Rhodium(II)-catalyzed intramolecular carbonyl ylide formation of  -diazo-  -ketoesters derived from N -phthaloyl-  -amino acids

Starting from L -alanine, L -phenylalanine, L -leucine, L -norleucine, or L -isoleucine, 2-diazo-3-oxo-4-phthalimido-alkanoates 8 were prepared in three steps. Considerable racemization occurred at the stage of the 3-oxo-4-phthalimido-alkanoates 7 . Dirhodium tetraacetate effectively catalyzed the intramolecular formation of carbonyl ylides 9 , which in the absence of a trapping reagent underwent a [3+3] cycloaddition reaction to form the dimers 10 . Carbonyl ylides 9 underwent [3+2] cycloaddition reactions with several electron-deficient alkenes and alkynes to give oxygen and nitrogen containing multicyclic systems 12 – 16 . The keto group of the  -oxy-  -ketoester moiety of cycloadducts 2 and 12 is easily hydrated to give the gem -diol.


Introduction
The intramolecular metallocarbenoid chemistry of -diazocarbonyl compounds has attracted much attention in recent years. 1,2While carbenoid C,H insertion and olefin cyclopropanation reactions give rise to carbocyclic frameworks, various heterocyclic ring systems become accessible in the presence of additional heteroatom-containing functional groups being able to participate in carbenoid reactions.Typcial examples are N-H and O-H insertion reactions as well as the formation and further transformation of various kinds of O-, S-, and N-ylides.Since -diazoketones and -diazo--ketoesters are frequently synthesized from carboxylic acids as starting materials, it is not far-fetched to consider amino acids as precursors for diazocarbonyl compounds incorporating an additional amine functional group and eventually a chiral center, if the naturally occurring -amino acids are considered.
In fact, -diazocarbonyl compounds derived from -amino acids have already been employed for various synthetic transformations.N-protected '-amino--diazoketones have been converted into -amino acid derivatives by Wolff rearrangement 3 and into 3-aminoalkylazetidin-2-ones (-lactams) by a Wolff rearrangement/[2+2] imine cycloaddition sequence. 4arious intramolecular carbenoid insertion (C-H, 5 N-H 6 ) and cyclopropanation 7 reactions have been achieved with -diazoketones derived from -amino acids.The Rh(II)-catalyzed dediazoniation of a diazoketone derived from N-Cbz-serine resulted mainly in an azetidin-3-one due to N-H insertion, the O-H insertion product and an oxonium ylide derived 1,3-oxazine-2,5dione were formed as by-products. 8A -amino--diazo--ketoester derived from Boc-tyrosine underwent Rh-catalyzed intramolecular aromatic C-H insertion. 9n the past two decades in particular, the tandem carbenoid carbonyl ylide formation/[3+2] cycloaddition sequence has been studied intensively. 10,11This synthetic strategy can be employed for the fast assembly of complex oxamulticyclic molecular frameworks on the way to natural product targets. 12,13Padwa and coworkers 11a, 14 have also observed that amido-functionalized diazoketones can undergo Rh(II)-catalyzed carbenoid cyclization to form five-, six-, and sevenmembered cyclic carbonyl ylides.In a related study, they found that the phthalimido-substituted -diazo--ketoester 1 underwent Rh-catalyzed formation of a carbonyl ylide which was trapped with N-phenylmaleimide to give the polyheterocyclic adduct 2 (Scheme 1). 14Similarly, the sacccharin-derived diazoester 3 gave cycloadduct 4. 15 Both 1 and 3 can be considered as glycine derivatives, although they were assembled by alkylation of the phthalimide 16 and saccharinate 15 anion, respectively.In this paper, we report on the use of several -alkyl-substituted, naturally occurring amino acids as starting materials for the preparation of the title compounds structurally related to 1.The generation of six-membered cyclic carbonyl ylides by intramolecular metallocarbenoid cyclization and some typical trapping reactions of the carbonyl ylides are also described.

Synthesis of -diazo--ketoesters 8
The synthesis of 2-diazo-3-oxo-4-phthalimido-alkanoates 8 is outlined in Scheme 2. -Amino acids L-alanine, L-phenylalanine, L-leucine, L-norleucine, and L-isoleucine (5a-e) were converted into their N-phthalolyl derivatives 6a-e by a published procedure 17 which uses a catalytic amount of triethylamine to lower the required reaction temperature.It was reported that for Lphenylalanine, no racemization occurs under these conditions.In the case of N-phthaloyl-Lisoleucine, however, the observation of two diastereomers in the ratio 97:3 by 1 H NMR analysis revealed a minor extent of epimerization at carbon atom C-2 ((2S,3S) isomer: (NCH) = 4.68 ppm, 3 J(H,H) = 8.4 Hz; (2R,3S) isomer:  = 4.74 ppm and J = 7.6 Hz; for assignments, see lit. 18).N-Protected amino acids 6 were then converted into -ketoesters 7a-e according to a published procedure; 19 this method gave yields in the range 37-54% (14% for 7e).Ketoesters 7 were transformed into -diazo--ketoesters 8a-e by standard diazo group transfer reactions using either p-tosyl azide or the recently introduced imidazole-1-sulfonylazide hydrochloride, 20 which allows for a simplified workup procedure.At the stage of -ketoesters 7, a considerable degree of racemization occurred.For ketoester 7e derived from L-isoleucine, the presence of two diastereomers in 56:44 ratio was indicated by a 1 H NMR spectrum.HPLC analysis of ketoester 7a and diazo esters 8a-e revealed more or less complete racemization.Furthermore, the formation of diastereomers of the carbonyl ylide derived products (vide infra) clearly showed the racemization at the chiral center (NCH).

Rhodium-catalyzed decomposition of diazoesters 8a-c
The Rh2(OAc)4-catalyzed dediazoniation of diazoesters 8a,b in boiling benzene produced one product in high yield according to the NMR spectra.Due to the limited stability of this product toward chromatographic conditions, even flash column chromatography over silica gel was accompanied by severe loss of material and complete purification was not possible, in particular the rhodium catalyst could not be removed completely.In the case of the product derived from alanine derivative 8a, however, single crystals suited for an X-ray structure analysis could be grown which established the structure of the oxazapolycycle 10a, the syn-dimer of carbonyl ylide intermediate 9a.The analogous carbonyl ylide dimers 10b and 10c were formed from diazoesters 8b and 8c, as was confirmed by the similarity of the relevant NMR data and the molecular ion peaks in the mass spectra.In the latter case, the formation of 10c was accompanied by intramolecular carbenoid insertion into the methine C-H bond giving rise to 2oxocyclopentanecarboxylate 11.Unfortunately, efforts toward chromatographic separation of the approximately 1:1 mixture of the two products were not successful.

Structure determination for carbonyl ylide dimer 10a
The molecular structure of 10a in the solid state is shown in Figure 1.The molecule has a C2 topology, which does not coincide, however, with a crystallographic twofold rotation axis; in fact it can be seen that the the two carboxylate groups occupy opposite positions with respect to the neighboring C-O bond of the epoxy bridge, one carbonyl group being almost syn-periplanar with that bond (O4-C13-C4-O1) and the other anti-periplanar (O9-C28-C19-O6).In this diastereomer, the two epoxy bridges are syn to each other, and the methyl groups occupy equatorial positions at the ring system.Since the compound crystallizes in a centrosymmetric space group, the two enantiomers are present, which confirms that racemization at the chiral center of the original -amino acid has occurred.An interesting structural detail is given by the unusually long C-C bonds connecting the two carbonyl ylide subunits (1.597 and 1.600 Å).
In agreement with the solid-state structure of 10a, the 1 H NMR signal of the ester-CH3 groups in the carbonyl ylide dimers has undergone a significant upfield shift compared with the precursors 8 (e.g.10a:  = 0.71 vs. 1.28 ppm) due to their position in the shielding area above the aromatic ring (as can be seen clearly in Figure 1 for the COOCH2CH3 group at the left-hand side).The formation of the syn-dimers 10a-c results from a [3+3] cycloaddition with an endo transition state structure, in which the substituent R at each carbonyl ylide molecule for steric reasons is oriented anti to the approaching second carbonyl ylide molecule and therefore ends up in the equatorial position of the cycloadduct.Several authors have mentioned earlier the formation of [3+3] carbonyl ylide dimers of the 2-benzopyrylium-4-olate type, but a rigorous structural proof has not been furnished. 21,22In one case, the tentative assignment of a head-to-tail dimer had to be corrected, when an X-ray structure analysis revealed the formation of a dimer with different constitution. 23Other studies have documented the complexity of dimerization reactions involving carbonyl ylides of this type. 24As far as we know, only one crystal structure determination of a carbonyl ylide dimer has been published so far. 25In that case, the dimer was derived from a five-membered cyclic carbonyl ylide and had the two epoxy bridges in anti orientation (i.e. the central 1,4-dioxane ring had an envelope conformation).The X-ray structure analysis of 10a, on the other hand, shows the two epoxy bridges in syn orientation, with a twisted boat-like conformation of the central 1,4dioxane ring.

Tandem carbonyl ylide formation / [3+2] cycloaddition reactions
The rhodium-catalyzed dediazoniation of diazoesters 8a and 8d was carried out in the presence of several electron-deficient olefinic and acetylenic dipolarophiles in order to intercept carbonyl ylides 9 by a [3+2] cycloaddition (Scheme 4).Besides the standard dipolarophiles Nphenylmaleimide (NPMI), maleic anhydride (MSA) and dimethyl acetylenedicarboxylate (DMAD), we also applied a cyclopropyl-substituted propyne iminium triflate 26d (CPI).In previous work, we have documented the reactivity of acetylenic iminium salts as dienophiles as well as dipolarophiles. 26Here, this type of an electron-deficient alkyne was used for the first time to trap a carbonyl ylide.In all cases, the 1:1 cycloaddition products were formed in good yield according to the 1 H NMR spectra.However, in some cases efforts of purification by crystallization were unsuccessful and column chromatography was accompanied by a strong loss of product.The structures of the prepared cycloadducts 12-16 are shown in Figure 2. In the case of 16, the regiochemistry of the cycloaddition reaction was established beyond doubt by NOESY correlations between an iminium N-methyl group ( = 4.17 ppm) and the proton in ortho-position of the phthaloyl ring ( = 7.76 ppm), this proton having been identified by 2D NMR experiments.For all cycloadducts 12-16, a mixture of two diastereomers was formed (Table 1).The similarity of the 1 H NMR chemical shifts of the bridgehead protons (CHCH), the NCH proton and the NCH-methyl protons (Table 1) suggests the same stereochemical characteristics for 12-14 on one hand and for 15 and 16 on the other.For cycloadducts 12-14, not only the configuration at the NCH carbon atom has to be assigned, but it is also of interest to know whether the dipolarophile has undergone an exo or an endo approch to the carbonyl ylide dipole.NOESY NMR studies for cycloadducts 12 and 13 clearly showed nuclear Overhauser effects between the two bridgehead protons and the methyl substituent in diastereomer A, and between the two bridgehead protons and the NCH proton in B (Figure 3; for A and B, see also Table 1).This means that the pyrrolidine ring occupies the exo position (syn to the epoxy bridge) in both diastereomers, and that diastereomer A has the methyl substituent in the endo position.By analogy, the same stereochemical assignments can be assumed for MSA adduct 14.Although diastereomer A, with the alkyl substituent in endo-position, is not in all cases the major isomer resulting from the cycloaddition reaction (Table 1), it appears to be the thermodynamically favored one.For the crude norleucine-derived cycloadduct 13 an A:B molar ratio of 0.31 was observed, which was reversed to 2.66 after chromatographic purification on silica gel.Epimerization at the NCH carbon atom was also found for alanine-derived 12; here, a solid containing only the epimer 12A (besides impurities) was obtained from an acetonitrile solution of the crude reaction product by precipitation with water, but again, chromatography over silica gel caused epimerization (A:B = 1.16).The two diastereomers of cycloadducts 15 and 16 must have the exo-or endo-methyl configuration, respectively.A single-crystal X-ray structure determination of 15 revealed the molecular structure of the major diastereomer 15A (Figure 4).In contrast to the structure found for 10a, the diastereomer with the methyl group in the pseudoaxial (endo) position at the ring was analyzed here.In the 1 H NMR spectra of both 15 and 16, the methyl signal of the NCHmethyl group in the major diastereomer A appears at a lower -value than in the minor one; this could be explained by its position in the shielding area of the magnetic anisotropy cone of the neighboring olefinic C=C bond.Again, the presence of the racemate in the crystal indicates racemization of the chiral center of the -amino acid during the synthesis.
The stereochemistry of cycloadduct 2 (Scheme 1) had not been assigned so far. 14Therefore, we have also performed NOESY experiments with 2 and are now able to establish the exoconfiguration for this compound, too.

Formation of gem-diols from ketones 2 and 12
As a side-result of our spectroscopic studies of cycloadduct 2, we found that it forms a stable gem-diol (ketone hydrate) 17 (Scheme 5).While it has been reported 14b that ketone 2 can be recrystallized from dichloromethane-hexane, we observed that our product precipitated after a few minutes from a chloroform solution.It was, however, soluble in more polar solvents such as DMSO, acetone, and acetonitrile.The identity of the precipitated product as the gem-diol 17 is in agreement with NMR and IR data and an elemental analysis.The mass spectrum (CI mode), on the other hand, showed the molecular ion peak corresponding to ketone 2, but not that of hydrate 17.In the 1 H NMR spectra, two singlets for OH protons are indicative; while one of them is observed in the range  = 5.5-5.8ppm irrespective of the solvent, the chemical shift of the second one is strongly solvent dependent ( = 4.07 (in chloroform), 6.30 (acetone), 6.90 (dimethyl sulfoxide)), suggesting a higher propensity to hydrogen-bond formation with solvent molecules.In the 13 C NMR spectra, the absence of a signal for a keto carbon atom around  = 192 ppm and the presence of an additional signal at  = 90 ppm clearly distinguish gem-diol 17 from ketone 2. In the IR spectrum of 17, the O-H stretching vibration appears at  = 3400-3140 cm -1 , while the C=O absorption at 1746 cm -1 exhibited by 2 is absent.The hydration of ketone 2 is reversible: gem-diol 17 is converted completely into 2 by dehydration at 130 o C in vacuo.When 2 was dissolved in [D6]DMSO containing the unavoidable amount of water, the NMR spectra showed the exclusive presence of 17, while the spectra of solutions of 2 in CDCl3 or [D6]acetone (both containing traces of water) displayed the signal sets of both 2 and 17.We have also checked briefly the formation of a gem-diol from alanine-derived cycloadduct 12.According to the complex 1 H and 13 C NMR spectra recorded for solutions of 12 in wet [D6]DMSO or in CD3CN to which increasing amounts of water are added, three major components are present.We tentatively assign the signal sets to the gem-diol forms of the two diastereomers of 12, one of which is in equilibrium with the original, non-hydrated keto form.The two isomeric gem-diols give rise to 13  The equilibrium between a ketone and its hydrated form, the gem-diol, is generally on the side of the ketone. 27Stable diols exist and can be isolated when strongly electron-withdrawing groups are attached to the gem-diol carbon atom (as in polyfluoro and polychloro ketones, in the bis(2-pyridyl)methanediol ligand, 28 but also in -ketoacid derivatives 29 ), and also when the transition from an sp 2 -to an sp 3 -hybridized carbon atom reduces the ring strain of cyclic ketones (such as in cyclopropanones and 7-norbornanones 30 ).However, hydrated keto forms can exist also in less electron-withdrawing molecular environments.In particular, they have been observed in ketosugars 31,32 and related compounds. 33In some cases, 32,33 the hydrates could be characterized in the solid state.The cycloadducts 2 and 12-16 reported here contain an -oxy-ketoester moiety.We are aware of only one related structure, a 4-oxo-4,8dioxabicyclo[3.2.0]octane-5-carboxylic ester, for which a gem-diol was also observed (albeit only in solution). 34

Conclusions
Several -amino acids featuring an unfunctionalized carbon chain have been converted into Nphthaloyl-4-amino-2-diazo-3-oxo-carboxylic esters in three steps.Starting with optically pure amino acids, racemization at the stage of the 4-amino-3-oxoesters could not be avoided.The Rh(II)-catalyzed carbenoid reactivity of these diazoesters is dominated by the intramolecular formation of carbonyl ylides involving a phthaloyl carbonyl group; only the intramolecular cyclopentane-forming insertion into a methine C-H bond could compete effectively with the ylide formation.These ylides could be trapped effectively with several electron-deficient dipolarophiles to give densely functionalized oxazapolycyclic ring systems which may be useful for further synthetic transformations.In the absence of trapping reagents, the carbonyl ylides form head-to-tail dimers by [3+3] cycloaddition via an endo transition state that brings the two epoxy bridges in a syn orientation.
Materials.L-Norleucine was purchased from Novabiochem, all other amino acids from Merck.

Figure 3 .
Figure 3. Major (A) and minor (B) diastereomer of alanine-derived cycloadduct 12 and NOESY relationships; the isoindoline ring has been omitted for clarity.

Table 1 .
Diastereomeric ratio (dr) and selected 1 H NMR data of cycloadducts 12-16 (CDCl3, 400.13 MHz, /ppm) a a Values are given in the order of isomer A/isomer B.bThe A:B ratio was 0.31 in the crude product mixture, and 2.66 after chromatographic separation.c NCHCH A CH B .