Facoltà di scienze matematiche fisiche e naturali
Dipartimento di chimica e chimica industriale
corso di laurea magistrale in chimica
tesi di laurea
Studies on asymmetric α–amination of
2-oxindoles with bis(2,2,2-trichloroethyl)
azodicarboxylate
relatore:
Dott. Alessandro Mandoli
controrelatore: Dott. Gaetano Angelici
candidato: Mattia Bondanza
tutto impossibile predire cosa avverrà all’incontro di due molecole moderatamente complesse. Che predire
sull’incontro di due esseri umani? O delle reazioni di un individuo davanti ad una situazione nuova? Nulla: nulla di sicuro, nulla di probabile, nulla di onesto.
List of abbreviations iii
Abstract v
1 Introduction 1
1.1 Asymmetric α-amination reactions with azodicarboxylates . . . 2
1.2 AαA on 3-substituted-2-oxindoles with azodicarboxylates . . . 5
1.2.1 Elaboration of AαA products derived from azodicarboxylates . . . 10
1.3 Applications of BTCEAD in organic synthesis . . . 12
1.3.1 Syntheses of BTCEAD . . . 13
1.3.2 Reactivity of BTCEAD . . . 13
1.3.3 Methods for the removal of Troc protecting groups . . . 15
1.4 Biological activity and synthesis of AG-041R . . . 16
1.4.1 Synthesis of AG-041R by attack of a carbon nucleophile on a ketimine . . 17
1.4.2 Synthesis of AG-041R by α-alkylation of a 3-amino-2-oxindole . . . 20
1.4.3 Synthesis of AG-041R by AαA . . . 22
1.4.4 Synthesis of AG-041R by other strategies . . . 23
1.4.5 Summary . . . 25
2 Results and Discussion 26 2.1 Preparation of materials . . . 26
2.1.1 Preparation of substituted-2-oxindoles . . . 26
2.1.2 Preparation of the aminating agents . . . 32
2.1.3 Preparation of dimeric Barbas’ catalyst . . . 33
2.1.4 Preparation of the catalyst by Zhao et al . . . 35
2.2 AαA with BTCEAD . . . 38
2.2.1 Preliminary screenings . . . 38
2.2.2 Elaboration of the products derived from AαA with BTCEAD . . . 40
2.2.3 Study of AαA on substrate 7 . . . 45
2.2.4 Study on AαA on 3-aryl substituted substrates . . . 49
2.3 Enhancements in the synthesis of AG-041R . . . 57
2.3.1 Application of Leblanc conditions to the elaboration of 10 . . . 57
2.3.2 Preliminary studies on oxidative cleavage of the allyl group . . . 59
3 Conclusion and outlook 64 4 Experimental Section 65 4.1 Reagents and general procedures . . . 65
4.2 Instrumentation . . . 65
4.3 3-substituted-2-oxindoles . . . 66
4.4 Azodicarboxylates . . . 73
4.5 Catalyst proposed by Barbas et al. . . 75
4.6 Catalyst proposed by Zhao et al. . . 76
4.7 Aminations and elaborations of aminated products . . . 78
4.8 Asymmetric α-aminations . . . 79 4.9 Synthesis of AG-041R . . . 81 Appendices 85 A NMR characterizations 86 B HPLC chromatograms 100 Bibliography 107
EDC · HCl N -(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride. iPrisopropyl. nBunormal butyl. tButertiary butyl. ee enantiomeric excess. 1,1,2-TCE1,1,2-trichloroethane.
AαA asymmetric α-amination.
Ac acetate.
Bn benzyl.
Boctert-butoxycarbonyl.
BTCEAD bis(2,2,2-trichloroethyl)
azodicar-boxylate.
Cbz benzyloxycarbonyl.
CSPchiral stationary phase.
CSP-HPLC high performance liquid
chro-matography on chiral stationary
phase.
D-A Diels-Alder.
d.r. diastereomeric ratio.
DBAD dibenzyl azodicarboxylate.
DCMdichloromethane.
DEADdiethyl azodicarboxylate.
DIADdiisopropyl azodicarboxylate.
DMAP N,N-dimethylpyridin-4-amine.
DMF N,N-dimethylformamide.
DMSOdimethylsulfoxide.
DTBADdi(tert-butyl) azodicarboxylate.
Etethyl.
LDAlithium diisopropyl amide.
LUMO lowest unoccupied molecular orbital.
M.M.molar mass.
Moz p-methoxybenzyloxycarbonyl.
MS 5Åmolecular sieve with 5Å cavities.
NBS N-bromosuccinimide.
SN nucleophilic substitution.
TFAtrifluoroacetic acid.
THF tetrahydrofuran. TMEDA N ,N,N’,N’-Tetramethylethane-1,2-diamine. Trtriphenylmethyl. Troc 2,2,2-trichloroethoxycarbonyl. iii
The asymmetric α-amination of 3-substituted-2-oxindoles 1 has attracted the interest of many organic synthesis researchers due to the possibility to prepare, through this reaction, a number of biologically active molecules. A particularly effective approach in this respect is the electrophilic attack of an azodicarboxylate (2) on a racemic oxindole (1) catalyzed by a chiral base, generally a cinchona alkaloid derivative, providing the product 3 that could be further elaborated to obtain the desired amino group.
chiral base cat. Multiple steps
R1 R2 O N R3 R3 O O O O N N R3 R3 O O O O R1 HN N N O R2 R1 NH2 N O R2 + PSfrag replacements 1 2 3 4
However, when azodicarboxylate with R3=Et or iPr are used, the conversions of 3 in 4
are generally low yielding due to the harsh cleavage conditions. Furthermore the catalytic hydrogenation step needed to break the N-N bond imposes strong limitations on the groups that could be present in the molecule. To overcome these problems we explored the use of bis-(2,2,2-trichloroethyl)-azodicarboxylate 5 as an alternative aminating agent that simplifies the subsequent conversion of the addition product 3 in the amine. The trasformation of bis-Troc-protected hydrazines into the corresponding amines have been reported by Leblanc and
Fitzsimmons under mild reductive conditions in a single step [1].
catalyst 10 mol% solvent, conditi : R2 = Ph : R2 = -CH 2-COOEt : R2 = Ph, e.e. 75% : R2 = -CH 2-COOEt, e.e. 65% * O NH R2 Troc N N Troc N NH O R2 HN Troc Troc Troc O O CCl3 = + PSfrag replacements 5 6 7 8 9
First of all, we focused on the optimization of the enantioselectivity of the α-amination reaction by testing different catalysts, solvents, and reaction conditions. With this screening we reached ees as good as 75% for 3-aryl-2-oxindoles, and ee up to 65% for 2-oxindoles bearing a
-CH2-COOEt chain at position 3. Both products 8 and 9 were subsequently converted into the
corresponding amines, with satisfactory yields and without affecting functional groups like C-C double bonds.
1. Moz cleavage
2. Leblanc reducing conditions Moz Moz O N N HN EtOOC EtOOC NH2 N O NH N O OEt OEt H N O N H O Tol PSfrag replacements 10 11 12
In the second part of this work we investigated the application of the new N-N cleavage conditions to hydrazines deriving from other azodicarboxylates. In fact we demonstrated that the α-amination product 10 could be converted in the amine 11 under Leblanc conditions. The resulting amine have been used to accomplish a formal synthesis of the biologically important molecule AG-041R 12 by using a new optimized series of reactions that does not involve the use of heavy metals.
Introduction
The synthesis of α-amino carbonyl compounds has attracted the interest of organic chemists for a long time. The main reasons of the interest in these compounds is their similarity to the natural occurring amino acids: being able to prepare synthetic analogues of these molecules could be of great interest for drug discovery purposes and for molecular biology applications.
The simplest way that one could imagine to prepare an α-amino carbonyl compound is to exploit the ‘natural’ reactivity of the carbonyl groups at α position to directly prepare the desired molecule; this approach is called α-amination. The problem that arises from this strategy is that the α position of a carbonyl has a nucleophilic character, so electrophilic nitrogen species should be used to attempt the reaction. Amines are the most widespread nitrogen compounds, both in nature and in chemical laboratories, but they are nucleophilic at the nitrogen atom and could not be used as partner for electrophilic α-amination. To overcome this reactivity mismatch, organic chemists have developed and studied many electrophilic nitrogen equivalents; in these species nitrogen is bonded to electron withdrawing groups or atoms. The most commonly used in α-amination reactions are by far azodicarboxylates, followed by hydroxylamines and sulphonylazides.
Some methodologies that imply a ‘Umpolung’ of the α position have recently been proposed
[2]. In these approaches a nucleophilic nitrogen species (such as sodium azide or a simple amine)
is used in combination with an oxidant reagent to obtain the α-amino carbonyl compound. These techniques, far from being well-tested, are still under development and so far electrophilic amination remains the first choice in the field.
When an α-amination is performed on a carbonyl compound bearing two different sub-stituents on the reactive carbon atom, a new stereogenic center is generated in the reaction. The configuration of the newly formed stereocenter could be of great importance for biological and pharmaceutical applications. For example many bioactive molecules with an α-carbonyl framework have been found to be active in just one of the two enantiomeric forms. This behav-ior is very common among chiral molecules interacting with biological targets; every structure derived from natural amino acids and sugars (such as proteins, enzymes, receptors, glycoproteins and so on) is chiral and can thus recognize one enantiomeric form of an interacting molecule from the opposite one. As a consequence, organic chemists endeavored to discover practical and economically viable methods to control the stereochemical outcome of the α-amination reac-tions. An α-amination reaction that produces optically active products from achiral or racemic substrates is called asymmetric α-amination, for short AαA; AαA can be performed either in a catalytic fashion or with stoichiometric chiral reagent. The ideal approach to the problem is asymmetric catalysis as it allows – under optimal conditions – to get an enantiomerically en-riched compound by using only small quantity of ‘precious’ chiral substance (the enantioselective catalyst).
As shown in figure 1.1, attention to AαA has grown steadily from the early nineties and
reaches a plateau a decade later. During all the first ten years of the new millennium the number of articles per year in the field have continuously been increasing at a rate similar to
the total literature concerning synthesis. 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 0 20 40 60 80 Year N um be r of pa pe rs
Total articles indexed by Scifinder containing ‘synthesis’ as concept (divided by 10)
Total articles indexed by Scifinder containing ‘asymmetric alpha-amination’ as concept Total articles indexed by Scifinder containing ‘asymmetric alpha-amination’ in the title
Figure 1.1: Trend of the number of scientific articles regarding AαA compared to total scientific
literature in the organic synthesis field (source: SciFinder [3]).
During these 25 years of intense research many interesting protocols have been published, and different methodologies outlined, developed and finally applied to the synthesis of complex molecules. In the next sections we will review the main results achieved in the field of AαA
with azodicarboxylates (section 1.1), including AαA on 3-substituted-2-oxindoles (section 1.2)
that are the the topic of the present work. A brief discussion about the known uses of bis(2,2,2-trichloroethyl) azodicarboxylate, the electrophilic nitrogen reagent selected for this work, and
the elaboration of its reaction products is subsequently presented (section 1.3). At the end of
this chapter we will carry out a review on the main researches about the biological activity
(section 1.4) and the synthesis (section1.4) of AG-041R, one of the most studied targets in this
field.
1.1
Asymmetric α-amination reactions with azodicarboxylates
The first published article about AαA appears in the eighties; in this study by Gennari et al.
a stereoselective synthesis of α-amino esters is proposed [4]. The approach, also pursued in a
further study [5], consists in performing the AαA on a quantitatively formed synthetic equivalent
of an enolate. Chirality is transferred to the system by by linking it to a chiral auxiliary: in these conditions the two possible product obtained in the amination reaction are diastereoisomeric. Consequently, the quantity of the two epimers formed are not equal in principle, but one can prevails on the other reflecting the different energy of the two transition states. For short, a diastereoselective synthesis is performed.
In Gennari’s approach the chirality is introduced by forming 13, the (1R, 2S)-N,N-dimethyl-ephedrine ester of a pro-chiral acid; the chiral ester 13 is activated by conversion into the cor-responding silyl enol ether 14 and then treated with di(tert-butyl) azodicarboxylate (DTBAD,
1 A, THF, -78 °C 2) TMSCl DTBAD, TiCl4 COOH R R O O Me Me2N Ph Ph NMe2 Me HO R OTMS O Me Me2N Ph R O O Me Me2N Ph N N N NH Boc Boc O O O O * DTBAD PSfrag replacements 13 14 16 15
Scheme 1.1: AαA approach proposed by Gennari et al.
An almost identical approach was used two years later by Evans et al. for preparing other
derivatives of chiral α-amino acids. As shown in scheme 1.2, in this case, chirality is introduced
by protecting the acid as the 2-oxazolidinone 17 bearing an asymmetric center at position 4.
17then undergoes to amination via quantitative lithium enolate formation, to give 18. Also in
this case, the electrophilic nitrogen source selected for the reaction is the commercially available azodicarboxylate 15. A, THF, -78 °C 2) DTBAD B O O N O R N O N O O R N H Boc Boc ( ) PSfrag replacements 17 18 15
Scheme 1.2: AαA approach proposed by Evans et al.
Despite the reported excellent yields and stereoselectivity, these approaches present two main common drawbacks:
(i) a stoichiometric chiral auxiliary is needed to perform the stereoselective reaction which rises cost issues especially for large scale applications.
(ii) both methods require the use of a stoichiometric amount of strong bases to generate more reactive species, instead of performing the reaction on the unmodified carbonyl compounds. This approach is less appealing for industrial scale applications because it presents either cost and safety issues.
To overcome these problems, in 1997, Evans and Nelson proposed a modification of their
pre-viously published work, [5] which represents the first known catalytic enantioselective approach
to AαA [6]. First, the group discovered that in presence of a catalytic amount of a
medium-strength base (e.g. a metal alkoxide) the reaction of scheme 1.2can still proceed smoothly. This
led the authors to speculate that, under optimized conditions, a catalytic amount of a suitable chiral base could promote an enantioselective transformation. By screening a series of chiral metal bases and conditions to optimize reaction performances, the most effective catalyst was found to be magnesium sulfonamide 19; the reaction was performed on many 2-oxazolidinone-protected-2-aryl-acetic acids with satisfactory yields and enantioselectivity.
DTBAD 2 To 10 mol% O O N O A N O N O O N H !" S N N Ph Ph # M$ O O O O % ) PSfrag replacements 19 19 15
Scheme 1.3: First example of catalytic enantioselective AαA.
Even if the scope of this reaction is rather limited and the carbonyl substrate still requires conversion into an oxazolidinone derivative the study had the great merit of overcoming the drawbacks of the diastereoselective approaches and to demonstrate that a catalytic enantiose-lective way to α-amino carbonyl was indeed possible.
Moreover it triggered a sort of ‘golden age of AαA’ with many more groups entering the fied around the world. While some researchers continued their studies on the catalysis performed
by metal complexes [7,8], some other focused on the development of fully organocatalytic AαA
methods. The first organocatalytic AαA was reported almost simultaneously by List [9] and
Jørgensen and Juhl (scheme 1.4) [10], in astonishing similar examples. Both groups reported
the use of L-proline (20) as an useful catalyst for AαA of aldehydes with azodicarboxylates. Moreover the conditions adopted (10% of catalyst loading, room temperature and reaction times shorter the three hours) and the outcome of the reactions (almost quantitative yield and ee rang-ing from 85% to 99%) are almost identical, with main differences restrang-ing in the selected solvent (acetonitrile in List’s article and dichloromethane in Jørgensen’s one) and azodicarboxylate.
DTBAD L-&'* +, ./03456 78 9 :; <= R O > ?@ CDE NH N O R O NH OH FG HIoline J K PSfrag replacements 21 20 15
Scheme 1.4: AαA catalyzed by L-proline as reported by B. List.
Bearing an ‘acidic’ proton in α position, the obtained α-hydrazino aldehydes 21 are
config-urationally unstable and undergo to fast racemization even just at room temperature [9, 10].
Therefore both groups adopted a reductive work-up (NaBH4) which provided configurationally
stable 1,2-hydrazino alcohols derivatives as reaction product.
The postulated transition state 22 of the considered reaction, depicted in figure 1.2, has been
reported many following publications and is often referred as metal-free Zimmermann-Traxler
transition state. [11] N H N N EtOOC O O EtOOC PSfrag replacements 22
Figure 1.2: Metal-free Zimmermann-Traxler transition state.
This reaction was the object of many further articles that disclosed other viable substrates
(such as ketons [12] and α, α-disubstituted aldheydes [13]), reaction conditions (such as
mi-crowave heating [14]), applications [15] and also autocatalysis effects [16]. However the fact that
the reaction probably proceeds through enamine formation limits its application to aldehyde and ketone substrates.
In the following years the group of Jørgensen tackled the AαA of other carbonyl compounds in a study that introduced in the field a versatile class of catalysts: cinchona alkaloids. These
natural occurring chiral amines and their derivatives, have been used since the beginning of
the 20th century [17, pg. 109] as catalysts in many different organic asymmetric reactions. In
particular the study by Jørgensen focuses on AαA of α-cyano esters and β-keto esters (‘acti-vated methylene compounds’) which with accurate selection of reaction conditions afforded the corresponding α-aminated products with good yield and enantioselectivity.
CN COOtNOP N N Q RT UV W COOtXYZ N CN NH [\] ^ _` N OH O H H N a βbICD cdef g hij klm np β-ICD * PSfrag replacements 15 23
Scheme 1.5: The cinchona-catalyzed AαA reported by Jørgensen et Al.
The publication introduces a new kind of catalysis with respect to the previously cited works by Jørgensen and List; in this case the transition state could not be an enamine-like derivative and the product is probably formed by reaction of the electrophilic nitrogen reagent with the small amount of ammonium enolate produced, at the equilibrium, by the cinchona alkaloid and carbonyl compound. The availability of many different mono- and bis- alkaloid derivatives in both pseudo-enantiomeric forms was an important boost to this research area. Indeed, many other groups were inspired by this work and then this class of organocatalysts
became quite popular for AαA [18–20]. Most important for the work discussed in the following,
cinchona alkaloids derivatives became the almost exclusively used catalysts for amination on 3-substituted-2-oxindoles.
1.2
AαA on 3-substituted-2-oxindoles with azodicarboxylates
q r 6 s t u v w NH 1 2 x O
Figure 1.3: Sturcture and numbering (according to IUPAC) of 2-oxindole ring system.
The 2-oxindole ring (fig. 1.3) is a common structure of many bioactive compounds including a
sub-set of derivatives that posses a nitrogen-substituted stereocenter at C3 (figure 1.4).
NITD609 in vivoy z{| }~ AG-041R - SSR149451 - Nelivaptan ¡¢£¤¥¦ §¨©ª «¬ ®¯ °±²³ ´µ ¶·¸ ¹º»¼½¾¿À ÁÂà ÄÅÆ NH HN F Cl NH O N O NH HN O NH O ÇÈ É Ê ËÌ N S O O O O Cl O N O NMe2 O OH
Figure 1.4: Some drugs containing the 2-oxindole ring system.
Given that the absolute configuration of such sterecenter often has a strong impact on
target for AαA. In this case the reaction is performed on racemic 3-monosubstituted-2-oxindole to give the corresponding enantiomerically enriched 3-aminated product. While amides have normally very low acidic protons at α position, in the case of 2-oxindoles, their acidity is en-hanced by the presence of the aromatic ring (that probably allows a partial delocalization of
the negative charge [22]). This fact has been exploited in different reactions and, for practical
purposes, 2-oxindoles (with reported pKa ≈ 18.5 for the enolate formation in DMSO) behave
as more easily enolizable compounds then ‘normal’ amides. As a consequence many studies succeeded in performing AαA on these substrates, under conditions similar to the ones reviewed
in section 1.1. In particular, most approaches are based on the use of azodicarboxylates as
electrophilic nitrogen source.
When analyzing the literature in this field we have to focus on some key-features of the reactions that greatly affect their scope and importance, especially from a practical point of view:
(i) the reaction condition, particularly temperature, solvent and reaction time. (ii) the catalyst used and its commercial availability.
(iii) the enantioselectivity and yield achieved.
(iv) the reaction scope, especially for what concerns the nature of substituents at the nitrogen atom, C3, and on aromatic ring.
(v) the ability to convert the AαA product into the corresponding amine without compromising the overall yield of the sequence.
While most of these aspects don’t need further explanations, it is interesting to point out that not every azodicarboxylate gives AαA products that can be elaborated to the corresponding
amines in a straightforward manner. This aspect will be examined further in section 1.2.1.
The first paper in this area appeared in 2009 and is due to Chen et al. [23]. The authors
selected the AαA of commercially available 3-methyl-2-oxindole as a the model reaction and optimized the relevant reaction parameters one by one. During such a screenings, they found
out that the most effective catalyst was the bis-cinchona alkaloid derivative (DHQD)2PHAL
in combination with diisopropyl azodicarboxylate 24 (DIAD) as the nitrogen source (scheme
1.6). Interestingly the article also reports a strong solvent effect on the enantioselectivity of
the reaction: the best solvent they found was the quite uncommon 1,1,2-trichloroethane (1,1,2-TCE), and after this study its use frequently appears in the field.
Í ÎÏ Ð , (DHQD)2PHAL 10 mol% 1,1,2-TÑ ÒÓ ÔÕÖ×Ø 24 - 48h, RT ÙÚÛÜÝÞßà á â ã ä Aryl O NH NH O Aryl N HN COOiPå COOiPæ N N Alk Alk N N Alk Alk N O N O N N O O O O Alk = (DHQN)2PHAL (DHQN)2PYR ç ) PSfrag replacements 25 26 24 24
Under these condition the reaction proceeds at room temperature in 1 – 2 days, to give the aminated products in good yields. Reasonable enantioselectivities (≥ 70% ee) are obtained for every tested substrate but 3-Ph-2-oxindole; conversely excellent ees (≥ 90%) are obtained only for oxindoles bearing a benzyl-type group at position 3 (25). Interestingly the authors noted that the presence of unprotected nitrogen on the oxindole ring is essential for the reaction to proceed since both NBoc and NMe substrates led to poor yield and enantioselectivity. Similar
results were reported by Zhou’s group [24]. The main differences with respect to the previous
paper stand in the selected catalyst ((DHQD)2PYRinstead of (DHQD)2PHAL) and solvent
(dichlormethane instead of 1,1,2-TCE). Again, the reaction works well only on unprotected oxindoles benzyl substituted at C3 and with DIAD as the nitrogen source.
In the same year the group of late prof. Barbas reported a third study [25] whose conclusions
look surprisingly different – and for some aspects complementary – to Chen’s ones. The model reaction selected in the investigation uses 3-methyl-N-Boc-2-oxindole as the substrate with di-ethyl azodicarboxylate (DEAD, 27) as the electrophilic nitrogen source. Rather surprisingly no attempt to performing the reaction on NH substrates were done; instead it was found that
N-benzyl oxindoles tolerate a more diverse range of substituent at C3 without loss of
perfor-mances, and were therefore used in further screening. Eventually, this led to select the use of
(DHQD)2PHALin Et2O as the best conditions for the reaction under exam. With this
proto-col AαA proved to have a very broad scope and could provide enantioenriched products 28 from oxindoles bearing C3 alkyl substituents ranging from simple ethyl to benzyl, allyl, cinnamyl etc.
èé ê ë , (DHQD)2PHAL 10 mol% Et2O ìíîïðñòóT ô õö ÷øùúû R O N Ph N O R N HN COOEt COOEt Ph O O O O N N üý þ ÿ ( ) PSfrag replacements 29 28 27 27
Scheme 1.7: Conditions for AαA of N-benzyl 2-oxindoles according to Barbas et al. Moreover, a single reaction is performed with DTBAD (15) as the nitrogen source gave an outcome similar to that of the corresponding reaction with DEAD 27. This last aspect is somehow interesting because Barbas used such a Boc derivative and not those obtained from amination with 27 to show the conversion of an AαA product into the corresponding amine. As
pointed out by Zhou et al. [26] and observed in our laboratory [27], the reason behind this choice
is probably that, the harsh conditions needed to cleave the ethyl and isopropyl carbamates lead to quick decomposition of AαA products.
In 2010, Barbas et al. published another paper [28] to address the issue of AαA on
3-aryl-2-oxindoles. In this study a new family of bis-cinchona alkaloid catalysts, previously developed by
the same group [29], was used. The AαA was performed and optimized using
N-Boc-3-phenyl-2-oxindole as the model substrate and DTBAD as the aminating reagent. Different catalysts, solvents, and temperatures were screened to find out that the most satisfying outcome was achieved at very low temperature (-70 °C), in toluene and with a totally new, non commercially available, bis-cinchona alkaloid catalyst (30). The reaction needs up to two days to complete, but very good yields (> 71%) and enantioselectivities (> 73%) were obtained with a number of 3-aryl substrates.
DTBAD , m t , 24 - 48h e Aryl O N Boc N O Aryl N HN Boc Boc Boc A O O Alk N O HO N = ( ) PSfrag replacements 31 32 30 30 15
Scheme 1.8: Conditions for AαA of N-Boc-3-aryl-2-oxindoles according to Barbas et al. It is noteworthy that in this paper Barbas et al. switched to the use of DTBAD as the aminating agent, even though the exact reasons behind this choice was not explained nor other azodicarboxylates were apparently included in the screening.
Another entry into the AαA of 3-aryl-2-oxindoles was provided by Zhou et al. in 2011 [26].
The investigation was prompted by the fact that none of the known methods allowed to perform AαA on N-unprotected 3-aryl-oxindoles, with a substantial disadvantage from an atom economy point of view. The Chinese group hence focused on amination of unprotected 3-aryl-2-oxindoles with DTBAD. During the screenings it was found that, in spite of a lower reaction rare, the use of DTBAD (15) could afford much better ees then DEAD (27) and DIAD (24). According to the authors the difference in reactivity could be explained by the greater electrophilic character
of DEAD and DIAD compared to DTBAD [30]. Subsequent screening delineated an effective
protocol (scheme 1.9) in which AαA requires the use of DTBAD, the catalyst is the thiourea
derivative 33, and the reaction is performed in 1,1,2-TCE at -10 °C; interestingly better results could be obtained when powdered MS 5Å were used as an addictive.
DTBAD , ! TC "#$ %&Å, - '*+. 3/0 12 e.e. > 81% R O NH NH O R N HN Boc Boc N O HN N HN S F3C CF3 * ( ) PSfrag replacements 34 35 33 33 15
Scheme 1.9: Conditions for AαA of 3-aryl-2-oxindoles according to Zhou et al.
Even though AαA was quite slow under these conditions, the reaction tolerates both aryl and benzyl substituent at C3, and also some substitution on the aromatic ring of oxindole framework. Yields are not always excellent, but ees were high in most of the reported examples. Finally two of the AαA products were efficiently converted in amines (yield > 73%) without loss of enantiomeric purity.
In the same year, a very different protocol was elaborated by Shibasaki et al. by the use
of a chiral binuclear Ni(II) complexe. In fact, this was not the first reported approach based
on metal catalysis as in 2010 scandium complexes had been used to perform AαA of 3-benzyl
oxindoles substrates with DEAD as the nitrogen source [32]. Conversely the paper by Shibasaki
et al., reports two slightly different sets of conditions for performing AαA respectively on 3-aryl and 3-alkyl N-Boc protected substrates. Both protocols use DTBAD as the aminating reagent and the chiral dinuclear complex 36 as the catalyst with the main differences consisting in the solvent, temperature and catalyst loading. By selecting the appropriate conditions, a very broad range of substrates could undergo AαA to provide high yields and ees.
DTBAD 4567 89 :; <=>? @BDEFG HIJK LMNAryl) ToO PQ RS TUVWXYZ[\ ( CHCl3]^ _`Å, 30 °C for R=Aryl) * Boc N O R R O N Boc N HN Boc Boc O O N N O O Ni Ni ( ) PSfrag replacements 36 36 15 37
Scheme 1.10: Conditions for AαA of N-Boc-oxindoles according Shibasaki et al.
As discussed further in section 1.4, the paper reports also the elaboration of 37(R =
– CH2– COOCH3) in a known intermediate of the synthesis of AG-041R (12). As far as we
known this is the only published example of direct application of AαA to the synthesis of a 3-amino-oxindole drug.
A very recent literature contribution led to further expansion in catalyst classes that can be
successfully used in these reactions [33]. In this case, the investigation due to Jin et al. found
that very highly enantioselective and fast AαA of N-Boc protected 3-aryl-2-oxindoles could be achieved by using chiral phosphines derived from natural α-amino acids. After screening of a number of solvent, catalysts, and azodicarboxylates, best e.e.s were attained in DCM with 38 –
in quite low catalytic loadings – and DTBAD as aminating agent(scheme 1.11).
a bcd N O Aryl Aryl O N fgh N HN ij k ln p PPh2 HN O F q C CF r su vw x yz {|} ~ PSfrag replacements 38 38 31 32 15
Scheme 1.11: Conditions for AαA under phosphine catalysis according to Zhao et al.
This work appears to be a considerable improvement compared to Barbas’ protocol [28] as it
drastically shortens the reaction time while while keeping yields and ees at a comparably high level. On the other hand, application of phosphine catalysis to these reactions is something of totally new and many details are not fully understood at present.
Since 2012 our research group was involved in AαA focusing on two different aspects: (i) development of supported catalysts for the reaction in batch and under continuous-flow
conditions;
(ii) elaboration of AαA products into bioactive derivative like AG-041R 12.
Polystyrene anchored cinchona alkaloids derivatives 39 were developed by Ravindra P. Jumde
(PhD thesis) [35, 36], and Anila Di Pietro (master thesis) [27] and used to perform AαA of
3-alkyl-2-oxindoles with DEAD and dibenzyl azodicarboxylate (DBAD, 40). Generally almost quantitative yields and high ees were obtained both in batch and in flow, in the case of N-benzyl
protected substrates were used [27]; on the contrary, ees dropped down when N-unprotected or
¡¢m THF, RT £¤¥¦ §¨© ª«¬®¯°±² ³´µ ¶·¸¹º »¼ ½ ¾¿ À Á à ÄÅÆ ÇÈÉ Ê ËÌÍÎ Ï ÐÑÒÓstem obÔÕÖ × Ø ÙÚÛÜÝ Þß àáâãä å æçè éê ë ìíî ï ðñ ò óôõö ÷øùú ûü ýl column. = R1 O N þ ÿ N N O OR2 O R2O N O R1 N HN COOR2 COOR2 P N N N N N O O Alk Alk A N OH O N 4 (R2 = Et) (R2 = Bn) R2 = Et R2 = Bn PSfrag replacements 29 28 27 40 39 39 41
Scheme 1.12: AαA conditions according to A. Mandoli, R. P. Jumde and A. Di Pietro. Apart from the possibility to use the supported catalyst more and more time (100 reaction cycles in batch, > 2500 h time-on-stream in flow), the approach under exam did not present
very different features with respect to the work reviewed above [23,25].
The development of an organocatalytic enantioselective synthesis of AG-041R (12) based on AαA was initially explored by A. Di Pietro but results were disappointing because 41 could
not be deprotected under a range of conditions [27]. As discussed in section 1.4.3 the problem
was eventually circumvented in Spadoni’s master thesis [37] by switching to the use of
bis(p-methoxybenzyloxycarbonyl) azodicarboxylate (42) and optimizing the conditions for the AαA
on the oxindole precursor 43 (scheme 1.13). However, given the fact that the study involved
just a limited number of substrates (chosen among possible precursors of 12), the exact scope of such protocol can be hardly asserted at present and will not be discussed further in this section dedicated to AαA. D ) 2 Et2O, RT N O EtOOC N N M N H N EtOOC O N O ! O O "# $% + PSfrag replacements 43 42 10
Scheme 1.13: AαA with 42 for preparing the intermediate 10.
1.2.1 Elaboration of AαA products derived from azodicarboxylates
As pointed out in section1.2, one of the main challenges to face with when looking to practical
application of AαA is the conversion of the products 3 into hydrazines 44 and amines 4.
R 2 N O & 1 N O ' 1 NH2 ( 2 ) 2 NH2 NH * 1 O N + 2 C,-. 3 / 012 5 HN N 6 1 O N 7 8 O O 9: ; O NN (i) (ii) PSfrag replacements 1 3 44 4
Scheme 1.14: Steps needed to convert AαA product into the corresponding hydrazine and amine derivatives.
(i) deprotection of the ‘carbamate’ groups on the hydrazine fragment. (ii) cleavage of N-N bond of the hydrazine.
Step (ii) is generally performed by using catalytic hydrogenation conditions whith Ni Raney
[9, 25, 26, 32] or Rh on carbon [31,37]. Both these conditions usually give good yields of the
desired product but, to avoid unwanted reaction, the molecular framework should not contain any other functional group sensitive to catalytic hydrogenation conditions (e.g. multiple C-C bonds, nitriles). Furthermore it was occasionally reported that, on certain substrates, only by
using Rh/C formation of a large amount of byproducts is avoided [31].
On substrates other then 2-oxindoles some other procedures have been proposed. For instance in early studies about AαA ,it was reported that N-N bond of 2-oxazolidinone derivative 45
could be broken under mild conditions by treatment with Zn dust, acetic acid and acetone [10,
12,38] or with NaNO2 in AcOH/HCl [13] (scheme 1.15).
< = > 2 ? 1 NH2 O N O O NH O @ 1 B 2 E F G H Z IJKcOH, Me 2CO or N LQ S 2, AcOH, HCl * * PSfrag replacements 45 46
Scheme 1.15: Condition for the cleavage of N-N bond in an oxazolidinone-like product derived from AαA
An alternative – and rather uncommon – protocol for the same purpose is the treatment of
Boc protected hydrazine with TFA in DCM, followed by SmI2 in organic solvent [39]. However,
as far as we, the use of these non-catalytic procedures have never been reported for 3-hydrazino-2-oxindoles, thereby limiting very much the synthetic flexibility of this critical step.
Even tighter constraints are imposed by the nature of group R3 of azodicarboxylate. As
mentioned already, Zhou et al. noticed that so far there are no practical methods for the cleavage
of -COOiPr groups in AαA products from DIAD(24) [26]. In fact, while it is known that such
a carbamate fragment is removed by refluxing the compound in concentrated hydrochloric acid
for 1 day [40], this protocol leads to extensive degradation in the case of substrates under exam
[26]. Similar conclusion were drawn for basic cleavage of -COOEt groups in the work of A. Di
Pietro [27, pg. 95]: in this case applied reaction conditions (KOH 2.5 M in iPrOH, reflux, 4 h)
afforded the deprotected product 44 in low yield (less then 20%), together with a large amount the retro-amination product 1.
N O U 1 N HN COOEt COOEt V 2 N O W 1 NH NH2 X 2 Y 1 O N [ 2 \]^_`abc d i erOH ref ughij Rk lm 2 no p + PSfrag replacements 1 47 44
Scheme 1.16: Basic cleavage of an AαA derived from DEAD as attempted by A. Di Pietro and A. Mandoli.
Moreover, when deprotection of Cbz groups of 3 (R2 = R3 = Bn) with concentrated HBr
in AcOH or water was attempted, as suggested by some authors [41], she never succeeded in
obtain the desired hydrazine 44 (R2 = Bn). Since for simple alkyloxycarbonyl groups (e.g. R3
= Et, iPr) no other approach for the cleavage is known, except from acid or basic treatments
[42, pg. 910], it is reasonable to postulate that at present time there is no method available for
the transformation of 3 with R3 = Et, iPr in the corresponding hydrazines.
On the contrary, standard methods for Boc cleavage usually work for performing the
of deprotection of AαA products: either HCl in organic solvent [26, 31] or TFA in DCM [25] have been successfully employed to give reasonable yields of the desired compounds.
A borderline situation is apparently met in the deprotection of 3 (R3 = Bn). In some early
works about AαA it was reported that Cbz protecting groups on hydrazine subunit are removed under catalytic hydrogenation with Ni/Raney with the simultaneous cleavage of the N-N bond
[9]; good results were also reported when the hydrogenolysis of 3 (R3 = Bn) was carried out
with Pd/C. In spite of this, use of the latter in the work of A. Di Pietro led invariably to poor results because of he lack of reactivity (with HCOOH in MeOH) or to extensive deamination
(C-N cleavage) to give the starting oxindole 3 (with HCO2NH4 or H2 in MeOH).
As anticipated, in order to solve this issue, in the work of A. Spadoni, it was introduced
the use of 42a bis(benzyl) azodicarboxylate with aeasier cleavage profile then 40 [37]. The idea
proved successful as condition could be found for deprotecting 10 in good yield (> 70%) by treatment with anisole in TFA/DCM at room temperature for less then 1 h. The main results
in deprotection of AαA products are summarized in table 1.1.
COOR3 Cleavage conditions Results References
COOEt KOH 2.5 M in iPrOH, reflux, 4h Yield < 20% [27]
COOiPr conc. HCl, reflux, 23h substrate degradation [26]
Boc HCl in organic solvents, RT, 2 – 3 h successful deprotection [26,31]
Boc TFA in DCM, RT, 1 h successful deprotection [25]
Cbz HBr in AcOH, 50 °C, 14h complex mixture [27]
Cbz Pd/C (10%), HCO2NH4, MeOH
reflux, 4h retro-amination occurs [27]
Cbz Pd/C (10%), H2 in MeOH, RT complex mixture,retro-amination [27]
Moz PhOMe, TFA in DCM, RT, 4h successful deprotection [37]
Table 1.1: Summary of deprotection conditions for substrates having generic structure 3.
1.3
Applications of BTCEAD in organic synthesis
Bis(2,2,2-trichloroethyl) azodicarboxylate (BTCEAD, 5) is a quite uncommon azodicarboxylate which had been used in organic synthesis only occasionally. It is a pale yellow solid that crystal-lizes in plates and it is usually stored at room temperature, protected from direct light exposure
[43]. Although commercially available [44, SigmaAldrich product n. 291536, December 2017],
it is quite expensive compared to other azodicarboxylates (about 10 000€ per mol compared to DEAD 306€ per mol and DTBAD 2 280€ per mol), and it is therefore preferentially pre-pared when needed. In general there are two main reasons for using BTCEAD instead of other
azodicarboxylates in synthesis [43]:
(i) it has a greater reactivity then other azodicarboxylates
(ii) trichloroethoxycarbonyl ester groups are removed in milder condition then simple alkyl carbamate.
Because these features were thought to be useful in the present thesis, this section, briefly sum-marizes the syntheses of 5 and the principal differences in reactivity with respect to mainstream azodicarboxylate as deduced from the literature (largely following in this the review by Little
et al. from Encyclopedia of Reagent for Organic Synthesis [45]); in addition, the most widely
used method for the removal of Troc protecting group from bis-Troc-protected hydrazines are reviewed in the end of this section.
1.3.1 Syntheses of BTCEAD
BTCEAD is generally prepared from hydrazine, trichloroethyl chloroformate and an oxidant. The proposed syntheses of this compound are generally similar to the ones of other azodicar-boxylates and consist of two steps: first the hydrazo dicarboxylate is formed under suitable conditions and then the N-N single bond is oxidized with an appropriate oxidant to form the desired azo compound.
A detailed description of the first step is given in an Organic Syntheses procedure [43], where
the reaction is performed using hydrazine hydrate and ethanol as solvent. Because the hydrogen
chloride formed in the course of the reaction protonates free – NH2 groups and prevents them
from attacking a second molecule of chloroformate (scheme1.17), it is necessary to neutralize the
developing acidity to deprotonate the amino group by adding aqueous Na2CO3together with the
second equivalent of trichloroethyl chloroformate, at such a rate that an excess of chloroformate is present at every time.
+ + + NH2 NH2 NH 2 HN CClq O O HCl Cl O O CCl r NH s HN CCl t O O Cl NH2 HN CCl v O O NaCl CO2 H2O Na2CO w NH HN CCl x O O O O ClyC PSfrag replacements 48 49 49 50 Scheme 1.17: Synthesis of 50.
Different method have been reported for the subsequent oxidation step. The one used in the Organic Syntheses’ procedure is probably the easiest and most convenient for large scale application, as the stoichiometric oxidant is the readily available and inexpensive concentrated
nitric acid [43]. Nonetheless it had been reported that using elemental bromine, a slightly better
yield is obtained, with formation of bromide anion as byproduct, instead of toxic nitrogen oxides
[46]. Nevertheless methods give good yields and use cheap starting materials and have been used
more and more times for preparing 5 on large scale.
1.3.2 Reactivity of BTCEAD
Although no specific study on this topic is known in literature, evidence shows how 5 is much more reactive than any other commonly used azodicarboxylate. Since azodicarboxylates are ba-sically electrophilic compounds, it is quite obvious that by enhancing the electron withdrawing effect of the substituents on the two nitrogen atoms, the electrophilicity of the whole com-pounds is then enhanced and therefore their reactivity. Especially this is a consequence of the trichloroethyl groups, that enhanced the electrophilic character of the N-N double bond and reduces the energy of the corresponding ‘lowest unoccupied molecular orbital’ (LUMO). This
fact has been confirmed in a recent paper [30] in which the reactivities of the most common
azodicarboxylates DEAD, DIAD, DTBAD and DBAD are compared. The authors establish an electrophilicity scale based on the rate of their reaction with some carbon nucleophiles (in the specific case enamines derived from cyclic ketones). As one could expect, the trend emerged
from this research, follows almost exactly the one of the electron withdrawing effect of the sub-stituent present on the carbamate moieties: DBAD (E = -8.89) > DEAD (E = -10.15) ≥ DIAD
(E = -10.71) > DTBAD (E = -12.23)1. Comparing these parameters with an electronic effect
index – for example Hammett’s σI – a nearly linear relationship between the two is apparent;
table 1.2collects some useful data [30,48,49] for the comparison.
R E for ROOC-N=N-COOR σI for R
tBu -12.23 -0.07
iPr -10.71 -0.03
Et -10.15 -0.04
Bn -8.89 0.07
–CH2CCl3 - 0.14
Table 1.2: Comparison between E parameters for azodicarboxylates and σI of the correspondent
R groups.
If the trend suggested by these data holds true also for BTCEAD (not included in the study) we could speculate that such an azodicarboxylate was about two order of magnitude more reactive then DBAD as electrophile.
Diels-Alder reactions BTCEAD has been used in hetero-D-A reactions, where it can react
either as a dienophile (in ‘normal’ electron demand reactions) or as a diene (in ‘inverse’ electron demand reactions). In both cases an enhanced reactivity has been noted compared to other
azodicarboxylates [1, 50]. For example reaction showed in scheme 1.18 is complete in 1h at 0
°C when R = – CH2CCl3 while requires more then three days in the same conditions when R =
Me [50]. N N O O z O O { NCOO| NCOO} +
Scheme 1.18: Normal electron demand Diels-Alder recations involving azodicarboxylates as
dienophiles (R = – CH3, – CH2CCl3).
Although somehow less intuitive, this compound may react as a diene in an inverse electron demand D-A reaction by means of the azo group and one of the two carbonyl groups present in the molecule. This reactivity has been exploited by Leblanc and Fitzsimmons to prepare D-A
products from glycals that are typical electron rich ene systems [1]. The reaction forms quite a
complex heterocycle that is further elaborated to prepare amino sugars (scheme 1.19).
hυ~ [4+2] cycloaddition 1.5 days + O OTBDMS TBDMSO TBDMSO N N O O CCl3 Troc CCl3 O Troc N N O TBDMSO TBDMSO TBDMSO O NHAc OH TBDMSO TBDMSO OTBDMS O
Scheme 1.19: An inverse electronic demand Diels-Alder with BTCEAD as the diene partner.
1
The E value specified in brackets is an electrophilicity parameter proposed by Kanzian and Mayr. The value is calculated from the reaction rates of the azodicarboxylate with nucleophiles of different strength. In particular E depends on the logarithm of reaction rates. Since according to Arrhenius equation, rate constant is an exponential function of activation energy, the scale should have an overall linear relationship with activation energies. For more detailed information about the method see [30,47].
It was noted that unless these D-A reactions are quite slow (18 h to 2 weeks) in every tested
case they are faster then the ones attempted with dimethyl azodicarboxylate [1].
Ene reaction Another distinctive reaction of BTCEAD is the ene reaction. Aza-ene reactivity
has been reported also for other azodicarboxylate but yield are generally poor [45]; by contrast,
when BTCEAD is used this reaction represents a useful route to allyl amines. Many papers have been published on the topic, reporting – inter alia – the remarkable possibility to use water as
the reaction medium [51–54]; in many of these works it is underlined the fact that BTCEAD is
more reactive than normal alkyl azodicarboxylates [53,54]. Together with the higher reactivity
of BTCEAD, the importance of these methodologies stands in the ease with which the amination
products can be converted into the corresponding allylic amines (see section 1.3.3).
N N Troc Troc N Troc NH Troc +
Scheme 1.20: An aza-ene reaction with BTCEAD by Leblanc et al.
Electrophilic aminaton BTCEAD also reacts smoothly with many carbon nucleophiles.
This fact is proved by its pronounced reactivity toward electron rich arenes. For example it was found that while DEAD reacts only with very nucleophilic aromatics such tin phenoxides
[55], BTCEAD easily reacts with phenols [56]. More recently BTCEAD was exploited to
per-form direct amination of phenylethers [57,58], anilines [59] and indoles [58] under acid catalysis.
Moreover it should be noted that unless quite uncommon, at least one example of AαA with
BTCEAD on an α-cyano ester is known in literature [39]; the authors, however, did not
inves-tigate in detail this chemistry due to the very poor ee obtained in the very first trial.
1.3.3 Methods for the removal of Troc protecting groups
Troc is a rather common protecting group both for alcohols and amines, often selected due to
the mild reducing conditions needed for its cleavage [42]. This aspect together with the useful
orthogonality with respect to other protecting groups, increase functional groups tolerance (e.g.
carbon-carbon multiple bonds [60,61]), thus expanding the scope of the protection method.
Most common conditions for Troc removal involve the use of a large excess of Zn dust in protic or slightly acidic medium. Many examples in this respect are found in literature; for instance the use of Zn in a mixtures of THF/aqueous buffer affords the deprotected product in
good to excellent yield in few minutes [60, 62]. Another widespread procedure uses acetic acid
as solvent which provide as well the necessary acidic environment. [63,64]. Some modifications
and alternatives to these general procedures have been proposed, including the use of metal couples (such as Zn/Pb or Zn/Cd), phthalocyanines-metal anions or electrochemical techniques. Nevertheless, apart in specific situations where milder conditions are required or when standard cleavage method are not effective, these techniques are not commonly found in literature as they often require more expensive – or toxic – reagents then the standard ones (for a full list of
cleavage methods for Troc group see [42]).
As far as we know, no insights on the mechanism of the reductive cleavage have been reported in literature, but it is likely that it proceeds through insertion of zinc in one of the C-Cl bond
followed by β-elimination to give one molecule of CO2 one of H2C –– CCl2 and the deprotonated
substrate as an amide anion that is promptly protonated by the acidic environment. Since both dichloroethylene and carbon dioxides are either gaseous or have very low boiling point, they are not found in the reaction mixtures; the only byproducts that are present at the end of the reaction are zinc salts.
As was noted by Leblanc and Fitzsimmons, when the cleavage of the Troc groups on an hydrazine derivative is carried out with zinc dust in acetic acid in the presence of acetone,
the N-N bond is simultaneously broken [1]. This methodology is very useful when BTCEAD
is used as aminating agent because the amino functionality is easily revealed in a single step.
Also in most recent works [65], the condition adopted for the reaction under exam are merely
the same as reported above by Leblanc and Fitzsimmons in their original article: acetic acid as the solvent and a very large excess of zinc dust (40 molar equivalents). N-N cleavage is supposed to proceed through an hydrazone intermediate that is then converted into the amine
by the reductive environment [1]. Despite the fact such a mechanism has been advocated also
in subsequent publications [65], as far as we know the only proof in support of this hypothesis
is the claim by Leblanc and Fitzsimmons that the intermediate hydrazones have been identified
“by monitoring the reaction (TLC and 1H-NMR)”, but details of these experiments were not
given in the paper nor in subsequent publications [1].
1.4
Biological activity and synthesis of AG-041R
AG-041R (12), was first prepared and tested as a cholecystokinin-B/gastrin antagonist. Its
activity was studied and compared to some other drugs in the same family [66,67] to conclude
that it is as effective as the most of them. Nevertheless some other aspects of its biological activity have attracted the interest of researchers: first of all it was found to suppress some factors involved in the neoplastic activity of a particular kind of gastric tumor in an animal
model [67]; as pointed out in the cited study, the activity of the drug against this cancer is
probably due to different factors. More recently it was discovered that its anti-tumor activity
is enhanced when used in combination with a COX-2 specific inhibitor [68]. Apart from
anti-cancer properties,much interest in AG-041R stands from its inherent activity as a stimulant of
chondrogenic2 processes in different mammals. Many studies [21, 69–72] have been done for
its use as cartilage repairing agent, either in vivo or in vitro and many promising results have been obtained. Furthermore it has been found that it enantiomer (AG-041S) has a much lower
activity, at least in these processes [21]. Nonetheless as far as we know in the last ten years no
new study had been published neither a process for commercialization of this drug for human application has begun. It is quite curious to note how chemical research for the total synthesis of this drug has begun simultaneously with the end of biological studies for its applications.
AG-041R has been considered as an interesting synthetic target by several research groups in view of its polyfunctional nature and the need of a stereoselective preparation. The first synthesis
of this compound was described in the original patent [73] and involved an optical resolution
with (-)-menthol as a chiral derivatizing agent. Since then, many alternative approaches have been explored and reported in the literature, whose results are briefly reviewed in this section. With this aim, the various procedures are subdivided according to the strategy adopted in the key-step that forms the tetrasubstituted stereocenter at C3 carbon atom.
Carbon nucleophile Nitrogen electrophile
Carbon electrophile N O N N O NH N O N O N (a) (c) (b)
Scheme 1.21: Main strategies for the synthesis of AG-041R.
2
As summarized in scheme1.21the three most common routes involves: (a) attack of a carbon nucleophile on a ketimine derived from isatin (b) attack of a carbon electrophile on a 3-amino-2-oxindole
(c) attack of a nitrogen electrophile on a 3-alkyl-2-oxindole (AαA)
1.4.1 Synthesis of AG-041R by attack of a carbon nucleophile on a ketimine
The strategy described in this section ranks among the most effective ones at present. So far at least 6 papers regarding this approach have been published, with the first work have been proposed by Shibata et al. in 2012. The key step is the nucleophilic decarboxylative addition of a malonic acid half-thioester to the N-Boc protected ketimine 51. This reaction is performed in a catalytic enantioselective manner, by using the cinchona alkaloid derivative 52; the addition product is obtained in 71% yield and 73% ee. Once the stereocenter is formed AG-041R is obtained in three steps with 54% overall yield from 51.
R + .) H ¡ ¢£¤¥¦ §fl¨© ª«¬ ® ¯°±²³ ´µ ¶ 2. ·¸¹º» ¼ 82% O N OEt EtO NBoc N O O S H N N N O O ½ ¾¿ HO O À Á BocNH EtO OEt N O O ÃÄ Å BocNH EtO OEt N O NCO O ÆÇÈ EtO OEt N O NH HN O Tol ÉÊËOH in EtOÌ ÍÎ 2O ÏÐÑÒÓ ÔÕ Ö× ØÙ ÚÛ ÜÝÞ ß àáâ ãäåæ ç è AG-041R éêë PSfrag replacements 51 52 52 53 54 55 12
Scheme 1.22: Synthesis of AG-041R by Shibata et al.
Even if the ee reported for the organocatalytic step is far from being impressive, intermediate
55could be enantiomerically enriched to up to 96% ee by crystallization.
Three years later a similar approach was followed by Wennemers et al. to prepare the methylated
analogue of AG-041R 56 [75]. In this case, the synthesis was achieved by attacking the malonic
half-thioester 57 to the Cbz-protected ketimine 58; the new C-C bond formation is catalyzed by the chiral thiourea introduced by Y. Takemoto (59): during the reaction two new stereocenters are formed in 60 both of them with a well defined prevalent configuration.
ìíî ï ð tolueneñò óôõö ÷24h øùúûüýþ ÿ5 Pp-methoxyphenyl p-methoxybenzyl + 1 A 2. Et3N ! " #$%&' ( 3. AgOTf, p-toluidine DMAP in DCM, 6h 1. O2/O3 in DCM, -78 °C 2. DMS, RT, 24h 3. CH(OEt)3, HCl, in EtOH, 4h, 80 °C 1. H2, Pd/C, MeOH 2. p-tolylisocyanide in DCM, 1h NCbz N O PMBO SPMP O O O N CbzNH H N O COOPMB O N CbzNH SPMP O Tol O N OEt CbzNH H N O Tol EtO O N OEt NH NH O Tol EtO NH O Tol NMe2 NH N H S CF3 CF3 69% 74% PSfrag replacements 58 59 59 57 60 61 62 56
Scheme 1.23: Synthesis of a methlated analogue of AG-041R (56) by Wennemers et al. Worth of note in this route are the stereoselective decarboxylation involved in the trans-formation of 60 in 61 and the conversion of the allyl group of the latter to introduce the
CH(OEt)2 group of 56. An explanation for the choice of using an allyl group as a masked form
of – CH2– CH(OEt)2 is that while N-allyl-isatin can be efficiently prepared by direct
alkyla-tion [37,76], the same reaction with Br – CH2– CH(OEt)2 (to obtain, e.g., the precursor of 51)
proceeds with very poor yields [77].
In a newer approach Enders et al. have studied the addition of nitroacetate esters to 51 [78].
Once again, the reaction is performed with a cinchona alkaloid derivative (63) as the asymmetric organocatalyst to provide desired product 64 in good yield (>80%) and excellent ee (>90%) under optimal conditions.
1. )* +, -./02C 3467 89: ;< => nBu 3SnH ?@BDC, toluene EFG HIJKL MO Q O N OEt EtO NBoc O OEt O2N O OEt BocNH EtO OEt N O HN N N + PSfrag replacements 51 63 63 64
Scheme 1.24: Formal synthesis of AG-041R by Enders et al.
However, in this formal synthesis of AG-041R the nitro group (needed to enhance the basic character of the α position of the ester) had to be removed in a subsequent step by the use
of an excess of toxic nBu
3SnH [78]. This shortcoming could be avoided in the organocatalytic
enantioselective addition of acetaldehyde to N-Boc ketimine 51 followed by oxidation of the resulting alcohol to the corresponding carboxylic acid; this sequence allowed to complete another
formal synthesis of AG-041R based on the Shibata’s sequence. 1. RSTUVWX YZ[\] ^_ `ma bc 2Cd H4CO2H e fg hijC, 72 h klm no 2PO4pqr st u 2, 2-methyl-2butene, t v wx y z{2O 5:1 |}~ 2CO3, MeCN 70%, 93% e.e. O N OEt EtO O O OMe EtO OEt N O tBu NH2 N + PSfrag replacements 51 65 65 54
Scheme 1.25: Formal synthesis of AG-041R by Shao et al.
The addition of carbon nucleophiles to imine-type substrates has been also used in
diastere-oselective syntheses: instead of using a chiral catalyst, in two recent papers [80, 81], a chiral
sulfonyl protecting group on the ketimine moiety is used to steer the attack of the nucleophile towards one of the stereo-faces of C –– N. In the first of these contributions the reaction was performed with a Reformatsky reagent, on 66, to afford 67 in quite good yield (>85%) and d.r. (>90:10). THF, 0 °C 1. HCl in A °C to RT 2. TFA, DCM, RT 3. MeOH, RT Ph Ph Ph tBu O S N O N COOEt N O HN S O tBu Ph Ph Ph O ¡ OEt COOEt NH O H2N PSfrag replacements 66 67 68
Scheme 1.26: Synthesis of AG-041R precursor by Su and Xu.
After removal of the sulfured chiral auxiliary and the triphenylmethyl (Tr) protecting group on nitrogen,the synthesis was stopped at the aminoester 68 as its conversion into AG-041R was
known in literature [82].
In a related approach the enantiomer of 66 has been alkylated under condition that avoid
the use of a organo-metal [81]; this was done by using S-phenyl thioacetate in combination with
trimethylsilyl triflate and a weak base (iP r
2EtN), to form in situ the corresponding trimethyl
silyl thioketene acetal. Stereoselectivity is more satisfying (>98:2), the use of Zn is avoided, and a complete sequence of reactions to prepare AG-041R was shown. Nevertheless, as in the previous procedure the need of stoichiometric amount of chiral auxiliary and the use of large Tr protecting group (required also for maximizing the stereoselectivity) impact negatively on the atom-economy of the whole sequence.
¢ £¤¥¦ §¨ iP © 2ª «¬ ®¯ °±, RT AG-041R 1. HCl in dio² ³ ´µ ¶·¸¹º»¼½ ¾¿ 3. p-tolylisocyanide in MeCN N O N À O t Á Ph PhPh SPh O Ph Ph Ph t ÃÄ O S HN O N COOSPh NH O NH COOSPh O N H Tol N O N HN O Tol O ÅÆ Ç È ÉÊ ËÌ ÍÎ Ï ÐÑ Ò t Ó ÔÕ Ö×Ø Ù 4N Ú Û -Ü Ýdimethylacetamide, Þß°C àáâã äå æç èéê ëì 2O, RT íîp-toluidineïð ñ ò·HCl ó ôõ ö÷øùT úûüýþÿ. 7 9 8 ent-PSfrag replacements 66 69 70 71 12
Scheme 1.27: Synthesis of AG-041R by Hajra et al.
In addition while these strategies are very appealing for their high stereoselectivity, the ketimines needed as substrates are not always straightforward to prepare from the commercially available – and inexpensive – isatin. For example the starting material 51 in the synthesis of Shibata et al., Shao et al. and Enders et al. is obtained by Shibata et al. a three steps sequence
(scheme 1.28) that requires the use of an organo-lithium, and gives only moderate yield [74] and
begin itself from the difficult to prepare alkylated isatin 72 [77].
n-B °C 1 -78 ° 2!"# 3 SiCl, -78 °$%&'T, 2h Si Boc H N N Boc Si E ( ) O* + O O N , - / 04 5 N O N Boc 6:; PSfrag replacements 51 72
Scheme 1.28: Synthetic sequence for the preparation of 51.
1.4.2 Synthesis of AG-041R by α-alkylation of a 3-amino-2-oxindole
Among all the stereoselective syntheses proposed for 12, just one example is based on an elec-trophilic alkylation step. As an improvement of the patented procedure noted above, Emura et al., at Chugai Pharmaceutical Co. examined the diastereoselective alkylation of 3-ureido-oxindole 73 with L-menthyl bromoacetate (74). At variance with the use of achiral
bromoac-etates [73], under these conditions (scheme1.29) the product 75 is formed with large prevalence
LiHMD<=> ? @AF°C 77% d.rGHIJK LOH, EtOH/H 2OrefluMNPQR Tol O NH N O NH OEt EtO O O EtO OEt NH O N NH O Tol O O ST OH O EtO OEt NH O N NH O Tol AG-041R EDC·HCl p-toluidine U°C 4h, then RT 1.5h VWXYZ [\]^ e_`a bcdf ghij k l PSfrag replacements 73 74 75 76 12
Scheme 1.29: Diastereoselective synthesis of AG-041R by Emura et al.
Despite the general disadvantages in the use of stoichiometric amounts of chiral auxiliary, it is worth noting that menthol is available in both enantiomeric forms, with the natural occurring
one – that used by Emura et al. – being a rather cheap reagent (about 9.3 € per mol [44]);
furthermore, it is in principle possible to recover the menthol after saponification of 75 to 76 and use it to prepare once again the alkylating reagent 74 by an efficient (> 90% in yield)
procedure [73].
It is noteworthy that the paper [77] dedicates special attention to the synthetic path needed to
prepare 73 from isatin (77). Two routes that differs only for the order of the steps in the route
were examined (scheme 1.30) to conclude that the one labeled as B was the only viable for the
preparation of 72. A B m no pq s tvwxy z{|} H2NOH·~ OA 1. Pd/C, H2 2. H2NOMe·HCl 2HPO4 MeOH, RT, 2h O O NH O O N OEt EtO N O NH OMe NOH O N OEt EtO N O N OMe OEt EtO OEt OEt OEt OEt t ¡¢£¤¥¦§¨©ª A«¬®¯° ± ²³ B´µ¶·¸ ¹º » ¼ ½¾¿ÀÁ  ÃÄ 1. Pd/C, H2 2. Å ÆÇ ÈÉ ÊËÌ ÍÎÏÐ ÑÒ Ó Ô Õ PSfrag replacements 73 77 72
Scheme 1.30: Synthesis of 73 proposed by Emura et al.
In this respect, the authors underline that the much worse outcome of sequence A is probably
due to the instability of 72 under the alkylation conditions [77]. Therefore the use of N-alkyl
isatin 72 as the starting material in any synthesis of AG-041R should be carefully considered and, if possible, avoided.
The overall yield of the synthesis of AG-041R discussed above is about 36 % from isatin. At present it is still the most high yielding approach and the only one actually employed for the ‘large scale’ preparations of AG-041R.
1.4.3 Synthesis of AG-041R by AαA
In the literature there is just one published formal synthesis of AG-041R based on AαA. The work is based on protocol of Shibasaki et al. which makes use of a homodinuclear chiral nickel
complex as catalyst (see section 1.1). Given that the same work had been published in two
different papers with only slightly difference in reaction conditions [31, 83], reference will be
made herein to the most recent one [31], that also report the best results. The AαA of oxindole
78was performed in excellent yield (98%) and enantioselectivity (ee > 95%) with a low catalytic
loading (1 mol%), as often happens for reactions catalyzed by chiral metal complexes. Once obtained, the AαA product 79 was transformed into the known intermediate of the synthesis of
AG-041R in two steps (scheme 1.31).
Ö× ØÙÚÛÜÝÞßàá. âãä åæ Tç èéêëìíîïðñ òóôõ 98%, 96% e.e. 1. 3 M HCl in ö÷ øù úûüýþÿ/ , RT, 2 h 2. Rh/C, H2 in MeOH, RT, 6 h 83% O O N N O O Ni Ni MeOOC O N B O NH NH2 MeOOC MeOOC HN N N O O NH NH MeOOC NH O Tol p l MeCN, RT, 2 h 9 !" #$% &' PSfrag replacements 36 36 80 81 78 78 79 12
Scheme 1.31: Synthesis of AG-041R proposed by Shibasaki et al.
In addition to the use of toxic metal in catalyst formulation this approach presents several drawbacks. One of these might be the alkylation of 81 that according to Iwabuchi et al. (vide
infra, scheme1.33) appears to proceed with very low efficiency3. However, the overall yield from
commercially available isatin can’t be determined, as the synthesis of the methyl ester 78 is not reported neither in the paper under exam nor in literature.
As anticipated, routes to AG-041R based on organocatalytic AαA were explored in unpub-lished work from our group. After unsuccessful attempts with aminated products from DEAD
and DBAD, in A. Di Pietro master thesis [27], these efforts let to a complete synthetic scheme
with the work of A. Spadoni (scheme 1.32, see also section 1.2.1) [37]. Our research group has
tried to address these issues during A. Di Pietro and A. Spadoni’s master theses. The results obtained are so far unpublished, but it is important for a complete understanding of present work to carry out a brief review of them. In A. Di Pietro’s work the focus was on application of heterogenized bis-cinchona alkaloid derivatives to synthesis of useful intermediates for AG-041R.
As pointed-out in sections 1.2 good results had been obtained in the amination of
N-benzyl-2-oxindole precursor of AG-041R with either 27 or 40; a further elaboration of its aminated product to prepare a known intermediate in the synthesis of AG-041R wasn’t however possible
(see section1.2.1).
The first key point in this approach was the use of PMB-azodicarboxylate 42 to provide good enantioselectivity in the AαA step and the possibility to deprotect the aminated product under
3
In this respect it should be noted, however, that alkylation of intermediate 70 in the synthesis of Hajra et al. is reported to provide a much better yield.
mild acidic conditions. Moreover, because AαA turned out to proceed with high enantioselec-tivity only in the case of N-protected oxindole substrates, the sequence started from the N-allyl
derivative 82. According to previous investigations [85, 86] and similarity to the approach of
Wennemers et al. (see section 1.4.1), the latter was meant to provide the required protection
during the AαA step and to be transformed into the 2,2-diethoxyethyl fragment of AG-041R in a later stage.
The route summarized in scheme1.32represent the first example of a synthesis of AG-041R
based on organocatalytic AαA. Even though overall yield after the enantioselective reaction (about 27%) was comparable to those of other routes reported in the literature (see section
1.4.5), several drawbacks are present. Most notably these include:
(i) the need to temporarily convert the C-C double bond of 10 into a 1,2-diol fragment, in order to cope with chemoselectivity problems under the acid removal of Moz groups (which turned out to be incompatible with the presence of the diethylacetal) and hydrogenolysis of N-N (which, of course, could not be performed in the presence of C-C double bond); (ii) the use of toxic osmium salts in the dihydroxylation step above;
(iii) poor atom economy by the use of 42 as aminating agent.
q( )* +,-. 01 2345678:; A <=> ?@ Cβ (1.4 g/mol) K2O DE4 · 2H2FGHIJLM N PQR S TU VWXY Z [\ ] ^_` aA in DCM 2. H2bc d efghijkm 64 % no rst u v wx yz{ |} ~ in MeCN 1. H 6 2O 2. (EtO)3CH, H in DCM AG-041R 97% Moz Moz HN N N O EtOOC EtOOC O N N HN Moz Moz HO HO EtOOC O N NH2 HO HO EtOOC O N HN HN O O O EtOOC O N HN HN O HO HO N O EtOOC N O NH O O O 70% 2. ¡¢ £¤ ¥¦§¨ ©ª« ¬® ¯°±² ³´ µ¶ · ¸¹ º» ¼n 1. EtOOC-CH2-PO3Et2 ½¾¿À Á  4 in MeOH Moz2N2 in Et2O ÃÄ ÅÆ ÇÈ ÉÊ Ë)2ÌÍÎÏ ÐÑ 28% Ò ÓÔÕÖ×ØÙps PSfrag replacements 77 82 43 10 83 84 85 86 12
Scheme 1.32: Synthesis of AG-041R developed by A. Mandoli e A. Spadoni.
1.4.4 Synthesis of AG-041R by other strategies
A last synthetic strategy that does not fit any of the approaches reviewed above was presented
