Clare H Crowston

A Different History Manifesto: Data Need not Be "Big" or "Clean"

This text draws on two ongoing conversations. The first conversation, centered on pedagogies in quantitative history (and in particular on good practices of data-set building), recently gave birth to a short introduction to "Quantitative Methods in the Humanities," published by Claire Lemercier and Claire Zalc with the University of Virginia Press. The second is a conversation among the three co-authors of an in-progress book manuscript on the history of apprenticeship in 18 th and 19 th -century France, (written by the two of us and Steven L. Kaplan). This is a conversation about the history of work, in which gender, occupations, and skill figure prominently. It is also a profoundly methodological conversation, due to the fact that we are writing a history that spans more than two centuries and attempts a national scale and the predominantly economic and quantitative approach that has been taken to apprenticeship in recent years. 1 The scale of our project and the need for comparison across time and space call for macro-level analysis; however, our commitment to reconstituting the complex contexts in which apprenticeship was conceived and practiced -including nuclear and extended families, the church, schools, law courts, etc.require micro-historical approaches. (These dilemmas of a longue durée study are similar to methodological problems raised in the context of "global" history).

In the paper that follows, therefore, we attempt to provide general statements about data and method (which may be familiar to our audience at SSHA but perhaps more surprising to the wider historical community) as they are provoked and illustrated by our ongoing research. In so doing, our aim is to show that these principles are not just abstract compromises to the classical dilemma of "quantitative vs. qualitative" history: they offer added value to research on our specific substantive topic. Coming back to the questions listed in the call for papers on "Data and its Discontents", we could sum up our principles as follows:

Data exists; it is as simple as notes taken from historical sources. We tend to call it "data" when we take our notes in a spreadsheet, but it is really any type of notes taken systematically from historical sources. Our spreadsheets are verbose and most "digital humanists" would want to "clean" them, but we cherish their dirtiness. It is a sign that the transformation from source to data (notes) happened through our own thought processes (not those of underlings paid to sweep the dirt under the rug) and retained the ambiguities of the sources. To make data better, and to have more colleagues crave it and fewer abhor it, we want to keep it as close as possible to the source, even though it will be dirtier, and more costly to produce in large quantities. But that's fine, because we do not believe data is good only if it is really big. It is good if it is complicated, 1 See for example, Stephan R. Epstein, "Craft guilds, apprenticeship and technological change in preindustrial

and thus rich in information, but still systematically acquired and noted in a structured way, so that we can simplify it in many different ways if we want to experiment with it. It is good for thinking, even, or especially, when it produces new questions rather than final answers. This was the manifesto in our title. 2 To flesh out what we mean, this paper will illustrate three main points through cases from our research on apprenticeship in France3 . First, data can help us say something about the meanings and values of the pastfor example on how work performed by different categories of people was valued differently than that of other categories -not just about economic or demographic behaviors. Second, trying to be systematic and to count, if we don't vacuum-clean missing data, can help us notice silences in the sources and thus address important questions, for example on female labor. Third, experimenting with alternative ways to categorize is the only way to learn something new: we strongly oppose attempts to offer tools to "harmonize," "standardize," or "categorize" data that can then putatively be used to respond to any research question. This last point has been at the center of our thinking about who was considered to be an apprentice and how this categorization related to the perceived hierarchy of trades.

I. Meanings from Data: The Value of Female Apprentices

We do not want our book to employ quantitative methods for the economic aspects of apprenticeship and qualitative methods for its cultural aspectsespecially as, in practice, sources and situations generally mix the economic and the cultural. Like other historians, notably those working in the methods of Italian micro-history 4 , we strive to read cultural meaning and value through quantitative data we have created from our reading of historical sources.

To take one example, we studied evidence on early termination of apprenticeship in the eighteenth and nineteenth centuries. One of the most common types of disputes involving apprenticeship had to do with apprentices leaving before the end of the contract (based on evidence from litigation, this was the most frequent complaint brought to the courts in mideighteenth-century Paris and Lyon and in mid-19 th century Paris). From the nineteenth century onward, economists, and commentators generally, claimed that apprentices would be most likely to leave after roughly two thirds of the time, at a moment when they would have learned enough to be able to be employed as waged workers 5 . Since masters and mistresses invested time and resources at the beginning of the contract and would not be remunerated by the apprentices' unpaid labor at the end, courts should redress this loss by granting damages. However, our results show that disputed departures did not occur at the moment identified by economists as the most propitious for an apprentice to depart. This is equally true of mid-19 th century Paris, based on our study of labor court decisions, as it was of Old Regime Lyonwhere detailed guild registers show that about 20% of apprentices from the late 1680s through the 1760s left early, but with no clear clustering of departures at any one point of the contract6 .

If apprentices did not choose to leave at the supposedly most economically profitable moment, nor did their masters and mistresses seem to ask for higher damages if departures happened when two thirds or three quarters of the duration had passed. And judges equally perversely failed to follow the economists' presumptions in their decisions. (This analysis is based on a regression involving judgments from several hundred labor court cases in mid-19 th century Paris that tried to disentangle the correlation between timing and damages from other correlations) So we have learned a little something, however indirect, about visions of the phases of the contract by actors who have not produced manifestoes, diaries, memoirs, or other written sources. But what is perhaps more important is that, for our mid-19 th century sample, the best predictor of damages granted is damages requested. And damages requested varied a great deal, all other things being equal, depending on the gender of the apprentice (not, or not significantly, according to the gender of the master or mistress). Our analysis shows that the mistress of a girl would ask for 95 francs less than the master of a boy, in a context where the median demand was 200 francs. At first sight, this result provides useful but hardly earth-shattering confirmation of the wellknown fact that female labor was valued less than male labor. Upon reflection, however, it raises interesting questions in the specific context of damages for an uncompleted apprenticeship. In particular this finding obliges us to consider the range of possible reasons why masters and mistresses asked for lower damages in these cases. For example, the loss of unpaid work might be less valued, because girls would receive lower wages anyway (this would be an economic calculation by the master or mistress); or the master or mistress might know that the court would not grant as much as for a boy, whatever the demand (especially as the judges were all male), and decide on a more "reasonable" claim. A third possibility is that the cost of the first years of apprenticeship was reckoned to be lower for girls, because it was more legitimate to ask them to perform "services" for the master or mistress' household. Thus, even lacking occupational skills, a girl could contribute valuable labor to the household through gendered domestic activities, such as cleaning, cooking and childcare. This indeed is what our qualitative analysis of a group of detailed cases involving complaints about domestic chores demanded of female apprentices suggests. Thus, our regression makes it clear that girls' labor was "valued" less than boys' labor and demands of us further thought and reflection on how and why this was the case.

II. Results from missing data

The issue of the "value" of apprentices' labor was a case where we had comparable, systematic data on girls and boys, because cases involving apprentices of the two genders were discussed in courts. But of course, the history of female labor is often a story of missing data, and our research is no exception 7 . We surmise, however, that the systematic gathering and quantitative analysis of data can be used to advance source criticism and make better sense of missing data. What was the share of girls among apprentices in Paris and what did they learn? Data gathered by other people offered us seemingly solid answers. The French national archives have created a dataset of metadata on all notarized contracts for 1761 8 . At that time, the notion of "apprenticeship" was supposed to apply only to contracts established in the context of a guild, and guilds mandated that the contracts be notarized. So, if we defined the category on the basis of these legal norms, we found 1,404 new apprentices in 1761; 11% were girls. One century later, the Paris Chamber of Commerce surveyed all industrial and artisanal firms: clerks went door to door to fill in forms and the Chamber published a one-thousand page book that was among the first to use cross-tabulations; in many ways, this enterprise resembles twentieth-century official surveys. 9 Entrepreneurs were asked about their apprentices; the category was not defined in the questionnaire but seemed taken for granted. The Chamber found 19,700 apprentices in 1860; 28% were girls.

Should we conclude that the abolition of the guild system, which had excluded most women from guild membership, had rendered apprenticeship more accessible for girls? As historians of female labor, we knew from experience that a little bit of source criticism was necessary before jumping to conclusions. The more general point here might seem obvious, but is still sometimes ignored by students and even colleagues: source criticism also applies to "data," especially when it was gathered by other people, and especially when it looks very clean. It happens that seamstresses, the largest female guild in Paris, mostly used one notary for their apprenticeship contracts; there were so many contracts that he stored them separately, and those contracts have apparently been lost for 1761. Based on my previous research on seamstresses, 10 I was able to estimate a number of new contracts for that year. Including seamstresses increases the share of girls among new apprentices from ca. 11% to ca. 30%. Did, then, the share of girls slightly decrease from 1761 to 1860, and should we blame the abolition of female guilds? Not exactly. We already knew from a pioneering chapter by Joan Scott that the survey by the Chamber of Commerce should not be taken at face value, especially as regards female labor. 11 But Scott had used external and internal criticism of the text of the 7 On research by "cunning historians" who have written the history of female labor from often missing data, see e.g. the recent survey by Raffaella Sarti, Anna Bellavitis and Manuela Martini, "Introduction", in Raffaella Sarti, Anna Bellavitis and Manuela Martini (eds.), What is Work? Gender at the Crossroads of Home, Family, and Business from the Early Modern Era to the Present, New York, Berghahn Books, 2018, p. 1-84. 8 It was one of the so-called "bases ARNO" and has now become part of the general online finding aid of the National Archives (https://www.siv.archives-nationales.culture.gouv.fr), but thanks to Gilles Postel-Vinay, we have been able to use a tabular version. 9 Statistique de l'industrie à Paris résultant de l'enquête faite par la Chambre de commerce pour l'année 1860, Paris, Chambre de commerce, 1864. The two surveys used the same methods, with small changes in the questionnaire and the presentation of results.

survey to point at its biases. We drew on her insights, but added data criticism based on more data gathering and data analysis. The Chamber of Commerce in fact published two surveys, one on the year 1848, the other on the year 1860. In the survey on 1848, gender was not systematically used as a category to present numbers of apprentices, but a few calculations allowed us to deduce that the Chamber found one thousand fewer female apprentices in 1860 than in 1848, even though the administrative limits of Paris had been expanded and the general population was higher. Comparing results at the scale of trades was not straightforward either, since the Chamber had changed some of its categories, but it led us to conclude that was had happened was most likely that in 1860, the Chamber did not register hundreds of apprentice linen-drapers (lingères), washerwomen and seamstresses. Those were female guilds in the eighteenth century; in the nineteenth century, these apprentices would have worked with female entrepreneurs, often subcontractors.

Our best guess as to the share of girls among Parisian apprentices is thus the one that we could reconstruct for 1848: roughly one third, similar to 1761a finding that we had not anticipated. We could then move on to discuss the fact that their occupations had become a bit more diverse by the mid-19 th century.

III. Experiments in categorizing occupation

As this last point suggests, our aim is not merely to explore differences between situations explicitly considered as "apprenticeship" by the actors, such as in the court cases discussed above. We are also interested in the boundaries of apprenticeship: why some situations were labeled to be "apprenticeships" and others were not, even though they were in many ways similar. We are also very much concerned with perceived hierarchies of skill among youths labeled as "apprentices". In workshops on the history of apprenticeship, we have regularly heard colleagues casually interpreting prices paid to masters by families, or the planned durations of apprenticeships, as being the obvious consequence of the fact that some trades were more "skilled" than others. Of course, you would need more time, and pay more, to become a silversmith than a washerwoman. If one is willing to study conceptions of "skill" among contemporaries rather than imposing one's own prejudices, and to hypothesize that contemporaries might not have all agreed on these conceptions, data on apprenticeship offers interesting ways to think about lived categories, and hierarchies, of occupations.

Our approach to these issues has mostly been to keep the terminology as written in our source and then to aggregate categories based on one specific analytic question after another, using specific criteria for each question. Our general tenet in addressing problems of categorization is that time spent refining our questions and exploring data, including exceptions, weird data, data that seems difficult to categorize is time well spent. As with missing and inconclusive data, weird data often helps to refine questions. In terms of substantive results, this is, we think, more efficient than having colleagues spend a lot of time establishing general reference lists purporting to make comparisons easier between occupations in, say, twelfth-century Iceland and twentiethcentury Nigeria, and other colleagues trying to interpret the exact phrasing of their sources with reference to such lists. We do not object at all to distant comparisons; but we do say that two occupations are equivalent if we decide to consider them as such, for specific substantive reasons they are not, in themselves, to be considered similar because they would be manual, textile, or, even worse, unskilled.

a. Boundaries of Apprenticeship

In the eighteenth century, our research has demonstrated the use of the terms "apprenticeship" and "apprentice" for situations clearly deviating from the model of training within the confines of the guild system with the goal of becoming a guild master. Once again, female labor provides one of the best demonstrations of the conceptual blurriness around what is and was taken as a wellestablished and taken for granted norm. In the thousands of contracts indexed by archivists for eighteenth-century Paris (all the notarized contracts for 1751 and 1761, plus a handful of smaller thematic datasets), I found 94 training contracts for girls with male guild masters, among which 38 girls were described as "apprentices". This was forbidden by guild statutes, but the contracts were still notarized. An even more dramatic appropriation of the term occurred in a number of charitable institutions in late seventeenth-century Paris in which female artisans taught vocational skills to poor female "apprentices" in large classrooms. This training, explicitly labeled as "apprenticeship", also included instruction religious devotion and reading and writing 12 . By contrast, male youths receiving professional training to become merchants, notaries and other skilled occupations were described as "clerks", rather than as apprentices.

After the abolition of the guilds in the eighteenth century, there was still a legal definition of apprenticeship, but it was no longer linked to guilds. As apprenticeship no longer conveyed legal privileges vis-à-vis guild monopolies, the boundary between apprentices and young workers became even more blurred. For example, when asked to count apprentices, administrators gave answers that were clearly based on different definitions of apprenticeship from region to region. 13 Therefore, the fact that we do find apprentices described as such in some census lists and not in others probably signals different readings of situations by the masters and mistresses or by the census clerks as well as empirically different organizations of labor. Census lists provide an invaluable source that places apprentices in the context of a household, giving information on their parents and siblings, or on their master and mistress, the master or mistress's family and the rest of the co-resident workforce. For the nineteenth century, they are also the main source of names and ages of apprentices, information that allows us to track them in other sources and say something about their trajectory. Therefore, the persons labelled "apprentices" in census lists are apprentices for us, because their master or mistress or a clerk described them as such (just as the eighteenth-century charity school girl was), and we compare girls and boys, apprentices in different cities and occupations, those who live with their master or mistress or with their parents, in order to better understand how apprenticeship worked in practice. But we also paid attention to, and gathered systematic data on other teenagers in the same city (in the censuses that we studied, mostly around 1850, few apprentices were younger than 13 or older than 18). This allowed us to derive the proportion of apprentices among teenagers, but also to systematically compare teenagers listed as "apprentices" with those ascribed an artisanal, industrial, or commercial occupation, without an explicit status or labeled as "workers", "boys", "girls", etc.

12 Clare H. Crowston, « L'apprentissage hors des corporations. Les formations professionnelles alternatives à Paris sous l'Ancien Régime », Annales. Histoire, Sciences Sociales, 60-2, 2005, p. 409-441. 13 See for example the answers of prefects in the 1880s in Archives nationales, F12 4831. The census lists that we discuss here have been digitized (as images) and are available on the website of department archives.

For example, in the Caen census of 1856 it is likely that the "baker boys" (garçons boulangers) were in the same social and legal situation as the "apprentice bakers" elsewhere, as we found no "apprentice baker" in Caen. Not noticing such differences in terminology would have led us to misinterpret overall proportions of apprentices in each city. Moreover, systematically comparing ways to describe teenagers across occupationsie those labeled "boys"/"girls," "apprentices," "workers," "clerks" (clerc or employé), "assistants" (commis), etc. or just with the name of the occupationprovides us with interesting hierarchies of occupations, not entirely consistent across places. As in the eighteenth century, a young lawyer would always, everywhere, be a clerk, not an apprentice. 14 In Caen in 1856, a young lacemakerthere were manywould be a lacemaker, not an apprentice or a worker; on the contrary, the two last statuses were mentioned for seamstresses. More generally, girls were rarely called "apprentices" in Caen in 1856, much less often than in Lyon in 1851, for example, in spite of the fact that female guilds had thrived in Caen before the Revolution.

What is crucial to note here is that non-consistent descriptions of teenagers at work in censusesand other documentsare not, for us, an annoyance, something that should disappear thanks to proper "data cleaning." We do not relegate the messy notes to paper in order to achieve a "clean" spreadsheet. On the contrary, a complicated spreadsheet including exceptions and multiple recategorizations is our primary tool. Then calculations can tell us something about the entangled questions of the definition of apprenticeship, on the one hand, and the occupational hierarchy, on the other. We know from discursive sources that apprenticeship was associated with trades that were deemed skilled, but were not considered as professions, like lawyers and notaries; from sources such as the census lists, we confirm this general association, but we can draw precise boundaries, show how these boundaries differed according to time and place, how tight or blurred they were, etc.

b. "Skills" and the division of labor

The same principles apply to the issue of categorizing occupations. Sometimes, a handful of weird cases stimulate ideas for a more general categorization. Not incidentally, some of the eighteenth-century female "apprenticeship" contracts described above labeled the trade to be learnt as a specialty, or a specific task, not by using the name of a guild. For example, the female apprentice of a gilder would learn to gild tobacco boxes. 15 This hints at a division of labor in workshops that was hidden by the names of guilds. One century later, the Chamber of Commerce, in its surveys, praised the economic efficiency of the division of labor and listed as distinct trades activities that had been mere specialties inside eighteenth-century guilds, such as "polishing for jewelers" (a mostly female trade). But it still counted these workers and apprentices as part of the overall "industry" of their masters. It is only incidentally that the survey mentioned that workers with many different specialties in fact still worked in each workshop. For example, the accompanying text on locksmith workshops listed 25 (all male) different names of occupations for their workers; but their respective numbers and wages were not investigated. So we cannot know, for example, how many apprentices in the workshops of locksmiths learned mechanics generally and went on to use this set of skills in a different trade.

Going back and forth between the weird elements of our eighteenth and nineteenth-century sources thus provides a warning against the prevalent idea that apprentices learned all of their master's or mistress's trade and just that; however, it does not allow us to directly measure the transfer of skills. But we can give quantitative answers to other aspects of the general question "what does the division of labor do to the transferability of skills?" We can categorize eighteenthcentury guilds as female, officially mixed, male with only male apprentices, and male with some female apprentices, or according to the uniformity or lack thereof or the description of skills imparted in notarized contracts 16 . Of course this is not direct information about what happened in workshops, but is also related to how individual masters and mistresses had recourse to notaries and the extent to which their occupational identities were encompassed by the guild to which they belonged. These ancillary issues must be taken into account when interpreting numbers. Nonetheless, paying close attention to trade descriptions given in these contracts provides some insight into an otherwise quite elusive question.

Likewise, the lists of workers' occupations in the Chamber of Commerce survey offer us scales of occupations, from those found in just one trade to the most ubiquitous. We thus find mechanics in 43 different trades in the survey for 1860, lathe hands (tourneurs) in 41 trades; and, among female occupations, polishers in 21 trades, burnishers (brunisseuses), who also treated the surface of metals, in 19. This is not to be taken as a direct and complete measurement of transferability either. It is likely, for example, that those who answered the questionnaire, the clerks, and the authors at the Chamber themselves, especially in the second survey, were less interested in the inner workings of workshops led by women than those led by men. Yet there are few if any other sources that give this level of detail on hundreds of trades.

Aware of these caveats, we used the indicator of the degree of division of labor, or diversity of skills, as one variable among others to describe each trade listed by the Chamber of Commerce. Other variables, such as the share of very small workshops, the proportion of female workers, or of apprentices in the workforce, were more directly copied or calculated from the survey. From a dozen such variables describing the workforce generally, we derived an automatic classification of 136 trades into four contrasted classes. 17 Then we checked the correlations between these classes of trades and variables that more specifically described the conditions of the apprenticeships. Our analysis showed that the four classes also differed in terms of conditions of apprenticeship, thus seemingly confirming the empirical evidence for the validity of the classification. For example, contracts were longer in one class than in the others; apprentices were more often only paid in kind in one of the classes. There is some correlation between these classes derived from data on the workforce and classical groupings, e.g. food vs. fashion, but not much, and there is almost no correlation with the fact that the trade had had a guild in the eighteenth century or not. We have thus taken data gathered, with many biases, by the Chamber of Commerce, we have processed it, on the basis of a critical scrutiny of the source, to build categories of trades that are absent from the source but, in our view, make sense as a description of the workforce. This analysis has produced new knowledge on apprenticeshipand possibly on Parisian industry generally. Yet we emphasize that a different research method could process the data differently and produce different, albeit equally valid, classes of trades.

*

In this presentation, we have given several short examples, at the expense of proving precise details on any of them, because it is important for us that the apprenticeship project relies on many different datasets, not just one. Comparing datasets, over time, space, and types of sources, helped us to better spot missing data, make sense of weird cases, and generally perform source criticism. It's not that the errors cancel themselves out, but the biases become more visible and we can make conscious decisions about what to do about them.

The consequence is also that we do not have one really big database, and that each is indeed quite small. For example, our census data is based on a sample of streets for Lyon and Caen, and we cannot dream of studying more than four or five places for one or two dates based on censuses. Well, we could, but we would need to divide labor much further and we have decided against it. We have inputted most of our data ourselves; for some of the sources that were easy to copy, especially censuses, we have used students, but we followed their work closely so as to incite them not to "clean" the data themselves, and we then categorized data in multiple ways, not just in order to produce results, but to grasp what was in the source as if we had read it (and we did so while striving to pay them a living wage for their labor). Colleagues often think that they will hate data if they input it themselves, because it will be so boring, and they will have to leave apart, or take as separate notes, everything that is really interesting in sourcesstories, exceptions, strange language. We think that we can make them crave data if we consider that constructing data is just a slightly different way to take notes. This implies that we, and they, have to learn to sample for rich data, rather than hiring armies of data workers. statistically associated or not to a series of other variables such as economic sectors defined by the Chamber of Commerce (food, clothing, etc.), the existence of a guild before 1791, etc. and to variables related to the conditions of apprenticeship (duration, etc.).

  10 Clare Haru Crowston, Fabricating Women : The Seamstresses of Old Regime France, 1675-1791 (Duke University Press, 2001). 11 Joan W. Scott, « Statistical Representations of Work: The Chamber of Commerce's Statistique de l'Industrie à Paris, 1847-48 », in Steven L. Kaplan & Cynthia J. Koepp (eds.), Work in France: representations, meaning, organization, and practice, Ithaca, Cornell University Press, 1986, p. 335-363, discussing Statistique de l'industrie à Paris résultant de l'enquête faite par la Chambre de Commerce pour les années 1847-1848, Paris, Guillaumin, 1851.

  The little something is interesting because it contradicts what almost everybody who had access to print wrote and what economic historians have long maintained about apprenticeship.

The title alluded to David Armitage et Jo Guldi, The History Manifesto, Cambridge, Cambridge University Press, 2014, which, in our view, only revived the "quantitative vs. qualitative history" divide and the lack of attention of some first-generation quantitative historians to the construction of data.

We give more details on most of these cases in Clare H. Crowston, Steven L. Kaplan, and Claire Lemercier, (2018), « Les apprentissages parisiens aux XVIII e et XIX e siècles », AnnalesHSS, vol. 73, n°

4, published in a special issue about the renewals in quantitative history (still forthcoming, in spite of the 2018 date, and to be published in English in 2020).4 One of our main references here is the use of prices (in the context of sales of land) to reveal values and social norms in Giovanni Levi, Inheriting power: the story of an exorcist, Chicago, University of Chicago Press, 1988.5 Patrick Wallis, "Apprenticeship and Training in Premodern England", Journal of Economic History,68-3, 2008, p. 832-861 discussed this in the context of twentieth-century economics, but this "two-stage model" of apprenticeship was already ubiquitous in texts by nineteenth-century commentators, for example Édouard Ducpétiaux, De la condition physique et morale des jeunes ouvriers et des moyens de l'améliorer. Tome 2, Bruxelles, Méline, Cans et cie, 1843, p. 400.

Ruben Schalk, Patrick Wallis, Clare Crowston and Claire Lemercier, "Failure or flexibility? Exits from apprenticeship training in pre-modern Europe", Journal of InterdisciplinaryHistory, 48-2, 2017, p. 131-158.

Sven Steffens, « Le nom de l'apprenti : une analyse du vocabulaire socioprofessionnel », Revue belge de philologie et d'histoire, 79-2, 2001, p. 591-617 offered a first foray into these differences in vocabularybut without any quantification.

For example, in eighteenth-century Dijon (Archives départementales de la Côte-d'Or), some masters promised to teach « la profession et l'art d'orfévrerie et bijouterie » (e.g. 4 E 12/10, 4 December

1743), others « la profession d'orfévrerie » (e.g., with the same notary, in the same year, 4 E 12/10, 22 November 1743); some mistresses promised to teach to or « blanchir et travailler en linges » (e.g. 4 E 12/1900, 18 August 1776), others the « profession de blanchisseuse » (e.g. 4 E 2/2198, 13 January 1859), others « le métier de blanchisseuse et à coudre le linge » (e.g. 4 E 12/15, 8 October 1747). We have not finished inputting this data and cannot therefore give definite numbers, but we consider it important not only to notice these variations but also to try to quantify them. 17 More specifically: we first used principal component analysis on 11 variables that described the workshops (with only one related to apprenticeship: the share of apprentices in the workforce). We then performed cluster analysis on the first five dimensions of the PCA (more specifically, a variant of hierarchical ascending classification that uses kmeans based on class paragons to stabilize the resultsthe hcpc procedure in the R-package FactoMineR: François Husson, Sébastien Lê and Jérôme Pagès, Exploratory Multivariate Analysis by Example Using R, Boca Raton, CRC Press, 2010). The algorithm suggested a solution in four classes. In plain English: the classes were grouped? by an algorithm so that trades in the same class would be as similar as possible to each other, and trades in different classes as different as possible from one another, based on our 11 primary variables. This analysis produced four classes, into which each of the trades was assigned. We then checked whether the trades in each of the classes were


Antonio Macchia

Andreas Eitzinger

Jean-François Brière
email: jean-francois.briere@insa-rouen.fr

Mario Waser
email: mario.waser@jku.at

Antonio Massa
email: amassa@unisa.it

Asymmetric synthesis of Isoxazol-5-ones and Isoxazolidin-5-ones

Keywords: Asymmetric catalysis, organocatalysis, metal catalysts, heterocycles, chiral building blocks. 17, 18, 19, 20, 21, 22 Figure 1. Isoxazole-based heterocycles

Isoxazol-5-ones and isoxazolidin-5-ones represent two important classes of heterocycles, with several applications as bioactive compounds and as versatile building blocks for further transformations. Unlike the parent aromatic isoxazoles, the presence of one or two stereocenters in the ring renders their asymmetric construction particularly important. In this review, starting from the description of general features and differences between these two related compound families, we present an overview on the most important enantioselective synthesis strategies to access these heterocycles. Both, chiral metal catalysts and organocatalysts, have been successfully employed for this task in the last years and some of the most promising approaches will be discussed herein.

1) Introduction

2) Isoxazol-5-ones as nucleophiles 3) Asymmetric construction of isoxazolidin-5-ones 4) Arylideneisoxazol-5-ones in conjugated addition 5) Conclusions

1) Introduction

Isoxazol-5-ones 2 and isoxazolidin-5-ones 3 are important classes of functional molecules belonging to a large family of heterocyclic compounds, the isoxazoles 1 (Figure 1). In particular, isoxazol-5ones and isoxazolidin-5-ones have been found in a variety of natural products (Figure 2), isolated for example from lentil seedlings (compounds 4 and 6) 1,2,3 , bacteria (5) 4 marine sponges (7) 5 and chrysomeline larvae (8). 6 Besides the naturally occurring derivatives, a great number of (synthetic) products with very interesting biological activities has been reported (Figure 2). For example, some of them show anti-obesity activity (like compound 9), 7 are used as anti-cancer agents (10) 8 , were employed for the treatment of bladder over-activity in central nervous system (CNS) diseases ( 11) 9 , or served as HNE (human neutrophil elastase) inhibitors with anti-inflammatory effects (12). 10 In addition they can show anti-bacterial (13) 11 and p38 MAP (mitogen-activated protein) kinase inhibition activity (14, 12 15 13 ). Compound 16 14 holds promise as an inhibitor of succinate dehydrogenase and derivatives 17 and 18 15 are promising HDAC (histone deacetylases) inhibitors. Furthermore 19-21 and 26 16 show antiandrogen activity as for blefoxatone and toloxatone and some derivatives also find applications as agrochemicals (22-25). Over the last years the development of asymmetric protocols for the syntheses of chiral isoxazol-5-ones 2 and isoxazolidin-5ones 3 have attracted considerable attention, highlighting several similarities but also some peculiarities between these two related classes of heterocycles. In a recent review, Jurberg et al. have described the general features of isoxazol-5-ones chemistry, focusing mainly on their preparation and further transformations. 23 Most of this knowledge is also based on the seminal works proposed by the group of Zard. [START_REF] Review: Zard | [END_REF]25 In a complementary review, Brière and coworkers analyzed the properties and the asymmetric construction of the isoxazolidin-5-ones up to the beginning of 2017, 26 but it should be emphasized that most of the articles regarding the use of these heterocycles in enantioselective transformation processes have been published subsequently over the last 3-4 years. Isoxazol-5-ones are characterized by relatively high acidity at C-4 because of resonance-stabilization of the resulting carbanion by the carbonyl and the imine group, thus resulting in pKa values comparable to carboxylic acids. As depicted on Scheme 1, isoxazol-5-ones possess two main nucleophilic sites, N2 and C4, while the exocyclic carbonyl O atom is usually less reactive. Regioselectivity issues are challenging in this case and depends on several factors, while, in contrast, N-protected isoxazolidin-5-ones find applications as C-nucleophiles mainly. For both the heterocycles, the N-O bond is relatively weak 27 and a CO2 molecule can also be eliminated under certain conditions. [START_REF] Review: Zard | [END_REF]25 Accordingly, a variety of transformations have been proposed giving access to more complex isoxazole-derived architectures or furnishing new acyclic building blocks like chiral alkynes and -aminoacids. In addition, new heterocycles like piperidines and aziridines can be obtained by ring expansion or contraction, respectively. On the other hand, unsubstituted or 4monosubstituted isoxazol-5-ones show complex tautomers 2 and 27 in equilibrium, due to the acidic C4-H of 2 and the relatively high stability of the conjugated NH-form 27a in comparison to aromatic HO-form, 27b (Scheme 1). Scheme 1. General reactivity of isoxazole-5-ones.

However, the prevalence of one tautomer strongly depends on the substitution pattern, on the solvent, and on the purification conditions. In most of the cases, mixtures of tautomers can be detected. This can be a limitation, not only for pharmaceutical applications, but it has also practical issues for product characterization, HPLC analysis and determination of diastereomeric and enantiomeric ratios.

Synthesis

Review / Short Review With respect to asymmetric syntheses of isoxazol-5-ones, the currently established methods reflect the above described features and are mainly based on the use of preformed heterocycles. Depending on their substitution patterns, these can serve either as nucleophiles, developing regioselective N-or C-alkylations (Scheme 1, left side), or as Michael acceptors, even in domino reactions (Scheme 1, right side).

On the other hand, isoxazolidin-5-ones 3 show less diverse inherent reactivity tendencies (Scheme 2). Because of the absence of the imine group they are, first of all, less acidic than isoxazole-5-ones 2. In addition, the usually protected nitrogen is not nucleophilic, and thus this class of molecules primarily reacts as C-nucleophiles. As a consequence of these features, the asymmetric synthesis of (functionalized) isoxazolidin-5-ones 3 is mainly based on two approaches. The historically wellestablished way to access isoxazolidin-5-ones relies on asymmetric annulation strategies of simple (prochiral) acyclic starting materials (strategies a-c). 28 In addition, over the last years, several reports described the asymmetric functionalization of racemic isoxazolidin-5-ones (strategy d, R [2][3][4] = H), which currently leads to relatively broad and diverse powerful synthetic strategies to access this valuable heterocyclic platform.

Scheme 2. General synthesis approaches to access chiral isoxazolidin-5-ones and most common applications of these heterocycles.

In this review we wish to provide an illustrative (but not encyclopedic) overview about the most relevant recent asymmetric synthetic strategies to access and/or to functionalize isoxazol-5-ones and isoxazolidin-5-ones. All the collected literature has been interpreted according to the above described features and we hope that the present review can inspire investigations toward the development of new methodologies and asymmetric transformations in this field. Therefore, besides discussing the fundamental concepts of the established approaches, we will mainly focus on recent emerging reports from the last few years within the following chapters.

2) Isoxazol-5-ones as C-nucleophiles

The existence of three potential nucleophilic sites (N2, C4 and the exocyclic carbonyl O atom in HO-form) usually gives rise to regioselectivity issues (see Scheme 1). 29 Epimerization and tautomerism limit the applications of the C-alkylations toward the synthesis of derivatives bearing a tetrasubstituted C-4 carbon. However, N-alkylations furnish stable derivatives in enamine-like form with a tertiary nitrogen atom and in these cases both 4-unsubstituted and 4-mono substituted isoxazol-5ones have been utilized. Nevertheless, regioselective asymmetric C-alkylations and N-alkylations have been developed and the respective methodologies will be discussed in the following two sections.

2.1) Isoxazol-5-ones as C-nucleophiles

A facile one-pot sequential conjugate addition/dearomative fluorination transformation of isoxazol-5(4H)-ones with nitroolefins and N-fluorobenzenesulfonimide (NFSI) has been developed by Ma and coworkers (Scheme 3). 30 By using an acetylated N-glucoside chiral tertiary amino-thiourea catalyst C1, a series of chiral fluorinated isoxazol-5(4H)-ones 31 containing one fluorine-substituted quaternary stereocenter was obtained in high yields and with high diastereo-and enantio-selectivities.

Scheme 3. Asymmetric one-pot sequential conjugate addition/dearomative. fluorination.

In order to obtain more information about this sequential transformation, several step-by-step control experiments have been performed. In the presence of the tertiary amino-thiourea catalyst C1, compound 29a was transformed into the Csubstituted intermediate Int-32a (Scheme 3), which was isolated in almost quantitative yield with 88% ee. Subsequent treatment of this intermediate Int-32a with Na2CO3 and NFSI in the absence of catalyst C1 afforded the dearomatization-fluorination product 31a in 90% yield with 95:5 dr and 84% ee. These results indicated that the chiral catalyst not only controls the first step, but also provides stereocontrol in the diastereoselective formation of the C-F bond in the subsequent transformation. In addition, sodium borohydride reduction of adduct 31b, followed by Bocprotection allowed the synthesis of an isoxazolidin-5-one derivative 33b with three contiguous stereocenters. In this case, only two diastereoisomers have been detected, even though with moderate diastereoselectivity (lower part of Scheme 3). Asymmetric fluorination of 4-substituted isoxazol-5-ones 34 was also achieved by using a bis-cinchona alkaloid catalyst the (DHQ)2PYR C2. 31 A series of derivatives with a fluorinecontaining tetrasubstituted stereocenter 35 was obtained in good to high yields and with good enantioselectivities as outlined in Scheme 4 (up to 91% yield, 85% ee).

Scheme 4. Asymmetric fluorination of 4-substituted isoxazol-5-ones.

High regio-and enantio-selectivities have been achieved by Peters and co-workers 32 in the Michael reaction between 4monosubstituted isoxazol-5-ones 36 with a series of vinyl ketones 37 in the presence of chiral palladium catalysts C3, leading to the synthesis of adducts bearing an all-carbon quaternary stereogenic center 38 (Scheme 5). Interestingly, very good yields and high C-regioselectivity were obtained using the bispalladacycle catalyst bearing a pentaphenylferrocene core. The proposed mechanistic models correlate the observed regioselectivity to the sterically demanding pentaphenylferrocene palladacycle catalyst (See Scheme 5). This directs the reactivity in the absence of a base nearly exclusively to the nucleophilic C atom, while at the same time it allows for high enantioselectivity and TONs up to 1900. The authors also reported further utilization of the hereby obtained Michael adducts for the asymmetric synthesis of 40 and 42 with a tetrahydro-4H-pyrano [3,2-d]isoxazole skeleton. These compounds are a motive of interest for the development of new herbicides (lower part of Scheme 5). Later, the same group reported that a combination of chiral irridacycle phosphoramidite catalysts C4 with Pd(OAc)2 (5 mol%) as cocatalyst allowed the first regioselective catalytic asymmetric C-allylations of isoxazolinones 43 (Scheme 6). 29 The use of the co-catalyst guarantees the observed high C/Nregioselectivity. Interestingly, this method delivers the linear allylation products 45, instead of branched ones. This was explained by a sequence of reactions starting from the regioand enantio-selective N-allylation reaction to provide a branched allylic system Int-46, followed by a [3,3]rearrangement with chirality translocation from the allyl part to the heterocycle via a chair-like transition state TS-47 (Scheme 6). Scheme 6. Iridium catalyzed regioselective asymmetric C-allylations of isoxazolinones.

2.2) Isoxazol-5-ones as N-nucleophiles

As described independently in 2020 by Pedro, Blay et al. 33 and by Wang, Xu and co-workers, 34 thiourea-and squaramidecontaining Brønsted base bifunctional catalysts C5 and C6 allowed the enantioselective 1,6-aza-Michael addition of isoxazol-5-ones to p-quinone methides 49 to give isoxazol-5ones 50 having a chiral diarylmethyl moiety attached to the nitrogen atom, with fair to good yields and enantiomeric excesses (Scheme 7). The protocol proved to be effective also on gram scale. 34 Even though both groups reported independently this first enantioselective N-alkylation which is effective even for C-4 unsubstituted isoxazol-5-ones (R 2 =H), unfortunately no explanation has been given for the observed N-regioselectivity.

Scheme 7. Enantioselective 1,6-aza-Michael addition of isoxazol-5-ones to pquinone methides. In a recent work Li, Shao and co-workers 36 have described a very interesting Pd-catalyzed asymmetric allenylic (4+1) formal cycloaddition, leading to the synthesis of 4-spiro isoxazol-5-one derivatives 58 (Scheme 9). The authors have demonstrated that tuning the Pd catalyst switched the reactivity toward an unprecedented (4+3) or (4+1) cycloaddition/cross-coupling in the case of pyrazolones, while only (4+1) reaction has been given for isoxazol-5-ones. A possible mechanism is proposed, suggesting two interesting catalytic cycles for the cycloaddition with palladium-butadienyls and the key intermediate Int-59, as described in Scheme 9.

2.3) Isoxazol-5-ones as C-nucleophiles in cyclization processes

Scheme 9. Pd-catalyzed asymmetric allenylic (4+1) cycloaddition.

3.1) Asymmetric construction of isoxazolidin-5-ones

The pioneering (asymmetric) approaches to access isoxazolidin-5-ones relied on annulation reactions. First of all, racemic and chiral auxiliary controlled aza-Michael type additions of substituted (chiral) hydroxylamine derivatives to various Michael acceptors were reported almost 40 years ago by Baldwin's group. 28a Over the years, this methodology allowed access to a variety of chiral -or ,-substituted isoxazolidin-5ones, but the first asymmetric reports essentially relied on the use of chiral auxiliaries. 37 In the early 2000s, a variety of versatile asymmetric catalytic strategies were reported. 38,39,40,41 Sibi's group was the first to developed a powerful chiral Mgcomplex-catalyzed protocol to facilitate enantioselective aza-Michael sequences by adding N-substituted hydroxylamines 62 to pyrrolidinone-containing amide Michael acceptors 61. This strategy gave access to highly enantioenriched -substituted isoxazolidin-5-ones 63 as shown in Scheme 10. 38 Template for SYNTHESIS © Thieme Stuttgart • New York 2020-12-03 page 7 of 16

Scheme 10. First catalytic asymmetric isoxazolidin-5-one synthesis report by Sibi's group.

The following years then witnessed the introduction of a variety of alternative organocatalytic approaches. In this context impressive methods making use of chiral phosphoric acid catalysis, 39 chiral Brønsted base-mediated approaches, 40 and chiral iminium activation were introduced. 41 The majority of these reports were discussed in much detail in a recent review. 26 Iminium activation of ,-unsaturated aldehydes with chiral secondary amine catalysts is also a very powerful methodology to obtain this heterocyclic platform (Scheme 11). 41 Hereby the classical Hayashi-Jørgensen catalyst C9 turned out to be well-suited and could even be used in a one-pot two-step protocol where the enal 65 was accessed in situ by cross metathesis and then directly underwent the cyclization reaction with 64, as demonstrated by Ge's group. 41c More recently, immobilized catalyst derivatives like C10 were also successfully used by Pericas and co-workers with high selectivities in batch and flow. 41d Compared to other approaches, this iminium strategy is also very interesting as the primarily obtained enantioenriched isoxazolidin-5-ols 66 have not only been oxidized to isoxazolidin-5-ones 67, but can also be directly utilized to access other molecules of interest, as demonstrated by Ge's group who synthesized sitagliptin phosphate monohydrate via such a strategy. 41e

Scheme 11. The general concept of using iminium catalysis to control aza-Michael type-cyclizations to access compounds 66 (and 67 successively).

The addition of N-nucleophiles to Morita-Baylis-Hillman (MBH) carbonates 68 can be considered as a powerful alternative to classical aza-Michael addition chemistry and, in 2012, Chen and co-workers nicely demonstrated that such a strategy allows to access the chiral spiroisoxazolidin-5-one 71 with high enantioselectivity (Scheme 12-A). 42 In their organocatalytic approach they found that the -isocupreidine derivative C11 allows for high yield and enantioselectivity in the addition of the carbamate derivative to the MBH carbonate 68 (giving the formal aza-Morita-Baylis-Hillman product 70). This compound can then be cyclized to the -methylene isoxazolidin-5-one 71 without loss of optical purity by desilylation, followed by basemediated transesterification. Similarly, Vesely and co-workers have recently shown that such a strategy afforded the chiral isoxazolidin-5-ones 73 with reasonable levels of enantioselectivity (Scheme 12). 43 In their approach isocupreidine (C12) turned out to be the catalyst of choice to control the N-addition of carbamate 69 to MBH carbonates 72, followed by desilylation and a Bu2SnO-mediated transesterification to access the -methylene isoxazolidin-5-one 73 (Scheme 12-B).

Scheme 12. Organocatalytic two-step isoxazolidin-5-one synthesis starting from Morita-Baylis-Hillman carbonates.

Very recently (Scheme 13), 44 utilizing Meldrum's acid 76, 45 Brière and co-workers extrapolated the multicomponent Knoevenagel-aza-Michael-Cyclocondensation reaction to readily available hydroxamic acids 75 derived from naturally occurring α-amino acids (αAA). The thus obtained novel isoxazolidin-5-ones 77 proved to be useful platforms for the diversity-oriented synthesis of /-dipeptide derivatives 78. The likely diastereoselective aza-Michael reaction, taking place onto the highly electrophilic in situ formed alkylidene Meldrum's acid intermediate Int-79, 45 turned out to be rather sensitive to the nature of the employed catalytic Brønsted base (R3N), among them the (DHQ)2PHAL C13 displayed the best outcome along with a significant match effect during a double induction process. A rather general approach to access highly functionalized substituted isoxazolidin-5-ones 83 relies on formal (3+2) annulation reactions of nitroso compounds with suited three carbon building blocks. 46,47 The groups of Zhang and Ying and, subsequently, Rodriguez and Coquerel achieved the transformation of nitroso compounds based on the use of carbene precatalysts which activate enals 80 to perform (3+2) annulations via the formation of Breslow intermediates Int-82, (Scheme 14). 46 Scheme 14. NHC-catalyzed formal (3+2) cycloaddition of nitroso reagents to access -substituted isoxazolidin-5-ones.

Alternatively, 1,4-dicarbonyl compounds like oxindole 84 were successfully used for nitroso aldol-esterification cascades under bifunctional thiourea catalysis to access the spirooxindoles 85 straightforwardly and with high enantioselectivities (Scheme 15). 47 Surprisingly however, to the best of our knowledge, no further developments this concept have been reported anymore.

Scheme 15. A Brønsted base-catalyzed formal (3+2) cycloaddition of nitroso reagent to access -substituted isoxazolidin-5-ones.

On the other hand, the use of nitrones as 1,3-dipolar building blocks in combination with suited two carbon synthons has been investigated in much details over the last years. 48,49 Since 2003, first reports by Shindo, Florio and others relied on diastereoselective approaches which led to high stereoselectivities with a limited scope however. 48 Over the last years, the group of Brière tackled the organocatalytic and asymmetric synthesis of chiral enantioenriched isoxazolidin-5-ones via a nitrone pathway starting from Meldrum's acid 76 and derivatives. 49 Especially, by utilizing the substituted Meldrum's acid 86 and N-hydroxysulfone 87, under basic and biphasic conditions, a straightforward synthesis of -substituted isoxazolidin-5-ones 88 occurred in high yields and with goods enantioselectivities (Scheme 16). It has been proposed that, upon a phase-transfer catalytic protocol, the Meldrum's acid anion Int-89 would undergo a formal (3+2) cycloaddition to the in situ generated nitrone. Then, this domino sequence would be terminated by the enantioselective protonation reaction of the corresponding enolate intermediate, thanks to the bifunctional cinchonaderived catalyst C15. It is worth noting that -substituted isoxazolidin-5-ones 88, after hydrogenolysis of the N-O bond, afford an access to  2 -AA, a highly versatile but difficult to access class of chiral -AA (further applications of these targets to access  2,2 -AA will be discussed in the next chapter).

Scheme 16. Catalytic stereoselective nitrone-based approaches to access αsubstituted isoxazolidin-5-ones.

3.2) Enantioselective -functionalizations of isoxazolidin-5-ones

Besides building the isoxazolidin-5-one motif via asymmetric cyclization strategies (as outlined above), the enantioselective modification of (racemic) isoxazolidin-5-ones 88, i.e. via functionalization approaches, became a powerful methodology over the last years. 50,51,52,53,54 The thereby accessed chiral products 91 not only serve as versatile masked  2,2 -amino acid derivatives 92 (Scheme 17-A), but may also undergo further heterocycle forming reactions as demonstrated by Noda and Shibasaki very recently (Scheme 17-B). 55 Scheme 17. (A) Isoxazolidin-5-ones to access (masked)  2,2 -AA and (B) to access cyclic -amino acids via electrophilic amination or C-H activation methods.

Brière and co-workers were the first to demonstrate that alkylated isoxazolidin-5-ones 88 can undergo highly enantioselective -functionalization reactions. 50 By using the commercially available Maruoka ammonium salt C16 as catalyst, 56 they established a straightforward protocol for the highly enantioselective -sulfanylation of 88 with the phthalimide-based S-transfer reagents 96 (Scheme 18-A). In this report, they also demonstrated that the chiral products may easily undergo ring-opening via reductive N-O bond cleavage, thus giving access to -sulfanylated  2,2 -AA. Very interestingly, a broad variety of other commonly established chiral ammonium salt catalyst were tested as well, 57 but none of them allowed for any noteworthy selectivity. This exclusive potential of the Maruoka catalysts C16 (and C17 as well) to control the asymmetric ammonium salt-catalyzed transformations of compounds 88 was also described in other recent investigations (vide infra), but the exact reasons for this effect remain yet unknown. Very recently, 52 the groups of Della Sala and Aleman as well as the groups of Cahard and Waser independently reported the asymmetric -trifluoromethylthiolation of -alkyl and -aryl-substituted substrates 88 using chiral ammonium salts C16 or C17 (Scheme 18-B). Further transformations of the products 100 like ring-opening reactions, direct KAHA (αketoacid-hydroxylamine)-type ligations 58 or S-oxidations to sulfone were successfully carried out, thus demonstrating the overall potential of this catalysis concept to access versatile chiral target molecules from a simple heterocyclic platform. With respect to further -heterofunctionalization reactions of compounds 102, it is fair to say that this approach is still in its infancy, and apart from the -sulfanylation and trifluoromethylthiolation approaches only one example of an asymmetric -amination reaction under asymmetric ammonium salt catalysis was reported by Brière so far (Scheme 19). 51a Scheme 19. Quaternary ammonium salt catalyzed asymmetric -amination reaction.

Asymmetric C-C bond forming reactions of pronucleophiles 88 were carried out under a variety of different catalytic conditions over the last 2-3 years. 51,53,54 First, enantioselective conjugate addition reactions were investigated. The Michael acceptors 105-107 were found to be well tolerated under chiral ammonium salt catalysis (again with catalysts C16 or C17), as demonstrated by Brière's group and Waser's group (Scheme 20). 51 Remarkably, while the addition of 102 to acrylates 105 and MBH-carbonates 106 required around 3-5 mol% of the catalysts, the reaction with para-quinone methides 107 could be carried out with as low as 20 ppm of the catalyst C16, which represents one of the lowest catalysts loadings reported in asymmetric organocatalysis so far.

Scheme 20. Asymmetric conjugate additions of pronucleophiles 1 under asymmetric phase-transfer catalysis.

Noda and Shibasaki recently investigated asymmetric Mannich type reactions compounds (Scheme 21). The addition of 88, having an aryl (R 1 ) pendant, the acceptor 111 was possible by using the commercially available organocatalyst C18, acting a Brønsted base. In a single case, 54a the authors also demonstrated that simple quinidine is also able to catalyze the asymmetric addition of 88 to nitrostyrene as Michael acceptor. On the other hand, the Mannich reaction with simple aldimines 112 and platform 88 with an alkyl (R 1 ) pendant, likely less acidic, required a very carefully optimized combination of AgPF6 with ligand L2, a diphosphineoxide additive and a phenolate base to achieve good reactivity and ees. Unfortunately, however, the obtained diastereoselectivities were found to be relatively low in this last case. 54b Scheme 21. Asymmetric Mannich type reactions.

In 2018, Noda and Shibasaki also introduced a highly enantioselective decarboxylative Pd-catalyzed -allylation protocol by starting from the racemic allyl esters 115 (Scheme 22). 53a In this report, they first demonstrated that isoxazolidin-5-ones can be directly employed in KAHA-type ligations. 58 Since then, this methodology emerged as a very powerful strategy to directly access /-dipeptides from this heterocyclic platform and it was recently demonstrated to be rather generally possible for other isoxazolidin-5-one derivatives 116 as well. 51c,5252b,54 Scheme 22. Asymmetric decarboxylative -allylation approach B.

The intermolecular Pd-catalyzed -allylation of -aryl isoxazolidin-5-ones was shortly after described by Arseniyadis and Cossy, giving access to a broad variety of highly

4) Arylideneisoxazol-5-ones in conjugated addition

Despite the high reactivity of arylideneisoxazol-5-ones in conjugated additions, 23 the obtained Michael adducts suffer from tautomeric equilibria according to Scheme 1, as for isoxazol-5-ones mono-substituted at C-4 position. Therefore, a relatively limited number of applications has been described in this field. Most of them are directed toward the synthesis of derivatives with a tetrasubstituted carbon, exploiting in these cases the reactivity of the enolate intermediate in domino reactions 59 or otherwise the selective in situ entrapping/protection of the NH-tautomer of the respective Michael adducts is necessary. 60 In addition, the obtaining of complex molecular architectures has also been of great utility in further transformations of the Michael adducts allowing for example an entry to versatile alkynes. 61 Although a great number of synthesis methodologies of arylideneisoxazol-5-ones have been reported 23,[59][60][61][62][63][64][65][66] and they have been sometimes represented with E-configuration, Z isomers are reported to be more stable. 62 X-ray structures confirm this outcome for a few derivatives. 61,62 In one of the first reports, an efficient organocatalytic diastereoand enantioselective cascade reaction between 3-isothiocyanato oxindoles 120 and unsaturated isoxazolones 121 has been described by Yuan 59 and co-workers in the presence of commercially available quinine as catalyst C19. This process consisting, of a domino Michael addition / cyclization sequence, has allowed the construction of spirocyclic oxindole derivatives 122 bearing two quaternary centers and three consecutive stereocenters in high to excellent yields with moderate to high diastereo-and enantio-selectivities (Scheme 24).

Scheme 24. Diastereo-and enantioselective cascade reaction between 3isothiocyanato oxindoles and unsaturated isoxazolones.

Very recently Pedro, Blay and co-workers reported a conceptually similar process in which enantioenriched spirocyclic compounds bearing three contiguous stereocenters were obtained from 4-arylideneisoxazol-5-ones 123 and isocyanoacetate esters 124 through a formal (3+2) cycloaddition reaction. 63 Interestingly, high enantioselectivity and only two diastereomers were obtained by means of cooperative catalysis combining a classical bifunctional organocatalyst derived from a Cinchona alkaloid and silver oxide as Lewis acid (Scheme 25).

Scheme 25. Enantioselective synthesis of spirocyclic compounds through a formal (3+2) cycloaddition reaction.

In 2017, Jurberg and co-workers 61 have developed an asymmetric Michael reaction of arylideneisoxazol-5-ones 123 with acyclic and cyclic ketones 127 in the presence of cinchona-derived aminocatalysts C21 and substituted benzoic acids as co-catalysts (Scheme 26). The best results were obtained with modified catalysts bearing hindered substituents on the quinoline ring and mechanistic models have been proposed to explain the observed selectivity. Instead of their isolation, the Michael adducts 128 were subjected to a controlled nitrosative degradation, according to Zard's conditions [START_REF] Review: Zard | [END_REF]25 leading to alkyne motifs 129 bearing two contiguous stereocenters. In 2018, the group of Chen and Ouyang 64 reported a diastereodivergent asymmetric formal (4+2) cycloaddition reaction, realized with Z-configured 4-alkylideneisoxazol-5-ones 123 and 2,4-dienone 130 in the presence of bifunctional chiral primary amine C22 as catalyst in combination with benzoic acid (Scheme 27-A). As a previous mechanistic study suggested, 65 the '-(4+2) reaction might proceed via iminium ion catalysis in a stepwise cascade manner rather than a concerted Diels-Alder cycloaddition pathway. The authors also investigated a threecomponent reaction of 2,4-dienone 132, 3-methylisoxazol-5(4H)-one 133, and benzaldehyde 53 (Scheme 27-B). 64 This reaction was efficiently promoted under the catalysis of bifunctional C22 and the acid A2, through a cascade Knoevenagel condensation / formal (4+2) cycloaddition process. The addition of 4 Å molecular sieves (MS) was beneficial for the enantioselectivity. These results also suggested the possibility to develop a more challenging and complicated four component cascade process (Scheme 27-C), 64 involving condensations of simple 3-methyl-2cyclohexenone and 3-methyl-isoxazol-5(4H)-one 133 with aldehydes 74, respectively, followed by the formal (4+2) cycloaddition. In this case the bifunctional amine-thiourea C22 failed to deliver the desired product probably because it might not be effective for the formation of dienone 130. However, the authors discovered that adding 10 mol % of cinchona-based amine C23, in combination with catalyst C24, could afford the cycloadducts ent-131 in moderate yields with high enantioselectivity, probably proceeding in a relay aminocatalytic manner. In 2019, Yu, Zhou et al. 66 reported a domino oxa-Michael/1,6addition reaction of orthohydroxyphenylsubstituted p-QMs 137 and unsaturated isoxazolones 136 (Scheme 28). Various new spiroisoxazolonechromans 138 were obtained in good yields (up to 89%) with excellent diastereoselectivities (>99:1 dr) in the presence of Et3N, while preliminary investigation of asymmetric versions in the presence of quinine allowed the obtaining of the target compound in high yield and moderate diastereo-and enantio-selectivity.

Template for SYNTHESIS © Thieme Stuttgart • New York 2020-12-03 page 13 of 16 On the basis of previous works in which the strategy of the entrapping of unstable intermediates allowed the isolation and transformation of challenging aldol adducts 67 or useful heterocycles, [68][69][70] very recently Massa et al. reported the first asymmetric Michael reaction of arylideneisoxazol-5-one 123 with 1,3-diesters 139 (Scheme 29). 60 Despite complex tautomer equilibria of the obtained Michael adducts (Int-141-143), as demonstrated by 1 H-NMR spectroscopy, the one-pot entrapping by the aid of different electrophiles/protecting groups (EX=(Boc)2O, Ac2O or CH3I) led to the regioselective isolation of diverse N-substituted isoxazol-5-ones 140 in very high overall yield and with good enantioselectivities up to 94/6 er. The reaction can be performed in two ways: in a sequential fashion, carrying out the Michael addition first and then quenching with (Boc)2O or Ac2O (Scheme 29-A), or in a truly one-pot procedure leading to comparable results in terms of yield and er (Scheme 29-B). Notably, the enantiopurity of several final products was further increased up to >99.9/0.1 er after a single crystallization in good overall yield. The use of quinidine C25 as a cheap and readily available catalyst also allowed the development of onepot four-component Knoevenagel / / tautomer trapping (Scheme 29-C). Also, in this case the reaction was highly regioselective and, despite the lower yield 146 (80%) and the only er (77/23), this procedure has the advantage to overcome the synthesis of the arylideneisoxazol-5-one 144.

Scheme 29. Asymmetric one-pot Michael reactions/tautomer trapping of arylideneisoxazol-5 ones.

Conclusions

In this review we have presented the most common strategies for the asymmetric construction of isoxazol-5-one and isoxazolidin-5-one heterocyclic compounds. On the basis of the examples herein analyzed, several similarities but also some differences are shown between these two groups of heterocycles. These features not only affect the asymmetric synthesis strategies but also their further transformations to access other useful building blocks or different heterocycles. Even though both chiral metal catalysts and organocatalysts have been successfully used in the last years, it clearly appears that this is a research field still under-explored and it is easy to predict that the closer future will bring other asymmetric strategies and new transformations which will enlarge the chemical diversity and the applications of these fascinating organic molecules.

Figure 2 .

 2 Figure 2. Selected natural and synthesis-derived biologically active derivatives.

Scheme 5 .

 5 Scheme 5. Asymmetric palladium catalyzed Michael reactions of 4monosubstituted isoxazol-5-ones and synthesis of new tetrahydro-4Hpyrano[3,2-d]isoxazole.

  Scheme 8. Asymmetric four-component (5+1+1+1) formal cycloaddition reaction of 3-substituted 2-cyclopentenones.

Scheme 13 .

 13 Scheme 13. Multicomponent organocatalytic synthesis of isoxazolidin-5-ones.

Scheme 18 .

 18 Scheme 18. Quaternary ammonium salt catalyzed asymmetric -sulfanylation reactions.

Scheme 26 .

 26 Scheme 26. Asymmetric Michael reaction of arylideneisoxazol-5-ones with ketones and further transformations.

Scheme 27 .

 27 Scheme 27. Diastereodivergent, asymmetric formal (4+2) cycloaddition reaction.

  Scheme28. Domino oxa-Michael/1,6-addition reaction of orthohydroxyphenylsubstituted p-QMs and unsaturated isoxazolones.

Funding Information

AM wants to thank the Ministero dell'Università e della Ricerca (MIUR) and Università degli Studi di Salerno for financial

Synthesis