

60

80

100

SyntheticIntermediates


(Dotted line)

Complexity (Continuous line)

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

300

250

200

150

100

50

0121110987654321

0

20

40

60

80

100



(Dotted line)


SilphineneCrimmins (11 Steps, 22%) Sternbach (10 Steps, 15%)

Wender (3 Steps, 20%)


metal centered strategy35 was skipped for sake of conci-sion.

4.2 Hirsutene (Schemes 9–26)

This sesquiterpene has been taken as a model for syntheticstrategies leading to the hirsutanes.36 The number of re-

ported syntheses led us to treat them in four groups. Thecriterion selected to classify these groups is overall yield.In Figure 7 the complexity and similarity profiles of thebiosynthetic pathway37 and the four most efficient strate-gies (by overall yield) are displayed. A rapid, early growthof complexity and similarity characterizes the Cohen38

and Iyoda40 strategies. The target complexity value ispractically obtained in three steps. Cohen's synthesis isparticularly spectacular from this point of view. Thetriquinane skeleton is built in a highly convergent way bya bis-enolate oxidative coupling step (Scheme 10). Thisone-pot procedure involves four elementary syntheticsteps. A characteristic shared by the three otherstrategies37,39,41 described in Figure 7 is that the increasein complexity precedes the increase in similarity. Thesame pattern is associated with the biosynthetic approach.Iyoda's synthesis (Scheme 12) displays the strategic pro-file closest to the biosynthetic route. Hudlicky'sapproach39 (Scheme 11) illustrates again the point men-tioned above with the Franck-Neumann silphinene syn-thesis. The comparative evolution of complexity and sim-ilarity (steps i,j) shows that a large increase in similarityoccurs (58 to 95%) without any change in complexity.

In Figure 8 three types of strategies appear. The Funk43

and Franck-Neumann45 strategies contain a step with astrong change in complexity about half way to the target.

a) 1. LiC(SPh)3. 2. s-BuLi. 3. FeCl3; 64%. b) Ni Raney; 93%. c)HO(CH2)2OH, TsOH; 86%. d) Li, NH3 liq.; 92%. e) 1. BuLi. 2.Cl2P(O)NMe2. 3. Me2NH. 4. Li, MeNH2 liq. 5. H2O, Me2CO, TsOH;82%. f) CH2=PPh3, KOt-Bu; 96%. (Overall yield : 37%)

Scheme 10. Cohen’s strategy for hirsutene synthesis38

Scheme 9. Biosynthesis of hirsutene37

a) OsO4, NaIO4. b) HOAc; 62% (2 Steps). c) CH2=CHMgBr; 91%. d) CH3C(OEt)3, Hg(OAc)2, EtCO2H. e) KOH, H2O; 82% (2 Steps). f)(COCl)2. g) CH3CHN2; 89% (2 Steps). h) Cu(acac)2; 94%. i) PbCO3, 580°C; 66%. j) H2/PtO2; 90%. k) See Cohen; 96% (1 Steps). (Overallyield: 22 %).

Scheme 11. Hudlicky’s strategy for hirsutene synthesis39

a) hν; 80%. b) TMSI; 95%. c) 1. Li, NH3 liq. 2. MeI; 47%. d) SeeCohen; 96% (1 Steps). (Overall yield: 33%).

Scheme 12. Iyoda’s strategy for hirsutene synthesis40


a) PhSeSO2Ph, hν. b) H2O2; 70% (2 Steps). c) 160°C. d) Jones’ reaction; 72% (2 Steps). e) hν, CH2=CH2. f) NaN(TMS)2, TBSCl. g) m-CPBA;68% (3 Steps). h) Al(Hg)x; 91%. i) Ph3P=CH2, (i-Pr)2O; 86%. j) I2; 91%. k) See Cohen; 96% (1 Steps). (Overall yield: 26%).

Scheme 13. Paquette’s strategy for hirsutene synthesis41

a) CH(OEt)3, TsOH; 95%. b) O3, Ph3P; 100%. c) 81%. d) LiAlH4; 99%. e) HCl; 100%. f) Na2SO4, Pyrrolidine; 99%. g) LiAlH4; 93%. h)Mesitylene; 70%. i) Jones’ reaction; 97%. j) O3, Me2S; 99%. k) Ac2O, Pyr.; 90%. l) Jones’ reaction; 95%. m) 1. (COCl)2. 2. 2-MercaptopyridinN-oxide, t-BuSH; 82%. n) MeOH, Et3N; 95%. o) Ph3PCH3Br, KHMDS; 86%. p) 1. NaH. 2. (COCl)2. 3. Me2CuLi; 97%. q) O3, Me2S; 80%. r)KOH; 97%. s) H2/PtO2; 100%. t) See Cohen; 96% (1 Steps). (Overall yield: 20%).

Scheme 14. Sternbach’s strategy for hirsutene synthesis4

300

250

200

150

100

50

0121110987654321

0

20

40

60

80

100


Similarity vshirsutene

(Dotted line)


Hirsutene

Biosynthesis (5 Steps)Iyoda (4 Steps, 33%)

Paquette (11 Steps, 26%)

Hudlicky (11 Steps, 22%)Cohen (6 Steps, 37%)

Figure 7. Evolution of skeleton complexities and similarities (withrespect of the target) in hirsutene synthesis (A)

Hirsutene

Sternbach (20 Steps, 20%)Franck-Neumann (10 Steps, 13%)

Curran (13 Stepas, 11%)Funk (12 Steps, 13%)

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In contrast, Curran’s approach44 saves the key step for thevery end of the synthesis. Sternbach's smooth approach42

provides the best efficiency by overall yield. This strate-gy, however, is the longest one in terms of steps and thecomplexity of the target is almost reached after only sevensteps (out of 17 overall), but to reach 100% similarity tohirsutene requires ten more steps. This part of the strategyhas been recently improved by Rawal46 using their ap-proach of forming a latent triquinane ((±) endo-hirsutene)out of a norbornane via a Paterno-Büchi reaction. Franck-Neumann’s strategy stands out in Figure 9 with similarityplotted against complexity. This corresponds to the sametype of approach for two similar targets (compare Figures6 and 9). For both targets the key step involves a decreasein complexity coupled with an increase in similarity.

Figures 10 and 11 reveal some new trends. Ley'sapproach48 resembles Funk’s discussed above. This re-semblance is partly fortuitous because our treatment ne-glects functionality changes. The comparison of the twostrategies calls attention to another limit of semi-quantita-tive approaches ranking the “quality” of strategies only in

terms of number of steps. Indeed, here, the shortest strat-egy (number of steps) is also the least efficient (overallyield). In the same spirit of skepticism one may note thatWender's strategy,47 which was a winner with silphineneor isocomene is not among the most competitive when ap-plied to hirsutene. In Weedon’s strategy,50 the intramolec-ular McMurry coupling reaction displays its efficiencymore clearly when monitored in terms of similarity thanwhen monitored in terms of complexity. Figure 11 pointsout one artifact caused by our treatment of similarity. InCossy's strategy49 the introduction of the gem-dimethylgroup by a cyclopropane opening appears as a discontinu-ity in the complexity-similarity diagram. This discontinu-ity has no strategic significance but just follows from ourchoice (Appendix I) to retain the number of rings in struc-tures as a key factor to establish their similarity.

Figure 12 gathers the syntheses with the lowest overallyields. One must stress again that classification by this cri-terion is just a matter of convenience. The gathering of allthe strategies on a single graph would have been undeci-

Figure 9. Complexities versus similarity (with respect of the target)in hirsutene synthesis (B)

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Figure 10. Evolution of skeleton complexities and similarities (withrespect of the target) in hirsutene synthesis (C)

Figure 11. Complexities versus similarity (with respect of the target)in hirsutene synthesis (C)

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Figure 12. Evolution of skeleton complexities and similarities (withrespect of the target) in hirsutene synthesis (D)

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pherable. The reader must keep in mind that: (1) a syn-thesis of 10 steps with an average 80% yield amounts toan overall yield of 10% whereas if the average yield is75% this value drops to 5.6% (2) our description doesnot account for the evolution of functional and stere-ochemical complexities. Of the five strategies displayedin Figure 12, two (Little52 and Mehta54) involve a holo-synthetic step. Mehta's starts with a double jump in com-plexity obtained by a sequence of [4+2] and [2+2] cy-cloadditions. This double jump yields a precursor whoseskeletal complexity exceeds hirsutene complexity by 60units. This excess has to be compensated in the next stepin which a 118 loss in complexity is compensated by a22% gain in similarity.

Returning to Figure 2, this strategy illustrates the situationwherein the climber follows a valley which leads him fur-ther off from the selected summit; he then has to go downinto another one to find his original direction. One maynote in Figure 12 that Hewson's strategy51 also contains aholosynthetic step which “overdoes” what it has beenplanned for. One may speculate about the advantages anddisadvantages of such types of strategy; the interestingfact about the graphical representation is that it revealsthis characteristic at first glance. Fukumoto's strategy53

again illustrates the point that, in terms of overall yield, asafe strategy may be as efficient as one containing half asmany steps. If one had, however, to extrapolate to largerscale preparations the shortest strategy would be, for agiven overall yield, the least costly.

The intramolecular allylsilane addition key step used byMajetich56 to assemble the polycyclic skeleton proved tobe efficient but the synthesis was not carried to the finaltarget. Thus this strategy was not discussed here. Twoother approaches of (±) hirsutene were also not dis-cussed here because they reach precursors on the way tothe target.57,58 For reasons explained in the introductionthe asymetric synthesis of hirsutene were not dealt withhere.59 The “metallo ene reaction–carboxylation” cascadestrategy60 was left aside for saving space.

Figure 13. Complexities versus similarity (with respect of the target)in hirsutene synthesis (D)

a) HO(CH2)2OH, TsOH. b) NaBH4. c) TsCl, Pyr. d) ∆; 50% (4 Steps).e) TiCl4; 71%; f) MeNHOH; 75%. g) MeI. h) H2/Pd; 89% (2 Steps).i) m-CPBA; 90%. j) PCC. k) H2/Pd; 65%. l) See Cohen; 96% (1 Step).(Overall yield : 13%).

Scheme 15. Funk’s strategy for hirsutene synthesis43

a) NaBH4, CeCl3. b) Ac2O, Pyr. c) CH2=CH(OTBS)2. d) ∆. e) PhSeCl. f) H2O2; 62% (6 Steps). g) 75%. h) DIBAH; 83%. i) (CF3CO)2O; Pyr.;81%. j) (n-Bu)4NI; 75%. k) LiC≡C-TMS. l) TBAF; 75% (2 Steps). m) (n-Bu)3SnH; 63%. (Overall yield : 11%).

Scheme 16. Curran’s strategy for hirsutene synthesis44

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4.3 Coriolin (Schemes 27–35)

The main structural characteristic of this triquinane ses-quiterpenoid is its considerable functionality: the carbonskeleton is substituted by two hydroxy and one ketogroup, as well as by two epoxides. We have purposely se-lected this target to show the limits of a “skeleton-onlycomplexity” approach.

Let us first consider the specific problem of the doubleepoxidation needed to obtain the target. Tatsuta64 per-formed this transformation by a one-pot reaction (62%).The same year, Danishefsky68 proposed a four-step trans-formation, far better in terms of stereochemical control,and of comparable overall yield (58%). For saving spacein Schemes 27–35 and Figure 14–16 we have retained the“shorter” Tatsuta's transformation.

In Figure 14 the graphical evolutions of skeletal complex-ities and similarities of the three “best” approaches (com-bination of yields and number of steps) are displayed.Only Curran's synthesis63 (Scheme 29) presents a holo-synthetic character in its last phase; the strategy used inthis phase had already met with success for hirsutene syn-thesis (Section 4.2). Ikegami61 and Ito62 classically builtthe triquinane skeleton starting from a precursor wheretwo out of the three rings constituting the triquinanic skel-eton are already present (Schemes 27 and 28).

Figures 15 and 16 gather the “average” synthesis. In Fig-ure 15, the graph describing Tatsuta’s approach64 undulysuggests a highly holosynthetic step in the first phase of thesynthesis. Actually, the great increase in complexity is theresult of addition of the complexity of the reagent to the oneof the substrate (steps f,g,h,i,j in Scheme 30). The same

a) 1. CuBr, Me2S. 2. HCl; 84%. b) PhCOCl, Pyr; 90%. c) Morpholine, TsOH; 91%. d) 57%. e) HI; 85%. f) H2/Pd; 91%. g) NaOMe; 95%. h)Electrochmical reduction: 45%. i) PCC; 100%. j) See Cohen; 96% (1 Steps). (Overall yield: 13%).

Scheme 17. Franck-Neumann’s strategy for hirsutene synthesis45

a) 1. Mg. 2. Ac2O; 79%. b) hν; 23%. c) 10-camphorsulfonic acid;71%. d) PhSH; 78%. e) H2, [Ir(cod)(pyr)(PCy3)]PF6; 80%. f) NaIO4;86%. g) P(MeO)3, 170°C; 60%. (Overall yield : 4%).

Scheme 18. Wender’s strategy for hirsutene synthesis47

a) 1. KDA. 2. LiAlH4; 86%. b) Me2N=CHBr+ Br-; 90%. c) 1. Mg. 2.CuI; 58%. d) NPSP, TiCl4; 45%. e) LDA, LiAlH4; 66%. f) NPSP, (n-Bu)3P. g) Ni Raney; 63% (2 Steps). h) See Cohen; 96% (1 Step).(Overall yield : 8%).

Scheme 19. Ley’s strategy for hirsutene synthesis48


holds true in Schuda’s synthesis66 (Scheme 32, steps a,b,c).In Tatsuta’s approach64 the key step is better displayed interms of similarity rather than in complexity change (stepsk, l, m, n). This synthesis clearly illustrates the shortcomingof the skeleton-only complexity approach when applied tohighly functionalized targets. Indeed, the graph (Figure 15)would suggest that not much has happened in the syntheticapproach between steps 9 and 19 (steps j to q in Scheme32). Actually this is not true in terms of functionality build-ing. Tatsuta’s approach similarly shows a deceptively inac-tive phase of 8 steps (Scheme 30, steps k to r).

The cyclopropanation technique used in Trost’s approach65

(step j, Scheme 31) introduces the hectic appearance of thesimilarity evolution; this has more to do with our similaritydefinition than with any significant strategic feature.

In Figure 16, Mehta’s54 (Scheme 35) and Wender’s67

(Scheme 33) strategies both stand out with an early holo-synthetic step which leads to precursors whose complexi-ty exceeds that of the target. Danishefsky’s strategy68 alsoallows a very efficient building of the coriolin skeleton.Nevertheless these three strategies which could be consid-ered as holosynthetic from a skeletal perspective are theones with the lower overall yields. These results, obtainedin three excellent synthetic groups, suggest that the use ofa skeletal-only holosynthetic strategy is not necessarily atrump card for any kind of target.

The compared scattering of the graphs displayed in Fig-ures 17 and 18 which plot the sum of the complexities ofprecursors versus the overall yield of the different synthe-ses shows in a different way that the skeleton-only ap-proach gives better results for targets less loaded withfunctionalities.

The recent Kuwajima’s group69 approach presents a verygood overall yield of 10.5%. The skeleton obtained in thiswork differs, however slightly from the actual skeleton ofcoriolin. V.Singh’s70 novel strategy for the construction

a) Pd(OAc)2, (i-PrO)3P; 60%. b) CH2N2, Pd(OAc)2; 99%. c) H2/PtO2;82%. d) KH; 71%. e) LiAlH4; 90%. f) KAPA; 86%. g) PCC; 96%. h)hν; 58%. i) 1. NiCl2(PPh3)2. 2. MeMgBr; 35%. (Overall yield : 5%).

Scheme 20. Cossy’s strategy for hirsutene synthesis49

a) hν; 29%. b) TBSCl, Pyr.; 89%. c) TiCl3, K; 55%. d) TBAF. e) H2/PtO2. f) Jones’ reaction; 62% (3 Steps). g) See Cohen; 96% (1 Step).(Overall yield : 9%).

Scheme 21. Weedon’s strategy for hirsutene synthesis50

a) NaH, TsSMe. b) HO(CH2)2OH, TsOH. c) NaIO4. d) CaCO3; 64% (4 Steps). e) EtNO2, Tetramethylguanidine; 93%. f) TiCl4; 77%. g) TFA;79%. h) NaH; 83%. i) LDA, MeI. j) ∆. k) N2H4, K2CO3. l) m-CPBA; 67% (4 Steps). m) NaH; 72%. n) NaHPO3; 87%. o) HCO2H; 56%. p)RuO2; 42%. q) See Cohen; 96% (1 Step). (Overall yield : 3%).

Scheme 22. Hewson’s strategy for hirsutene synthesis51


a) NaBH4; 74%. b) DIBAH; 76%. c) Ph3PCH=CH2; 88%. d) PCC; 88%. e) Et2NH; 91%. f) . g) KO2CN=NCO2K; 87% (2 Steps). h) 1.Electrochemical reduction ; 55%. i) ∆; 63%. j) 1. BH3. 2. PCC, CeCl3; 56%. k) NaOMe, EtOCHO; 96%. l) n-BuSH, TsOH, MgSO4; 82%. m)KOt-Bu, MeI; 62%. n) KOH, HO(CH2)2OH; 51%. o) See Cohen; 96% (1 Step). (Overall yield : 2%).

Scheme 23. Little’s strategy for hirsutene synthesis52

a) I2, KI, NaHCO3. b) DBU. c) LiAlH4; 58% (3 Steps). d) TBSCl. e) Ac2O, Pyr. f) TBAF; 82% (3 Steps). g) O3, Me2S; 93%. h) Ph3P=CHCOMe.i) PPTS, MeOH; 69% (2 Steps). j) TsOH; 86%. k) LiOH. l) ortho-NO2PhSeCN, (n-Bu)3P. m) H2O2; 66% (3 Steps). n) 1. LDA. 2. TMSCl. 3.Pd(OAc)2; 99%. o) H2/Pd. p) Ph3P=CH2. q) CH2I2, Et2Zn; 50% (3 Steps). r) HClO4. s) Ph3P=CH2; 61% (2 Steps). t) PCC. u) PdCl2, CuCl, O2.v) (n-Bu)4NOH, KOH. w) H2/PtO2; 84%; (4 Steps). x) PCC; 74%. y) See Cohen; 96% (1 Step). (Overall yield : 3%).

Scheme 24. Fukumoto’s strategy for hirsutene synthesis53


of linearly fused cis:anti:cis tricyclopentanoids could pro-vide a rapid access to coriolin in the future.

5 Holosynthons

5.1 Definition and Further Development

The preceding sections have shown that several strategieswere characterized by a step involving a large change incomplexity and/or similarity. In such steps, the transfor-mation is “spread” over several bonds. This “spreading”corresponds, at the conception stage, to a global view ofthe structure as opposed to a more classical disconnectionof one bond at a time. We coined the word holosynthon(holos = global in Greek) to characterize this type of strat-egy.71 A holosynthon is a structural entity specificallydesigned to make a major change of complexity and/orsimilarity possible in a one-pot reaction.

This definition focuses on the kind of starting structureneeded to design a synthesis with a holosynthetic keystep. By extension, one may define a holosynthetic mix-

a) 80˚C; 90%. b) hν; 85%. c) 500˚C; 100%. d) benzyl benzoate,317˚C; 53%. e) H2/Pd; 95%. f) NaH, MeI; 65%. g) Ph3P=CH2; 84%.h) LiAlH4; 90%. i) NaH, Imidazole, CS2, MeI; 88%. j) (n-Bu)3SnH;19%. (Overall yield : 3%).

Scheme 25. Mehta’s strategy for hirsutene synthesis54

a) K2CO3, TsN3. b) hν; 82% (2 Steps). c) NaBH4. d) SOCl2, Pyr.; 72% (2 Steps). e) DBU; 94%. f) NaOH; 96%. g) (COCl)2; 68%. h) AgBF4;38%. i) 1. MeLi. 2. HgCl2, HgO; 93%. j) 1. BuLi. 2. CuI. 3. BF3-OEt2; 60%. k) BzEt3N

+Cl-, KF; 84%. l) TsCl, Pyr.; 94%. m) LiN(TMS)2; 75%.n) NaBH4. o) CS2, NaH, MeI. p) (n-Bu)3SnH, AIBN; 70% (3 Steps). (Overall yield : 3%).

Scheme 26. Magnus’ strategy for hirsutene synthesis55

a) H2O2. b) 40˚C; 66% (2 Steps). c) NaH, BzBr; 91%. d) NBS. e) H2/Pd; 80% (2 Steps). f) PCC. g) TBSCl. h) DBU; 80% (3 Steps). i) Me2CuLi;95%. j) KOt-Bu, MeI; 77%. k) Li, NH3; 63%. l) DHP. m) TBAF. n) PCC; 90% (3 Steps). o) NaH; 94%. p) PdCl2, CuCl; 77%. q) KOt-Bu; 83%.r) LDA, MeI; 78%. s) 1. LDA, PhSeBr. 2. H2O2. t) HOAc; 50% (2 Steps). u) KOt-Bu. v) m-CPBA. w) DBU; 48% (3 Steps). x) See Danishefsky;58% (1 Step). (Overall yield : 1.1%).

Scheme 27. Ikegami’s strategy for coriolin synthesis61


a) AlCl3; 90%. b) NaBH4. c) Jones’ reaction. d) KOt-Bu, MeI; 65% (3 Steps). e) LiAl(OMe)3H; 98%. f) O3, Me2S. g) Jones’ reaction; 76% (2Steps). h) ∆; 84%. i) 1. NaOAm. 2. H2O. 3. CH3I; 100%. j) 1. AlH3. 2. MsCl, LiCl. 3. LiAlH4. k) MsCl, Pyr.; 80% (2 Steps). l) KO2. m) NaBH4;82% (2 Steps). n) BzCl, Pyr. o) BH3, H2O2. p) Jones’ reaction. q) KOt-Bu; 54% (4 Steps). r) Hg(OAc)2; 100%. s) KOH; 60%. t) Isoprenylacetate, TsOH; 90%. u) 1. m-CPBA. 2. NaHCO3, LiOH; 75%. v) DHP. w) LDA, MeI. x) LDA, PhSeBr. y) H2O2. z) HOAc; 65% (5 Steps). aa)See Danishefsky; 58% (1 Step). (Overall yield : 2%).

Scheme 28. Ito’s strategy for coriolin synthesis62

a) NaBH4, CeCl3. b) Ac2O, Pyr; 95% (2 Steps). c) CH2=C(OTBS)2. d) ∆. e) PhSeCl. f) H2O2; 62% (4 Steps). g) Li, CuBr. h) LiAlH4; 90% (2Steps). i) PCC. j) LiC≡C__TMS. k) PCC. l) HO(CH2)2OH. m) TBAF. n) PCC; 30% (6 Steps). o) SmI2. p) TsOH; 60% (2 Steps). q) LDA,TMSCl; 89%. r) DDQ; 72%. s, t, u) See Ikegami; 48% (3 Steps). v) See Danishefsky; 58% (1 Step). (Overall yield : 1.7%).

Scheme 29. Curran’s strategy for coriolin synthesis63


ture using the above definition where “structural entity” isreplaced by “set of reagents”. This extension has applica-tions in terms of combinatorial chemistry.72 The transfor-mations to be applied on the starting holosynthon havebeen the center of much attention during the last decade.The first review to gather data related to this idea was pro-vided by Posner.73 Since this time several reviews havebeen published to cover tandem reactions,74 cascade reac-tions,75 domino reactions;76 a special issue of ChemicalReviews77 edited by Wender (see also ref. 13e) superbly

a) Br2. b) TsOH. c) KOt-Bu. d) NBS. e) AcOAg; 54% (5 Steps). f) hν;35%. g) NaBH4. h) MOMCl. i) NaOMe; 74% (3 Steps). j) TsCl. k)KHCO3, 85˚C; 90% (2 Steps). l) NaI; 81%. m) H2SO4; 94%. n) OsO4;86%. o) CH3C(OMe)2CH3, TsOH; 98%. p) PCC; 89%. q) NaH, Me-thyl-2-nitro-phenyl disulfide; 80%. r) Th(NO3)3; 68%. s) MeLi; 60%.t) Li, NH3; 75%. u) TFA; 93%. v) Ac2O, Pyr.; 78%. w) MeSO2Cl,Pyr. x) LiOH; 46% (2 Steps). y) See Danishefsky; 58% (1 Step).(Overall yield : 0.3%).

Scheme 30. Tatsuta’s strategy for coriolin synthesis64

a) Pd(P(Ph)3)4, DBU; 76%. b) NBS; 89%. c) 1.P(Ph)3. 2. K2CO3. 3. 40˚C; 79%. d) MeSH. e) HO(CH2)2OH; 92% (2 Steps). f) KH, (MeS)2;79%. g) KH; 72%. h) m-CPBA; 63%. i) TBAF; 87%. j) CH2I2, ZnEt2; 82%. k) H2/PtO2; 94%. l) SOCl2; 92%. m) m-CPBA; 87%. n) HClO4. o)DBU; 91% (2 Steps). p) Sodium naphthalenide. q) DBU; 52% (2 Steps). r) Li, NH3 liq. s) m-CPBA; 63% (2 Steps). t) CF3C(O)N(TMS)2. u)LDA, TMSCl. v) Me3N

+,I-. w) MeI. x) DBU; 46%. y) HF; 85%. z) See Danishefsky; 58% (1 Step). (Overall yield : 0.7%).

Scheme 31. Trost’s strategy for coriolin synthesis65

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Figure 14. Evolution of skeleton complexities and similarities (withrespect of the target) in coriolin synthesis (A)


gathered most of the relevant contributions to this idea for“making much chemistry in one step”.

This information theory approach is really not needed torecognize these reactions in a given strategy. When wefirst coined the term holosynthon we were not even awareof Bertz’s approach. We believe, however, that the defini-tion of holosynthon given in terms of complexity and orsimilarity is more closely defined than the intuitive viewsthat we had at first. The graphical representation of strat-egies complements the classical approaches in terms ofnumber of steps and key steps.78 It is particularly appro-priate for polycyclic targets which are not too heavilyfunctionalized.

In Section 4.3. we saw that Bertz’s complexity was rathergood at describing carbon-skeleton complexity changes butrather poor at describing the functional and stereochemicalaspects of complexity. The unsatisfactory treatment of co-riolin strategies above demonstrated the limits of such anarrow view. On the other hand, if one accepts the idea thatcomplexity could be sub-divided into three components theholosynthon approach touches the heart of efficient synthe-sis. Indeed the following examples show that a functionalholosynthon could be a structural unit for which largechanges of functional complexity and/or similarity canbe achieved in a one-pot reaction. Equations (4)79 and(5)80 provide examples of such functional holosynthons:

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Figure 15. Evolution of skeleton complexities and similarities (withrespect of the target) in coriolin synthesis (B)

Figure 16. Evolution of skeleton complexities and similarities (withrespect of the target) in coriolin synthesis (C)

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a) HO(CH2)2OH; 70%. b) 1. Br2. 2. NaOMe. 3. HCl; 59%. c) LiAl(OMe)3H, CuBr; 84%. d) KOt-Bu, MeI; 85%. e) Li, NH3 liq.; 70%. f) KH,BzBr; 89%. g) OsO4; 96%. h) NaIO4. i) NaBH4; 85% (2 Steps). j) t-BuCOCl, Pyr; 48%. k) (CF3SO2)2O, Pyr. l) TBAI. m) Zn; 81% (3 Steps).n) KOH; 100%. o) RuO2, NaIO4; 93%. p) HCl; 85%. q) CH(OMe)3, TsOH. r) 160˚C; 82% (2 Steps). s) Hg(OAc)2; 89%. t) KOt-Bu. u) TsOH;80%. v, w, x) See Ikegami; 48% (3 Steps). y) See Danishefsky; 58% (1 Step). (Overall yield : 0.7%).

Scheme 32. Schuda’s strategy for coriolin synthesis66


a) 1. Li. 2. NH3 liq. 3. Ac2O; 80%. b) O3; 61%. c) Ph3PCH=CH(OEt)2, NaOEt; 55%. d) hν; 15%. e) PhSH, 100˚C; 72%. f) Li, NH3 liq; 80%.g) 1. m-CPBA. 2. H2O; 67%. h) BF3. i) LDA, TMSCl. j) Pd(OAc)2. k) LDA, PhSSO2Ph; 42% (4 Steps). l) HOAc; 100%. m) 1. m-CPBA. 2.77˚C; 64%. n) See Danishefsky; 58% (1 Step). (Overall yield : 0.4%).

Scheme 33. Wender’s strategy for coriolin synthesis67

a) NaH CO2; 63%. b) NaOMe, MeOH; 85%. c) TsOH; 51%. d) 120˚C. e) PhSeCl. f) H2O2; 57% (3 Steps). g) MeLi; 73%. h) O3. i) CrO3. j)Ba(OH)2. k) Pb(OAc)4; 46% (4 Steps). l) KOt-Bu. m) TsOH; 71% (2 Steps). n) KOt-Bu. o) HOAc; 63% (2 Steps). p) DIBAH. q) Li, NH3 liq.r) m-CPBA. s) PCC; 55% (4 Steps). t) 1. LDA. 2. Phenyl(thiophenyl)sulfonate; 40%. u) 1. m-CPBA. 2. 77˚C; 64%. v) H2O2, 0˚C; 58%. (Overallyield : 0.2%).

Scheme 34. Danishefsky’s strategy for coriolin synthesis68


a-f) See Mehta’s synthesis of hirsutene ; 18% (6 Steps). g) MeMgI; 90%. h) POCl3, Pyr.; 75%. i) Li, NH3 liq. 63%. j) m-CPBA; 100%. k)BF3-OEt2; 80%. l) LDA, TMSCl. m) Pd(OAc)2; 90% (2 Steps). n) LDA, PhSeBr. o) H2O2; 35% (2 Steps). p, q, r) See Ikegami; 48% (3 Steps).s) See Danishefsky; 58% (1 Step). (Overall yield: 0.8%).

Scheme 35. Mehta’s strategy for coriolin synthesis54

Figure 17. Overall value of complexities (addition of the complexity of each intermediate) versus overall yield for coriolin.

Figure 18. Overall value of complexities (addition of the complexity of each intermediate) versus overall yield for hirsutene.


Equation 479

Equation 580

The same holds true for stereochemical holosynthons,which would contain a structural unit in which large chang-es of stereochemical complexity and/or similarity could bebrought about in a one-pot reaction. Many recent examplesillustrate this point. We selected only a recent one81 (equa-tion 6) to save space. The endiandric acid cascade (equation7), in a single operation, converts a simple achiral polyeneinto the tetracyclic endiandric acid A methyl ester withcomplete control over eight stereogenic centers.82 This isprobably the most spectacular example showing the syner-gistic action of skeleton and stereochemical complexities inthe synthesis of natural products.

Equation 681

The overall complexity of a structure is the result of thesethree subcomponents. One should strive toward a treat-ment making possible a semi-quantitative treatment of ho-losynthons whose quality derives from their ability to un-dergo one-pot reactions which drastically improve theircomplexity in terms not only of skeleton but also of func-tionality and stereochemistry, or any combination of thethree.

5.2 Good and Less Good Holosynthons

Fukumoto’s approach of hirsutene53 shows that goodstrategies yield efficient results without involving a ho-losynthetic key step. Others, clearly centered on a holo-synthetic key step, were not outstanding in terms ofoverall yields (Section 4.2). This leads to a considerationof which qualities are to be expected for good holosyn-thons and good holosynthetic transformations. A goodholosynthon must be of easy access. If the pleasure ofhaving a spectacular key step is to be paid for by manysupplementary steps, the apparent benefit of the holosyn-thetic transformation has been wasted before the very startof the reaction. The holosynthetic step should have a yieldwhich is not lower than the average yield of the overallsynthesis. Since the holosynthetic step yield is the productof the yields of its component elementary reactions, thiscondition would eliminate many holosynthetic reactionsfrom the box “good holosynthetic reactions”.

Mother Nature is expected to use the concept in biosyn-thetic pathways if it is really efficient, and one should findsome examples of holosynthons in the biosynthesis of nat-ural products. This is indeed the case. The enzyme cata-lyzed conversion of squalene oxide to the plant triterpe-noid dammaradienol (equation 8) illustrates this pointquite explicitly.83

Equation 883

Even more striking in this example is that this holosynthetictransformation is enzymatically catalyzed. Nature makes aformidable challenge to the chemists devoted to the synthe-sis of natural products: to be able to reach the complexity ofthese compounds by a series of catalytic reactions leadingto almost quantitative overall yields. Biosynthetic path-ways, which are less and less studied because they demandtoo much work, should pave the way to a new generation ofstrategies dominantly biomimetic. The key to complexityin natural products is, however, not necessarily enzymati-cally driven as the formation of endiandric acid in naturefrom polyunsaturated precursors proves.84

Equation 782


On the other hand, the critical examination of various holo-synthons in this work suggests that the strategy yielding themost impressive overall yield is not necessarily holosyn-thetic in essence. A critical question before selecting an ef-ficient strategy remains “would this kind of target be adapt-ed to a holosynthetic approach?”. The question is still diffi-cult to answer because new holosynthetic strategies keepappearing in the litterature with a high frequency.

Appendix

Our approach to similarity is comparable to Bertz’scomplexity4 and adapted to be an efficient monitor ofskeletal differences for compounds containing only car-bons and hydrogens. Therefore for compounds like corio-lin the target is simplified by replacing all the functional-ities by the appropriate number of hydrogens. Four struc-tural parameters have been selected to describe everyintermediate in the synthetic tree:

(1) Number of carbon atoms present in the principal skeleton(2) Types of bonds(3) Types of rings(4) Types of bicyclic sub-units.

To make clear the calculation we have treated typical ex-amples in Tables 1–4. Every structural parameter yields avalue of similarity and the average of the four values intaken as an overall index. To calculate the average twomethods are available. The first is just to make the ratio ofthe number of relevant elements (for example atoms) be-tween the two compared molecules. If one compares onemolecule with three carbon atoms in its skeleton with an-other having four, the similarity index associated with thiselement of comparison will be 3/4 × 100 = 75%:

The second method is to add the number of elementsshared by the two molecules and to divide the obtainednumber by the total number of elements. The precedingcase treated according to this scheme would yield a simi-larity of 6/7 × 100 = 86%:

If one had compared a compound containing two ringswith one having three this second method would have giv-en (2+2)/5 × 100 = 80%:

The first type of calculation has been adopted for the cal-culation of similarity associated with the number of car-

Table 1. Similarity of acyclic skeletons

Table 2. Similarity of cyclic skeletons

Table 3. Similarity of polycyclic skeletons (* see Fig. 19)

Figure 19. Types of bicyclic compounds.


bon atoms in the skeleton. The second type has beenadopted for the calculation of similarity associated withthe number of bonds and the number of rings. Since thesimilarity is centered on the carbon skeleton, doublebonds are considered as totally equivalent to simple bondsin the skeleton. This comes to considering that a totallysaturated skeleton is similar to the same skeleton in whichone or several CH2CH2 fragments have been replaced byCHCH fragments. Heteroatoms present in the structureare simply suppressed. The consequence is that the moni-tor of similarity is blind to rings containing heteroatoms;these rings become simple appendages linked to the car-bon skeleton (epoxides are not seen).

The main merit of this crude similarity modelling is its “backof an envelope” character. It was compared with much moreelaborate approaches in the case of coriolin. The results ob-tained with these more elaborate models did not bring muchmore insight for the perspective considered here.

We thank Dr. C. Meyer from Tripos Inc. for applying the algorithm“Unity” from Sybyl to coriolin and its precursors) and Professor G.Maury for stimulating discussions.

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