A Case for Bond‐Network Analysis in the Synthesis of Bridged Polycyclic Complex Molecules: Hetidine and Hetisine Diterpenoid Alkaloids

Abstract A key challenge in the synthesis of diterpenoid alkaloids lies in identifying strategies that rapidly construct their multiply bridged polycyclic skeletons. Existing approaches to these structurally intricate secondary metabolites are discussed in the context of a “bond‐network analysis” of molecular frameworks, which was originally devised by Corey some 40 years ago. The retrosynthesis plans that emerge from a topological analysis of the highly bridged frameworks of the diterpenoid alkaloids are discussed in the context of eight recent syntheses of hetidine and hetisine natural products and their derivatives. This Minireview highlights the extent to which network analyses of the type described here sufficed for designing synthesis plans, as well as areas where they had to be amalgamated with functional group oriented synthetic planning considerations.


Retrosynthesis and Bondsets
Retrosynthesis has been adopted as the standard approach to identifying synthetic strategies to construct organic molecules.F or many practitioners of organic synthesis, generating as ynthetic plan for the preparation of ac omplex molecule without undertaking ar etrosynthetic analysis is unfathomable. [1] Retrosynthesis,w hich involves breaking the bonds that will be formed in the forward (synthetic) direction, is often guided by knowledge of known transformations to forge those bonds.O ver the years,t he way in which retrosynthetic analyses are conducted has been formalized, led principally by the "Logic of Chemical Synthesis" introduced by Corey. [2] In one approach to retrosynthesis,t he bonds chosen for disconnection are marked on the structure of the target molecule and designated as the bondset for the intended synthesis. [3] Thes election of the individual bonds to be included in abondset hinges upon the topology of the target framework, as well as upon consideration of which functional groups in the target structure may be leveraged to achieve bond formation in the course of the forward synthesis.T hus, consideration of both how to minimize structural complexity in the retrosynthetic direction, as well as what reactions can be employed in the synthetic direction, are taken into account in retrosynthetic analyses. [2] Since ab ondset does not specify the sequence in which individual bonds are to be forged in the synthetic direction, the order in which the bonds are broken must also be considered. In the end, the sequence that emerges for bond formation should correspond to an efficient forward synthesis, in which the attributes of aconvergent versus linear synthesis are maximized. [3] In general, step count in complex molecule synthesis is minimized when an exponential increase in the structural complexity of the intermediates is achieved en route to the target. [4] In the context of ar etrosynthesis,t his requires judicious choice of disconnections that will lead to maximal simplification at each stage.
Ultimately,t he step count and elegance of as ynthesis are heavily influenced by the choice of which bonds are placed in the bondset and when they are generated in the forward synthesis.

Diterpenoid Alkaloids:AClass of Highly Bridged Natural Products
Thed iterpenoid alkaloids are atopologically complex group of molecules that have been shown to possess interesting biological activity,p rimarily in modulating voltage-gated ion channels. [5] Them ost well-known of the diterpenoid alkaloids,t he toxin aconitine,h as long been recognized as an activator of sodium ion channels, [6] whereas the related alkaloid lappaconitine is an anti-arrhythmic agent that functions by blocking sodium ion channels ( Figure 1). [7] On the other hand, talatisamine instead blocks potassium ion channels.T his contrasting biological activity has raised questions about structure-activity relationships among diter-A key challenge in the synthesis of diterpenoid alkaloids lies in identifying strategies that rapidly construct their multiply bridged polycyclic skeletons.Existing approaches to these structurally intricate secondary metabolites are discussed in the context of a"bond-network analysis" of molecular frameworks,w hichwas originally devised by Corey some 40 years ago.T he retrosynthesis plans that emerge from atopological analysis of the highly bridged frameworks of the diterpenoid alkaloids are discussed in the context of eight recent syntheses of hetidine and hetisine natural products and their derivatives.T his Minireview highlights the extent to whichnetwork analyses of the type described here sufficed for designing synthesis plans,aswell as areas where they had to be amalgamated with functional group oriented synthetic planning considerations. penoid alkaloids and their derivatives.This myriad activity,in conjunction with their impressive architecture,h as sparked interest in the total synthesis of diterpenoid alkaloids.
Although several hundred diterpenoid alkaloids have been structurally characterized, [5] only ah andful of these intricate molecules had been synthesized in the laboratory at the beginning of the 21st century. [8] Notably,a fter highly insightful seminal contributions by Wiesner and co-workers [9] on delphinine-type alkaloids,s ynthetic studies toward diterpenoid alkaloids lay practically dormant for almost thirty years.O nly in the last two decades have these natural products come back into focus as targets for chemical synthesis. [10] Thel ack of progress toward the diterpenoid alkaloids can likely be attributed to the challenge posed by the structural complexity of their multiply bridged polycyclic skeletons,a si llustrated by the hexacyclic hetidines and the heptacyclic hetisines ( Figure 2).
Given the complex framework of the diterpenoid alkaloids,afirst level of analysis in generating ap lan for their syntheses is to focus on the molecular skeleton. Hence, abondset might be generated without regard to the functional groups.Clearly,todisregard functional groups in determining the bondset, or to postpone it to al ater phase of synthesis planning,i su nusual. Throughout the 20th century,c hemists have adhered to synthesis strategies that prioritize functional group considerations (functional group oriented synthesis). [11] However,n ature follows ad ifferent scenario in the biosynthesis of terpenes and hence terpene-derived (terpenoid) alkaloids: [12] Them olecular framework of terpenoid molecules is assembled first from alinear precursor containing all the carbon atoms in a" cyclase" phase,f ollowed by as econd "oxidase" phase,i nw hich the skeleton is decorated with functional groups through oxygenation. In terpenoid alkaloids,the incorporation of nitrogen atoms is believed to occur through aM annich condensation or Prins cyclization (with participation of ah ydride), either immediately prior to or during the oxidase phase. [5b] Unsurprisingly,t he way in which terpenoids are constructed in nature has been challenging to mimic in the laboratory setting. [13] Even though mimicking the "cyclase" phase through ac ationic polyene cascade is well-established, [14] accompanying rearrangement steps (e.g.m ethyl shifts,W agner-Meerwein-type rearrangements) can be low yielding in some cases.H owever,t he advent of positionselective C À Ha ctivation/functionalization reactions has paved the way for several impressive syntheses of terpenoids. [15] Thus,although the relatively limited ability to mimic the oxidase phase prevents synthetic chemists from pursuing atruly biomimetic approach to terpenoid synthesis at present, we may still take our cue from nature and consider the skeleton of these topologically complex molecules,independent of functional groups,i nt he initial phase of designing aretrosynthesis.

Where Does One Begin To Identify aBondset?
If retrosynthetic analyses were guided solely by the reactions one would seek to employ in the forward sense, they would be inherently biased toward transformations already known to the practitioner.O nt he other hand, topological analysis of the target, which is carried out without regard for functional groups,m ay identify different disconnections.Since the development of new modes of reactivity is agoal of synthesis,this more objective method can illuminate gaps in the known chemical space.I nt he case of bridged polycycles,s uch as longifolene (1;F igure 3), the most highly

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Chemie bridged ring incarnates the complexity of the system and is, thus,the focus of most topology-based retrosyntheses of these scaffolds.
As the most highly bridged ring is necessarily central to ap olycyclic ring system, it would seem reasonable to select this ring as the starting point for as ynthesis,a nd to sequentially anellate all other rings to this central platform. Such an anellation approach would, however,l ead to as ynthesis with, at best, an inefficient linear increase in complexity. [16] An alternative approach was pointed out by Corey and co-workers in 1975. [18] These authors recognized that retrosynthetic disconnection of certain bonds in the most highly bridged ring would lead to the largest reduction in structural complexity.T oidentify these bonds,one must first identify all the sites at which each primary ring [19] is bridged, keeping in mind that an atom may be bridging relative to one ring but not to another.I nt he case of 1,t he maximally bridged ring is easily identified (see emphasis in 1a). Form ore highly bridged polycycles,i tm ay be beneficial to automate this portion of the retrosynthesis,afeature that Corey and coworkers built into LHASA [18] and Sarpong and co-workers have since adapted into aw eb-based program. [20] It is important to note that not every bond in the most highly bridged ring provides equal simplification upon disconnection. Fore xample,d isconnection of some bonds in 1 (marked red in 1b)w ould generate ap recursor with aprimary ring larger than seven-membered, which is considered challenging to construct in the forward synthesis direction. [18] Therefore,t he remaining bonds (marked green in 1b)are designated as strategic.Further analysis [18] must be applied to rank the merits and importance of the individual bonds marked in green. This additional analysis includes considerations of whether bridging is drastically reduced in the retrosynthetic direction, whether the change in complexity is maximized, [4] and whether dangling substituents are minimized as one disconnects the strategic bonds.
Form olecules that incorporate heteroatoms into their skeleton, separate consideration must be given to any CÀX bonds to determine whether these bonds should be considered strategic. [18] This is due to the relative ease of forming CÀXb onds (the Xg roup is inherently af unctional group). Therefore,o nly as ubset of Coreysr ules apply.I mportantly, C À Xbonds may be considered strategic even if they are part of alarge ring or one that is not maximally bridged.
TheC orey network analysis essentially identifies which skeletal bond(s) of at arget are best constructed last in asynthesis.Ittherefore defines the skeleton of apenultimate intermediate that lacks either the most highly bridged ring or as trategic C À Xb ond. This intermediate is subjected to network analysis to identify the strategic bond(s) for the next disconnection. In doing so recursively, [20] one generates ac omplete bondset, as well as timing for each ring-closing step in the forward synthesis.Atone extreme,anopen-chain precursor containing all skeletal atoms of the target would be generated, [21] and that precursor would then be advanced through n steps into ap olycycle that possesses n rings,w ith each synthetic step closing one additional ring.
An even more rapid increase in complexity would be provided by reactions that form two skeletal bonds at atime, such as cycloadditions, [22] or (if target-relevant) greater than two bonds at atime.Such bicyclizations (or polycyclizations) close multiple rings in one stroke.W hent his concept is applied to the most highly bridged ring, bonds other than those well-suited to one-bond disconnection (cf. 1b)m ay be considered for two-bond (bond pair) disconnection (see 1c). This version of Corey network analysis,w hich has been modified to allow consideration of multiple-bond disconnections in the context of the maximally bridged ring, [23] is referred to herein as bond-network analysis.
Selecting one of several strategic bonds for disconnection is where we see that bond-network analysis does not fully supplant the idea of functional group oriented synthesis,b ut instead complements it. Retrosynthetic disconnections should be chosen at this level to take advantage of inherent functionality in the target molecule where possible,t hereby minimizing the number of peripheral modifications required in the forward synthesis.T he introduction of additional functional handles (and the attendant increase in step count) should be balanced against their ability to facilitate the efficient formation of skeletal bonds.
This approach should enable arational plan to synthesize complex polycyclic targets,s uch as the bridged, architecturally intricate diterpenoid alkaloids.Acritical evaluation of eight relatively recent total syntheses of the hexacyclic hetidine and heptacyclic hetisine classes of alkaloids provides asense of the state of the art. Particular attention is directed to how well each synthesis adheres to the concept of bondnetwork analysis.

Hetidine Syntheses
In the hetidine skeleton (2, Figure 4), ring Fisrecognized as the most highly bridged ring (see emphasis in 2a). This ring is joined to an azabicyclo[3.3.1]nonane skeleton (rings Aand E) as well as to abicyclo[2.2.2]octane ring system (rings Cand D). Hence,retrosynthetic disconnection of either the C9ÀC10 or C14ÀC20 bond in ring Fw ould provide the greatest simplification (see 2b)i ft he analysis were restricted to onebond disconnections.T he set of strategic bonds also includes the two C À Nb onds.
Ad ifferent picture arises when two-bond disconnections (such as the Diels-Alder transform) are considered. To attain maximal retrosynthetic simplification, one of the rings targeted for the two-bond disconnection should still be the most highly bridged ring. Of note,b onds targeted for two-bond disconnection may differ from those designated as strategic for one-bond disconnection. Examples of possible two-bond disconnections of the hetidine skeleton are shown in 2c and 2d.
To address the question of where the community currently stands with regard to achieving the total synthesis of these bridged polycycles,w ea nalyze the reported syntheses of hetidine derivatives.T hese analyses emphasize the framework-forming transformations of intermediates that already contain most or all of the skeletal atoms.
In their synthesis of ahetidine core structure,Sarpong and co-workers [24] sought to employ alate-stage formal bicyclization to construct the [2.2.2] bicycle resident in the framework (Scheme 1). Thek ey bond-forming process started from precursor 3 that contained rings Aa nd D, which were connected by parts of rings Ba nd F. From there,t hey constructed the azabicyclo[3.3.1]nonane system by closing ring E. Thereafter,aseries of refunctionalization steps led to dearomatized intermediate 4.Isomerization to 5 closed rings Fa nd Bb yf orming the C8ÀC9 bond. Although not considered strategic for one-bond disconnection in the full hetidine scaffold (as doing so would form amacrocycle), the C8 À C9 bond is strategic in scaffolds where ring Ci sn ot yet closed, as is the case here.T he latter ring was closed in the final ascent from 5 to give the heptacyclic target. This synthesis followed ar etrosynthetic plan that was identified using bond-network analysis,w hich suggested al ate-stage closure of rings Ca nd Ft hrough ab icyclization transformation (cf. 2c). However,t he analysis did not predicate ao nestep bicyclization, but rather left room for variants in the synthetic direction.
In their approach to the hetidine framework, Qin and coworkers [25] started the late-stage cyclization phase of their synthesis from atricyclic precursor (6;Scheme 2) that already possessed an azabicyclo[3.3.1]nonane system (rings Aand E) and an attached ring D. Thef irst key transformation was ab icyclization that simultaneously formed rings Ba nd Ct o give ketal 7.T hen followed seven refunctionalization steps before ring Fw as closed at the strategic C14 À C20 bond. In accordance with bond-network analysis,the final ring formed in the Qin approach was the maximally bridged ring. Awellprecedented oxidative dearomatization/intramolecular Diels-Alder cascade [26] was applied to forge the bicyclo[2.2.2] framework that preceded the final bond-forming step to construct the hetidine skeleton.
Thea pproach by the Li group to the highly bridged polycyclic framework of septedine [27] started from tricyclic precursor 8,inwhich rings A, B, and Cwere already anellated (Scheme 3). Bicyclization simultaneously closed rings Da nd Scheme 1. Key cyclization steps from the synthesis of ahetidine core structure by Sarpong and co-workers. [24] Scheme 2. Late-stagering formation steps in the synthesis of ahetidine derivative by Qin and co-workers. [25] PIFA = phenyliodine(III) bis(trifluoroacetate).

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Ft og ive pentacycle 9.T his Diels-Alder-type cycloaddition deviates from that seen in the other alkaloid syntheses discussed here in that it is initiated by formation of an enolate rather than by oxidative dearomatization to am asked oquinone.W ith 9 in hand, several steps were undertaken to adjust peripheral substituents,b efore ring Ew as closed in af inal sequence to access septedine.T he Li approach conformed to bond-network analysis in that ab icyclization is employed to construct the maximally bridged ring in the penultimate cyclization step of the synthesis,after which ring Ei sc losed by forging strategic C À Nb onds.I na ddition, the synthesis by Li and co-workers contained elements of ap otentially biomimetic approach in that the nitrogen atom was incorporated at al ate stage through ad ouble reductive amination with ethanolamine.
Liu and Ma [28] addressed the synthesis of the proposed structure of navirine Ci nasynthesis (Scheme 4) that conceptually resembles that of Qin and co-workers, [25] although these efforts were likely pursued contemporaneously.The conceptual similarities are readily apparent in both the retrosynthetic disconnections chosen and how starting material 10 for the synthesis by Liu and Ma resembles compound 6 in the synthesis by Qin and co-workers.H owever,inthe former case,ring Ehad yet to be closed, thereby avoiding complications that would have arisen regarding position-selective (C19 versus C20) attachments to ring E.
Thef irst step involved the well-established oxidative dearomatization of ring D, which enabled formation of the [2.2.2] bicycle within 11 and the simultaneous closure of rings Band C. At this stage,following five refunctionalization steps to generate 12,L iu and Ma employed ah ydrogen-atom transfer [29] to the C13 À C14 double bond to close ring F through the strategic C14 À C20 bond. This process generated 13 with the necessary functionality for the concluding formation of ring E. Overall, this synthesis may be thought of as ah ybrid approach that combines elements of bond-network analysis with bio-inspiration. Then itrogen atom resident in the hetidine framework is introduced early in the form of an itrile group,w hich is critical to the later construction of the maximally bridged ring Fi namanner somewhat reminiscent of the Mannich approach proposed for the biosynthesis of the related aconitine skeleton. [30] In this way,the disconnections utilized by Liu and Ma are potentially biomimetic,but the actual reactions employed in the forward sense are quite dissimilar from the conditions likely in the biosynthesis.
To facilitate comparison of the four syntheses of hetidine derivatives,the following overview illustrates the bondset and timing adopted by each group for the assembly of the hexacyclic skeleton ( Figure 5): Ad ominant feature in all four syntheses is the focus on ac ycloaddition approach to the bicyclo[2.2.2]octane portion (rings Cand D) of the hetidines.Each synthesis incorporates one of these two rings at an early stage to facilitate ab icyclization. Additionally,n one of the syntheses started with ac ompleted ring F, which was closed somewhere along the synthesis route.T ow hat extent did the individual researchers avail themselves of bond-network analysis?T his would be reflected in the closure of ring Finthe last skeletal C À Cb ond-forming step.T his holds for the synthesis by Qin and co-workers [25] of ah etidine derivative which featured early installation of the nitrogen-containing ring E, then followed an optimal plan to assemble the hexacyclic skeleton, ending with formation of the strategic C14ÀC20 bond. Likewise,L iu and Ma [28] formed the C14ÀC20 bond as part of the endgame in conjunction with the closure of ring Eatthe C19 À Nb ond. These approaches are contrasted by the syntheses executed by the groups of Sarpong [24] and Li, [27] in which the researchers instead closed ring Ft hrough bicyclization strategies that utilized bonds that were not considered strategic for one-bond disconnection, and would thus be excluded under Coreyso riginal network analysis.N onetheless,a ll four syntheses adhere to the suggestions of the expanded bond-network analysis in their own way,t hus showcasing how this type of analysis guides retrosyntheses without prescribing the transformations to be used in the forward synthesis.

Hetisine Syntheses
Theh eptacyclic hetisine skeleton (14;F igure 6) contains two primary rings (F and G, labeled differently from hetidine) which are equally highly bridged. Application of bondnetwork analysis [18] to the hetisine skeleton unveils two strategic bonds (C14 À C20 and C9 À C10, see 14 a)i nr ing G, as seen previously in the hetidine analysis (cf. 2a). Bondnetwork analysis of the other maximally bridged ring (ring F) reveals two additional strategic bonds (NÀC6 and NÀC20), as indicated in 14 b.
As examination of the two primary rings (i.e.Fand G) did not point to asingularly attractive synthetic pathway,itwould be appropriate to extend the analysis to af our-t os evenmembered secondary ring. [18] Fort he hetisine skeleton (14), this applies to the highly bridged envelope of rings Ba nd G (cf. 14 c). However,bond-network analysis doesntreveal any further options for late-stage closure of this ring;t he only strategic bond is shared with ring G. Instead, since many bonds in this ring are red-flagged for one-bond disconnection-and here is at wist of the network analysis-this ring could instead be generated early and maintained throughout the synthesis as the majority of strategic disconnections would leave it intact.
Thee xisting syntheses of hetisine natural products and their closely related derivatives are summarized in the following schemes,w ith emphasis on transformations that contribute directly to the formation of skeletal bonds.
In their synthesis of the hetisine alkaloid nominine, Muratake and Natsume [31] utilized tricyclic precursor 15 comprising rings A, B, and an envelope of rings Ca nd Do f the target structure (Scheme 5). They rigidified the system by closing the C14ÀC20 bond, namely ring G. Al engthy sequence following formation of the C14ÀC20 bond culminated in the closure of ring Eb yf orming the C6ÀNb ond to give carbamate 16.M uratake and Natsume then addressed the assembly of the bicyclo[2.2.2] ring system (rings Cand D), followed by several steps to adjust the functionality therein. It was only at the very end of the synthesis that the C20 À Nbond was formed to close ring F, in accord with bond-network analysis (cf. 14 b). Although the penultimate ring closure to form ring Cdid not involve the maximally bridged ring at that stage,a ll other ring-closing steps did align with the bondnetwork analysis.
As econd synthesis of nominine by Peese and Gin [32] followed ad rastically different approach, which focused on early generation of the two most highly bridged rings (Scheme 6). Thea dvanced intermediate (17)t hat was employed contained ring Ac onnected through C19 to an isoquinolinium moiety,r epresenting ring Da nd elements of rings Fa nd G. Thea scent to the nominine skeleton was Scheme 5. Synthesis of hetisine-type diterpenoid alkaloid nominine by Muratake and Natsume. [31] AIBN = azobisisobutyronitrile,C bz = benzyloxycarbonyl, Piv = pivaloyl, py. = pyridine.
Scheme 6. Late-stage cyclization steps in the synthesis of nominine by Peese and Gin. [32] Angewandte Chemie initiated through an inventive 1,3-dipolar cycloaddition that closed rings Ea nd F. After six refunctionalization steps, as econd bicyclization closed rings B, C, and Gi naDiels-Alder reaction. In both bicyclization steps,b onds were formed that were undesirable for one-bond disconnection approaches based on bond-network analysis (see Figure 6). Foremost, this synthesis impresses by its rapid increase in target-relevant complexity,a dvancing from the starting tricycle to the heptacyclic hetisine structure in only two skeleton-building steps.T his underscores the power of bicyclization reactions in the synthesis of bridged polycyclic targets.
In their synthesis of spirasine IV,Z hang et al. [33] initiated their final set of ring-forming reactions from the rather simple precursor 18 (Scheme 7), which possesses only two directly connected rings (A and C). Essential skeletal atoms for rings B, D, F, and Gw ere attached to this bicycle,t hereby facilitating their subsequent assembly.T he ring formations were initiated by a1 ,3-dipolar cycloaddition to form rings F and G, as imilar approach as in the synthesis by Peese and Gin. [32] At this stage,t he remaining atoms,C 18 and C19, of ring Ew ere introduced, and ring Ew as closed to afford pentacyclic intermediate 19.A fter af ew refunctionalization steps,ring Bwas closed through afree-radical addition to the aromatic ring C. Another series of functional group adjustments set the stage for an aldol reaction to close ring Da nd completion of the synthesis in four additional steps.O verall, the synthetic approach adopted here is of the anellation type, where "construction of the most highly bridged core occurs first followed by subsequent crocheting of the remaining rings". Nonetheless,t he synthetic ascent to the hetisine skeleton as at arget is marked by as teady increase in complexity over the four steps that lead to the skeleton. It eschews the principles of bond-network analysis,b ut profits from aw ell-chosen starting point.
In their synthesis of cossonidine,S arpong and co-workers [34] drew upon the groupsp rior synthesis [24] of an avirine precursor by using at ricyclic starting compound (20; Scheme 8) containing rings Aa nd Dc onnected by an envelope of rings Ba nd G, thereby realizing the analysis depicted by 14 c.A si nt he previous synthesis of the hetidine framework, they first forged the C20ÀNb ond. This was followed immediately by formation of the C6 À Nbond, which closed rings Ea nd Ft og ive pentacycle 21.T he ultimate heptacyclic skeleton was reached following the approach used by Peese and Gin [32] to close rings Ba nd Ci naD iels-Alder reaction. Finally,t he functionalities were adjusted in as eries of redox manipulation steps to reach cossonidine in as equence that does not quite give an exponential increase in complexity,b ut does fully align with bond-network analysis.
To facilitate acomparison of the four syntheses of hetisine derivatives in the context of bond-network analysis,t he following overview illustrates the bondset and timing of bond formation chosen by the different groups for the assembly of the heptacyclic skeleton ( Figure 7): As with the hetidine syntheses,b icyclizations are embraced in constructing the hetisine skeleton. These powerful transformations dramatically reduce the number of ringclosing steps required. Another unifying theme that emerged was the manner in which each research group leveraged the nitrogen atom inherent in the framework of the hetisines for strategic bond formation. This is immediately apparent in the three syntheses which utilize aC À Nb ond to close rings directly,b ut is also instrumental to the 1,3-dipolar cycloaddition strategies used in the syntheses by both Zhang et al. [33] and Peese and Gin. [32]

Summary and Outlook
Sections 3a nd 4d etailed the state of the art in the synthesis of bridged polycyclics keletons.T ow hat extent did the scientists behind these syntheses avail themselves of the considerations outlined in Section 2? Af ull answer to that question would require knowledge of all disconnections considered, including the original retrosynthesis and any failed routes.Although this is unfortunately not feasible,one can still discern that the majority of the syntheses described here have several features in common, which provide insight into the elements of asuccessful synthesis.
First, each of the syntheses of bridged polycyclicd iterpenoid alkaloids covered here comprise two phases.T he first phase addresses reaching afully assembled "base camp" (i.e. ak ey intermediate compound), which already contains an umber of connected rings (in the present examples,t wo or three), but with the rigidifying bridges yet to be installed. Attached to the skeleton of the key intermediate are side chains,w hich provide the skeletal atoms of the yet-to-beclosed rings.The second phase of the syntheses comprises the elevation of the key intermediate to the desired hexa-or heptacyclic skeleton of the target by forming strategic bonds to forge the bridging rings.Although "phase one" efforts are not reviewed in the present context, the efforts of "phase two" are highlighted, albeit without significant discussion relating to the functionality present in the target structures.
Asecond trend apparent across the eight syntheses is the preference for bicyclization reactions,w hich achieve particularly rapid increases in target-relevant complexity.I ns even of the eight examples,bicyclization reactions were employed, most often for the construction of the bicyclo[2.2.2]octane ring system present in both the hetidine and hetisine scaffolds.
Thea nellation approach to build bridged polycyclic compounds by the early introduction of the maximally bridged ring (as discussed in Section 2) is adumbrated in only one of the eight syntheses covered (spirasine IV by Zhang et al. [33] ). Ther emainder of the syntheses that were surveyed largely follow bond-network analysis at the retrosynthetic level, even if these disconnections did not translate perfectly to the forward synthesis (see the synthesis of the hetidine core by Sarpong and co-workers [24] ). It is our opinion that abondnetwork analysis approach to retrosynthesis is not consistently employed or considered by the synthetic community at present, but that the degree to which the precepts of bondnetwork analysis are adhered in reported syntheses nevertheless validates the principles outlined in Section 2.
On the other hand, bond-network analysis may not necessarily be the most effective approach in all cases, depending on the functional groupings on at arget molecule. This situation is particularly appreciated in light of previous reports, [35] in which solely following ab ond-network analysis in forward syntheses led to conflicts with the functionalities that needed to be generated. However,t here is value in the fact that bond-network analysis sometimes suggests disconnections where the forward synthesis has no precedent and an ew reaction may need to be developed. Finding creative solutions to challenging problems that may arise in this manner is the lifeblood of organic synthesis.R eaction development enables synthesis,which in turn highlights areas where further reaction development is needed. That cycle advances the frontiers of chemistry and can be driven forward by looking for strategies to accomplish these objectively identified disconnections,e specially when we challenge ourselves to exploit native functionality to do so.
On the basis of the widespread application-conscious or unconscious-of bond-network analysis in successful syntheses of hetidine-and hetisine-type diterpenoid alkaloids,o ne should consider undertaking ab ond-network analysis when planning the synthesis of abridged polycyclic target structure, performing recursive network analyses to obtain hints on disconnections to give key intermediates.S earching within these for hints of the potential application of bicyclization strategies is of paramount importance in assuring ar apid increase in complexity.The final stage in the planning process would then be to ascertain the compatibility of the intended bondset with the functionalities present in the target structure,a sw ell as to consider which transformation and functional group based strategies may be employed to capitalize upon the disconnections identified through bond-network analysis.