I2-mediated carbamate annulation: scope and application in the synthesis of azasugars

Carbohydrate Research 356 (2012) 163–171

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I2-mediated carbamate annulation: scope and application in the synthesis of azasugars Bridget L. Stocker a,⇑, Anna L. Win-Mason b, Mattie S.M. Timmer b,⇑ a b

Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand

a r t i c l e

i n f o

Article history: Received 13 January 2012 Received in revised form 13 March 2012 Accepted 13 March 2012 Available online 23 March 2012 Keywords: Azasugars Iminosugar Carbamate Protecting-group-free Synthesis Halocyclisation

a b s t r a c t The I2-mediated carbamate annulation provides an efficient and highly stereoselective route for the synthesis of a variety of pyrrolidines and piperidines, both in the presence and absence of protecting groups. Evidence for the formation of an iodoamine intermediate during the annulation is provided and, for the first time, we explore possible mechanisms of the annulation. The high cis-selectivity of the carbamate annulation is also compared to other N-halocyclisations and aminomercurations and some general conclusions about the diastereoselectivity of these types of reactions are made. Ó 2012 Elsevier Ltd. All rights reserved.

1. Introduction Azasugars, or iminosugars, are a valuable class of compounds that play an important role in drug discovery, primarily due to their ability to mimic oxocarbenium ion transition states of glycosidase reactions,1 though other biological activities, such as their ability to act as molecular chaperones,2 as immunomodulators,3 or as inhibitors of other enzymes and proteins4,5 has also been noted. Azasugars sparked scientific interest in the early 1960s with the almost simultaneous reports of the syntheses of ‘piperidinoses’, sugar derivatives containing a nitrogen atom in the ring, by the groups of Jones and co-worker,6 Paulsen,7 and Hanessian and Haskell.8 Shortly thereafter, the first azasugar, nojirimycin (1) (Fig. 1), was isolated from Streptomyces reseochromogenes and found to possess anti-microbial activity,9 and it’s 1-deoxy analogue deoxynojirimycin (DNJ, 2), initially prepared by Paulsen et al.,10 was later isolated from Mulberry trees11 and shown to be a potent a-glycosidase inhibitor.12 The D-gluco chiral scaffold of the nojirimycin family has subsequently played an important role in the development of anti-diabetic drugs, such as GlysetÒ (3),13 and represents just one of the many types of azasugars that have been isolated, synthesised and their biological activity explored in an effort to find therapeutic activities.14,15 In addition to the aforementioned

⇑ Corresponding authors. Tel.: +64 4 499 6914x813; fax: +64 4 499 6915. E-mail addresses: [email protected] (B.L. Stocker), mattie.timmer@vuw. ac.nz (M.S.M. Timmer). 0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.carres.2012.03.015

nojirimycin derivatives (1–3), which belong to the piperidine class of azasugars, other structural classes of azasugars include the pyrrolidines [e.g., 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine 4, (DMDP, R = H)],4,16,17 the pyrrolizidines, [e.g., casuarine (5)],18 the indolizidines [e.g., swainsonine (6)],19 and the nortropanes [e.g., calystegine A3 (7)].20 Given the enormous therapeutic potential of azasugars, it is not surprising that much effort has been spent in determining efficient and novel ways to synthesise these carbohydrate-mimics, with strategies including the use of ring-closing metathesis, reductive amination, aldol reactions and pericyclic reactions.15 Our interest, however, was in developing a carbamate annulation, which, in addition to providing the chemist with an additional ‘synthetic tool’, would allow for the synthesis of azasugars without the need for protecting groups.21 It goes without question that the use of protecting groups adds to the total number of steps in a synthetic sequence and leads to reduced overall efficiencies,22 and because of this, ‘protecting-group-free’ methodology has received much attention in recent years.23 That said, it can often be difficult to design or implement a protecting-group-free synthesis due to the competing ‘reactive’ centres around a molecule. Accordingly, we became interested in determining the versatility of our carbamate annulation for the synthesis of azasugars, both in the presence and absence of protecting groups. This mini-review highlights this work and outlines the scope and limitations of our carbamate annulation for the synthesis of pyrrolidine and piperidines, and also explores how this annulation relates to similar electrophilic cyclisations.

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OH

HO

H N

OH

R1

N

HO

HO

OH

OH

HO

Cl

Me

O

Na2CO3 DMSO

O

NH2 HBr

n

3, Glyset

4, DMDP

Me O

Et4NHCO3

Br

(1)

NH

48%

OH

OH

1, R = OH, Nojirimycin 2, R = H, Deoxynojirimycin

NH2 HBr

Ph

HO

OH

OH

H N

Ph

O

CH3CN

NH

(2)

n = 1, 56% n = 2, 42%

n

O

HO

N N

HO HO

H

OH

OH OH

5, Casuarine

HO HO

HO NH

H OH HO

6, Swainsonine

OR NH2

H N

I

'CO2'

O N

(3)

Base

OR

7, Calystegine A3

I2

RO

OR

RO

OR

Scheme 1. The potential of 1,2-haloamines in the synthesis of carbamates.

Figure 1. Representative azasugars.

2. Carbamate annulation: synthesis of pyrrolidines and piperidines Organic carbamates have found wide application in chemistry with their use as pharmaceuticals and pharmaceutical intermediates, as agrochemicals, as linkers in combinatorial chemistry, and as protecting-groups during peptide couplings.24 It is thus not surprising that a number of strategies have been developed for the synthesis of carbamates and these include the reaction of amines with phosgene (or derivatives), carbon dioxide (gaseous, electrochemical and supercritical), carbonate esters and salts, or the use of amides in, for example, Hoffmann, Curtius and Lossen rearrangements.24 In particular, we became interested in the seminal work by Hassner and Burke25 and Inesi et al.26 who illustrated that cyclic carbamates could be prepared, in modest yield, from the reaction of acyclic amines equipped with a halogen-leaving group and either sodium carbonate or tetraethylammonium bicarbonate, respectively (Eqs. 1 and 2, Scheme 1). Tamaru et al. have also used sodium bicarbonate and iodine in the halocyclisation of preformed olefinic carbamates (methoxycarbonyl amides), but cyclisation of these substrates was slow and poor-yielding and often led to mixtures of five- and six-membered cyclic amides.27 Notwithstanding much optimisation, we thus saw the potential of extending this type of halocyclisation to allow for the synthesis of carbamates from unprotected alkenylamines in a one-pot process, whereby the intermediate halide would be formed in situ and subsequently cyclised in the presence of ‘CO2’ (Eq. 3; Scheme 1). The annulation, in turn, would form an integral part of our strategy for the synthesis of azasugars. To examine the potential of a carbamate annulation in the synthesis of azasugars, we envisioned a retrosynthetic strategy whereby the target compounds A could be readily prepared from the precursor carbamates B via base-mediated hydrolysis (Scheme 2). Carbamates B, in turn, could be formed via our proposed I2-mediated annulation, with the pre-requisite alkenylamines C being prepared from the parent sugars D via a Vasella reaction28 and either a reductive amination29 or a Strecker reaction.30 In this manner, five-membered azasugars (e.g., n = 2, R1 = H or R1 = CH2NH2) and six-membered azasugars (e.g., n = 3, R1 = H) could be readily prepared. With this general approach in mind, we first considered the potential of our carbamate annulation in the protecting-group-free synthesis of pyrrolidines (Scheme 3).21,31,32 Here, the parent pentose 8 was readily converted into the corresponding alkenylamine 9 via a Vasella reaction followed by our protecting-group-free reductive amination,29 and then subjected to a solution of I2 and various saturated carbonates in H2O. While there is much precedent for the formation of iodomethylpyrrolidines when treating

pentenylamines with I2 and molar equivalents of NaHCO3,33,34 we were delighted to observe that the desired carbamate 10 could be formed in one step and excellent yield and diastereoselectivity when excess NaHCO3 was used.21 The carbamate annulation favours formation of the 2,3-cis pyrrolidine (d.s. > 20:1, as evidenced by 1H NMR of the crude reaction mixture), with the stereochemistry at the 3-position exerting stereocontrol over the cyclisation. Using this strategy, a variety of carbamates were prepared, including those derived from 2-deoxy-D-ribose (R1 = H),31 and these were subsequently treated with NaOH in refluxing EtOH to give the desired pyrrolidines 11 [1,4-dideoxy-1,4-imino-L-xylitol,32 1,4dideoxy-1,4-imino-D-lyxitol,32 1,4-dideoxy-1,4-imino-D-xylitol,21 1,4-dideoxy-1,4-imino-L-lyxitol21 and 1,2,4-trideoxy-1,4-imino-Lxylitol31] in excellent (48–57%) overall yields. Having illustrated the application of the carbamate annulation for the synthesis of hydroxy-pyrrolidines, we then explored the potential of this methodology in the synthesis of aminoiminohexitols, which in turn have shown great promise in the treatment or diagnosis of numerous diseases including osteoarthritis,35,36 bacterial infection,37 and lysosomal storage disorders.38,39 We initially envisioned another protecting-group-free synthesis, whereby the unprotected methyl 5-deoxy-5-iodo-D-arabinoside (12, R1 = H) could be transformed into a-aminonitrile 13 via a Vasella reaction and subsequent Strecker condensation, however, under all conditions attempted, at best, only minor amounts (<5%) of the desired a-aminonitrile could be isolated and significant product degradation was observed (Scheme 4).40 Though disappointing, hydroxyaldehydes are well known to be prone to decomposition,41 so we turned our attention to the use of a protected furanoside as a starting substrate, confident that our cabamate annulation methodology would still allow for a competitive synthetic route. To this end, protected arabinoside 12 (R1 = Bn) was subjected to a Vasella reaction and the corresponding aldehyde was formed in excellent (97%) yield. After optimisation, it was found that a good (88%) yield and diastereoselectivity (9:1; syn:anti) for the Strecker reaction could be obtained when TMSCN was used as the source of nitrile and NH4OAc as the source of amine, with a Cram-chelate transition state explaining the preferred syn stereoselectivity.40 The a-aminonitriles were readily separated by flash column chromatography and the major diastereomer (syn-13) was treated with a solution of I2 and NaHCO3 (satd) in a mixed solvent system (THF/H2O, 1:1) to solubilise the lipophilic a-aminonitrile while allowing for sufficient dissolution of NaHCO3. We were unsure whether our carbamate annulation would occur in a mixed solvent system, and moreover, whether we would generate the primary iodide, as suggested by the literature.33,34,42 We were therefore delighted to observe the smooth transformation of syn-13 into carbamate 14 (85% yield), thus highlighting the potential of our methodology during more conventional organic syntheses. As with the

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B. L. Stocker et al. / Carbohydrate Research 356 (2012) 163–171

O O

H N

HO

R3

N

R1 n

OH A

R1

O

I NH2

OMe

n

n

OR2

OR2

OH

B

C

D

R1 = H, CH2NH2 R2 = H, Bn R3 = H, CN

n

Carbamate Annulation

Scheme 2. Retrosynthesis for the formation of azasugars.

HO O

1) MeOH, AcCl OH 2) PPh3, I2, Imid. R1

HO

8 R1 = H, OH

HO

R1 NH2

3) Zn, NH4OAc NaCNBH3 54-65% (3 steps)

OH

H N

HO

9

OH

9

NaHCO3 I2, H2O 93-97%

NH2

Figure 2. Novel methodology.

HO

HO

NH2

H N

HO

HO

OH

prepared

OH

11

10 aminoiminohexitols

NH2

H N

by

carbamate

annulation

O HO

O

H N

NaOH, EtOH

N

97-99% HO

11

R1

HO

10

R1

2,3-cis product exclusively Scheme 3. Carbamate annulation en route to the synthesis of hydroxypyrrolidines.

I O

OMe 1. Zn, EtOH, 97%

R1O

12

OR1 NH2

CN

2. NH4OAc TMSCN

OR1

OR1 NH2 OR1

CN OR1

syn-13

anti-13 R1 = H; <5% R1 = Bn; 88%, dr = 9:1

NaHCO3, I2 THF:H2O 85% O HO

NH2

H N

HO

OH

15

1) H2, Pd(OH)2/C 2M HCl 2) NaOH 96% (2 steps)

O N BnO

CN OBn

14

Scheme 4. Synthesis of aminoiminohexitols via carbamate annulation.

1,4-dideoxy pyrrolidines, only the cis-isomer was observed, which was subsequently treated with Pd(OH)2/C in the presence of 2 M HCl then NaOH to generate L-ido-aminoiminohexitol 15 in an excellent overall yield of 39%.40 Using a similar strategy, several other aminoiminohexitols were synthesised, including three previously undisclosed stereoisomers: D-galacto 9 (36% overall yield), L-altro 10 (37% overall yield) and 43 D-talo isomer 11 (8% overall yield), (Fig. 2). To allow for these and other aminoiminohexitols to be prepared, different chiral starting materials were used and both the minor and major Strecker products were subjected to the I2-promoted carbamate annulation. Although the cis-carbamate was always the preferred diastereomer, for some substrates also minor amounts of the

trans-product (up to 20%) were observed. Our proposed explanation for this will be discussed in Section 4. Having illustrated the potential of the carbamate annulation for the synthesis of pyrrolidines, we then extended the scope of this methodology to the synthesis of piperidine azasugars, and in particular, to that of 1-deoxygalactonojirimycin (DGJ), which is undergoing clinical evaluation for the treatment of Fabry’s disease.44,45 Because of the added efficiencies that can be gained from a protecting-group-free approach, we sought to use a strategy similar to that developed for the 1,4-dideoxy pyrrolidines. However, from the outset, we anticipated several challenges, the most notable being controlling the chemoselectivity of the reaction to favour N- over O-cyclisation and the formation of a six- rather than a five-membered ring during the annulation.46 To begin the synthesis of DGJ, an efficient route for the synthesis of the precursor methyl iodo-glycoside was required. To this end, commercially available methyl a-D-galactopyranoside was treated with triphenylphosphine, imidazole and iodine, however, in addition to the anticipated product 12 (49% yield), a 45% yield of methyl 3,6-anhydro-a-D-galactopyranoside was obtained,47 which was formed via nucleophilic attack of the 3-hydroxyl onto C-6 in the 6-O-phosphonium intermediate. Accordingly, a second route for the synthesis of 12 was developed which involved the installation of acetonides at the 1,2- and 3,4-O-positions of D-galactose, iodination and subsequent removal of the acetonides and anomeric methylation via treatment with MeOH and HCl. As all intermediates in this second route could be purified by crystalisation or distillation,48,49 this was the preferred approach when multi-gram quantities of 12 were required. Methyl iodo-glycoside 12 was then subject to a Vasella reaction with reductive amination to give alkenylamine 13 in good (85%) yield (Scheme 5). With the precursor alkenylamine 13 in hand, attempts were then made to form the desired carbamate 14a whilst limiting the formation of the corresponding trans-isomer 14b or furan 14c. Several different reaction conditions were investigated (including the use of different carbonate bases, reaction temperatures, and quantities of iodine), and it was observed that the optimum ratio could be obtained (14a:14b:14c; 3:1:1) when a large excess of iodine was added and the reaction was performed at 50 °C. From this mixture, 14b could be isolated by column chromatography, however separation of 14a and 14c proved difficult and the mixture was thus treated with NaOH. Following hydrolysis, DGJ could be readily isolated in 40% yield (from 13), thus providing a remarkably short

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B. L. Stocker et al. / Carbohydrate Research 356 (2012) 163–171

O

I

OMe

HO

NH2

Zn, NH4OAc NaCNBH3,85%

OH

HO

OH

OH

OH

12

13 NaHCO3 I2, H2O O

H N

HO HO

NaOH OH

OH

O N

40% (from 13)

O

O

O

O N

+

HO

OH HO

OH

OH

15

HO

OH

14a

NH O

+

OH

14c

14b (3:1:1)

Scheme 5. Application of the carbamate annulation for the synthesis of DGJ.

O NH2 HO

I2

H N

I

NaHCO3 (excess)

HO

9

OH

HO

16 H N I HO

OH

OH

OH

17

CN OBn

syn-13

OH

10

H N

I

BnO

N

H2O

OH

H2N

O

NIS, CH2Cl2 79%; or I2, NaHCO3 (1.2 equiv.) THF:H2O (1:1), 80%

18

I

BnO

H N

O CN

I2, NaHCO3 (sat.)

OBn THF:H2O (1:1), 85%

O N

BnO

19

CN OBn

14

Scheme 6. Formation of iodoamines en route to the synthesis of carbamates.

synthesis of this important azasugar.48 Again, use of the carbamate annulation proved to be key in the synthesis and the ability to favour N-cyclisation and formation of the six-membered ring suggests that this methodology holds much promise for the synthesis of other piperidines. 3. Carbamate annulation: mechanistic considerations The formation of the cyclic carbamate can be rationalised by the in situ reaction of the initially formed haloamine in a tandem carbonylation reaction, similar to that described for the addition of CO2 to 1,2-hydroxyhalides50 (cf. 16 ? 10, Scheme 6). To support such a mechanism, we investigated the role of the base in the reaction and observed that subjection of alkenylamine 9 to N-iodosuccinimide (NIS), or iodine in the presence of DBU or NaOH, gave an inseparable mixture of products which included the five- and six-membered iodoazasugars 17 and 18 (Scheme 6) presumably formed from 9 via aziridine formation and subsequent opening of the three-membered ring by nucleophilic iodide.33 Moreover, in all experiments, there was no evidence for the forma-

tion of the corresponding carbamate, suggesting that the ‘CO2’ required for the reaction is generated via the dissolution of NaHCO3 in water. Attempts were then made to determine if an iodoamine was indeed a key intermediate that could then undergo a carbamate annulation. As previously mentioned, we were unable to prepare a pure sample of iodoamine 16 from the unprotected alkenylamine 9 through the use of other halo-cyclisation methodologies, however information about the mechanism of the reaction could be gained via the successful preparation of a protected iodoamine and subsequent transformation into the corresponding carbamate. Accordingly, alkenylamine syn-13 was treated with either NIS in CH2Cl2 or the addition of 1.2 equiv of NaHCO3 in THF/H2O (1:1) to generate iodoamine 19 in good (80% yield). Subjection of iodide 19 to excess NaHCO3 then leads to the smooth transformation of 19 into carbamate 14, again in good (85%) yield. Having established that iodoamine 19 could be converted to the carbamate, we then repeated the carbamate annulation and through careful analysis by tlc, mass spectroscopy and NMR, observed that 19 was formed en route to the synthesis of carbamate 14, thus confirming its role as an intermediate during the reaction. These

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B. L. Stocker et al. / Carbohydrate Research 356 (2012) 163–171

N I.

HO "CO2"

O

NH2

I2

H N

I

CO32-

I

NaHCO3

HO

HO

O

OH N

O

H

O N

HO

"CO2"

-O

I

II.

HO O N

HO

III.

Scheme 7. Possible mechanisms for the carbamate annulation.

I

H N

BnO

O CN OBn

19

Ag2CO3, THF rt, 20 h, 70%

N

CN

H BnO

OBn

20

O

NaHCO3 (30 eq.), I2 (2 eq.)

x

N

THF:H2O (1:1), rt, 2 d NaHCO3 (30 eq.)

BnO

x

CN OBn

14

THF:H2O (1:1), rt, 7 d NaHCO3 (30 eq.,) I2 (2 eq.)

x

KI (2 eq.),THF:H2O (1:1) rt, 18 d Scheme 8. Aziridine formation and attempted transformation into carbamate.

findings also support literature precedent whereby the reaction of alkenylamines with NaHCO3 (ca. 1–3 equiv) was found to yield iodo-amines.33,34,42 Having provided evidence to support our theory that the intermediate haloamine reacts with CO2 formed in situ via the dissolution of NaHCO3 in water en route to the synthesis of the carbamate, the next question to address was the mechanism of formation of the carbamate. For this purpose, we have proposed three reaction pathways (Scheme 7). The first involves the formation of an aziridine, (which has been previously observed in halo-cyclisation studies performed by Verhelst et al.),33 and the subsequent ringopening of the aziridine by CO2. The second pathway implicates a carbonate as a key intermediate, while the third proposed mechanism occurs via the formation of carbamic acid, which subsequently cyclises with displacement of iodide. To provide some insight into the mechanism of the annulation, we herein explore, for the first time, the potential of converting aziridine into carbamate when subjected to the carbamate annulation conditions (Scheme 8). To this end, iodo-amine 19 was treated with Ag2CO3 (2 equiv) to yield aziridine 20 [Rf = 0.19 (hexanes/ EtOAc, 1/1, v/v), [M+Na]+ = 343.1416] in good (70%) yield. The structure of 20 was established by 1D and 2D NMR with characteristic 1H resonances observed at d 2.66 (ddd, J = 5.4, 5.1, 3.6 Hz) for the aziridine methine proton, and at d 1.87 (dd, J = 5.5, 1.5 Hz) and d 1.76 (dd, J = 3.6, 1.5 Hz) for the aziridine methylene protons [see Supplementary data for full experimental details]. Aziridine 20 was then treated with excess NaHCO3 for 2 days, 7 days, or 18 days (with the co-addition of KI), however in all instances, there was no trace of the corresponding carbamate 14 (as judged by 1H NMR of the crude reaction mixture) and only starting material was observed. Failure to form the carbamate suggests that the

annulation does not occur via an aziridine intermediate (Route I), and that either carbonate (Route II) or carbamic acid (Route III) is formed during the annulation. Literature precedent suggests that carbamic acids readily form upon the exposure of amines to CO2,51–53 and thus an annulation mechanism involving a carbamic acid intermediate seems plausible. This is an avenue of research we will continue to investigate.

4. Diastereoselectivity of the carbamate annulation In addition to the high yields and short number of linear steps, another remarkable feature of our strategy for the synthesis of azasugars is the high degree of diastereoselectivity observed in the carbamate annulation reaction. The stereochemistry at the allylic position exerts stereocontrol on the cyclisation and this appears to be independent of stereochemistry at the homoallylic position (Table 1, entries 1 and 2),21 or lack thereof (entry 3).31 Given that iodoamine appears to be a key intermediate in the carbamate annulation, it is not surprising that similar 4,5-cis-diastereoselectivity has been observed for the halo-cyclisation or amidomercuration of a number of N-substituted alkenylamines, including N-sulfonyl (e.g., entry 4),34 N-t-butyloxycarbonyl,54 N-methoxycarbonyl (e.g., entry 5),27 and N-benzyloxycarbonyl55 derivatives. Although slight differences in diastereoselectivity were observed by changing the solvent, reaction temperature, or choice of iodinating reagent, the cis-isomer was predominantly the major product. When the carbamate annulation methodology was used to prepare aminoiminohexitols, however, on occasion, a decrease in the diastereoselectivity was observed. While the syn-Strecker product from D-arabinose led to exclusive formation of one diastereomer

168

B. L. Stocker et al. / Carbohydrate Research 356 (2012) 163–171 Table 1 Diastereoselectivity of halo-cyclisation Entry

Cyclic producta

Alkenylamine

OH

d.s. (cis:trans)

Yield (%)

Ref.

>95:5

99

21

>95:5

99

21

>95:5

90

31

96:4

86

34

93:7

83

27

>95:5

85

40

6:1

95

43

3:1

80

42

<5:95

50

56

3:1:1 (cis:trans: furan)

85

48

>95:5b or 1:1c

80 or 90

57 or 58

O O NH2

1

N

OH

HO

OH

OH

O O NH2

2

N

OH HO

OH

OH

O O NH2

3

N

HO OH NHSO2Tol

4

SO2Tol N

I HO

OH NHCO2Me

5

CO2Me N

I HO

OBn NH2

O O

CN

6

N

CN

OBn BnO BnO

NH2

O

O

CN

7

OBn O O N

BnO N

Ph

Ph CO2tBu

CN

BnO

OBn Bn N

I

N

CN

OBn

OBn Bn N

CO2tBu I

CO2tBu

+

8

O

O

O

BzCHN

OBn

O

O

O

CBz OBn N

I

9

BnO

OBn BnO

OBn

OH OH

O NH2

10

O N

OH

OH

NHBn 11

HO

OH HgBr

H N

H N

or OBn

HO

OH OH

NH O

+

OH HgBr

O

N + OH HO

HO OBn OBn

O

O

O

HO

OH OH

OH

169

B. L. Stocker et al. / Carbohydrate Research 356 (2012) 163–171 Table 1 (continued) Entry

Cyclic producta

Alkenylamine

OBn OBn

OBn NHBn

12

OBn

H N

BnO

OBn

d.s. (cis:trans)

Yield (%)

Ref.

>95:5

80

59

CH2I

OBn OBn

a b c

Unless otherwise stated, reaction performed via I2-mediated cyclisation in the presence of NaHCO3. Reaction performed under the mediation of Hg(OCOCF3)2 then KBr. Reaction performed under the mediation of HgBr2.

I

I

π

H

H

H H H

H N

H

H σ*

H HO

H H H H

OH

I

(favoured)

(unfavoured)

R

I

π

H H

C OBn-in-plane

H H σ*

C H OBn N H

H BnO

H

Only Product Observed

H

N

H

N C H R

I

I

I

H

B H-in-plane -> trans

I

HH

H

A O-in-plane -> cis

N

N

π

N

H σ* H H

H

N C H

H

π

H H

H N H σ* H BnO

H

H OBn C N H

D OBn-in-plane Major Product

Figure 3. Transition states leading to the formation of carbamates. The alkenylamine can adopt either the favoured ‘O-in-plane’ conformer A (leading to the cis-product), or the unfavoured ‘H-in-plane’ conformer B. The orientation of the nitrile also affects transition state energies with only the cis-product being observed when the dihedral angle between the nitrile dipole and the electron pair on the amine is approximately 90° (as in C), while a dihedral angle of approximately 180° (as in D) leads to an unfavourable interaction and consequently a mixture of diastereomers, with the cis-isomer predominating.

(Table 1, entry 6),40 the anti-Strecker product gave a mixture of diastereomers (6:1; syn:anti; entry 7).43 To explain this observation, and indeed the excellent cis diastereoselectivity observed during the synthesis of the hydroxypyrrolidines (Table 1, entries 1–5), the work by Chamberlin et al.60–62 and Gouverneur and co-workers63 for the halocyclisations of furans can be extended to aminocyclisations. Thus, we propose that the attack of the internal-nucleophile on the I2–alkene complex takes place via a five-membered ring transition state in which the nitrogen approaches the double bond in an envelope conformation and follows a Bürgi–Dunitz-like trajectory.64 The stereo-directing hydroxyl (or ether) can be positioned either in the plane of the double bond (A, O-in-plane, ?cis-product) or almost perpendicular to that plane (B, H-in-plane, ? trans-product), of which the latter has overlapping hydroxyl rC—O and double bond pC@C orbitals, which destabilises the I2-complex and leads to a higher energy (disfavoured) transition state ( Fig. 3). Similarly, one can view the more favourable transition state (A) as having the carbon–oxygen bond in the plane of the double bond to minimise unfavourable electrostatic interactions.65 When examining the synthesis of the aminoiminohexitols, the influence that the dipole moment of the nitrile group has on the electron density on the nitrogen nucleophile also needs to be considered. For example, during cyclisation of the D-arabinose derived syn-Strecker product, the dihedral angle between the nitrile dipole and the attacking lone pair of electrons on the amine for the ‘O-inplane’ conformer in transition state C is approximately 90°. This conformation does not adversely affect the electron density of the p-system, and thus, transition state C dominates, leading to exclusive formation of the cis-carbamate. In contrast, cyclisation of the anti-Strecker product for the ‘O-in-plane’ transition state D

places the dipole of the nitrile at approximately 180° to the electrons of the amine. This leads to electron density being withdrawn from the amine through n—rCCN overlap, which raises the energy of the ‘O-in-plane’ transition state and makes it closer in energy to the analogous ‘H-in-plane’ conformer, thus giving a 6:1 ratio of cis:trans diastereomers. Similar observations and analysis can also be applied to the cyclisation of the D-ribo series.43 It should also be noted that in the work by Davies et al.,42 the presence of a CH2CO2tBu group at the C-1 position appears to influence the stereochemical outcome of their I2-mediated iodoamination (with concomitant N-debenzylation). Though the 4,5-cis product is the major diastereomer (e.g., Table 1, entry 8), the relative stereochemistry of the chiral-auxiliary and C-1 can reduce, or even reverse, this selectivity. This cis-selectivity is thought to occur via the rapid equilibrium of the two diastereomeric iodonium ions and subsequent cyclisation as the rate-determining step. Surprisingly, halocyclisation or amidomercuration of a per-Obenzylated N-benzyloxylcarbonyl protected alkenylamine derived from D-arbinose, however, resulted in preferential formation of the 4,5-trans-diastereomer (entry 9).56 This trans-selectivity was attributed to the differential steric requirements in the transition states, and may reflect the added steric-considerations that need to be taken into account when both a C1-substituent and an Nprotecting group are present.56,66 For example, O-cyclisation of a similar system (where NHCBz = OH) gives the cis-diastereomer preferentially (9:1; cis:trans).67 When considering the formation of piperidines using the carbamate annulation, it is similarly proposed that formation of the cyclic iodide determines the stereochemical outcome of the reaction, and thus similar halocyclisations or aminomercurations

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provide useful points of comparison. During our synthesis of DGJ, three products were observed in the I2-mediated annulation: ciscarbamate, trans-carbamate, and the corresponding cis-furan in a 3:1:1 ratio (Table 1, entry 10). Cyclisation of the analogous protected-alkenylamine (entry 11) under the mediation of Hg(OCOF3)2–KBr (kinetic conditions) led to exclusive formation of the cis-product,57 though a 1:1 ratio of the cis:trans products was observed upon treatment with HgBr2 (thermodynamic conditions).58 The I2-mediated cyclisation or aminomercuration of the D-gluco analogue (kinetic conditions) also resulted in little preference for either diastereomer,68–70 though changes to the solvent and/or equivalents of reagents could slightly alter the diastereomeric ratio. Aminomercuration of the D-manno isomer (kinetic conditions) once again favoured the cis-product (7:1; cis:trans).68 For a-benzyloxymethyl substituted amines (e.g., entry 12), the C-3 substituent (allylic position) of the starting heptitol often governs the diastereoselectivity. Only the cis-isomer was observed for the NIS-mediated cyclisation of a-D-gluco, b-L-altro, and a-D-galacto 1,2,3-trideoxy-2,6-iminohepitol derivatives, with the anomaly being the formation of the 2,3-trans (L-ido) epimer, which is thought to occur because of unfavourable steric interactions.59 Amidomercurations mediated by Hg(CF3CO2)2 also gave the cis-product exclusively for the a-D-galacto imino-1-iodoheptitol derivative.71,72 Taken together, these findings point to a slight preference for the formation of the cis-isomer during the electrophilic cyclisations to form piperidines, however, steric effects (including 1,3-diaxial interactions) also play an important role and the outcomes are less predictable than is the case with the pyrrolidines. 5. Conclusion The I2-mediated carbamate annulation provides entry into the synthesis of a variety of pyrrolidines and piperidines with generally good cis-diastereoselectivity and yield. This annulation occurs both in the presence and absence of protecting groups, and thus is envisioned to find wide application in the synthesis of azasugars and other compounds of pharmaceutical interest. Within our laboratory, we will continue to explore the scope and mechanism of this highly efficient chemical transformation. Acknowledgements The authors would like to acknowledge the financial contributions of Victoria University of Wellington (Postgraduate Scholarship, Curtis-Gordon Research Scholarship, A.L.W.-M.), the Wellington Medical Research Foundation (B.L.S.), and the NZ Lotteries Health Research Grant (B.L.S and M.S.M.T). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.carres.2012.03. 015. References 1. Sinnott, M. L. Chem. Rev. 1990, 90, 1171–1202. 2. For reviews on the use of azasugars as molecular chaperones see: (a) Fan, J. Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nat. Med. 1999, 5, 112–115; (b) Dwek, R. A.; Butters, T. D.; Platt, F. M.; Zitzmann, N. Nat. Rev. Drug Disc. 2002, 1, 65–75; (c) Kolter, T.; Wendeler, M. Chem. Bio. Chem. 2003, 4, 260–264; (d) Parenti, G. EMBO Mol. Med. 2009, 5, 268–279; (e) Benito, J. M.; Fernández, J. M.; Ortiz Mellet, C. Expert Opin. Ther. Pat. 2011, 21, 885–903. 3. (a) Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause, B. L.; Oredipe, O. A.; Newton, S. A.; White, S. L. Pharmacol. Ther. 1991, 50, 285–290; (b) Nash, R. J.; Watson, A. A.; Parry, P. Patent 20090117083, 2009. 4. Wigler, P. W. J. Bioenerg. Biomembr. 1996, 28, 279–284.

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