Cyanohydrins and Aminocyanides as Key Intermediates to Various Spiroheterocyclic Sugars

  • Solen JosseEmail author
  • Denis Postel
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 57)


Derivatives with a double functionalization attract great interest in organic synthesis. The association on the same carbon atom of a nitrile group and a hydroxyl or amine function allows access to promising heterocyclic compounds of particular interest resulting from reactions taking advantage of the electrophilic character of the cyano group and the nucleophilic character of hydroxyl and amino groups. Thus, α-hydroxynitriles (cyanohydrins) or α-aminonitriles represent important classes of organic intermediates. The development of these families in glycochemistry has allowed syntheses of compounds with chain elongations (Kiliani-Fischer synthesis, Strecker synthesis) or even the preparation of chiral building blocks versatile in asymmetric syntheses of biologically active compounds or their intermediates. In this chapter, we summarize the synthesis of quaternized glycoderivatives such as cyanohydrins or glycoaminonitriles and their uses as intermediates to access spiro-heterocycles. Beyond the great structural diversity, stereochemical aspects will also be identified.


Aminocyanides Carbohydrates Cyanohydrins Spiro-heterocycles 

1 Synthesis of Cyanohydrins

The synthesis of sugar-derived cyanohydrins is widely reported in the literature. It is relatively simple and carried out by the addition of cyanide ions to a carbonyl derivative. Thus, the cyanohydrin can be formed and isolated or used as intermediate using the reactions of Kiliani-Fischer, Strecker, or Bucherer-Bergs from aldoses or uloses. However, depending on the conditions used, the stereochemistry of the quaternized center may be oriented.

Bourgeois et al. [1, 2, 3] studied the addition of cyanide ions on ulose 1 to access aminonitrile 2 (Scheme 1). Using Strecker conditions, only decomposition of the 1,2:5,6-di-O-isopropylidene-α-d-ribo-hexofuranos-3-ulose (1) was observed. The cyanohydrins 3 and 4 were synthetized in order to be used as precursor of 2. Treated by an alkaline cyanide, the conversion rate of 13 remained low (10–20%). A control of the pH by adding buffer (HCO3, CO32−) allowed isolating 4 with an efficiency of over 90% yield. In addition, the 3-R cyanohydrin 3 can be easily converted into the 3-S epimer 4 as on standing in solution cyanohydrins reversed to ulose.
Scheme 1

Cyanohydrins formation on C3 position

Addition of methyl nitroacetate (MNA) [4] contributed to improve the stereoselectivity of the access to cyanhydrins with d-allo (4) and d-gluco (3) configuration, respectively, using Kiliani-Fischer conditions especially by controlling the order of addition of the reagents. Thus, the addition of MNA after the reaction of ulose 1 with the cyanogen agent led to the formation of the preferred d-gluco configuration (57%), while adding 1 to the mixture of NaCN and MNA later gave the d-allo product with a high stereoselectivity (85%).

It has been confirmed more recently that it was possible to control access to the d-gluco or d-allo epimers of cyanohydrin resulting from the addition of cyanide ions onto 1. Thus, while the use of the classically applied mixture (Et2O-H2O, NaHCO3) led to the d-allo compound [5], the use of NaCN in MeOH led to the d-gluco counterpart [6].

This cyanation reaction in C3 position of pentuloses has been widely used to obtain d-ribo and d-xylo epimers as precursors of [2′,5′-bis-O-(tert-butyldimethylsilyl)-d-ribofuranosyl]-3-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (TSAO) nucleoside compounds containing the sugar-embedded 3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) ring system. The authors have studied the synthesis of the TSAO from nucleoside scaffolds or by total synthesis starting from a pentose. Thus, the cyanation of 7, obtained from 1-(β-d-ribofuranosyl)thymine (5) [7, 8], previously protected in the 2′- and 5′-positions by a TBDMS group followed by oxidation of 6 at C3′ to 7, was carried out in a biphasic system (Et2O-H2O) by addition of NaCN in the presence of sodium bicarbonate (Scheme 2). The two cyanohydrin epimers (d-xylo 8; d-ribo 9) were obtained (85%) in a 12:1 mixture and mesylated without being isolated to give compounds 10 and 11 in 53% and 10% yield, respectively.
Scheme 2

Cyanohydrins formation on C3’ position

From pentulose 12, the cyanation achieved under the same conditions provided the kinetic derivative 13 stereoselectively with a d-ribo configuration (94%) (Fig. 1) [9]. Compound 13 was easily epimerized into the d-xylo-configured cyanohydrin 14 (89%) by treatment with DBU in acetonitrile. This difference in stereoselectivity observed between the reactivity of a nucleoside and that of a pentulose highlighted the importance of steric constraints in the approach of the cyanide ion, including thymine (or another bulky group at C1) [10] or the isopropylidene group in the 1,2-position. Thus, starting from pentulose 18, the d-xylo-configured cyanohydrin 19 was obtained as the main compound. The same scaffold with various groups on C5′ led stereoselectively to the d-ribo-cyanohydrins 1516a–c. On performing the reaction on an l-lyxo pentulose with a benzoyl group on C5′ 17 was obtained [11, 12]. The cyanohydrin 21 resulted from addition of the cyano group from the upper side onto C2 of the corresponding ulose in 66% yield [13].
Fig. 1

Cyanohydrins derivatives obtained from pentulose

The stereoselectivity observed during formation of cyanohydrin 17, resulting from the addition of cyano group from opposite side of the benzoyloxymethyl group, was confirmed by Zhang during the cyanation of 5-O-benzoyl-1,2-O-isopropylidene-α-d-erythro-pentos-3-ulose (22) to synthesize 23 in 90% yield (Scheme 3) [14].
Scheme 3

Cyanohydrin formation on benzoylated derivative

Introduction of a cyano group was also applied to hexopyranosid-3- and 2-uloses 24, 26, and 28 (Scheme 4) [9]. Even if the corresponding cyanohydrins were not isolated, the stereochemistry of the resulting cyanomesylates obtained in the next step illustrated that an O-benzoate in position 2 (compound 24) led to the axial CN (25) under thermodynamic control, while a bulky group such as TBDMS in compound 26 led to the equatorial CN (27) under kinetic control. However, the authors noted that by using the conditions to get CN in the equatorial position from 3-ulose 26 to give 27, the nitrile group was obtained at the axial position from 2-ulose 28 to yield compound 29.
Scheme 4

Cyanohydrins formation on hexopyranosid-3 and 2-uloses

The cyanation was also developed on disaccharidic skeletons similar to trehalose in order to obtain compounds that may have interesting biological activities. Starting from the corresponding uloses, the reactions yielded all the epimeric forms for cyanohydrins without observing stereoselectivity (compounds 3034) (Fig. 2) [15].
Fig. 2

Cyanohydrins obtained from disaccharides

More recently, a very interesting study was carried out by Koos et al. [16, 17] on the formation of cyanohydrin on a 6-deoxy-2,3-O-isopropylidene-α-l-lyxo-hexofuranosid-4-ulose derivative (35 or 36) through Bucherer-Bergs, Strecker, and Kiliani reactions, respectively (Scheme 5). They reported the relationship between reaction conditions and the final distribution of cyanohydrins resulting from the addition of the cyanide on the uloses 35 and 36. Thus, the conditions of Bucherer-Bergs (KCN, (NH4)2CO3, EtOH-H2O 1:1) and the conditions of Strecker (KCN, NH4Cl, NH3 gas, MeOH anh.) led in a preferred way to the formation of the cyanohydrins 37 and 38 in a 1:2 ratio. In this case, the addition of cyanide ions on the ulose was faster than the base-catalyzed isomerization of 3536. This same responsiveness was observed from 36, allowing the formation of the cyanohydrins 39 and 40 in a 2:1 ratio. The use of Kiliani conditions (KCN, NaHCO3, H2O) at low temperature could increase the observed stereoselectivity in getting from the uloses 35 and 36 the cyanohydrins 37 and 39, respectively, as major compounds in a 6:1 ratio compared to their respective epimers. The preferential formation of 38 (α-l-manno) over 37 (α-l-talo) was surprising because the CN group must access the C4 carbonyl group from the more hindered concave face of the pyranose ring.
Scheme 5

Stereoselectivity obtained depending of the reaction conditions

A wide range of cyanohydrins (4153) has been synthesized by our group to study the reactivity of alkylidene carbenes on hexopyranose derivatives (Fig. 3) [18, 19]. On all the structures studied, the reaction of Kiliani was used without isolating the cyanohydrins before in situ mesylation. These compounds were intended for use as precursors to the corresponding exomethylidene carbenes; therefore, identification of the stereoisomers and proportion of each of them were not carried out.
Fig. 3

Cyanohydrins on hexopyranose derivatives

The use of a biphasic medium associated with phase-transfer catalyst was reported by Yu et al. [20] in order to prepare oxadiazolyl derivatives of β-d-psicopyranose. The addition of NaCN onto 1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranose-3-ulose in the presence of TBAB in a mixture of CH2Cl2:H2O 1:1 led thus to cyanohydrin 54 (Fig. 3) with a total stereoselectivity and high yield (95–97%).

2 Synthesis of Glyco-α-Aminonitriles

The application of the Strecker reaction to carbohydrate substrates has been known for more than hundred years. It was used to prepare many aminosaccharides, by homologation reaction, taking advantage of the aldehyde group. However, very few investigations were conducted on other sites in order to get the carbohydrate derivatives with α-aminonitrile functions. Many attempts of application of Strecker reactions to uloses resulted in obtaining only cyanhydrins as in the work of Bourgeois, mentioned previously. In the same way, Czernecki et al. [21, 22] applied the Strecker conditions (KCN, NH4Cl, NH3 gas, MeOH anh.) to the 1,2:3,4-di-O-isopropylidene-α-d-galacto-hexodialdo-1,5-pyranose (55) to obtain only the mixture of the two cyanohydrin epimers. Compound 55 was then subjected to Knoevenagel-Bucherer conditions (NaHSO3, NaCN, rt) to lead to a mixture of α-aminonitriles 56 and 57. Regardless of the nature of the amine, the α-aminonitriles were obtained with 56 of R configuration as the major diastereomer (Scheme 6).
Scheme 6

Aminonitriles obtained from Knoevenagel-Bucherer conditions

Steiner et al. [23] reported the result of Strecker reaction on a methyl 6-deoxy-2,3-O-isopropylidene-α-l-lyxo-hexopyranosid-4-ulose (35). In this study, the authors pointed out the importance of the temperature on the α-aminocyanation and α-hydroxycyanation competition. Thus, the treatment of 35 by gaseous ammonia in methanol in the presence of NaCN and NH4Cl led after 4 days at 40°C to a mixture of α-aminonitriles (58 and 59 in 54% and 12% yield, respectively) (Route A) and hydroxynitrile (60, 3%), whereas at 20°C, using the same reagents (Route B), the final mixture was mostly made up of hydroxynitrile 60 (49%) (Scheme 7).
Scheme 7

Controlled formation of cyanohydrins or aminonitriles

The presence of the methyl 4-amino-4-cyano-4,6-dideoxy-2,3-O-isopropylidene-β-d-allopyranoside (59) can be explained by base-catalyzed epimerization of 35 into the d-ribo uloside (36). Furthermore, the use of ammonium carbonate exclusively led to the formation of the hydroxynitrile 60 (73%) (Route C). The latter, placed in conditions similar to Route A, gave, after 4 days, the α-aminonitrile 58 as the major compound (Route D). The authors did not specify if in those circumstances, the reactive intermediate was hydroxynitrile (Tiemann reaction) or imine (Strecker reaction).

Our group widely studied the conditions for efficient synthesis of quaternary glyco-α-aminonitriles [24]. Treatment of the ulose derivative 1 using classical Strecker synthesis (KCN, NH4Cl) and either octylamine or benzylamine gave exclusively the cyanohydrin 4 (Scheme 8).
Scheme 8

Aminonitriles formation using Ti(OiPr)4

In order to increase the electrophilic character of the ulose carbonyl, the aminocyanation was performed in the presence of Ti(OiPr)4 as a Lewis acid catalyst. Starting with NH3, methylamine, octylamine, and benzylamine, respectively, the (Z/E) imine intermediates 61/61′ were not isolated, and the cyanating agent TMSCN was added after 12 h. Under these conditions, the α-aminonitrile derivatives 62a–d were obtained in 50–98% yield.

Similarly, ulose derivatives 63–65 and 66 stereoselectively led to the α-aminonitriles 67–69 and 70, respectively, in 60–98% yields (Fig. 4) [24].
Fig. 4

Structural variety of aminonitriles obtained

Probably Ti(OiPr)4 acts as both a dehydrating agent and a Lewis acid to give the imine intermediate and induce stereoselectivity by chelating the N-atom of the imine group and the O-atom at C-2; such a complex would hinder the α-face of the sugar ring and give preference for the addition of CN at the β-face (Fig. 5).
Fig. 5

Proposed role of Ti(OiPr)4 to explain stereoselectivity of the reaction

The Strecker reaction was also studied using amino acids instead of alkylamines [25]. A series of l-amino acid esters was added onto hexulose 1 and pentuloses 63 and 64 [1.2 eq. Ti(OiPr)4, R2OOC-CHR1-NH2.HCl, TEA, MeOH (24 h); (ii)TMSCN (1 night)]. The glyco-α-aminonitriles 7186 were obtained in 15–78% yield (Fig. 6).
Fig. 6

Aminonitriles obtained from amino acids

The same reaction applied to d-amino acids led to a significant increase in the rate of aminocyanation [25]. This difference in reactivity could be explained by steric congestion linked to the R1 group, involved in the transition state during the addition of cyanide ions (Fig. 7). The geometry would be conditioned by chelation involving the titanium atom, the carbonyl group as well as the imine nitrogen atom. This phenomenon would increase the steric congestion of the β-face of the carbohydrate.
Fig. 7

Steric congestion during cyanide ions addition

3 Spiro-heterocycles from Cyanohydrins

Cyanohydrins and their O-substituted derivatives are useful synthetic intermediates, which have been used to access a variety of organic functions. Among the cycles easily accessible, we can note cycles fused with the saccharidic cycle or even integrating an atom of this scaffold and forming a spiro-cycle [26].

3.1 Oxathiole

The introduction of a sulfonyl group on the cyanohydrins resulting in the corresponding alkanesulfonates may allow cyclization reactions through an α-sulfonyl carbanion. It has been shown that a large range of bases, from n-BuLi to DBU, were able to abstract protons in α positions to sulfur atoms in alkanesulfonates to give reactive carbanion species that reacted with various electrophiles such as nitriles.

Our group has named and classified these transformations as CSIC reactions, taken from the initials of the keywords that describe and define the process for the intermolecular [carbanion-mediated sulfonate (or sulfonamide) intermolecular coupling] and intramolecular [carbanion-mediated sulfonate intramolecular cyclization] conversions [27].

De las Heras and co-workers [28] reported the first example of a CSIC reaction on a sugar cyanomesylate. Mesylation of 13 and 14 with mesyl chloride in pyridine yielded α-mesyloxynitriles 87 (80%) and 88 (71%), respectively, as syrups (Scheme 9). Treatment of 87 and 88 with DBU in acetonitrile afforded 3-spiro-d-ribo-oxathiole 89 and the 3-spiro-d-xylo-oxathiole isomer 90.
Scheme 9

Synthesis of spiro-oxathiole on C3 position

The work initiated by De las Heras has been widely developed by Camarasa and her team to prepare more than 700 spiro-nucleoside derivatives which represent a particular type of specific HIV-1 reverse transcriptase (RT) inhibitor known as TSAO derivatives ([2′,5′-bis-O-(tert-butyldimethylsilyl)-d-ribofuranosyl]-3-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide)) (Fig. 8).
Fig. 8

Structural variety of TSAO derivatives

Two synthetic routes have been developed by Camarasa to access the TSAO. The first was to operate from a nucleoside and build on it the oxathiole heterocycle [29, 30].

The key intermediate was obtained by a base-catalyzed addition of cyanide ions onto the ketonucleoside I in a biphasic medium (Et2O/H2O, NaHCO3). The hydroxynitrile was obtained as a mixture of two epimers (II, Scheme 10). These were not isolated due to instability but treated by mesyl chloride in pyridine to give the d-ribo- (IIIa minor) and d-xylo- (IIIb major) configured 3′-C-cyano-3′-O-mesyl derivatives with an overall yield of approximatively 60% [29].
Scheme 10

TSAO synthesis starting from a nucleoside

The cyclization was conducted according to a carbanionic heterocyclization (CSIC reaction), the carbanion being generated at the α-carbon of the mesylate group. Treatment of the cyanomesylate derivatives IIIa and IIIb with a base (Cs2CO3 or DBU) gave the spiro-heterocyclic derivatives IVa and IVb with yields ranging between 69% and 87% for the CSIC reaction. This strategy, although involving a reduced number of steps, has the major disadvantage of leading to a mixture of epimers. In addition, the use of a natural nucleoside limits the number of TSAO that can be prepared in this way.

For these reasons, a second method was developed by Camarasa consisting in functionalization on the C-3 of a non-nucleosidic substrate followed by introduction of the nucleobase to the anomeric carbon using a classical Vorbrüggen glycosylation (Scheme 11) [30].
Scheme 11

TSAO synthesis from a carbohydrate derivative

This strategy involved eight steps from the protected and oxidized carbohydrate derivative 22. The d-ribo-cyanohydrin 91 obtained with a total control of stereoselectivity was mesylated to 92 which was deprotected with aqueous TFA to give 93, and subsequent acetylation led to the 1,2-di-O-acetylated compound 94 (95%). Silylated thymine (thymine, HMDS, (NH4)2SO4) was applied in the presence of 94 and TMSOTf to give the 3′-C-cyano-3′-O-mesyl nucleoside 95 (77%). Treatment of the obtained nucleoside with Cs2CO3 yielded the spiro-oxathiole derivative 96 (65%). This heterocyclic derivative was debenzoylated and deacetylated with a saturated methanolic ammonia solution to furnish 3′-spiro-nucleoside 97 in 66% yield. TSAO derivative 98 was finally obtained by silylation (74%). The TSAO-m3T (abbreviation for TSAO alkylated in N-3 position with a methyl) derivative (99) was obtained by alkylation, (MeI, K2CO3) with a yield of 55%.

The biological study of the TSAO structures with the spiro ring on C-3′ (d-ribo and d-xylo configuration) or C-2′ (d-ribo configuration) (Fig. 9) was carried out [11, 29, 31]. An activity as anti-HIV-1 inhibitor was observed only for the derivative 3′-spiro-d-ribo (EC50 = 0.06 μM). Other derivatives, 3′-spiro-d-xylo, 2′-spiro-d-ribo, and 3′-spiro-l-lyxo showed no activity [12].
Fig. 9

TSAO analogs

Among all the structural variations described by Camarasa, a large number corresponded to pentofuranose derivatives. Other studies also reported the introduction of the oxathiole cycle on the C3 and C2 positions of hexopyranoses. Treatment of the benzoate 103 obtained from 25 after mesylation gave a mixture of spiro compounds 104 (12%) and its N-benzoyl derivative 105 in 20% yield (the formation of 105 can be explained by the migration of the benzoyl group in position 2) [9]. Treatment of the cyanomesylates 106 and 108, easily obtained by in situ mesylation of the corresponding cyanohydrins 27 and 29, with DBU in acetonitrile, afforded spiro derivatives 107 and 109 in 77% and 73% yields, respectively (Scheme 12).
Scheme 12

Synthesis of spiro-oxathiole on C3 and C2 positions of hexopyranoses

Kiritsis et al. reported the synthesis of pyranosyl nucleosides starting from 2′-C-cyano pyranonucleosides of uracil and fluorouracil protected as acetal derivatives. Mesylation of the 2′-C-cyanohydrins 110a,b and 111a,b led to 112a,b and 113a,b, respectively (Scheme 13). The desired 2′-spiro pyrimidine pyranonucleosides were obtained through a subsequent treatment with DBU in acetonitrile in fair to good yields (114a 60%, 114b 74%, 115a 70%) [32].
Scheme 13

Synthesis of 2’ spiro-oxathiole pyrimidine pyranonucleosides

3.2 Oxathiole Fused with Another Cycle

Chamorro et al. [33] highlighted the formation of compounds resulting from an intramolecular cyclization from 5′-O-tosylate via a SN2 reaction involving the enamino group of the spiro ring and the 5′-leaving group. These early results led Cordeiro et al. [34] to study this cyclization starting from the d-ribofuranose derivative 118 (Scheme 14). It was demonstrated that the reactivity of this substrate in the presence of a non-nucleophilic base (DBU) yielded 119 in 76% via an intramolecular cyclization in only 15 min at 80°C. After 1 h reaction, intermolecular addition of 119 gave the dimer 120 in 67% yield.
Scheme 14

Fused cycles obtained from oxathiole derivative

The authors focused on exploring the reactivity of 119 toward various nucleophiles including amino acids. When methanol, ethanol, and ethanethiol were used, the corresponding O- and S-substituted tricyclic sugars 121 were obtained in 60–70% yields (Scheme 15). When cyanide was used as the nucleophile, nitrile derivative 122 was isolated in 60% yield. All of these additions were fully regio- and stereoselective [34].
Scheme 15

Reactivity of fused spiro-oxathiole cycles with nucleophiles

3.3 Oxazolone and Oxathiazole

The influence of the nature of the spiro ring has also been studied by comparing the activity of TSAO-T, 4-amino-2-oxazolone derivatives, and 4-amino-1,2,3-oxathiazole-2,2-dioxide. Synthesis of these compounds consisted of the reaction between cyanohydrin 91 and chlorosulfonyl isocyanate (CSI) leading, via intermediate A, exclusively to the carbamoyl derivative 123 (60%) (Scheme 16) [35, 36]. The latter seems to be the intermediate which, on subsequent treatment with NaHCO3, may lead to the oxazolone derivative. Thus, treatment of 91 with CSI followed by addition of NaHCO3 in situ led to the spiro derivative 124 with 76% yield.
Scheme 16

Spiro-oxazolone synthesis

The spiro moiety at the 3-position of compound 124 existed in different tautomeric forms I–III shown in Fig. 10. NMR analysis demonstrated that tautomer II was the most preponderant one.
Fig. 10

Tautomeric forms of oxazolone

On the other hand, the action of sulfamoyl chloride on cyanohydrin 91 using dimethylaminopyridine in dry dioxane yielded, via intermediate B, the corresponding 3-spirooxathiazole-S,S-dioxide 125 in 63% yield (Scheme 17).
Scheme 17

Spiro-oxathiazole synthesis

Similar to what was observed for compound 124, the spiro derivative 125 was supposed to exist as tautomers I–III (Fig. 11); however, NMR analysis identified tautomer II as the only form.
Fig. 11

Tautomeric forms of oxathiazole

3.4 Hydantoin

In some cases, cyanohydrin-like intermediates can be used in an efficient reaction pathway for the synthesis of spiranic heterocycles through a subsequent conversion to another intermediate. Kooś et al. demonstrated the effective achievement of the 4′-spiro hydantoin (126) by a two-step procedure consisting in reaction of 35 with KCN (80% yield) followed by heating the cyanohydrin 60 with (NH4)2CO3 to give 126 in 80% yield (Scheme 18). The authors highlighted that this two-step procedure (conditions a + b) was more advantageous than direct transformation of the ketose 35 with KCN and (NH4)2CO3 in aqueous ethanol (conditions c) where 126 was obtained in 35% yield or than starting from the aminonitrile 58 (conditions b) where 126 was obtained only in 25% yield [17].
Scheme 18

Spiro-hydantoin synthesis

3.5 Oxaphospholene

Phosphorus-containing molecules are popular targets for the development of new biologically active compounds. We investigated the synthesis of new families of nucleosidic reverse transcriptase (RT) inhibitors, analogs of TSAO derivatives, with an O-P bond in the spiro ring at position 3″. Such compounds, named P-TSAO-T, would also be unusual analogs of nucleoside cyclic phosphates [37, 38].

The synthesis strategy for accessing phosphorus compounds can be considered as a simple transposition of the methodology used for TSAO. In this case, the cyclization reaction would form a carbanion next to phosphorus. But the presence of phosphorus instead of sulfur resulted in a difference in the reactivity.

The phosphonylation step was performed by the reaction of cyanohydrins with methyl methylphosphonochloridate, which was prepared from dimethyl methylphosphonate (CH3PO(OCH3)2) and PCl5. The reaction of cyanohydrins 91 and 15 with methyl methylphosphonochloridate and DMAP in pyridine allowed the exclusive formation of the kinetic products 128 and 129 in 90% and 56% yields, respectively, as mixtures of two diastereomers which could not be separated by chromatography (Scheme 19).
Scheme 19

Phosphonylation of cyanohydrins

During attempts for ring closure in the presence of t-BuOK, DBU, NaH, or HMDS, only the starting material was recovered from reactions of 128 or 129. In the presence of Cs2CO3 or BuLi, a mixture of several derivatives was obtained with the major products characterized as mixtures of d-xylo- and d-ribo-cyanohydrins resulting from the phosphonate degradation under basic conditions. With these results in hand, we envisaged that introduction of an electron-withdrawing group α to the phosphorus atom should facilitate the cyclization. A series of phosphonochloridate derivatives with electron-withdrawing groups (COOEt, CN, Ph, and COOMe) was prepared and reacted with 91 to give, e.g., 130. Upon treatment of derivative 130 with LDA or NaH, the desired oxaphospholene 131 was obtained in 56% or 70% yield, respectively (Scheme 20).
Scheme 20

Carbanion intramolecular cyclization

Using NaH, it was possible to carry out the synthesis in a one-pot procedure. Starting from cyanohydrins 91 and 15, oxaphospholenes were obtained with yields ranging from 41 to 70% as mixtures of separable (131 and 132) or inseparable diastereomers (133) or as a pure compound (134) (Fig. 12).
Fig. 12

Spiro-oxaphospholene derivatives

When using the benzylphosphonochloridate 135, it was not possible to carry out a one-pot reaction, as the cyclization step with NaH did not occur. The cyclized compound 136 was obtained only with LDA (78% yield) as a mixture of two diastereomers (Scheme 21).
Scheme 21

Spiro-oxaphospholene from benzylphosphonochloridate

4 Spiro-heterocycles from α-Aminonitriles

The use of α-aminonitriles to access spiro-heterocycles on carbohydrate scaffolds has been widely described. Syntheses of imidazoline [5], imidazolidin-2-one or 2-thione [39, 40], oxopiperazine [25, 41], cyclic peptide analogs [25], hydantoin, thiohydantoin [42, 43], isothiazole [44], and azaphospholene [37] are found in the literature (Fig. 13).
Fig. 13

Spiro-heterocycles described on saccharidic scaffold from aminonitriles

It is possible to identify two major routes for the synthesis of these compounds (Scheme 22). The first is a reduction of the nitrile group and then functionalization of amines; in the second, a functionalization of the amine function takes place in a first step, and then the expected heterocycles are obtained after cyclization.
Scheme 22

Synthesis strategies

We will first focus on the strategy of reducing the nitrile and then achieving functionalization of the diamine obtained. Next we will discuss the synthetic routes starting with a functionalization of the amino group followed by a cyclization reaction.

4.1 Strategy Reduction/Functionalization

This synthetic strategy allowed to achieve the formation of 5- or 6-membered rings of imidazoline, imidazolidin-2-one or 2-thione, and oxopiperazine type and also an access to cyclic peptides.

4.1.1 Imidazoline

Merino-Montiel described in 2012 the syntheses of spiro imidazoline at C3 position starting from aminonitrile 2 [5]. After reduction of the aminonitrile by LiAlH4, the obtained diamine 137 was condensed with benzamidine or acetamidine hydrochloride, which led to the formation of the protected cyclized compounds 138a,b and the partially deprotected ones 139a,b, respectively, in a 4:1 ratio (Scheme 23). By liquid/liquid extraction, it was possible to separate compounds 138a and 139a. Imidazoline 138a could be purified by chromatography and obtained pure with 12% yield.
Scheme 23

Spiro-imidazoline synthesis

The mixture of the two derivatives 138b and 139b could not be separated and purified, and so it was used directly for the deprotection step consisting of an acid treatment to remove the isopropylidene groups to give compound 140b in a pyranose form with 14% yield starting from 137 (Scheme 24). Starting from 138a compound 140a was obtained with a quantitative yield.
Scheme 24

Access to deprotected spiro-imidazoline derivatives

Inhibitory properties of compounds 140a and 140b were evaluated against different glycosidases and against glycogen phosphorylase; both of them had poor inhibition properties.

From diamine 137, the authors also described the coupling reaction with isothiocyanates (Scheme 25) [5].
Scheme 25

Spiro-imidazoline synthesis using isothiocyanates

The reaction on the primary amine allowed the formation of thioureas 141 with very good yields. These compounds then underwent a reaction of cyclodesulfurization in the presence of yellow HgO which resulted in the formation of spiro amino-imidazoline 142 with yields ranging from 50% to quantitative. The reaction might have proceeded via a carbodiimide to react with the free NH2 on C3 as a nucleophile. The deprotected analogs 143 were obtained with very good yields after acid hydrolysis.

4.1.2 Imidazolidine-2-one or 2-Thione

Our group also described the synthesis of imidazolidine-2-one or 2-thione derivatives in 2002 [39]. Thus, condensation of the diamine 137 with carbonyldiimidazole or thiocarbonyldiimidazole directly gave spiro imidazolidine-2-one or 2-thione 144 and 145 with 50% and 75% yield, respectively. Further deprotection of the hydroxyl groups was performed by hydrochloric acid treatment (Scheme 26).
Scheme 26

Spiro imidazolidine-2-one or 2-thione synthesis

Access to spiro imidazolidine-2-thione 145 was also described in 2009 according to an identical synthetic pathway [40]. Further deprotection of the hydroxyl groups of compound 145 was performed by hydrochloric acid treatment (Scheme 26).

4.1.3 Oxopiperazine

Starting from aminonitrile derivatives obtained by condensation of ester protected amino acids on ulose previously described in part I [25], it was possible to form spirooxopiperazines (Scheme 27) [25, 41]. The nitrile group was reduced in the presence of NaBH4-CoCl2, and the primary amine obtained spontaneously reacted with the ester to form the heterocycle. Compounds 147–156 could thus be obtained with good yields ranging from 50 to 78%.
Scheme 27

Spiro-oxopiperazine synthesis

4.1.4 Cyclic Peptides

Starting from oxopiperazine derivative 147, the spirocyclic tetrapeptide 161 was synthesized (Scheme 28) [25]. In the presence of NaOH and N-protected glycine p-nitrophenyl ester, compound 157 was obtained in 56% yield. Peptide coupling between the COOH function and methyl ester protected alanine with DCC gave compound 158 with 67% yield. Compound 159, obtained quantitatively after deprotection of COOH and NH2, was then cyclized in the presence of DPPA (diphenyl phosphoryl azide) and TEA to form the spiro tetrapeptide derivative 160 with 56% yield. Acidic treatment in the presence of TFA and H2O removed the isopropylidenes to isolate 161 with 94% yield.
Scheme 28

Cyclic peptides synthesis

4.2 Strategy Functionalization/Cyclization

In this strategy, the amine function was functionalized as a carbamoyl ester, an amide, a lactam, a succinimide, a sulfonate, or a phosphonate, and then an intramolecular cyclization reaction allowed the formation of hydantoin, thiohydantoin, imidazoline, isothiazole, or azaphospholene ring.

4.2.1 Hydantoin and Thiohydantoin

In 2001, our group described the synthesis of hydantoin and thiohydantoin derivatives [42, 43]. The reaction of aminonitrile 2 with either benzyl or phenylchloroformate allowed the formation of carbamoyl esters 162 and 169 with comparable yields of 45% and 44%, respectively (Scheme 29). Otherwise, the basic treatment to form the carboxamidoisocyanate 163, which then spontaneously cyclized to give spirohydantoin, gave much better results from compound 162 (80%) than from compound 169 (20%).
Scheme 29

Spiro-hydanthoine synthesis

By treatment with HCl, the partially deprotected compound 165 was obtained with a 52% yield. The totally deprotected spirohydantoin 166 was obtained with a 97% yield by reaction with a TFA-H2O mixture.

From spirohydantoin 167, prepared in an analogous way as described for 164 derivative, 168 was obtained with a quantitative yield (Scheme 29.)

The synthesis of spirohydantoin 164 has also been described by direct condensation of carbon dioxide or ammonium carbonate on aminonitrile with 80% yield.

This spirohydantoin 164 was also synthesized with a better yield of 97% using a very large excess of ammonium carbonate [39]. Starting from aminonitrile 2, the authors also described the synthesis of spirothiohydantoin 170 by reaction of CS2 in the presence of potassium carbonate with a low yield of 30% (Scheme 30).
Scheme 30

Spiro-thiohydanthoine synthesis

4.2.2 Imidazoline

Spiroimidazoline derivatives were obtained after cyclopropanation reaction on the nitrile [45]. Prior to the cyclopropanation key step, the primary amine was protected as amide (173a–d), lactam (174a–d), or succinimide (175). A variety of substrates was obtained (Scheme 31).
Scheme 31

Functionalization of aminonitriles as amides, lactams, or succinimide derivatives

A two-step procedure was used to obtain amide derivatives (173a–d): reaction with benzoyl chloride and then methylation with methyl iodide. For the lactam derivatives (174a–d), condensation of amine with 4-bromobutyryl chloride gave amide, and an intramolecular nucleophilic substitution in the presence of NaH allowed the formation of the desired compounds with moderate yields. Succinimide derivative 175 was obtained by reaction with succinic anhydride first and then thionyl chloride.

The cyclopropanation key step was performed using the conditions described by Szymoniak et al. [46]. A titanium cyclopropane was formed first by the reaction of EtMgBr with Ti(OiPr)3Me, and after addition on the nitrile, a cyclic titanium iminate (A) was obtained. Treatment with BF3·OEt2 allowed the formation of cyclopropyl derivatives 176 and 177 with poor yields starting from amides and lactams (Scheme 32).
Scheme 32

Cyclopropanation key step on amides or lactams derivatives

Starting from succinimide 175, after activation of the nitrile as cyclic titanium iminate (A), no cyclopropyl derivative was recovered. The imine derivative 178 was formed first, and then isomerization into enamine B took place before reaction of the amine with one carbonyl group of succinimide to give the tricyclic compound 179 which was isolated with 23% yield (Scheme 33).
Scheme 33

Cyclopropanation key step on succinimide derivative

4.2.3 Isothiazole

From the aminonitrile it is possible to introduce an isothiazole unit on the monosaccharide (Scheme 34) [44]. The amine was first functionalized as a methanesulfonate. On this N-H form (compounds 180182), a carbanion-mediated sulfonamide intramolecular cyclization (CSIC) occurred using BuLi. Compounds 184, 185, and 186 were obtained with good to very good yields (60–98%), respectively. One equivalent of BuLi was necessary to form the amine salt, and a second equivalent was used to form the carbanion able to react on CN to give the isothiazole. Starting from 183, no cyclized derivative was formed, and even the starting material was not recovered.
Scheme 34

Spiro-isothiazole synthesis

The reaction was also studied starting from N-CH3 compounds 188–191 obtained by reacting methyl iodide with N-H compounds 180–183 (Scheme 35). From these N-CH3 derivatives, the cyclization reaction was studied in the presence of NaH and Cs2CO3. Apart from the trityl derivative 189 which, in the presence of Cs2CO3, gave the cyclized 193 with a very good yield of 90%, the other derivatives cyclized to give the corresponding 192, 194, and 195 in modest yields ranging from 25 to 61%. However, it is important to point out that compound 183 which did not afford the isothiazole derivative in the presence of BuLi, led, after methylation and reaction with Cs2CO3, to the spiro isothiazole analog 194.
Scheme 35

N-methylated spiro-isothiazole synthesis

Following the same strategy, starting from methansulfonamido-nitrile or benzylsulfonamido-nitrile, a series of isothiazole derivatives were prepared (196–199) (Fig. 14) [47, 48]. The CSIC key step reaction was performed using different bases (K2CO3, CsCO3, LDA, and n-BuLi).
Fig. 14

Spiro-isothiazole derivatives

4.2.4 Azaphospholene

A phosphonate version of the CSIC reaction was studied a few years ago by our group to introduce an azaphospholene heterocycle on the saccharidic scaffold (Scheme 36) [37, 38]. The phosphonylation step was performed using methyl methylphosphonochloridate with DMAP on aminonitrile 68. The methyl-phosphoramidyl-α-d-ribofuranose 200 was obtained as a mixture of two diastereomers in 86% yield. After cyclization with LDA, the azaphospholene derivative 201 was isolated with 60% yield. Starting from the N-methylated derivative 202, the CPIC (carbanion-mediated phosphonate intramolecular cyclization) allowed the formation of the cyclized derivative 203 with 70% yield always as a mixture of two diastereomers not separable by chromatography.
Scheme 36

Spiro-azaphospholene synthesis

5 Conclusion

We presented the syntheses of aminonitrile- or cyanohydrin-type compounds on saccharidic scaffolds that served as precursors to introduce spiro-heterocycles. The vast majority of derivatives found in the literature concerned the functionalization of position 3 of pentose units allowing access to heterocycles with oxygen, sulfur, nitrogen, and/or phosphorus.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources (UMR7378)AmiensFrance
  2. 2.Institut de Chimie de Picardie (FRE 3085), UFR des Sciences-UPJVAmiensFrance

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