A Convenient Approach towards the Synthesis of ADMDP Type Iminosugars and Nojirimycin Derivatives from Sugar-Derived Lactams

An efficient method for the synthesis of nojirimycin- and pyrrolidine-based iminosugar derivatives has been developed. The strategy is based on the partial reduction in sugar-derived lactams by Schwartz’s reagent and tandem stereoselective nucleophilic addition of cyanide or a silyl enol ether dictated by Woerpel’s or diffusion control models, which affords amino-modified iminosugars, such as ADMDP or higher nojirimycin derivatives.


Introduction
Iminosugars are a large group of carbohydrate analogues that have received a lot of attention due to their ability to inhibit enzymes responsible for the formation or cleavage of glycosidic bonds [1][2][3][4][5]. They have been recognized as potent active agents in the treatment of various diseases, such as diabetes, lysosomal storage disorder, viral infection, and cancer [1,[6][7][8][9]. Some drugs based on iminosugars are already in use, while a few others are in clinical trials. For example, Glyset ® is used to treat non-insulin-dependent diabetes, and Zavesca ® is used in Gaucher's disease treatment. Another piperidine-originated iminosugar, 1-deoxynojirimycin (DNJ), and its amino derivative (4b), displayed similar inhibition to α-glucosidase [10]. α-Homonojirimycin is a powerful α-glucosidase inhibitor and is expected to be a drug candidate for antidiabetic therapy [11].

Introduction
Iminosugars are a large group of carbohydrate analogues that have received a lot of attention due to their ability to inhibit enzymes responsible for the formation or cleavage of glycosidic bonds [1][2][3][4][5]. They have been recognized as potent active agents in the treatment of various diseases, such as diabetes, lysosomal storage disorder, viral infection, and cancer [1,[6][7][8][9]. Some drugs based on iminosugars are already in use, while a few others are in clinical trials. For example, Glyset ® is used to treat non-insulin-dependent diabetes, and Zavesca ® is used in Gaucher's disease treatment. Another piperidine-originated iminosugar, 1-deoxynojirimycin (DNJ), and its amino derivative (4b), displayed similar inhibition to α-glucosidase [10]. α-Homonojirimycin is a powerful α-glucosidase inhibitor and is expected to be a drug candidate for antidiabetic therapy [11].
The high potential of amino-iminosugars has resulted in the development of various methods for their synthesis. The first preparation methods of ADMDP and its isomers were concerned with the transformation of naturally occurring DMDP (and its stereo analogues) by selective conversion of one of the side-chain hydroxyl groups into an amino functionality [13].Other strategies include intramolecular cyclization of C2-symmetric amino alcohols [18], transformation of non-racemic γ-lactams [19], nucleophilic ring opening of sugar-derived bis-aziridines [20], and nucleophilic addition of cyanide to sugarderived cyclic nitrones, followed by reduction [21,22]. Stocker and colleagues [23] reported the synthesis of ADMDP and analogues by carbamate annulation, whereas the group of Ramesh reported their synthesis via deamination of glycals [24]. In our previous work, we found that the furanosyl and pyranosyl imines can be obtained from sugar-derived lactams via a Schwartz's-reagent-mediated partial reduction in amide function [25]. Moreover, we demonstrated that these cyclic imines could be directly used (without isolation) in further transformations [25][26][27], leading to, for example, highly functionalized pyrrolidine and piperidine iminosugars via a tandem one-pot reduction/Grignard reagent or allyltributyltin addition sequence (Scheme 1a) [25]. This developed protocol was applied for the preparation of two pyrrolidine derivatives: 6-deoxy-DMDP and radicamine B [25]. Developing our group's program on reductive sugar-derived lactam functionalization [25][26][27], we report herein the flexible and robust access to amino-iminosugars, such as ADMDP and higher derivatives, via a gluco-or arabino-lactam reduction/cyanide ion or silyl enol ether addition sequence (Scheme 1b).

Results and Discussion
Our synthesis of amino-modified iminosugars started with the synthesis of initial sugar-derived lactams. We chose gluco-1a and arabino-1b lactam, obtained from the corresponding commercially available glucose and arabinose, as model starting materials for further studies (Figure 1) [25,28].
The high potential of amino-iminosugars has resulted in the development of various methods for their synthesis. The first preparation methods of ADMDP and its isomers were concerned with the transformation of naturally occurring DMDP (and its stereo analogues) by selective conversion of one of the side-chain hydroxyl groups into an amino functionality [13].Other strategies include intramolecular cyclization of C2-symmetric amino alcohols [18], transformation of non-racemic γ-lactams [19], nucleophilic ring opening of sugar-derived bis-aziridines [20], and nucleophilic addition of cyanide to sugar-derived cyclic nitrones, followed by reduction [21,22]. Stocker and colleagues [23] reported the synthesis of ADMDP and analogues by carbamate annulation, whereas the group of Ramesh reported their synthesis via deamination of glycals [24]. In our previous work, we found that the furanosyl and pyranosyl imines can be obtained from sugar-derived lactams via a Schwartz's-reagent-mediated partial reduction in amide function [25]. Moreover, we demonstrated that these cyclic imines could be directly used (without isolation) in further transformations [25][26][27], leading to, for example, highly functionalized pyrrolidine and piperidine iminosugars via a tandem one-pot reduction/Grignard reagent or allyltributyltin addition sequence (Scheme 1a) [25]. This developed protocol was applied for the preparation of two pyrrolidine derivatives: 6-deoxy-DMDP and radicamine B [25]. Developing our group's program on reductive sugar-derived lactam functionalization [25][26][27], we report herein the flexible and robust access to amino-iminosugars, such as ADMDP and higher derivatives, via a glucoor arabino-lactam reduction/cyanide ion or silyl enol ether addition sequence (Scheme 1b). The high potential of amino-iminosugars has resulted in the development of various methods for their synthesis. The first preparation methods of ADMDP and its isomers were concerned with the transformation of naturally occurring DMDP (and its stereo analogues) by selective conversion of one of the side-chain hydroxyl groups into an amino functionality [13].Other strategies include intramolecular cyclization of C2-symmetric amino alcohols [18], transformation of non-racemic γ-lactams [19], nucleophilic ring opening of sugar-derived bis-aziridines [20], and nucleophilic addition of cyanide to sugarderived cyclic nitrones, followed by reduction [21,22]. Stocker and colleagues [23] reported the synthesis of ADMDP and analogues by carbamate annulation, whereas the group of Ramesh reported their synthesis via deamination of glycals [24]. In our previous work, we found that the furanosyl and pyranosyl imines can be obtained from sugar-derived lactams via a Schwartz's-reagent-mediated partial reduction in amide function [25]. Moreover, we demonstrated that these cyclic imines could be directly used (without isolation) in further transformations [25][26][27], leading to, for example, highly functionalized pyrrolidine and piperidine iminosugars via a tandem one-pot reduction/Grignard reagent or allyltributyltin addition sequence (Scheme 1a) [25]. This developed protocol was applied for the preparation of two pyrrolidine derivatives: 6-deoxy-DMDP and radicamine B [25]. Developing our group's program on reductive sugar-derived lactam functionalization [25][26][27], we report herein the flexible and robust access to amino-iminosugars, such as ADMDP and higher derivatives, via a gluco-or arabino-lactam reduction/cyanide ion or silyl enol ether addition sequence (Scheme 1b).

Results and Discussion
Our synthesis of amino-modified iminosugars started with the synthesis of initial sugar-derived lactams. We chose gluco-1a and arabino-1b lactam, obtained from the corresponding commercially available glucose and arabinose, as model starting materials for further studies ( Figure 1) [25,28].

Results and Discussion
Our synthesis of amino-modified iminosugars started with the synthesis of initial sugar-derived lactams. We chose gluco-1a and arabino-1b lactam, obtained from the corresponding commercially available glucose and arabinose, as model starting materials for further studies ( Figure 1) [25,28]. With appropriate substrates (1a and 1b) in hand, we investigated a one-pot lactam reduction/cyanide addition reaction (Scheme 2). Arabino-lactam 1a was treated with 1.6 equiv of Schwartz's reagent Cp2Zr(H)Cl, leading to appropriate imine 2a in almost quantitative yield according to the NMR analysis of the crude reaction mixture. The progress of the reaction can easily be followed thanks to simple direct observation: initially white, then heterogeneous mixture turns to a clear solution upon reduction completion (approximately 10 min). Subsequent treatment of the in situ generated imine 2a with trimethylsilyl cyanide (2.0 equiv) in the presence of TMSOTf (1.0 equiv) gave a mixture of two nitriles 3a and 2-epi-3a in a ratio of 60:40 and with an overall yield of 88% after two steps (Scheme 2). Hydrogenation of 3a and 2-epi-3a under the conditions reported by Cheng et al. [22] gave ADMDP and its 2-epimer (2-epi-ADMDP) in 73% and 69% yield, respectively (Scheme 2). The same approach was successfully applied for the synthesis of the six-membered amino-iminosugar. Thus, treatment of gluco-lactam 1b with Schwartz's reagent, followed by TMSOTf-mediated addition of trimethylsilyl cyanide gave nitrile 3b in 65% yield as a single isomer. Its hydrogenolysis under the conditions presented above afforded gluconojirimycin derivative 4b in 66% yield (Scheme 2). Elsewhere, Cheng et al. [22] reported the transformation of nitrile 2-epi-3a to 2-epi-DMDP. We expect that the same strategy can be used for the synthesis of DMDP and α-homonojirimycin starting form 3a and 3b, respectively (Scheme 2). Configuration of the newly generated stereochemical center in nitriles 3a, 2-epi-3a, and 3b have been established by NOE experiments. Addition of TMSCN to gluco-imine 2b proceeded syn to the BnO substituent at the C-3 position. This is a result of conformational control of the process, according to Woerpel's model (Figure 2a) [29][30][31][32][33][34]. In the latter case, the nucleophilic addition of TMSCN to arabino-imine 2a occurs with low stereoselectivity, leading to the separable mixture of isomers 3a and 2-epi-3a in a ratio of 60:40.
The same modest diastereoselectivity was observed by Woerpel in the reaction of TMSCN with cyclic oxocarbenium ions [35]. Woerpel postulated that this effect can be With appropriate substrates (1a and 1b) in hand, we investigated a one-pot lactam reduction/cyanide addition reaction (Scheme 2). Arabino-lactam 1a was treated with 1.6 equiv of Schwartz's reagent Cp 2 Zr(H)Cl, leading to appropriate imine 2a in almost quantitative yield according to the NMR analysis of the crude reaction mixture. The progress of the reaction can easily be followed thanks to simple direct observation: initially white, then heterogeneous mixture turns to a clear solution upon reduction completion (approximately 10 min). Subsequent treatment of the in situ generated imine 2a with trimethylsilyl cyanide (2.0 equiv) in the presence of TMSOTf (1.0 equiv) gave a mixture of two nitriles 3a and 2-epi-3a in a ratio of 60:40 and with an overall yield of 88% after two steps (Scheme 2). Hydrogenation of 3a and 2-epi-3a under the conditions reported by Cheng et al. [22] gave ADMDP and its 2-epimer (2-epi-ADMDP) in 73% and 69% yield, respectively (Scheme 2). The same approach was successfully applied for the synthesis of the six-membered amino-iminosugar. Thus, treatment of gluco-lactam 1b with Schwartz's reagent, followed by TMSOTf-mediated addition of trimethylsilyl cyanide gave nitrile 3b in 65% yield as a single isomer. Its hydrogenolysis under the conditions presented above afforded gluconojirimycin derivative 4b in 66% yield (Scheme 2). Elsewhere, Cheng et al. [22] reported the transformation of nitrile 2-epi-3a to 2-epi-DMDP. We expect that the same strategy can be used for the synthesis of DMDP and α-homonojirimycin starting form 3a and 3b, respectively (Scheme 2). With appropriate substrates (1a and 1b) in hand, we investigated a one-pot lactam reduction/cyanide addition reaction (Scheme 2). Arabino-lactam 1a was treated with 1.6 equiv of Schwartz's reagent Cp2Zr(H)Cl, leading to appropriate imine 2a in almost quantitative yield according to the NMR analysis of the crude reaction mixture. The progress of the reaction can easily be followed thanks to simple direct observation: initially white, then heterogeneous mixture turns to a clear solution upon reduction completion (approximately 10 min). Subsequent treatment of the in situ generated imine 2a with trimethylsilyl cyanide (2.0 equiv) in the presence of TMSOTf (1.0 equiv) gave a mixture of two nitriles 3a and 2-epi-3a in a ratio of 60:40 and with an overall yield of 88% after two steps (Scheme 2). Hydrogenation of 3a and 2-epi-3a under the conditions reported by Cheng et al. [22] gave ADMDP and its 2-epimer (2-epi-ADMDP) in 73% and 69% yield, respectively (Scheme 2). The same approach was successfully applied for the synthesis of the six-membered amino-iminosugar. Thus, treatment of gluco-lactam 1b with Schwartz's reagent, followed by TMSOTf-mediated addition of trimethylsilyl cyanide gave nitrile 3b in 65% yield as a single isomer. Its hydrogenolysis under the conditions presented above afforded gluconojirimycin derivative 4b in 66% yield (Scheme 2). Elsewhere, Cheng et al. [22] reported the transformation of nitrile 2-epi-3a to 2-epi-DMDP. We expect that the same strategy can be used for the synthesis of DMDP and α-homonojirimycin starting form 3a and 3b, respectively (Scheme 2). Configuration of the newly generated stereochemical center in nitriles 3a, 2-epi-3a, and 3b have been established by NOE experiments. Addition of TMSCN to gluco-imine 2b proceeded syn to the BnO substituent at the C-3 position. This is a result of conformational control of the process, according to Woerpel's model (Figure 2a) [29][30][31][32][33][34]. In the latter case, the nucleophilic addition of TMSCN to arabino-imine 2a occurs with low stereoselectivity, leading to the separable mixture of isomers 3a and 2-epi-3a in a ratio of 60:40.
The same modest diastereoselectivity was observed by Woerpel in the reaction of TMSCN with cyclic oxocarbenium ions [35]. Woerpel postulated that this effect can be Configuration of the newly generated stereochemical center in nitriles 3a, 2-epi-3a, and 3b have been established by NOE experiments. Addition of TMSCN to gluco-imine 2b proceeded syn to the BnO substituent at the C-3 position. This is a result of conformational control of the process, according to Woerpel's model (Figure 2a) [29][30][31][32][33][34]. In the latter case, the nucleophilic addition of TMSCN to arabino-imine 2a occurs with low stereoselectivity, leading to the separable mixture of isomers 3a and 2-epi-3a in a ratio of 60:40.
The same modest diastereoselectivity was observed by Woerpel in the reaction of TMSCN with cyclic oxocarbenium ions [35]. Woerpel postulated that this effect can be attributed to the high reactivity of the nucleophilic species involved [36]. The silyl cyanides require activation by a nucleophile in solution (such as the counterion of the Lewis acid) to form a pentacoordinate siliconate ion that transfers the cyano group. This activation step is slow relative to nucleophilic addition. A detailed, step-by-step description of this process has been explained by Woerpel in his vital paper from 2006 [35]. It can be assumed that a similar effect applies in the TMSOTf-mediated addition of TMSCN to arabino-imine 2a (Figure 2b).
attributed to the high reactivity of the nucleophilic species involved [36]. The silyl cyanides require activation by a nucleophile in solution (such as the counterion of the Lewis acid) to form a pentacoordinate siliconate ion that transfers the cyano group. This activation step is slow relative to nucleophilic addition. A detailed, step-by-step description of this process has been explained by Woerpel in his vital paper from 2006 [35]. It can be assumed that a similar effect applies in the TMSOTf-mediated addition of TMSCN to arabino-imine 2a (Figure 2b). Subsequently, other types of nucleophiles, such as silyl enol ethers 5a, 5b, and 5c, were examined in the tandem one-pot reduction/nucleophilic addition protocol (Scheme 3). Gluco-lactam 1b was selected as a model compound for this part of the study. On the basis of previous examples, a solution of gluco-lactam 1b was added to a suspension of Schwartz reagent (1.6 equiv) in THF. After the initially white suspension turned clear, the enol silyl ether (2 equiv) and Yb (OTf)3 (10 mol%) were added at −25 °C, and the reaction mixture was warmed slowly to room temperature. The desired functionalized piperidines 6a, 6b, and 6c were obtained in 88%, 68%, and 43% yields, respectively, and with a high level of stereoselectivity (Scheme 3). The stereochemical structure of piperidines 6a, 6b, and 6c were confirmed by NOE experiments. The stereochemistry between the substituent at C-2 and the benzyloxy group at C-3 was determined to be in a syn arrangement for all piperidines 6a, 6b, and 6c. We are dealing here with the same model of stereocontrol as shown in Figure 2a. Obtained compounds 6a-c are attractive building blocks for the synthesis of functionalized nojirimycin derivatives.  Subsequently, other types of nucleophiles, such as silyl enol ethers 5a, 5b, and 5c, were examined in the tandem one-pot reduction/nucleophilic addition protocol (Scheme 3). Gluco-lactam 1b was selected as a model compound for this part of the study. On the basis of previous examples, a solution of gluco-lactam 1b was added to a suspension of Schwartz reagent (1.6 equiv) in THF. After the initially white suspension turned clear, the enol silyl ether (2 equiv) and Yb (OTf) 3 (10 mol%) were added at −25 • C, and the reaction mixture was warmed slowly to room temperature. The desired functionalized piperidines 6a, 6b, and 6c were obtained in 88%, 68%, and 43% yields, respectively, and with a high level of stereoselectivity (Scheme 3). The stereochemical structure of piperidines 6a, 6b, and 6c were confirmed by NOE experiments. The stereochemistry between the substituent at C-2 and the benzyloxy group at C-3 was determined to be in a syn arrangement for all piperidines 6a, 6b, and 6c. We are dealing here with the same model of stereocontrol as shown in Figure 2a. Obtained compounds 6a-c are attractive building blocks for the syn thesis of functionalized nojirimycin derivatives. attributed to the high reactivity of the nucleophilic species involved [36]. The silyl cyanides require activation by a nucleophile in solution (such as the counterion of the Lewis acid) to form a pentacoordinate siliconate ion that transfers the cyano group. This activation step is slow relative to nucleophilic addition. A detailed, step-by-step description of this process has been explained by Woerpel in his vital paper from 2006 [35]. It can be assumed that a similar effect applies in the TMSOTf-mediated addition of TMSCN to arabino-imine 2a (Figure 2b). Subsequently, other types of nucleophiles, such as silyl enol ethers 5a, 5b, and 5c, were examined in the tandem one-pot reduction/nucleophilic addition protocol (Scheme 3). Gluco-lactam 1b was selected as a model compound for this part of the study. On the basis of previous examples, a solution of gluco-lactam 1b was added to a suspension of Schwartz reagent (1.6 equiv) in THF. After the initially white suspension turned clear, the enol silyl ether (2 equiv) and Yb (OTf)3 (10 mol%) were added at −25 °C, and the reaction mixture was warmed slowly to room temperature. The desired functionalized piperidines 6a, 6b, and 6c were obtained in 88%, 68%, and 43% yields, respectively, and with a high level of stereoselectivity (Scheme 3). The stereochemical structure of piperidines 6a, 6b, and 6c were confirmed by NOE experiments. The stereochemistry between the substituent at C-2 and the benzyloxy group at C-3 was determined to be in a syn arrangement for all piperidines 6a, 6b, and 6c. We are dealing here with the same model of stereocontrol as shown in Figure 2a. Obtained compounds 6a-c are attractive building blocks for the synthesis of functionalized nojirimycin derivatives.

Conclusions
In conclusion, we have presented a convenient route for the synthesis of aminomodified iminosugars, such as ADMDP, based on the reductive activation of sugar-derived lactones and silyl cyanides. The presented method is one of the shortest preparations of ADMDP. In contrast to similar strategies based on nucleophilic addition to cyclic nitrones, our method uses the more easily available and stable lactams. An additional advantage of the current method over nitrone-based strategies [21,22] is the fact that it can also be successfully applied to the synthesis of six-membered analogues of ADMDP (4d). The former method is limited due to the more challenging synthesis and limited stability of six-membered nitrones compared to their five-membered counterparts [37]. Moreover, we have presented that other types of nucleophile, such as silyl enol ethers, can be applied, leading to functionalized nojirimycin derivatives.

General Information
1 H NMR and 13 C NMR spectra were recorded on Varian VNMRS 500 and Varian VNMRS 600 spectrometers, in CDCl 3 , unless otherwise stated, and with TMS used as an internal standard. Chemical shifts (δ) were given in ppm and coupling constants (J) were given in Hertz (Hz). Infrared spectra were recorded on an FT-IR Jasco 6200 and FT-IR Spectrum 2000 Perkin Elmer spectrophotometer. High-resolution mass spectra were recorded on an ESI-TOF Mariner Spectrometer, SYNAPT G2-S HDMS, or AMD 604 mass spectrometer. Optical rotations were measured with a Jasco P-2000 polarimeter. Thin-layer chromatography was performed on Merck aluminium sheet Silica Gel 60 F254. Column chromatography was carried out using Merck silica gel (230-400 mesh).

One-Pot Reduction/TMSCN Addition to Sugar-Lactams 1a and 1b-General Procedure for The Synthesis of 3a, 2-Epi-3a, and 3b
A solution of sugar lactam 1a or 1b (0.5 mmol) in THF (5 mL) was added dropwise to a suspension of Cp 2 Zr(H)Cl (1.6 equiv, 0.8 mmol, 206 mg,) in THF (5 mL) under an argon atmosphere. The mixture was stirred until the white suspension disappeared (ca. 10 min) to form a clear solution. Next, the imine solution was cooled to −25 • C and TMSOTf was added (1.0 equiv, 0.5 mmol, 60 µL). The mixture was stirred for 10 min and TMSCN (2.0 equiv, 1.0 mmol, 125 µL) was added dropwise. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by addition of aq. NaHCO 3 and stirred for 30 min. After dilution with Et 2 O (5 mL), the aqueous phase was separated and washed twice with Et 2 O (2 × 5 mL). The combined organic solutions were dried over anhydrous MgSO 4 , filtered, and solvents were removed under reduced pressure. The residue was chromatographed on silica gel to afford the corresponding amine derivatives 3a, 2-epi-3a, and 3b.