One-pot tandem strecker reaction and iminocyclisations: Syntheses of trihydroxypiperidine α-iminonitriles

FULL PAPER

DOI: 10.1002/ejoc.201301705

One-Pot Tandem Strecker Reaction and Iminocyclisations: Syntheses of

Trihydroxypiperidine α-Iminonitriles

Benjamin J. Ayers*^[a]and George W. J. Fleet^[a]

Keywords: Synthetic methods / Carbohydrates / Iminosugars / Nitrogen heterocycles / Cyanides / Cyclization

Unbranched, and α- and β-methyl-branched, trihydroxypip- sation. These trihydroxypiperidine α-iminonitriles are pre-

eridine α-iminonitriles have been obtained in a single step

cursors to trihydroxypipecolic acids. No formation of pyrrol-

from protected 5-O-tosylate pentoses. This reaction com- idine products was observed.

prises a one-pot tandem Strecker reaction and iminocycli-

Introduction

Iminosugars are monosaccharide analogues that have an

endocyclic nitrogen in place of oxygen, and they are

immensely important due to their inhibition of glycosidases

and other carbohydrate-processing enzymes.^[1]The bio-

logical properties of trihydroxypipecolic acids,^[2]iminosugar

mimics of uronic acids, have sparked interest in their syn-

thesis. gluco-Configured BR1 1 (Figure 1) has been isolated

in Nature from both Baphia racemosa^[3]and Baphiopsis par-

viflora.^[4]This trihydroxypipecolic acid has subsequently re-

ceived some synthetic attention,^[5–13]it has also been shown

to inhibit both human liver β-d-glucuronidase and α-l-idu-

ronidase,^[14]and it has demonstrated antimetastatic proper-

Figure 1. Iminosugar pipecolic acids and amide; piperidine α-

ties.^[15]The galacto-configured epimer (i.e., 2) has also

shown promising inhibitory activity.^[16,17]Other derivatives

of hydroxylated pipecolic acids have also been studied, in-

cluding hydroxymethyl-branched derivative 3, which

showed potent activity towards β-N-acetylglucosaminidase

(human placenta, IC₅₀90 nM).^[18]Therefore, there is an in-

creasing interest in the development of efficient synthetic

routes that allow access to these, and related, pipecolic acid

targets. It was envisaged that trihydroxypiperidine α-imino-

nitriles 4 would serve as flexible precursors to trihydroxy-

pipecolic acids. This paper describes the development of a

new one-pot method comprising a key tandem Strecker re-

action and iminocyclisation (TSI), which leads to tri-

hydroxypiperidine α-iminonitriles Ϫ potential precursors to

trihydroxypipecolic acids and their functional analogues.

The expansion of the method to encompass the formation

of α- and β-methyl-branched trihydroxypiperidine α-imino-

nitriles is also described.

iminonitrile precursor.

Results and Discussion

It was proposed that trihydroxypiperidine α-iminonitrile

I would be obtained by the treatment of C-5-activated hem-

iacetal V with an amine and cyanide in a single synthetic

step (Scheme 1). This would proceed by formation of open-

chain imine IV, with subsequent intramolecular displace-

ment or attack by cyanide to form iminium II or α-amino-

nitrile III intermediates, respectively; thus cyanide addition

can precede or follow the formation of the piperidine ring.

Similar strategies have been used to access piperidine α-

iminonitriles.^[5,19–34]However, in these cases, the addition of

cyanide and the iminocyclisation were conducted sepa-

rately, and not in a single one-pot procedure. A one-pot

method has been successfully used in the synthesis of pyr-

rolidine-based iminosugars.^[35]

[a] Chemistry Research Laboratory, Department of Chemistry,

University of Oxford, UK,

Tosyl hemiacetal 6 (Scheme 2, a), readily accessible from

d-ribose 5,^[36]was the ideal starting point. Reaction of tosyl

hemiacetal 6 with benzylamine and potassium cyanide did

not result in the formation of a piperidine α-iminonitrile,

but gave instead the 1,5-anhydro compound (i.e., 7; 78%)

Oxford, OX1 3TA, UK

E-mail: benjamin.ayers@chem.ox.ac.uk

http://research.chem.ox.ac.uk/george-fleet.aspx

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201301705.

Eur. J. Org. Chem. 2014, 2053–2069

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B. J. Ayers, G. W. J. Fleet

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are highly tentative. This is in analogy with the multistep

Kiliani reaction in which diastereoselectivity is rationalised

by Felkin–Anh-directed approach by cyanide.^[39,40]

Table 1. Reaction conditions for the formation of piperidine α-imi-

nonitriles.

Entry

Amine

T [°C]

Yield [%]

8:9

1

2

3

4

5

6

7

8

9

BnNH₂

PMBNH₂

BzhNH₂

NonylNH₂

NH₄OAc

BuNH₂

r.t.

40

65

r.t.

35

65

90

82

1:0

Ͼ19:1^[a]

1.7:1^[a]

1:0

90

73^[b]

79^[c]

65

Scheme 1. Retrosynthesis of trihydroxypiperidine α-iminonitriles.

1:0

59

60

1:0

r.t.

4.8:1^[a]

arising from intramolecular displacement under the basic

reaction conditions. Neutralisation with acetic acid pre-

vented the base-catalysed reaction, and led to the com-

pletely stereoselective formation of piperidine α-iminonitrile

8a (65%, Table 1, entry 1) by the first tandem Strecker reac-

[a] Ascertained by integration of ¹H NMR spectra. [b] TMSCN

used as cyanide source. [c] Based on recovered starting material

(b.r.s.m.).

An increase in the temperature of the TSI reaction

tion and iminocyclisation (TSI). Competing formation of (Table 1, entries 2–3) led to an increase in the yield (82–

pyrrolidine by-products IX (Scheme 2, b) via epoxide VIII 90%), but also to a decrease in the stereoselectivity of the

was not observed.^[35,37]The structure of piperidine α-imino- cyanide addition (8/9, 1.7:1). 4-Methoxybenzylamine

nitrile 8a was unequivocally established by X-ray diffrac- (PMBNH₂) gave a better result at room temp., with the

tion^[38]and NOE enhancements (Figure 2). From the pro- highly stereoselective formation of 8b (90%, Table 1, en-

posed reaction pathways shown in Scheme 1, the observed try 4). Switching to trimethylsilyl cyanide (TMSCN,

specificity in the cyanide addition may arise from attack on Table 1, entry 5) resulted in a decreased yield (73%). The

either the open-chain imine VI^[29](A), or the cyclic iminium excellent 90% yield obtained with PMBNH₂is an improve-

ion VII (B), so rationales based on kinetic attack by cyanide ment over previous two-step methods to synthesise piperi-

Scheme 2. a) Tandem Strecker reaction and iminocyclisation (TSI) giving access to trihydroxypiperidine α-iminonitriles from d-ribose;

b) potential route to pyrrolidine by-products.

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One-Pot Iminosugar Synthesis

Figure 2. X-ray diffraction structure^[38]and NOE enhancements of piperidine α-iminonitrile 8a (arrows show correlations between pro-

tons).

dine α-iminonitriles, which usually proceeded in only mod-

erate yields (Ͻ70%).^{[5,20–26,28–34]}The best two-step yields

were reported by Paulsen (73%)^[19]and Wong (78%).^[27]

The secondary alkylamine benzhydrylamine (BzhNH₂;

Table 1, entry 6), nonylamine (Table 1, entry 7), and ammo-

nium acetate^[41](Table 1, entry 8) all gave the corresponding

piperidine α-iminonitrile products with complete diastereo-

selectivity, in moderate to excellent yields [i.e., 8c (79%), 8d

(65%), and 8e (59%), respectively]. Only with butylamine

was a non-stereoselective reaction observed, and in this

case, a mixture of piperidine α-iminonitriles 8f/9f (4.8:1,

60%) was formed (Table 1, entry 9).

To assess the tolerance of the TSI conditions towards

different substrates, C-4-epimeric lyxo-configured tosyl

hemiacetal 13 was prepared (Scheme 3). The synthesis of

tosyl l-lyxonolactone 12 has been previously reported from

2,3-acetonide 10 via lactone 11.^[42,43]Subsequent reduction

of lactone 12 with diisobutylaluminium hydride (DIBAL-

H) gave the desired l-lyxo configured tosyl hemiacetal (i.e.,

13) in a 94% yield. Subjection of this compound to the TSI

conditions with benzylamine gave a separable mixture of

epimeric piperidine α-iminonitriles 14a and 15a (1:1, 77%,

Table 2, entry 1), in contrast to the stereoselective reaction

of the ribo epimer. This reaction was also performed on the

enantiomeric system (1:1, 82%). An identical result was

seen with PMBNH₂, and piperidine α-iminonitriles 14b and

15b (1:1, 82%) were formed (Table 2, entry 2), and similarly

for the enantiomeric system (1:1, 84%). It is tentatively pro-

posed that the formation of epimer 15 may arise from at-

tack by cyanide on an alternative boat-like iminium inter-

mediate (Figure 3). An increase in temperature (Table 2, en-

tries 3–4) led to an increase in the formation of the Felkin–

Anh product (i.e., 14b), which is the opposite result to that

seen for d-ribose, where a decrease in the Felkin–Anh prod-

Scheme 3. Tandem Strecker reaction and iminocyclisation (TSI)

giving access to trihydroxypiperidine α-iminonitriles from l-

lyxonolactone.

Table 2. Reaction conditions for the formation of piperidine α-

iminonitriles.

Entry Amine

T (°C)

Yield [%]

14:15

1

2

3

4

5

BnNH₂

r.t.

40

65

40

77 (82)^[a]

82 (84)^[a]

84 (85)^[a]

83 (88)^[a]

51^[c]

1:1 (1:1)^[b]

1.4:1 (2:1)^[b]

2:1 (2.3:1)^[b]

1.8:1^[d]

PMBNH₂

NH₄OAc

[a] Yield with enantiomeric starting material. [b] Ratio with enan-

tiomeric starting material. [c] Reaction not performed for the

1

enantiomer. [d] Ascertained by integration of H NMR spectra.

The 2-C-methyl-branched lactone derivative of d-ribose

uct (i.e., 8a) was observed (Scheme 2). Finally, reaction of 16 is readily accessible from d-glucose,^[40,44–46]and it would

tosyl hemiacetal 13 with ammonium acetate proceeded only permit access to β-branched piperidine α-iminonitriles and

at elevated temperature (40 °C), and gave a mixture of pi- an assessment of the compatibility of the TSI conditions

peridine α-iminonitriles 14c and 15c (1.8:1, 51%, Table 2, towards more sterically demanding substrates (Scheme 4).

entry 5).

Tosyl lactone 18 was prepared from methyl-branched

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Table 3. Reaction conditions for the formation of piperidine α-

iminonitriles.

TSI from tosyl hemiacetal 19

Entry

Amine

T [°C]

Yield [%]

20:21

1

2

3

4

5

6

BnNH₂

PMBNH₂

NH₄OAc

r.t.

40

65

r.t.

40

51

79

73

68

79

71

1:0

15:1^[a]

4.4:1^[a]

1:0

Ͼ19:1^[a]

1:0

TSI from tosyl hemiacetal 24

Entry

Amine

T [°C]

Yield [%]

73

25:26

[a]

7

8

PMBNH₂

NH₄OAc

50

1:3.8

–

[b]

–

1

[a] Ascertained by the integration of H NMR spectra. [b] Decom-

posed.

Figure 3. Reaction rationale and NOE enhancements of the piper-

idine α-iminonitriles 14 and 15 (arrows show correlations between

protons).

16,^[47,48]and reduction with DIBAL-H gave the desired to-

syl hemiacetal substrate (i.e., 19; 94%). Reaction under the

TSI conditions at room temp. with benzylamine gave β-

methyl-branched piperidine α-iminonitrile 20a selectively in

a moderate yield (51%, Table 3, entry 1), as confirmed by

X-ray diffraction^[49]and NOE enhancements (Figure 4).

The addition of the methyl branch resulted in a lower yield

of the TSI product, and the reaction required a longer time

at room temp. Heating led to a significant increase in the

yield but also to a loss of selectivity (Table 3, entries 2–3).

PMBNH₂proved to be a better nucleophile, and piper-

idine α-iminonitrile 20b was formed in higher yield at room

temp. with complete stereoselectivity (68%, Table 3, en-

try 4). Increasing the reaction temperature to 40 °C

(Table 3, entry 5) resulted in an identical yield to that ob-

tained with benzylamine, but with an enhanced diastereo-

selectivity (Ͼ19:1, compared to 15:1). Reaction with ammo-

nium acetate gave product 20c stereoselectively (71%,

Table 3, entry 6).

Figure 4. X-ray diffraction structure^[49]of piperidine α-iminonitrile

20a, and NOE enhancements of 20a, 25a, and 26a (arrows show

correlations between protons).

As with the unbranched systems, inversion of the config-

uration at C-4 has been described previously, and C-4-in- 17.^[47]The C-5 hydroxy group of lactone 22 was sub-

verted lyxonolactone 22 can be formed from ribonolactone sequently activated as the tosylate to give 23 (90%), and the

Scheme 4. Access to β-branched trihydroxypiperidine α-iminonitriles.

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One-Pot Iminosugar Synthesis

lactone moiety was reduced with DIBAL-H to give tosyl anhydro species 34 (51%) was the major product. The pro-

hemiacetal 24 (91%). The reaction with PMBNH₂under pensity for 1-deoxy-d-psicose to form anhydro derivatives

the TSI conditions proved sluggish, and only proceeded at has been described previously.^[51]In contrast to the parent

elevated temperature to give a mixture of piperidine α- unbranched system, the presence of the α-methyl branch

iminonitriles 25a and 26a (1:3.8, 73%, Table 3, entry 7). The resulted in the selective formation of the unexpected epimer

structure of each of these compounds was confimed by (the NOE enhancements of this compound were compar-

NOE analysis (Figure 4). The presence of the methyl able to those observed for 9a).

branch in this case led to a selectivity opposite to that seen

Similarly, lyxo-configured lactone 11 was protected as

in the unbranched system (15/16, 2:1, Table 2). The reaction silyl ether 35 (97%, Scheme 6),^[52]and addition of meth-

with ammonium acetate did not result in an isolable prod- yllithium gave protected ketose 36 (83%). TBAF-induced

uct.

silyl deprotection gave lactol 37 (93%), which underwent C-

Following the synthesis of piperidine α-iminonitriles con- 5-activation to give tosylate 38 (87%). Again, this ketose

taining a β-tertiary centre, the feasibility of constructing an substrate proved slow to react, and high temperatures were

α-tertiary centre under the TSI conditions was assessed, required to induce a TSI and formation of α-branched pip-

and this required access to the tosyl hemiacetal of 1-C- eridine α-iminonitrile 39 (13%; the NOE enhancements of

methyl-branched

d-ribose

(1-deoxy-d-psicose)

32 this compound were comparable to those observed for 16a).

(Scheme 5). The C-5 hydroxy group of protected lactone

Having achieved the introduction of methyl branches at

27 was activated as the tosylate to give 28 (79%),^[43]but the α- and β-positions, the possibility of introducing both

subsequent treatment with methyllithium met with failure. methyl branches was probed. 2-C-Methyl-branched lactone

In an alternative route, the C-5 hydroxy group of lactone 17 (Scheme 7) was protected as silyl ether 40 (91%), and

27 was protected as a silyl ether by treatment with tert- addition of methyllithium gave protected, branched ketose

butyldimethylsilyl chloride (TBSCl) and pyridine to give 29 41 (70%). Deprotection of the silyl ether in 41 with TBAF

(91%), and subsequent treatment with methyllithium suc- gave lactol 42 (85%), along with the unexpected formation

cessfully led to protected ketose 30 (88%).^[50]The silyl ether of 2,6-anhydro by-product 43 (5%). C-5-Activation gave

was cleaved with TBAF (tetrabutylammonium fluoride) tosyl hemiacetal 44 (76%), again accompanied by by-prod-

(84%),^[50]and lactol 31 was activated as the tosylate to give uct 43 (6%). Unfortunately, subjection of tosyl hemiacetal

32 (92%). The reaction of tosyl hemiacetal 32 with 44 to the TSI conditions did not give any ofthe desired α,β-

PMBNH₂under the TSI conditions proved to be extremely dimethyl-branched piperidine α-iminonitrile (i.e., 45). The

sluggish, but at elevated temperature and with long reaction only product observed was the 2,6-anhydro species (i.e., 43;

times, α-methyl-branched piperidine α-iminonitrile 33 was 70%).

formed, albeit in a low yield (14%). This demonstrated that

In a similar approach, lyxo-configured 2-C-methyl-

a tertiary centre could be established under the TSI condi- branched lactone 22 (Scheme 8) was protected as silyl ether

tions; however, despite attempted optimisation, the 2,6- 46 (97%), and subsequent addition of methyllithium gave

Scheme 5. Access to a d-ribo-configured, α-branched trihydroxypiperidine α-iminonitrile.

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B. J. Ayers, G. W. J. Fleet

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Scheme 6. Access to an l-lyxo-configured, α-branched trihydroxypiperidine α-iminonitrile.

Scheme 7. Towards an α,β-dimethyl-branched trihydroxypiperidine α-iminonitrile.

Scheme 8. Towards an α,β-dimethyl-branched trihydroxypiperidine α-iminonitrile.

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One-Pot Iminosugar Synthesis

1,5-Anhydro-2,3-O-isopropylidene-

D

-ribose

(7):

Benzylamine

protected, branched ketose 47 (90%). In contrast to pre-

vious systems, TBAF-mediated deprotection of the silyl

group led to a mixture of pyranose and furanose hemiacet-

als 48, but chemoselective esterfication with tosyl chloride

specifically gave the furanose tosylate hemiacetal 49 (89%).

This substrate was subjected to the TSI conditions, but de-

spite the inability of this substrate to give an anhydro by-

product, the additional steric crowding prevented the for-

mation of any TSI products.

(70 μL, 0.64 mmol) and potassium cyanide (23 mg, 0.35 mmol)

were added to a solution of tosylates 6^[36](100 mg, 0.29 mmol) in

anhydrous methanol (2 mL) at room temp. After 4 h, TLC analysis

(49:10:1, toluene/acetone/triethylamine) indicated the complete

consumption of the starting materials (R_f= 0.45) and the forma-

tion of a single product (R_f= 0.62). The reaction mixture was fil-

tered through glass fibre (GF/B), and the filtrate was concentrated

in vacuo. The crude residue was purified by flash chromatography

(49:1 to 47:3, toluene/acetone) to give 1,5-anhydro compound 7

(39 mg, 78%) as a white crystalline solid. Selected data: [α]²_D⁵

=

–72.1 (c = 1.0, acetone) [ref.^[53][α]²_D⁵= –64.7 (c = 1.00, acetone)],

m.p. 62–63 °C [ref.^[53]m.p. 60–61 °C]. ¹H NMR [400 MHz, (CD₃)₂-

CO, 20 °C]: δ = 5.32 (s, 1 H, 1-H), 4.66 (d, J_4,5b= 3.5 Hz, 1 H, 4-

H), 4.41 (d, J_2,3= 5.6 Hz, 1 H, 2-H), 4.21 (d, J_3,2= 5.6 Hz, 1 H,

3-H), 3.32 (d, J_5a,5b= 7.2 Hz, 1 H, 5a-H), 3.28 (dd, J_5b,5a= 7.2,

J_5b,4= 3.5 Hz, 1 H, 5b-H), 1.34, 1.23 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm.

¹³C NMR [100 MHz, (CD₃)₂CO, 20 °C]: δ = 112.3 [C(CH₃)₂], 100.5

(C-1), 82.2 (C-3), 80.2 (C-2), 78.4 (C-4), 63.5 (C-5), 26.4, 25.5

[C(CH₃)₂] ppm.

Conclusions

This paper describes the synthesis of eight tosyl hemi-

acetals by short synthetic routes, and the development of a

one-pot tandem Strecker reaction and iminocyclisation

(TSI) methodology to give both unbranched and α- and β-

methyl-branched piperidine α-iminonitriles. The un-

branched piperidine α-iminonitriles were formed in good

yields Ϫ higher than those achieved in previous methods

over two steps. Increased branching of the substrates led

to lower overall yields. These compounds are precursors to

biologically relevant trihydroxypipecolic acids and related

iminosugars. Under all TSI conditions, no competing pyr-

rolidine ring formation was observed; thus piperidine ring

closure competes successfully with the formation of epox-

ides. Many of these reactions showed considerable dia-

stereostereoselectivity in the cyanide addition. Work

towards accessing an α,β-dimethyl-branched piperidine α-

iminonitrile has also been described, and the results indi-

cate a limitation to this strategy for the formation of highly

branched carbon systems.

2

2-N-Benzyl-2,6-dideoxy-2,6-imino-3,4-O-isopropylidene-

nitrile (8a) and 2-N-Benzyl-2,6-dideoxy-2,6-imino-3,4-O-isopropyl-

idene- -altrononitrile (9a)

D-allono-

D

Method A (room temp.): See General Procedure. Benzylamine

(0.21 mL, 1.92 mmol), potassium cyanide (68 mg, 1.05 mmol), and

tosylate 6^[36](300 mg, 0.87 mmol) at room temp. for 16 h gave α-

iminonitrile 8a (164 mg, 65%) as a pale yellow crystalline solid.

Method B (40 °C): See General Procedure. Benzylamine (0.24 mL,

2.20 mmol), potassium cyanide (76 mg, 1.17 mmol), and tosylate 6

(335 mg, 0.97 mmol) at 40 °C for 17 h gave a Ͼ19:1 (A:B) insepa-

rable mixture of α-iminonitriles 8a and 9a (238 mg, 68%) as a pale

yellow oil that crystallised on standing.

Method C (65 °C): See General Procedure. Benzylamine (0.22 mL,

2.01 mmol), potassium cyanide (72 mg, 1.11 mmol), and tosylate 6

(315 mg, 0.92 mmol) at 65 °C for 17 h gave a 1.7:1 (A:B) insepa-

rable mixture of α-iminonitriles 8a and 9a (237 mg, 82%) as a pale

yellow oil that crystallised on standing.

Experimental Section

General Methods: All commercially sourced reagents were used as

supplied. Unless otherwise stated, all reactions were performed un-

der an inert atmosphere (argon or nitrogen). Thin-layer chromatog-

raphy (TLC) was performed on aluminium sheets coated with 60

F₂₅₄silica. Plates were visualised using a spray of cerium(IV) sulf-

ate (0.2% w/v) and ammonium molybdate (5%) in sulfuric acid

(2 m aq.). Flash chromatography was performed on Sorbsil C60

Data for α-iminonitrile 8a: HRMS (ESI): calcd. for

[C₁₆H₂₀N₂O₃+ Na]⁺311.1366; found 311.1365, m.p. 69–71 °C. [α]_D²⁰

= +20.3 (c = 1.75, MeOH). IR (film): ν = 3461, 2234 cm^–1. ¹H

˜

NMR [500 MHz, (CD₃)₂CO, 20 °C]: δ = 7.35–7.29 (m, 5 H, H-Ar),

4.47 (dd, J_4,3= 5.3, J_4,5= 3.3 Hz, 1 H, 4-H), 4.44 (a-t, J_3,2= J_3,4

2

= 5.8 Hz, 1 H, 3-H), 4.06 (d, J_gem= 13.2 Hz, 1 H, CHa 2-N-Bn),

2

3.97–3.95 (m, 1 H, 5-H), 3.59 (d, J_gem= 13.2 Hz, 1 H, CHb 2-N-

40/60 silica. Melting points were recorded on a Kofler hot block.

Bn), 3.52 (d, J_2,3= 6.1 Hz, 1 H, 2-H), 2.70 (dd, ²J_6a,6b= 11.1, J_6a,5

1

2

Concentrations for optical rotations are quoted in g100 mL^–1. H = 4.8 Hz, 1 H, 6a-H), 2.40 (a-t, J_6b,6a= J_6b,5= 10.2 Hz, 1 H, 6b-

and ¹³C NMR spectra were assigned by using 2D COSY, HSQC,

and HMBC spectra. Residual signals from the solvents were used

as an internal reference. HRMS measurements were made using a

micrOTOF mass analyser.

H), 1.50, 1.34 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C NMR (100 MHz,

CD₃CN, 20 °C): δ = 137.7 (C-i 2-N-Bn), 130.0, 129.4, 128.6 (C-Ar),

118.5 (CN), 111.1 [C(CH₃)₂], 76.1 (C-3), 75.3 (C-4), 65.4 (C-5), 59.8

(CH₂2-N-Bn), 56.5 (C-2), 52.1 (C-6), 27.5, 26.0 [C(CH₃)₂] ppm.

MS (ESI): m/z (%) = 599 (35) [2M + Na]⁺, 311 (100) [M + Na]⁺.

General Procedure for Tandem Strecker Reaction and Iminocyclis-

ation (TSI): A solution of acetic acid in methanol (1:5, v/v;

3.4 mmol) was added to a solution of amine (2.2 mmol) or ammo-

nium acetate (22.0 mmol), potassium cyanide (1.2 mmol), and tosyl

hemiacetal (1.0 mmol) in methanol (8 mL) under argon. The reac-

tion mixture was stirred until the starting material had been con-

sumed [as judged by TLC analysis (toluene/acetone or dichloro-

methane/diethyl ether)]. The reaction mixture was concentrated in

vacuo, the residue was dissolved in CH₂Cl₂, and this solution was

washed with aqueous sodium hydrogen carbonate. The crude prod-

uct was purified by flash chromatography (toluene/acetone).

Partial data for the inseparable 8a^A/9a^Bmixtures: ¹H NMR

[400 MHz, (CD₃)₂CO, 20 °C]: δ = 7.38–7.16 (m, 10 H, H^A-Ar, H^B-

Ar), 4.57 (a-t, J_4,3= J_4,5= 4.8 Hz, 1 H, 4^B-H), 4.48 (dd, J_4,3= 5.3,

J_4,5= 3.3 Hz, 1 H, 4^A-H), 4.44 (a-t, J_3,2= J_3,4= 5.8 Hz, 1 H, 3^A-

H), 4.40 (dd, J_3,2= 7.9, J_3,4= 5.4 Hz, 1 H, 3^B-H), 4.20 (br. d, J_2,3

2

= 7.9 Hz, 1 H, 2^B-H), 4.06 (d, J_gem= 13.2 Hz, 1 H, CHa^A2-N-

Bn), 3.99–3.91 (m, 2 H, 5^A-H, 5^B-H), 3.73 (d, ²J_gem= 13.4 Hz, 1 H,

2

CHa^B2-N-Bn), 3.71 (d, J_gem= 13.4 Hz, 1 H, CHb^B2-N-Bn), 3.60

2

(d, J_gem= 13.2 Hz, 1 H, CHb^A2-N-Bn), 3.52 (d, J_2,3= 6.1 Hz,

2

1 H, 2^A-H), 2.71 (a-dd, J_6a,6b= 11.1, J_6a,5= 4.8 Hz, 2 H, 6a^A-H,

Eur. J. Org. Chem. 2014, 2053–2069

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2059

B. J. Ayers, G. W. J. Fleet

FULL PAPER

6a^B-H), 2.56 (a-t, J_6b,6a= J_6b,5= 10.4 Hz, 1 H, 6b^B-H), 2.40 (a-t,

²J_6b,6a= J_6b,5= 10.2 Hz, 1 H, 6b^A-H), 1.68, 1.35 [2 s, 2ϫ 3 H,

C(CH₃)^B], 1.50, 1.34 [2 s, 2ϫ 3 H, C(CH₃)^A, C(CH₃)^B] ppm. ¹³C

NMR [100 MHz, (CD₃)₂CO, 20 °C]: δ = 138.2 (C^B-i 2-N-Bn), 137.7

(C^A-i 2-N-Bn), 129.8, 129.7, 129.6, 129.4, 129.3, 129.0, 128.4, 128.4

2

(158 mg, 0.46 mmol) at room temp. for 2 d gave α-iminonitrile 8d

(55 mg, 65 %) as a pale yellow oil. HRMS (ESI): calcd. for

[C₁₈H₃₂N₂O₃+ Na]⁺347.2305; found 347.2298. [α]²_D⁰= –10.1 (c =

1.11, CHCl ). IR (film): ν = 3448, 2247 cm^–1. ¹H NMR (400 MHz,

˜

3

CDCl₃, 20 °C): δ = 4.35 (dd, J_3,4= 5.3, J_3,2= 4.0 Hz, 1 H, 3-H),

(C^A-Ar, C^B-Ar), 118.7 (CN^A, CN^B), 111.1 [C(CH₃)₂^B], 110.9 4.28 (dd, J_4,3= 5.3, J_4,5= 4.0 Hz, 1 H, 4-H), 3.90 (a-dt, J_5,6b= 7.0,

[C(CH₃)₂^A], 76.4 (C-3^A), 75.9 (C-4^A), 75.1 (C-4^B), 72.8 (C-3^B), 66.6 J_5,4= J_5,6a= 3.8 Hz, 1 H, 5-H), 3.74 (d, J_2,3= 4.0 Hz, 1 H, 2-H),

2

(C-5^B), 65.6 (C-5^A), 60.0 (CH₂^B2-N-Bn), 59.9 (CH₂^A2-N-Bn), 57.0 2.75 (dd, J_6a,6b= 12.0, J_6a,5= 3.7 Hz, 1 H, 6a-H), 2.69 [dt, J_gem

(C-2^B), 56.9 (C-2^A), 52.2 (C-6^A), 49.8 (C-6^B), 27.7, 26.0 = 12.6, J = J = 7.2 Hz, 1 H, NCHa(CH₂)₇CH₃], 2.60 (dd, ²J_6b,6a

=

2

[C(CH₃)₂^A], 26.2, 25.8 [C(CH₃)₂^B] ppm.

12.0, J_6b,5= 7.2 Hz, 1 H, 6b-H), 2.52 [dt, J_gem= 12.6, J = J =

7.2 Hz, 1 H, NCHb(CH₂)₇CH₃], 1.56, 1.37 [2 s, 2 ϫ 3 H,

C(CH₃)₂], 1.47 [quin., J = 7.1 Hz, 2 H, NCH₂CH₂(CH₂)₆CH₃],

1.28–1.24 [m, 12 H, N(CH₂)₂(CH₂)₆CH₃], 0.86 [s, 3 H,

N(CH₂)₈CH₃] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 116.3

(CN), 110.7 [C(CH₃)₂], 74.6 (C-4), 73.8 (C-3), 65.3 (C-5), 55.5 (C-

2), 55.2 [NCH₂(CH₂)₇CH₃], 51.9 (C-6), 31.9, 29.6, 29.5, 29.3, 27.1,

26.7, 22.7 [NCH₂(CH₂)₇CH₃], 26.6, 26.0 [C(CH₃)₂], 14.2

[N(CH₂)₈CH₃] ppm. MS (ESI): m/z (%) = 360 (45) [M + K]⁺, 347

(100) [M + Na]⁺, 325 (55) [M + H]⁺.

2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-2-N-(4-methoxybenz-

yl)-D-allononitrile (8b)

Method A (KCN): See General Procedure. 4-Methoxybenzylamine

(0.25 mL, 1.92 mmol), potassium cyanide (85 mg, 1.31 mmol), and

tosylate 6 (300 mg, 0.87 mmol) at room temp. for 19 h gave α-

iminonitrile 8b (250 mg, 90%) as a white crystalline solid.

Method B (TMSCN): See General Procedure. 4-Methoxybenzyl-

amine (0.19 mL, 1.45 mmol), trimethylsilyl cyanide (0.18 mL,

1.45 mmol), and tosylate 6 (200 mg, 0.58 mmol) at room temp. for 2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-

D-allononitrile (8e): See

24 h gave α-iminonitrile 8b (136 mg, 73%) as a white crystalline

solid.

General Procedure. Ammonium acetate (356 mg, 4.62 mmol), po-

tassium cyanide (76 mg, 1.15 mmol), and tosylate 6 (159 mg,

0.46 mmol) at room temp. for 1 d, then at 35 °C for 1 d, gave α-

iminonitrile 8e (54 mg, 59%) as a pale yellow oil. HRMS (ESI):

Data for α-iminonitrile 8b: HRMS (ESI): calcd. for [C₁₇H₂₂N₂O₄

+ Na]⁺341.1472; found 341.1467. [α]²_D⁰= +36.1 (c = 2.41, CHCl₃),

calcd. for [C₉H₁₄N₂O₃+ Na]⁺221.0897; found 221.0901. [α]²_D⁰

=

m.p. 142–144 °C. IR (film): ν = 3482, 2221 cm^{–1 1}H NMR

.

˜

1

–32.1 (c = 2.77, CHCl ). IR (film): ν = 3292, 2249 cm^–1. H NMR

˜

3

(400 MHz, CDCl₃, 20 °C): δ = 7.25 (d, J = 8.5 Hz, 2 H, H-Ar),

(400 MHz, CDCl₃, 20 °C): δ = 4.40 (a-t, J_4,3= J_4,5= 4.7 Hz, 1 H,

4-H), 4.25 (dd, J_3,2= 6.8, J_3,4= 5.1 Hz, 1 H, 3-H), 3.89 (a-dt, J_5,6b

= 8.7, J_5,4= J_5,6a= 4.4 Hz, 1 H, 5-H), 3.71 (d, J_2,3= 6.8 Hz, 1 H,

6.89 (d, J = 8.5 Hz, 2 H, H-Ar), 4.39 (a-t, J_3,2= J_3,4= 4.8 Hz, 1 H,

2

3-H), 4.31 (a-t, J_4,3= J_4,5= 4.8 Hz, 1 H, 4-H), 3.92 (d, J_gem

=

13.1 Hz, 1 H, CHa 2-N-PMB), 3.92–3.88 (m, 1 H, 5-H), 3.81 (s,

3 H, CH₃2-N-PMB), 3.70 (d, J_2,3= 4.0 Hz, 1 H, 2-H), 3.57 (d,

²J_gem= 13.1 Hz, 1 H, CHb 2-N-PMB), 2.78 (dd, ²J_6a,6b= 12.0, J_6a,5

2

2-H), 3.02 (dd, J_6a,6b= 12.5, J_6a,5= 4.7 Hz, 1 H, 6a-H), 2.76 (dd,

²J_6b,6a= 12.5, J_6b,5= 8.7 Hz, 1 H, 6b-H), 1.54, 1.38 [2 s, 2ϫ 3 H,

C(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 118.7

(CN), 110.6 [C(CH₃)₂], 74.5 (C-4), 74.4 (C-3), 65.3 (C-5), 49.6 (C-

2), 46.3 (C-6), 27.6, 25.9 [C(CH₃)₂] ppm. MS (ESI): m/z (%) = 370

{100) [M + (M – CN^–)]⁺}, 221 (25) [M + Na]⁺, 199 (10) [M +

H]⁺.

2

= 3.5 Hz, 1 H, 6a-H), 2.60 (dd, J_6b,6a= 12.0, J_6b,5= 7.1 Hz, 1 H,

6b-H), 2.37 (d, J_OH,5= 9.9 Hz, 1 H, 5-OH), 1.57, 1.38 [2 s, 2ϫ 3 H,

C(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 159.5 (C-

p 2-N-PMB), 130.5 (C-Ar), 127.6 (C-i 2-N-PMB), 116.3 (CN),

114.2 (C-Ar), 110.8 [C(CH₃)₂], 74.5 (C-3), 73.8 (C-4), 65.3 (C-5),

58.9 (CH₂2-N-PMB), 55.4 (CH₃2-N-PMB), 54.6 (C-2), 51.8 (C-

6), 26.8, 26.0 [C(CH₃)₂] ppm. MS (ESI): m/z (%) = 329 (92) [M +

Na]⁺, 307 (100) [M + H]⁺.

2-N-Butyl-2,6-dideoxy-2,6-imino-3,4-O-isopropylidene-

nitrile (8f) and 2-N-Butyl-2,6-dideoxy-2,6-imino-3,4-O-isopropylid-

ene- -altrononitrile (9f): See General Procedure. Butylamine

D-allono-

D

(0.13 mL, 1.31 mmol), potassium cyanide (86 mg, 1.31 mmol), and

tosylate 6 (180 mg, 0.52 mmol) at room temp. for 2 d gave a 4.8:1

(A:B) mixture of α-iminonitriles 8f^Aand 9f^B(80 mg, 60%) as a

pale yellow oil. HRMS (ESI): calcd. for [C₁₃H₂₂N₂O₃+ Na]⁺

2-N-Benzhydryl-2,6-dideoxy-2,6-imino-3,4-O-isopropylidene-D-al-

lononitrile (8c): See General Procedure. Benzhydrylamine (0.14 mL,

0.79 mmol), potassium cyanide (52 mg, 0.79 mmol), and tosylate 6

(109 mg, 0.32 mmol) at room temp. for 3 d gave α-iminonitrile 8c

(78 mg, 68%; 79% b.r.s.m.) as a white crystalline solid, and reco-

vered starting material 6 (15 mg, 14%). Data for α-iminonitrile 8c:

HRMS (ESI): calcd. for [C₂₂H₂₄N₂O₃+ Na]⁺387.1679; found

387.1683. [α]²_D⁰= +5.6 (c = 1.05, CHCl₃), m.p. 152–154 °C. IR

277.1523; found 277.1520. IR (film): ν = 3332, 2241 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃, 20 °C): δ = 4.47 (t, J_4,3= J_4,5= 5.2 Hz, 1 H,

4^B-H), 4.34 (a-t, J_3,2= J_3,4= 5.1 Hz, 1 H, 3^A-H), 4.31 (dd, J_3,2

=

8.1, J_3,4= 5.2 Hz, 1 H, 3^B-H), 4.28 (a-t, J_4,3= J_4,5= 5.0 Hz, 1 H,

4^A-H), 4.02 (d, J_2,3= 8.1 Hz, 1 H, 2^B-H), 3.89 (br. s, 2 H, 5^A-H,

(film): ν = 3461, 2251 cm^–1. ¹H NMR (400 MHz, CDCl , 20 °C): δ

˜

3

2

5^B-H), 3.71 (d, J_2,3= 4.3 Hz, 1 H, 2^A-H), 2.78 (dd, J_6a,6b= 11.9,

= 7.48–7.45 (m, 4 H, H-Ar), 7.35–7.30 (m, 4 H, H-Ar), 7.27–7.21

(m, 2 H, H-Ar), 4.74 (s, 1 H, CH 2-N-Bzh), 4.39 (dd, J_3,4= 6.1,

J_6a,5= 6.6 Hz, 1 H, 6a^B-H), 2.74 (dd, ²J_6a,6b= 11.9, J_6a,5= 3.8 Hz,

2

1 H, 6a^A-H), 2.69 [dt, J_gem= 12.7, J = J = 7.8 Hz, 1 H,

J_3,2= 1.8 Hz, 1 H, 3-H), 4.34 (dd, J_4,3= 6.1, J_4,5= 4.3 Hz, 1 H, 4-

NCHa^A(CH₂)₂CH₃], 2.71–2.66 [m, 1 H, NCHb^B(CH₂)₂CH₃], 2.58

2

H), 4.03 (br. s, 1 H, 2-H), 3.99 (br. s, 1 H, 5-H), 2.92 (dd, J_6a,6b

=

2

(dd, J_6b,6a= 11.9, J_6b,5= 7.3 Hz, 1 H, 6b^A-H), 2.51 [dt, J_gem

=

2

12.2, J_6a,5= 6.4 Hz, 1 H, 6a-H), 2.63 (dd, J_6b,6a= 12.2, J_6b,5

12.7, J = J = 7.8 Hz, 1 H, NCHa^A(CH₂)₂CH₃], 2.61–2.43 [m, 2 H,

NCHb^B(CH₂)₂CH₃, 6b^B-H], 1.73, 1.37 [2 s, 2ϫ 3 H, C(CH₃)₂^B],

1.54, 1.36 [2 s, 2ϫ 3 H, C(CH₃)₂^A], 1.46 (a-quin., J = 7.3 Hz, 4 H,

NCH₂CH₂CH₂CH₃^A, NCH₂CH₂CH₂CH₃^B), 1.31 [sext, J = 7.3 Hz,

4 H, N(CH₂)₂CH₂CH₃^A, N(CH₂)₂CH₂CH₃^B], 0.90 [t, J = 7.3 Hz,

3 H, N(CH₂)₃CH₃^A], 0.87 [t, J = 7.3 Hz, 3 H, N(CH₂)₃CH₃^B] ppm.

¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 116.3 (CN^A), 116.3

(CN^B), 112.2 [C(CH₃)₂^B], 110.7 [C(CH₃)₂^A], 74.6 (C-4^B), 73.8 (C-

4^A), 73.6 (C-3^A), 71.9 (C-3^B), 66.0 (C-5^B), 65.2 (C-5^A), 56.7 (C-2^B),

55.5 (C-2^A), 55.1 [NCH₂(CH₂)₂CH₃^B], 54.8 [NCH₂(CH₂)₂CH₃^A],

4.0 Hz, 1 H, 6b-H), 2.50 (br. s, 1 H, 5-OH), 1.70, 1.38 [2 s, 2ϫ 3 H,

C(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 140.7,

139.6 (C-i 2-N-Bzh), 129.3, 129.0, 128.2, 128.1, 127.8, 127.8 (C-Ar),

115.5 (CN), 110.8 [C(CH₃)₂], 74.3 (C-3), 73.4 (C-4), 73.0 (CH 2-N-

Bzh), 65.2 (C-5), 52.5 (C-2), 49.9 (C-6), 26.4, 25.6 [C(CH₃)₂] ppm.

MS (ESI): m/z (%) = 387 (100) [M + Na]⁺.

2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-2-N-nonyl-D-allono-

nitrile (8d): See General Procedure. Nonylamine (0.21 mL,

1.15 mmol), potassium cyanide (75 mg, 1.15 mmol), and tosylate 6

2060

www.eurjoc.org

Eur. J. Org. Chem. 2014, 2053–2069

One-Pot Iminosugar Synthesis

51.8 (C-6^A), 49.8 (C-6^B), 29.2 (NCH₂CH₂CH₂CH₃^B), 28.6 (C-3), 68.8 (C-5), 59.3 (CH₂2-N-Bn), 55.1 (C-2), 51.8 (C-6), 28.1,

(NCH₂CH₂CH₂CH₃^A), 26.7, 25.9 [C(CH₃)₂^A], 25.9, 25.7 26.4 [C(CH₃)₂] ppm. MS (ESI): m/z (%) = 311 (100) [M + Na]⁺,

[C(CH₃)₂^B], 20.2 [N(CH₂)₂CH₂CH₃^A, N(CH₂)₂CH₂CH₃^B], 13.9 289 (50) [M + H]⁺. For the enantiomer: [α]²_D⁰= –5.7 (c = 1.39,

[N(CH₂)₃CH₃^A, N(CH₂)₃CH₃^B] ppm. MS (ESI): m/z (%) = 290 (15)

CHCl₃).

[M + K]⁺, 277 (100) [M + Na]⁺, 255 (65) [M + H]⁺.

Data for α-iminonitrile 15a: HRMS (ESI): calcd. for [C₁₆H₂₀N₂O₃

+ Na]⁺311.1366; found 311.1364. [α]²_D⁰= +13.5 (c = 1.15, CHCl₃).

2,3-O-Isopropylidene-5-O-p-tolylsulfonyl-L-lyxofuranose (13): Diiso-

IR (film): ν = 3461, 2252 cm^{–1 1}H NMR (400 MHz, CDCl₃,

.

˜

butylaluminium hydride (1.5 m in toluene; 5.4 mL, 8.06 mmol) was

added dropwise over 15 min to a solution of lactone 12^[42,43](2.3 g,

6.71 mmol) in anhydrous dichloromethane (25 mL) at –78 °C. The

reaction mixture was stirred for 1.5 h, after which TLC analysis

(5:1, toluene/acetone) indicated the complete consumption of the

starting material (R_f= 0.47) and the formation of a major product

(R_f= 0.56). The reaction mixture was diluted with ethyl acetate

(100 mL) and warmed to room temp., and a mixture of water and

saturated sodium potassium tartrate solution (1:3; 100 mL) was

added. The biphasic mixture was stirred vigorously for 1.5 h, after

which the phases were separated, and the aqueous layer was ex-

tracted with ethyl acetate (6ϫ 25 mL). The combined organic frac-

tions were dried (MgSO₄), filtered, and concentrated in vacuo. The

crude residue was purified by flash chromatography (3:1 to 1:4,

cyclohexane/ethyl acetate) to give lactols 13 (2.17 g, 94 %) as a

white crystalline solid, as a 5.6:1 (A:B) mixture of anomers. HRMS

(ESI): calcd. for [C₁₅H₂₀O₇S + Na]⁺367.0822; found 367.0826,

20 °C): δ = 7.37–7.30 (m, 5 H, H-Ar), 4.34 (dd, J_3,2= 7.8, J_3,4

5.8 Hz, 1 H, 3-H), 4.27 (dd, J_4,3= 5.7, J_4,5= 2.2 Hz, 1 H, 4-H),

4.06 (a-q, J_5,4= J_5,6a= J_5,6b= 2.5 Hz, 1 H, 5-H), 4.02 (dd, J_2,3

=

2

7.8, J_2,6a= 0.9 Hz, 1 H, 2-H), 3.75 (d, J_gem= 12.9 Hz, 1 H, CHa

2-N-Bn), 3.68 (d, ²J_gem= 12.9 Hz, 1 H, CHb 2-N-Bn), 3.04 (br. dd,

2

²J_6a,6b= 12.9, J_6a,5= 2.2 Hz, 1 H, 6a-H), 2.76 (br. d, J_6b,6a

=

13.2 Hz, 1 H, 6b-H), 1.70, 1.36 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C

NMR (100 MHz, CDCl₃, 20 °C): δ = 135.9 (C-i 2-N-Bn), 129.2,

129.0, 128.3 (C-Ar), 115.8 (CN), 111.0 [C(CH₃)₂], 75.5 (C-4), 69.7

(C-3), 65.5 (C-5), 59.9 (CH₂2-N-Bn), 56.1 (C-2), 50.7 (C-6), 26.0,

25.5 [C(CH₃)₂] ppm. MS (ESI): m/z (%) = 311 (100) [M + Na]⁺,

289 (45) [M + H]⁺. For the enantiomer: [α]²_D⁰= –17.2 (c = 1.24,

CHCl₃).

2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-2-N-(4-methoxybenz-

yl)-

L

-talononitrile (14b) and 2,6-Dideoxy-2,6-imino-3,4-O-isoprop-

-galactononitrile (15b)

ylidene-2-N-(4-methoxybenzyl)-

L

m.p. 116–118 °C. [α]²_D⁰= –7.0 (c = 1.11, CHCl ). IR (film): ν =

˜

3

Method A (r.t.): See General Procedure. 4-Methoxybenzylamine

(0.31 mL, 2.40 mmol), potassium cyanide (156 mg, 2.40 mmol),

and tosylate 13 (331 mg, 0.96 mmol) at room temp. for 2 d gave α-

iminonitriles 14b (124 mg, 41%) and 15b (126 mg, 41%) as pale

yellow oils. α-Iminonitrile 15b crystallised on standing to form a

white crystalline solid.

3459, 1359, 1175 cm^–1. ¹H NMR (400 MHz, CDCl₃, 20 °C): δ =

7.80 (d, J = 8.3 Hz, 4 H, H^A-Ar, H^B-Ar), 7.34 (d, J = 8.1 Hz, 4 H,

H^A-Ar, H^B-Ar), 5.36 (s, 1 H, 1^A-H), 4.99 (d, J_1,2= 3.3 Hz, 1 H, 1^B-

H), 4.72 (dd, J_3,2= 5.8, J_3,4= 3.6 Hz, 1 H, 3^A-H), 4.67 (dd, J_3,2

=

6.3, J_3,4= 3.5 Hz, 1 H, 3^B-H), 4.58 (d, J_2,3= 5.8 Hz, 1 H, 2^A-H),

4.50 (dd, J_2,3= 6.3, J_2,1= 3.4 Hz, 1 H, 2^B-H), 4.36 (a-q, J_4,3= J_4,5

= J_4,5a= 4.0 Hz, 1 H, 4^A-H), 4.30 (a-dd, ²J = 10.6, J = 4.3 Hz,

Method B (40 °C): See General Procedure. 4-Methoxybenzylamine

(0.31 mL, 2.40 mmol), potassium cyanide (156 mg, 2.40 mmol),

and tosylate 13 (330 mg, 0.96 mmol) at 40 °C for 30 h gave α-

iminonitriles 14b (150 mg, 49%) and 15b (107 mg, 35%) as pale

2

2 H, 5a^A-H, 5a^B-H), 4.18 (dd, J_5b,5a= 10.6, J_5b,4= 7.6 Hz, 1 H,

2

5b^A-H), 4.13 (dd, J_5b,5a= 10.6, J_5b,4= 6.1 Hz, 1 H, 5b^B-H), 3.80

(td, J_4,5b= J_4,5a= 6.1, J_4,3= 3.5 Hz, 1 H, 4^B-H), 2.44 (s, 6 H, CH₃

A

5-O-Ts, CH₃^B5-O-Ts), 1.40, 1.31 [2 s, 2ϫ 3 H, C(CH₃)₂^B], 1.33, yellow oils. α-Iminonitrile 15b crystallised on standing to form a

1.25 [2 s, 2ϫ 3 H, C(CH₃)₂^A] ppm. ¹³C NMR (100 MHz, CDCl₃, white crystalline solid.

20 °C): δ = 145.1 (C^A-p 5-O-Ts, C^B-p 5-O-Ts), 132.8 (C^A-i 5-O-Ts,

Method C (65 °C): See General Procedure. 4-Methoxybenzylamine

(0.34 mL, 2.62 mmol), potassium cyanide (171 mg, 2.62 mmol),

and tosylate 13 (361 mg, 1.05 mmol) at 65 °C for 1 d gave α-imino-

nitriles 14b (187 mg, 56%) and 15b (90 mg, 27%) as pale yellow

oils. α-Iminonitrile 15b crystallised on standing to form a white

crystalline solid.

C^B-i 5-O-Ts), 129.9 (C^B-Ar), 129.9 (C^A-Ar), 128.2 (C^A-Ar, C^B-Ar),

113.7 [C(CH₃)₂^B], 113.0 [C(CH₃)₂^A], 101.3 (C-1^A), 97.2 (C-1^B), 85.4

(C-2^A), 79.6 (C-3^A), 79.2 (C-3^B), 78.6 (C-2^B), 77.7 (C-4^A), 73.4 (C-

4^B), 68.2 (C-5^A), 67.3 (C-5^B), 25.9, 24.7 [C(CH₃)₂^A], 25.8, 24.9

[C(CH₃)₂^B], 21.8 (CH₃^A5-O-Ts, CH₃^B5-O-Ts) ppm. MS (ESI): m/z

(%) = 367 (100) [M + Na]⁺. For the enantiomer: M.p. 116–118 °C.

[α]²_D⁰= +6.1 (c = 2.39, CHCl₃).

Data for α-iminonitrile 14b: HRMS (ESI): calcd. for [C₁₇H₂₂N₂O₄

+ Na]⁺341.1472; found 341.1474. [α]²_D⁰= +37.6 (c = 1.95, CHCl₃).

IR (film): ν = 3482, 2260 cm^{–1 1}H NMR (500 MHz, CDCl₃,

.

2-N-Benzyl-2,6-dideoxy-2,6-imino-3,4-O-isopropylidene-L-talono-

˜

nitrile (14a) and 2-N-Benzyl-2,6-dideoxy-2,6-imino-3,4-O-isoprop-

ylidene- -galactononitrile (15a): See General Procedure. Benzyl-

20 °C): δ = 7.25 (d, J = 8.6 Hz, 2 H, H-Ar), 6.87 (d, J = 8.6 Hz,

2 H, H-Ar), 4.40 (dd, J_3,4= 5.3, J_3,2= 3.3 Hz, 1 H, 3-H), 4.10 (a-

t, J_4,3= J_4,5= 5.6 Hz, 1 H, 4-H), 3.89 (d, J_2,3= 3.3 Hz, 1 H, 2-H),

L

amine (0.14 mL, 1.31 mmol), potassium cyanide (85 mg,

1.31 mmol), and tosylate 13 (180 mg, 0.52 mmol) at room temp. for

3 d gave separable α-iminonitriles 14a (56 mg, 37 %) and 15a

(60 mg, 40%) as colourless oils.

2

3.86 (br. s, 1 H, 5-H), 3.82 (d, J_gem= 13.1 Hz, 1 H, CHa 2-N-

2

PMB), 3.80 (s, 3 H, CH₃2-N-PMB), 3.58 (d, J_gem= 13.1 Hz, 1 H,

2

CHb 2-N-PMB), 2.71 (dd, J_6a,6b= 12.2, J_6a,5= 4.3 Hz, 1 H, 6a-

2

H), 2.51 (dd, J_6b,6a= 12.2, J_6b,5= 8.7 Hz, 1 H, 6b-H), 1.51, 1.36

Data for α-iminonitrile 14a: HRMS (ESI): calcd. for [C₁₆H₂₀N₂O₃

+ Na]⁺311.1366; found 311.1368. [α]²_D⁰= +3.1 (c = 1.20, CHCl₃).

[2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C NMR (125 MHz, CDCl₃, 20 °C):

δ = 159.3 (C-p 2-N-PMB), 130.2 (C-Ar), 127.8 (C-i 2-N-PMB),

115.4 (CN), 114.1 (C-Ar), 110.5 [C(CH₃)₂], 78.1 (C-4), 74.3 (C-3),

68.8 (C-5), 58.6 (CH₂2-N-PMB), 55.3 (CH₃2-N-PMB), 54.6 (C-

2), 51.7 (C-6), 28.0, 26.3 [C(CH₃)₂] ppm. MS (ESI): m/z (%) = 341

IR (film): ν = 3476, 2251 cm^{–1 1}H NMR (400 MHz, CDCl₃,

.

˜

20 °C): δ = 7.36–7.28 (m, 5 H, H-Ar), 4.40 (dd, J_3,4= 5.2, J_3,2

=

3.6 Hz, 1 H, 3-H), 4.10 (a-t, J_4,3= J_4,5= 5.7 Hz, 1 H, 4-H), 3.92

2

(d, J_gem= 13.1 Hz, 1 H, CHa 2-N-Bn), 3.90–3.87 (m, 2 H, 2-H, 5-

(100) [M + Na]⁺, 319 (15) [M + H]⁺. For the enantiomer: [α]²_D⁰

–38.2 (c = 1.84, CHCl₃).

=

2

H), 3.65 (d, J_gem= 13.1 Hz, 1 H, CHb 2-N-Bn), 2.72 (dd, J_6a,6b

2

= 12.3, J_6a,5= 4.1 Hz, 1 H, 6a-H), 2.52 (dd, J_6b,6a= 12.3, J_6b,5

=

8.2 Hz, 1 H, 6b-H), 1.52, 1.36 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C Data for α-iminonitrile 15b: HRMS (ESI): calcd. for [C₁₇H₂₂N₂O₄

NMR (100 MHz, CDCl₃, 20 °C): δ = 135.9 (C-i 2-N-Bn), 129.0,

128.8, 128.1 (C-Ar), 115.6 (CN), 110.7 [C(CH₃)₂], 78.0 (C-4), 74.4

+ Na]⁺341.1472; found 341.1468, m.p. 84–86 °C. [α]²_D⁰= –72.4 (c

= 1.73, CHCl ). IR (film): ν = 3488, 2230 cm^–1

.

¹H NMR

˜

3

Eur. J. Org. Chem. 2014, 2053–2069

www.eurjoc.org

2061

B. J. Ayers, G. W. J. Fleet

FULL PAPER

(500 MHz, CDCl₃, 20 °C): δ = 7.22 (d, J = 8.6 Hz, 2 H, H-Ar),

3.82 (d, J_OH,1= 10.1 Hz, 1 H, 1^A-OH), 2.93 (d, J_OH,1= 4.3 Hz,

6.87 (d, J = 8.6 Hz, 2 H, H-Ar), 4.31 (dd, J_3,2= 7.8, J_3,4= 5.8 Hz, 1 H, 1^B-OH), 2.45 (s, 6 H, CH₃5-O-Ts, CH₃5-O-Ts), 1.51, 1.43

1 H, 3-H), 4.26 (dd, J_4,3= 5.6, J_4,5= 2.0 Hz, 1 H, 4-H), 4.05 (br. [2 s, 2ϫ 3 H, C(CH₃)₂^A], 1.49 (s, 3 H, 2-CH₃^A), 1.42, 1.39 [2 s, 2ϫ

A

B

s, 1 H, 5-H), 4.00 (dd, J_2,3= 7.8, J_2,6a= 1.0 Hz, 1 H, 2-H), 3.80 (s,

3 H, C(CH₃)₂^B], 1.40 (s, 3 H, 2-CH₃^B) ppm. ¹³C NMR (100 MHz,

2

3 H, CH₃2-N-PMB), 3.69 (d, J_gem= 12.6 Hz, 1 H, CHa 2-N- CDCl₃): δ = 145.5 (C^A-p 5-O-Ts), 145.3 (C^B-p 5-O-Ts), 132.7 (C^B-

2

PMB), 3.61 (d, J_gem= 12.6 Hz, 1 H, CHb 2-N-PMB), 3.02 (dd,

i 5-O-Ts), 132.3 (C^A-i 5-O-Ts), 130.2 (C^A-Ar), 130.1 (C^B-Ar), 128.2

(C^B-Ar), 128.1 (C^A-Ar), 114.1 [C(CH₃)₂^B], 113.2 [C(CH₃)₂^A], 104.8

(C-1^B), 102.4 (C-1^A), 91.8 (C-2^B), 88.0 (C-2^A), 87.5 (C-3^B), 86.5 (C-

2

²J_6a,6b= 12.9, J_6a,2= 1.0 Hz, 1 H, 6a-H), 2.76 (br. d, J_6b,6a

=

12.9 Hz, 1 H, 6b-H), 2.58 (br. s, 1 H, 5-OH), 1.70, 1.36 [2 s, 2ϫ

3 H, C(CH₃)₂] ppm. ¹³C NMR (125 MHz, CDCl₃, 20 °C): δ = 3^A), 83.0 (C-4^B), 79.3 (C-4^A), 70.5 (C-5^A), 69.9 (C-5^B), 28.2, 27.8

A

159.6 (C-p 2-N-PMB), 130.4 (C-Ar), 127.8 (C-i 2-N-PMB), 115.8

[C(CH₃)₂^B], 27.3, 27.0 [C(CH₃)₂^A], 21.8 (2-CH₃^A), 21.7 (CH₃5-

(CN), 114.3 (C-Ar), 111.0 [C(CH₃)₂], 75.6 (C-4), 69.7 (C-3), 65.5 O-Ts, CH₃5-O-Ts), 20.2 (2-CH₃^B) ppm. MS (ESI): (%) = 739

B

(C-5), 59.2 (CH₂2-N-PMB), 55.9 (C-2), 55.4 (CH₃2-N-PMB), 50.5 (100) [2M + Na]⁺, 381 (22) [M + Na]⁺.

(C-6), 26.0, 25.6 [C(CH₃)₂] ppm. MS (ESI): m/z (%) = 341 (100)

2-N-Benzyl-2,6-dideoxy-2,6-imino-3,4-O-isopropylidene-3-C-methyl-

[M + Na]⁺, 319 (20) [M + H]⁺. For the enantiomer: M.p. 84–86 °C.

D

-allononitrile (20a) and 2-N-Benzyl-2,6-dideoxy-2,6-imino-3,4-O-

[α]²_D⁰= +70.1 (c = 1.65, CHCl₃).

isopropylidene-3-C-methyl-D-altrononitrile (21a)

2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-

and 2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-

L

-talononitrile (14c)

-galactononitrile

Method A (r.t.): See General Procedure. Benzylamine (0.20 mL,

1.84 mmol), potassium cyanide (70 mg, 1.07 mmol), and tosylate

19 (300 mg, 0.84 mmol) at room temp. for 4 d gave α-iminonitrile

20a (130 mg, 51%) as a pale yellow oil that crystallised on standing.

L

(15c): See General Procedure. Ammonium acetate (546 mg,

7.09 mmol), potassium cyanide (115 mg, 1.77 mmol), and tosylate

13 (244 mg, 0.71 mmol) at 40 °C for 3 d gave an inseparable 1.8:1

(A:B) mixture of α-iminonitriles 14c^Aand 15c^B(71 mg, 51%) as a

pale yellow oil. HRMS (ESI): calcd. for [C₉H₁₄N₂O₃+ Na]⁺

Method B (40 °C): See General Procedure. Benzylamine (0.20 mL,

1.84 mmol), potassium cyanide (70 mg, 1.07 mmol), and tosylate

19 (300 mg, 0.84 mmol) at 40 °C for 2 d gave a 15:1 (A:B) mixture

of α-iminonitriles 20a^Aand 21b^B(201 mg, 79%) as a pale yellow

oil that crystallised on standing.

221.0897; found 221.0895. IR (film): ν = 3488, 2234 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃, 20 °C): δ = 4.34 (a-t, J_3,2= J_3,4= 5.6 Hz, 1 H,

3^B-H), 4.30 (dd, J_3,2= 7.0, J_3,4= 5.1 Hz, 1 H, 3^A-H), 4.27 (d, J_2,3

= 5.3 Hz, 1 H, 2^B-H), 4.20–4.17 (m, 2 H, 4^A-H, 4^B-H), 3.96–3.91

(m, 2 H, 5^A-H, 5^B-H), 3.73 (d, J_2,3= 7.0 Hz, 1 H, 2^A-H), 3.22 (dd,

Method C (65 °C): See General Procedure. Benzylamine (0.20 mL,

1.84 mmol), potassium cyanide (70 mg, 1.07 mmol), and tosylate

19 (300 mg, 0.84 mmol) at 65 °C for 1 d gave a 4.4:1 (A:B) mixture

of α-iminonitriles 20a^Aand 21b^B(185 mg, 73%) as a pale yellow

oil that crystallised on standing.

²J_6a,6b= 13.4, J_6a,5= 3.3 Hz, 1 H, 6a^B-H), 2.93 (dd, J_6a,6b= 13.6,

2

J_6a,5= 3.3 Hz, 1 H, 6a^A-H), 2.88 (dd, ²J_6b,6a= 13.6, J_6b,5= 4.5 Hz,

2

1 H, 6b^A-H), 2.78 (dd, J_6b,6a= 13.4, J_6b,5= 4.5 Hz, 1 H, 6b^B-H),

1.61, 1.36 [2 s, 2 ϫ 3 H, C(CH₃)₂^B], 1.49, 1.35 [2 s, 2 ϫ 3 H,

C(CH₃)₂^A] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 118.5

(CN^A), 118.3 (CN^B), 110.7 [C(CH₃)₂^B], 110.5 [C(CH₃)₂^A], 76.5 (C-

4^A), 76.2 (C-4^B), 72.9 (C-3^A), 70.5 (C-3^B), 66.2 (C-5^A, C-5^B), 49.9

(C-2^A), 48.4 (C-2^B), 46.8 (C-6^A), 45.1 (C-6^B), 28.2, 26.2

[C(CH₃)₂^A], 26.6, 25.4 [C(CH₃)₂^B] ppm. MS (ESI): m/z (%) = 221

(100) [M + Na]⁺, 199 (85) [M + H]⁺.

Data for α-iminonitrile 20a: HRMS (ESI): calcd. for [C₁₇H₂₂N₂O₃

+ Na]⁺325.1523; found 325.1522, m.p. 121–122 °C (ethyl acetate/

cyclohexane). [α]²_D⁰= +39.7 (c = 5.5, MeOH). IR (film): ν = 3427,

˜

1

2239 cm^–1. H NMR [500 MHz, (CD₃)₂CO, 20 °C]: δ = 7.38–7.28

2

(m, 5 H, H-Ar), 4.18 (d, J_4,5= 3.2 Hz, 1 H, 4-H), 4.16 (d, J_gem

=

13.2 Hz, 1 H, CHa 2-N-Bn), 4.05 (br. s, 1 H, 5-OH), 3.88–3.84 (m,

2

1 H, 5-H), 3.56 (s, 1 H, 2-H), 3.52 (d, J_gem= 13.2 Hz, 1 H, CHb

2,3-O-Isopropylidene-2-C-methyl-5-O-p-tolylsulfonyl-D-ribofuranose

2

2-N-Bn), 2.72 (dd, J_6a,6b= 10.7, J_6a,5= 5.7 Hz, 1 H, 6a-H), 2.28

(19): Diisobutylaluminium hydride (1.5 m in toluene; 12.0 mL,

17.5 mmol) was added dropwise over 15 min to a solution of lact-

one 18^[47,48](5.2 g, 14.6 mmol) in anhydrous dichloromethane

(50 mL) at –78 °C. The reaction mixture was stirred for 1 h, after

which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated the

incomplete consumption of the starting material (R_f= 0.54) and

the formation of a major product (R_f= 0.50). The reaction mixture

was diluted with ethyl acetate (200 mL) and warmed to room

temp., and a mixture of water and saturated sodium potassium

tartrate solution (1:3; 200 mL) was added. The biphasic mixture

was stirred vigorously for 2.5 h, after which the phases were sepa-

rated, and the aqueous layer was extracted with ethyl acetate (6ϫ

50 mL). The combined organic fractions were dried (MgSO₄), fil-

tered, and concentrated in vacuo. The crude residue was purified

by flash chromatography (19:1 to 1:1, cyclohexane/ethyl acetate) to

give lactols 19 (4.9 g, 94%) as a yellow oil, as a 2:1 mixture of

anomers (A:B). HRMS (ESI): calcd. for [C₁₆H₂₂O₇S + Na]⁺

2

(a-t, J_6b,6a= J_6b,5= 10.9 Hz, 1 H, 6b-H), 1.57 (s, 3 H, 3-CH₃),

1.48, 1.35 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C NMR [125 MHz, (CD₃)

₂CO, 20 °C]: δ = 137.8 (C-i 2-N-Bn), 129.7, 129.2, 128.3 (C-Ar),

118.2 (CN), 110.0 [C(CH₃)₂], 81.3 (C-4), 80.5 (C-3), 65.4 (C-5), 62.0

(C-2), 60.0 (CH₂2-N-Bn), 53.3 (C-6), 28.3, 26.7 [C(CH₃)₂], 20.4 (3-

CH₃) ppm. MS (ESI): m/z (%) = 627 (100) [2M + Na]⁺, 325 (87)

[M + Na]⁺, 303 (32) [M + H]⁺.

Data for the mixture of α-iminonitriles 20a^Aand 21b^B: HRMS

(ESI): calcd. for [C₁₇H₂₂N₂O₃+ Na]⁺325.1523; found 325.1520.

IR (film): ν = 3441, 2241 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO,

˜

20 °C]: δ = 7.39–7.13 (m, 10 H, H^A-Ar, H^B-Ar), 4.24 (d, J_4,5

=

4.5 Hz, 1 H, 4^B-H), 4.18 (d, J_4,5= 3.2 Hz, 1 H, 4^A-H), 4.16 (d, ²J_gem

2

= 13.2 Hz, 1 H, CHa^A2-N-Bn), 4.16 (d, J_gem= 12.5 Hz, 1 H,

CHa^B2-N-Bn), 4.05–4.07 (m, 2 H, 5^A-OH, 5^B-OH), 3.98–3.83 (m,

2 H, 5^A-H, 5^B-H), 3.71 (s, 1 H, 2^B-H), 3.56 (s, 1 H, 2^A-H), 3.55 (d,

²J_gem= 12.5 Hz, 1 H, CHb^B2-N-Bn), 3.52 (d, ²J_gem= 13.2 Hz, 1 H,

381.0978; found 381.0973. [α]²_D⁰= +6.4 (c = 1.52, CHCl₃). IR (film):

CHb^A2-N-Bn), 2.72 (dd, J_6a,6b= 10.7, J_6a,5= 5.7 Hz, 1 H, 6a^A-

2

ν = 3485, 1363, 1177 cm^–1. H NMR (400 MHz, CDCl , 20 °C): δ

H), 2.71 (dd, J_6a,6b= 10.6, J_6a,5= 5.0 Hz, 1 H, 6a^B-H), 2.31 (a-t,

1

2

˜

3

= 7.79 (a-t, J = 8.6 Hz, 4 H, H^A-Ar, H^B-Ar), 7.36 (a-d, J = 8.3 Hz,

²J_6b,6a= J_6b,5= 11.4 Hz, 1 H, 6b^A-H), 2.28 (a-t, J_6b,6a= J_6b,5

=

2

4 H, H^A-Ar, H^B-Ar), 5.24 (d, J_1,OH= 4.3 Hz, 1 H, 1^B-H), 4.93 (d, 11.1 Hz, 1 H, 6b^B-H), 1.68 (s, 3 H, 3-CH₃^B), 1.57 (s, 3 H, 3-CH₃^A),

J_1,OH= 10.1 Hz, 1 H, 1^A-H), 4.40 (d, J_3,4= 1.0 Hz, 1 H, 3^A-H), 1.48, 1.35 [2 s, 2 ϫ 3 H, C(CH₃)₂^A], 1.43, 1.37 [2 s, 2 ϫ 3 H,

4.24–4.21 (m, 3 H, 3^B-H, 4^A-H, 4^B-H), 4.13 (dd, ²J_5a,5b= 10.6, J_5a,4C(CH₃)₂^B] ppm. ¹³C NMR [100 MHz, (CD₃)₂CO, 20 °C]: δ = 138.1

= 2.5 Hz, 1 H, 5a^A-H), 4.16–4.12 (m, 1 H, 5a^B-H), 4.09–4.02 (m,

(C^B-i 2-N-Bn), 137.8 (C^A-i 2-N-Bn), 129.7, 129.7, 129.5, 129.3,

2

1 H, 5b^B-H), 4.05 (dd, J_5b,5a= 10.6, J_5b,4= 3.5 Hz, 1 H, 5b^A-H),

129.3, 129.2, 129.0, 128.4, 128.3, 128.1 (C^A-Ar, C^B-Ar), 118.1

2062

www.eurjoc.org

Eur. J. Org. Chem. 2014, 2053–2069

One-Pot Iminosugar Synthesis

(CN^A), 117.2 (CN^B), 110.5 [C(CH₃)₂^B], 110.0 [C(CH₃)₂^A], 81.3 (C- calcd. for [C₁₆H₂₀O₇S + Na]⁺379.0822; found 379.0819. [α]²_D⁵

=

1

4^A, C-4^B), 80.5 (C-3^A), 79.8 (C-3^B), 66.2 (C-5^B), 65.4 (C-5^A), 62.4 –41.6 (c = 2.87, CHCl ). IR (film): ν = 1792, 1364, 1190 cm^–1. H

˜

3

(C-2^B), 61.9 (C-2^A), 60.1 (CH₂^B2-N-Bn), 59.9 (CH₂^A2-N-Bn), 53.2 NMR (400 MHz, CDCl₃, 20 °C): δ = 7.80 (d, J = 8.2 Hz, 2 H, H-

(C-6^A), 50.3 (C-6^B), 28.3, 26.7 [C(CH₃)₂^A], 26.4, 26.0 [C(CH₃)₂^B],

21.4 (3-CH₃^B), 20.4 (3-CH₃^A) ppm. MS (ESI): m/z (%) = 627 (85)

[2M + Na]⁺, 325 (100) [M + Na]⁺, 303 (40) [M + H]⁺.

Ar), 7.36 (d, J = 8.2 Hz, 2 H, H-Ar), 4.62 (ddd, J_4,5b= 7.3, J_4,5a

=

5.1, J_4,3= 3.3 Hz, 1 H, 4-H), 4.41 (d, J_3,4= 3.3 Hz, 1 H, 3-H), 4.36

2

(dd, J_5a,5b= 11.1, J_5a,4= 5.1 Hz, 1 H, 5a-H), 4.25 (dd, J_5b,5a

=

11.1, J_5b,4= 7.3 Hz, 1 H, 5b-H), 2.45 (s, 3 H, CH₃5-O-Ts), 1.53 (s,

3 H, 2-CH₃), 1.34, 1.33 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C NMR

(100 MHz, CDCl₃, 20 °C): δ = 175.4 (C-1), 145.5 (C-p 5-O-Ts),

132.3 (C-i 5-O-Ts), 130.1 (C-Ar), 128.2 (C-Ar), 113.8 [C(CH₃)₂],

82.9 (C-2), 80.1 (C-3), 75.1 (C-4), 66.8 (C-5), 26.8, 26.7 [C(CH₃)₃],

21.8 (CH₃5-O-Ts), 18.1 (2-CH₃) ppm. MS (ESI): m/z (%) = 395

(48) [M + K]⁺, 379 (100) [M + Na]⁺.

2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-2-N-(4-methoxybenz-

yl)-3-C-methyl-D-allononitrile (20b)

Method A (r.t.): See General Procedure. 4-Methoxybenzylamine

(0.28 mL, 2.14 mmol), potassium cyanide (75 mg, 1.15 mmol), and

tosylate 19 (340 mg, 0.95 mmol) at room temp. for 3 d gave α-

iminonitrile 20b (208 mg, 68%) as a white crystalline solid.

Method B (40 °C): See General Procedure. 4-Methoxybenzylamine

(0.28 mL, 2.14 mmol), potassium cyanide (75 mg, 1.15 mmol), and

tosylate 19 (340 mg, 0.95 mmol) at 40 °C for 2 d gave α-iminonitrile

20b (250 mg, 79%; Ͼ95% b.r.s.m.) as a white crystalline solid.

2,3-O-Isopropylidene-2-C-methyl-5-O-p-tolylsulfonyl-L-lyxofuranose

(24): Diisobutylaluminium hydride (1.5 m in toluene; 4.3 mL,

6.33 mmol) was added dropwise over 10 min to a solution of lact-

one 23 (1.88 g, 5.28 mmol) in dichloromethane (20 mL) at –78 °C.

The reaction mixture was stirred for 2 h, after which TLC analysis

(5:1, toluene/acetone) indicated the complete consumption of the

starting material (R_f= 0.60) and the formation of a major product

(R_f= 0.49). The reaction mixture was diluted with ethyl acetate

(100 mL) and warmed to room temp. A mixture of water and so-

dium potassium tartrate solution (1:3; 100 mL) was added, and the

biphasic mixture was stirred vigorously for 2.5 h. The phases were

separated, and the aqueous layer was extracted with ethyl acetate

(6ϫ 30 mL). The organic fractions were combined, dried (MgSO₄),

filtered, and concentrated in vacuo. The crude residue was purified

by flash chromatography (19:1 to 7:3, cyclohexane/ethyl acetate) to

give lactols 24 (1.73 g, 91%), as a 2:1 (A:B) anomeric mixture, as

a white crystalline solid. HRMS (ESI): calcd. for [C₁₆H₂₂O₇S +

Na]⁺381.0978; found 381.0973, m.p. 112–114 °C. [α]²_D⁵= +4.9 (c =

Data for α-iminonitrile 20b: HRMS (ESI): calcd. for [C₁₈H₂₄N₂O₄

+ Na]⁺355.1628; found 355.1623, m.p. 150–152 °C. [α]²_D⁰= +35.6

(c = 0.99, CHCl ). IR (film): ν = 3384, 2230 cm^{–1 1}H NMR

.

˜

3

(500 MHz, CDCl₃, 20 °C): δ = 7.22 (d, J = 8.6 Hz, 2 H, H-Ar),

6.87 (d, J = 8.6 Hz, 2 H, H-Ar), 4.13 (d, J_4,5= 3.9 Hz, 1 H, 4-H),

2

4.13 (d, J_gem= 12.8 Hz, 1 H, CHa 2-N-PMB), 3.88–3.84 (m, 1 H,

2

5-H), 3.81 (s, 3 H, CH₃2-N-PMB), 3.43 (d, J_gem= 12.8 Hz, 1 H,

CHb 2-N-PMB), 3.36 (s, 1 H, 2-H), 2.85 (dd, ²J_6a,6b= 11.0, J_6a,5

=

5.9 Hz, 1 H, 6a-H), 2.17 (a-t, ²J_6b,6a= J_6b,5= 10.9 Hz, 1 H, 6b-H),

1.60 (s, 3 H, 3-CH₃), 1.51, 1.39 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C

NMR (125 MHz, CDCl₃, 20 °C): δ = 159.3 (C-p 2-N-PMB), 130.5

(C-Ar), 128.0 (C-i 2-N-PMB), 117.1 (CN), 114.0 (C-Ar), 110.2

[C(CH₃)₂], 80.2 (C-4), 80.0 (C-3), 65.2 (C-5), 61.0 (C-2), 59.1 (CH₂

2-Ni-PMB), 55.4 (CH₃2-N-PMB), 52.8 (C-6), 28.2, 26.7

[C(CH₃)₂], 20.5 (3-CH₃) ppm. MS (ESI): m/z (%) = 355 (100) [M

+ Na]⁺, 333 (45) [M + H]⁺.

2.6, CHCl ). IR (film): ν = 3493, 1361, 1190 cm^{–1 1}H NMR

.

˜

3

(400 MHz, CDCl₃, 20 °C): δ = 7.82–7.79 (m, 4 H, H-Ar), 7.34 (d,

J = 8.1 Hz, 4 H, H-Ar), 5.19 (s, 1 H, 1^B-H), 4.63 (br. s, 1 H, 1^A-

H), 4.37 (ddd, J_4,5b= 7.6, J = 4.0, J = 3.3 Hz, 1 H, 4^B-H), 4.30–

2,6-Dideoxy-2,6-imino-3,4-isopropylidene-3-C-methyl-D-allono-

2

4.26 (m, 3 H, 3^A-H, 5a^A-H, 5a^B-H), 4.18 (dd, J_5b,5a= 10.4, J_5b,4

nitrile (20c): See General Procedure. Ammonium acetate (508 mg,

6.59 mmol), potassium cyanide (107 mg, 1.65 mmol), and tosylate

19 (236 mg, 0.66 mmol) at 40 °C for 4 d gave α-iminonitrile 20c

(93 mg, 71 %) as a pale yellow oil. HRMS (ESI): calcd. for

[C₁₀H₁₆N₂O₃+ Na]⁺235.1053; found 235.1058. [α]²_D⁰= –19.1 (c =

= 7.6 Hz, 1 H, 5b^B-H), 4.17 (dd, ²J_5b,5a= 10.4, J_5b,4= 6.3 Hz, 1 H,

5b^A-H), 3.82 (a-td, J = J = 6.1, J = 3.3 Hz, 2 H, 3^B-H, 4^A-H), 2.44

A

B

(s, 6 H, CH₃5-O-Ts, CH₃5-O-Ts), 1.46 (s, 3 H, 2-CH₃^B), 1.43

(s, 3 H, 2-CH₃^A), 1.39, 1.38 [2 s, 2ϫ 3 H, C(CH₃)₂^A], 1.33, 1.31 [2

s, 2 ϫ 3 H, C(CH₃)₂^B] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C):

δ = 145.1 (C^A-p 5-O-Ts), 145.0 (C^B-p 5-O-Ts), 132.8 (C^B-i 5-O-Ts),

132.7 (C^A-i 5-O-Ts), 129.9, 128.3 (C^A-Ar, C^B-Ar), 113.5

[C(CH₃)₂^A], 113.4 [C(CH₃)₂^B], 103.3 (C-1^B), 101.3 (C-1^A), 92.4 (C-

2^B), 86.6 (C-2^A), 86.0 (C-3^B), 84.5 (C-3^A), 77.4 (C-4^B), 72.8 (C-4^A),

68.1 (C-5^B), 67.1 (C-5^A), 27.7, 27.4 [C(CH₃)₂^B], 26.9, 26.8 [C(CH₃)

1.52, CHCl ). IR (film): ν = 3321, 2240 cm^–1. ¹H NMR (400 MHz,

˜

3

CDCl₃, 20 °C): δ = 4.15 (d, J_4,5= 3.8 Hz, 1 H, 4-H), 4.11 (br. s,

1 H, 5-OH), 3.83 (ddd, J_5,6b= 10.7, J_5,6a= 5.7, J_5,4= 3.8 Hz, 1 H,

2

5-H), 3.70 (s, 1 H, 2-H), 3.06 (dd, J_6a,6b= 11.7, J_6a,5= 5.7 Hz,

2

1 H, 6a-H), 2.68 (a-t, J_6b,6a= J_6b,5= 11.5 Hz, 1 H, 6b-H), 1.52,

1.38 [2 s, 2ϫ 3 H, C(CH₃)₂], 1.51 (s, 3 H, 3-CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃, 20 °C): δ = 117.8 (CN), 110.0 [C(CH₃)₂], 80.6

(C-4), 79.2 (C-3), 66.0 (C-5), 54.5 (C-2), 47.7 (C-6), 28.3, 26.8

[C(CH₃)₂], 18.6 (3-CH₃) ppm. MS (ESI): m/z (%) = 235 (100) [M

+ Na]⁺, 213 (82) [M + H]⁺.

A

B

^A], 21.8 (CH₃5-O-Ts), 21.6 (CH₃5-O-Ts) ppm. MS (ESI): m/z

2

(%) = 397 (50) [M + K]⁺, 381 (100) [M + Na]⁺.

2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-2-N-(4-methoxybenz-

yl)-3-C-methyl-L-talononitrile (25a) and 2,6-Dideoxy-2,6-imino-3,4-

2,3-O-Isopropylidene-2-C-methyl-5-O-p-tolylsulfonyl-

L

-lyxono-1,4-

O-isopropylidene-2-N-(4-methoxybenzyl)-3-C-methyl-L

-galactono-

lactone (23): p-Toluenesulfonyl chloride (2.8 g, 14.8 mmol) was

added in one portion to a solution of lactone 22^[47](1.2 g,

5.93 mmol) in pyridine (6 mL) at 0 °C. The reaction mixture was

allowed to warm to room temp. and stirred for 14 h, after which

TLC analysis (2:3, cyclohexane/ethyl acetate) indicated the com-

plete consumption of the starting material (R_f0.43) and the forma-

tion of a major product (R_f= 0.86). The reaction mixture was

diluted with ethyl acetate (100 mL) and washed with hydrochloric

acid (2 m aq.; 3ϫ 20 mL). The organic phase was dried (MgSO₄),

filtered, and concentrated in vacuo. The crude residue was purified

by flash chromatography (19:1 to 7:3, cyclohexane/ethyl acetate) to

give tosylate 23 (1.91 g, 90%) as a clear, viscous gel. HRMS (ESI):

nitrile (26a): See General Procedure. 4-Methoxybenzylamine

(0.18 mL, 1.40 mmol), potassium cyanide (91 mg, 1.40 mmol), and

tosylate 24 (200 mg, 0.59 mmol) at 50 °C for 2 d gave an insepa-

rable 3.8:1 (A:B) mixture of α-iminonitriles 25a^Aand 26a^B(142 mg,

73 %) as a yellow oil. HRMS (ESI): calcd. for [C₁₈H₂₄N₂O₄

+

Na]⁺355.1628; found 355.1625. IR (film): ν = 3389, 2239 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃, 20 °C): δ = 7.21 (d, J = 8.6 Hz, 4 H, H-

Ar), 6.86 (d, J = 8.6 Hz, 4 H, H-Ar), 4.15 (d, ²J_gem= 13.1 Hz, 1 H,

CHa^B2-N-PMB), 4.02 (br. d, J_5,OH= 6.8 Hz, 1 H, 5^A-H), 4.00–

3.98 (m, 2 H, 4^A-H, 4^B-H), 3.96–3.91 (m, 1 H, 5^B-H), 3.78 (s, 6 H,

A

B

2

CH₃2-N-PMB, CH₃2-N-PMB), 3.69 (d, J_gem= 12.8 Hz, 1 H,

CHa^A2-N-PMB), 3.60 (s, 1 H, 2^A-H), 3.58 (d, J_gem= 12.8 Hz,

2

Eur. J. Org. Chem. 2014, 2053–2069

www.eurjoc.org

2063

B. J. Ayers, G. W. J. Fleet

FULL PAPER

1 H, CHb^A2-N-PMB), 3.47 (d, J_gem= 13.1 Hz, 1 H, CHb^B2-N- d, J_5b,5a= 11.4 Hz, 1 H, 5b-H), 1.48, 1.39 [2 s, 2 ϫ 3 H,

2

PMB), 3.36 (s, 1 H, 2^B-H), 3.02 (dd, J_6a,6b= 13.1, J_6a,5= 1.5 Hz,

C(CH₃)₂], 0.88 [s, 9 H, SiC(CH₃)₃], 0.07, 0.06 [2 s, 2 ϫ 3 H,

2

1 H, 6a^A-H), 2.75 (dd, J_6a,6b= 12.4, J_6a,5= 2.5 Hz, 1 H, 6a^B-H), Si(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 174.2 (C-

2

2.51 (br. d, J_6b,6a= 13.1 Hz, 1 H, 6b^A-H), 2.40 (dd, ²J_6b,6a= 12.4,

1), 113.0 [C(CH₃)₂], 82.3 (C-4), 78.4 (C-3), 75.8 (C-2), 62.9 (C-5),

26.8, 25.6 [C(CH₃)₂], 25.7 [SiC(CH₃)₃], 18.2 [SiC(CH₃)₃], –5.7, –5.8

J_6b,5= 1.8 Hz, 1 H, 6b^B-H), 2.29 (br. d, J_OH,5= 6.8 Hz, 1 H, 5^A-

OH), 1.66 (s, 3 H, 3-CH₃^A), 1.65 (s, 3 H, 3-CH₃^B), 1.44 [s, 3 H, [Si(CH₃)₂] ppm. MS (ESI): m/z (%) = 325 (100) [M + Na]⁺, 320

C(CH₃)^B], 1.39 [s, 3 H, C(CH₃)^A], 1.36 [s, 3 H, C(CH₃)^A], 1.35 [s,

3 H, C(CH₃)^B] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ =

159.5 (C^A-p 2-N-PMB), 159.3 (C^B-p 2-N-PMB), 130.5 (C^B-Ar),

130.2 (C^A-Ar), 128.0 (C^A-i 2-N-PMB), 127.6 (C^B-i 2-N-PMB),

116.9 (CN^B), 116.0 (CN^A), 114.2 (C^A-Ar), 114.1 (C^B-Ar), 109.9

[C(CH₃)₂^A], 109.4 [C(CH₃)₂^B], 80.5 (C-4^A), 80.1 (C-4^B), 78.3 (C-

3^B), 76.7 (C-3^A), 65.2 (C-5^A), 64.7 (C-5^B), 62.1 (C-2^B), 61.7 (C-2^A),

(78) [M + NH₄]⁺.

6-O-tert-Butyldimethylsilyl-1-deoxy-3,4-O-isopropylidene-D-psico-

furanose (30):^[50]Methyllithium (1.6 m in Et₂O; 4.75 mL,

7.56 mmol) was added dropwise over 15 min to a solution of lact-

one 29 (2.2 g, 6.87 mmol) in THF (20 mL) at –78 °C. The reaction

mixture was stirred for 2 h, after which TLC analysis (5:1, cyclo-

hexane/ethyl acetate) indicated the consumption of the starting ma-

terial (R_f= 0.71) and the formation of a major product (R_f= 0.62).

Water (20 mL) was added dropwise to the reaction mixture, and

the resulting biphasic mixture was allowed to warm to room temp.

and stirred for a further 15 min. Ethyl acetate was added (50 mL),

the phases were separated, and the aqueous layer was extracted

with ethyl acetate (3ϫ 50 mL). The organic fractions were com-

bined, dried (MgSO₄), filtered, and concentrated in vacuo. The

crude residue was purified by flash chromatography (39:1 to 4:1,

cyclohexane/ethyl acetate) to give lactol 30 (2.04 g, 88%) as a white

crystalline solid, as a single anomer. HRMS (ESI): calcd. for

[C₁₅H₃₀O₅Si + Na]⁺341.1755; found 341.1750, m.p. 42–44 °C.

[α]²_D⁰= –21.0 (c = 1.15, CHCl₃) [ref.^[50][α]²_D¹= –13.1 (c = 0.99,

A

B

A

59.2 (CH₂2-N-PMB), 58.9 (CH₂2-N-PMB), 55.3 (CH₃2-N-

PMB, CH₃2-N-PMB), 53.3 (C-6^B), 50.5 (C-6^A), 28.1, 26.7

B

[C(CH₃)₂^B], 26.3 (3-CH₃^A), 26.1, 25.7 [C(CH₃)₂^A], 21.8 (3-CH₃

)

B

ppm. MS (ESI): m/z (%) = 371 (25) [M + K]⁺, 355 (100) [M +

Na]⁺, 333 (55) [M + H]⁺.

2,3-O-Isopropylidene-5-O-p-tolylsulfonyl-D-ribono-1,4-lactone

(28):^[43]A solution of p-toluenesulfonyl chloride (4.6 g, 23.9 mmol)

in pyridine (6 mL) was added dropwise to a solution of lactone

27^[42](1.5 g, 7.97 mmol) in pyridine (8 mL) at 0 °C. The reaction

mixture was allowed to warm to room temp. and stirred for 5 h,

after which TLC analysis (2:3, cyclohexane/ethyl acetate) indicated

the complete consumption of the starting material (R_f= 0.56) and

the formation of a major product (R_f= 0.80). The reaction mixture

was diluted with ethyl acetate (150 mL) and washed with hydro-

chloric acid (2 m aq.; 3ϫ 30 mL). The organic phase was dried

(MgSO₄), filtered, and concentrated in vacuo. The crude residue

was purified by flash chromatography (19:1 to 1:1, cyclohexane/

ethyl acetate) to give tosylate 28 (2.17 g, 79%) as a white crystalline

solid. HRMS (ESI): calcd. for [C₁₅H₁₈O₇S + Na]⁺365.0665; found

365.0663, m.p. 112–116 °C [ref.^[43]m.p. 116–118 °C]. [α]²_D⁰= –18.2

(c = 1.20, acetone) [ref.^[43][α]²_D⁴= –15.5 (c = 2.4, acetone)]. IR

CHCl )]. IR (film): ν = 3445 cm^–1. ¹H NMR (400 MHz, CDCl₃,

˜

3

20 °C): δ = 5.16 (s, 1 H, 2-OH), 4.80 (br. d, J_4,3= 5.8 Hz, 1 H, 4-

H), 4.44 (d, J_3,4= 5.8 Hz, 1 H, 3-H), 4.26 (br. s, 1 H, 5-H), 3.80

2

(dd, J_6a,6b= 11.1, J_6a,5= 1.8 Hz, 1 H, 6a-H), 3.76 (dd, J_6b,6a

=

11.1, J_6b,5= 2.0 Hz, 1 H, 6b-H), 1.52, 1.50 [2 s, 2 ϫ 3 H,

C(CH₃)₂], 1.35 (s, 3 H, 1-H), 0.93, [s, 9 H, SiC(CH₃)₃], 0.15, 0.14

[2 s, 2ϫ 3 H, Si(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C):

δ = 112.4 [C(CH₃)₂], 106.5 (C-2), 88.0 (C-3), 85.8 (C-5), 82.0 (C-

4), 64.9 (C-6), 25.7 [SiC(CH₃)₃], 26.6, 25.1 [C(CH₃)₂], 21.2 (C-1),

18.2 [SiC(CH₃)₃], –5.7, –5.8 [Si(CH₃)₂] ppm. MS (ESI): m/z = 341

(100) [M + Na]⁺.

(film): ν = 1793, 1369, 1180 cm^–1. ¹H NMR (400 MHz, CD₃CN,

˜

20 °C): δ = 4.89 (d, J_2,3= 5.8 Hz, 1 H, 2-H), 4.81 (d, J_3,2= 5.8 Hz,

1 H, 3-H), 4.69 (a-t, J_4,5a= J_4,5b= 3.3 Hz, 1 H, 4-H), 4.38 (dd,

1-Deoxy-3,4-O-isopropylidene-D

-psicofuranose (31):^[50]Tetra-n-

²J_5a,5b= 12.4, J_5a,4= 3.0 Hz, 1 H, 5a-H), 4.25 (dd, J_5b,5a= 12.4,

2

butylammonium fluoride (1 m in THF; 8.2 mL, 8.2 mmol) was

added dropwise to a solution of silyl ether 30 (2 g, 6.28 mmol) in

THF (20 mL) at room temp. The reaction mixture was stirred for

4 h, after which TLC analysis (1:1, cyclohexane/ethyl acetate) indi-

cated the complete consumption of the starting material (R_f= 0.93)

and the formation of a major product (R_f= 0.30). The reaction

mixture was concentrated in vacuo, and the crude residue was puri-

fied by flash chromatography (3:1:0 to 0:9:1, cyclohexane/ethyl

acetate/methanol) to give lactol 31 (1.08 g, 84%) as a colourless oil,

which crystallised on standing to form a white solid. HRMS (ESI):

calcd. for [C₉H₁₆O₅+ Na]⁺227.0890; found 227.0890, m.p. 73–

75 °C [ref.^[50]m.p. 72–74 °C]. [α]²_D⁰= –11.1 (c = 0.95, CHCl₃) [ref.^[50]

J_5b,4= 3.6 Hz, 1 H, 5b-H), 2.45 (s, 3 H, CH₃5-O-Ts), 1.38, 1.32 [2

s, 2 ϫ 3 H, C(CH₃)₂] ppm. ¹³C NMR (100 MHz, CD₃CN, 20 °C):

δ = 174.5 (C-1), 147.1 (C-p 5-O-Ts), 132.9 (C-i 5-O-Ts), 131.3 (C-

Ar), 128.9 (C-Ar), 114.3 [C(CH₃)₂], 80.3 (C-3), 78.3 (C-4), 75.9 (C-

2), 70.1 (C-5), 26.9, 25.5 [C(CH₃)₂], 21.8 (CH₃5-O-Ts) ppm. MS

(ESI): m/z (%) = 397 (47) [M + MeOH + Na]⁺, 365 (100) [M +

Na]⁺, 360 (35) [M + NH₄]⁺.

5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-D-ribono-1,4-lact-

one (29):^[50]tert-Butyldimethylsilyl chloride (1.8 g, 12.0 mmol) was

added to a solution of lactone 27^[42](1.5 g, 7.97 mmol) in pyridine

(15 mL) at room temp. The reaction mixture was stirred for 15 h,

after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated

the complete consumption of the starting material (R_f= 0.24) and

the formation of a major product (R_f= 0.83). The reaction mixture

was diluted with ethyl acetate (100 mL) and washed with hydro-

chloric acid (2 m aq.; 3ϫ 25 mL). The organic phase was dried

(MgSO₄), filtered, and concentrated in vacuo. The crude residue

was purified by flash chromatography (19:1 to 9:1, cyclohexane/

ethyl acetate) to give silyl ether 29 (2.2 g, 91%) as a white crystalline

solid. HRMS (ESI): calcd. for [C₁₄H₂₆O₅Si + Na]⁺325.1442; found

325.1436, m.p. 68–70 °C [ref.^[50]m.p. 70–71 °C]. [α]²_D⁰= –51.7 (c =

[α]²_D¹= –15.0 (c = 1.11, CHCl )]. IR (film): ν = 3388 cm^–1. ¹H NMR

˜

3

(400 MHz, CDCl₃, 20 °C): δ = 4.89 (d, J_4,3= 5.9 Hz, 1 H, 4-H),

4.47 (d, J_3,4= 5.9 Hz, 1 H, 3-H), 4.29 (br. s, 1 H, 5-H), 3.80–3.68

(m, 2 H, 6a-H, 6b-H), 1.54, 1.50 [2 s, 2ϫ 3 H, C(CH₃)₂], 1.33 (s,

3 H, 1-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 112.4

[C(CH₃)₂], 106.7 (C-2), 87.0 (C-3), 86.2 (C-5), 82.0 (C-4), 63.7 (C-

6), 26.5, 24.9 [C(CH₃)₂], 22.3 (C-1) ppm. MS (ESI): m/z (%) = 227

(100) [M + Na]⁺.

1-Deoxy-3,4-O-isopropylidene-6-O-p-tolylsulfonyl-D-psicofuranose

1.1, CHCl₃) [ref.^[50][α]²_D³= –49.0 (c = 1.16, CHCl )]. IR (film): ν =

(32): A solution of p-toluenesulfonyl chloride (583 mg, 3.06 mmol)

in pyridine (1 mL) was added dropwise to a solution of lactol 31

(500 mg, 2.45 mmol) in pyridine (4 mL) at –30 °C. The reaction

mixture was warmed to 0 °C after 1 h, and after a further 1 h, it

˜

3

1775 cm^–1. ¹H NMR (400 MHz, CDCl₃, 20 °C): δ = 4.73 (d, J_2,3

=

5.8 Hz, 1 H, 2-H), 4.71 (d, J_3,2= 5.8 Hz, 1 H, 3-H), 4.60 (br. s, 1 H,

2

4-H), 3.89 (dd, J_5a,5b= 11.4, J_5a,4= 1.5 Hz, 1 H, 5a-H), 3.80 (br.

2064

www.eurjoc.org

Eur. J. Org. Chem. 2014, 2053–2069

One-Pot Iminosugar Synthesis

was warmed to room temp. After 6 h at room temp. TLC analysis

(1:1, cyclohexane/ethyl acetate) indicated the partial consumption

of the starting material (R_f= 0.30) and the formation of a major

product (R_f= 0.66). The reaction mixture was cooled to 0 °C and

an additional portion of p-toluenesulfonyl chloride was added

(230 mg, 1.21 mmol). After 15 min, the reaction mixture was

warmed to room temp. and stirred for 17 h. After this time, TLC

analysis indicated the complete consumption of the starting mate-

rial and the presence of the major product. The reaction mixture

was diluted with ethyl acetate (100 mL) and washed with hydro-

chloric acid (2 m aq.; 3ϫ 20 mL). The organic phase was dried

(MgSO₄), filtered, and concentrated in vacuo. The crude residue

was purified by flash chromatography (9:1 to 7:3, cyclohexane/ethyl

acetate) to give tosylate 32 (812 mg, 92%) as a pale yellow oil,

which crystallised on standing to give a white crystalline solid, as

a 2.6:1 (A:B) ratio of anomers. HRMS (ESI): calcd. for [C₁₆H₂₂O₇S

+ Na]⁺381.0978; found 384.0972, m.p. 80–82 °C. [α]²_D⁰= –63.7 (c

= 5.5 Hz, 1 H, 3-H), 3.52 (dd, ²J_6a,6b= 7.1, J_6a,5= 4.0 Hz, 1 H, 6a-

2

H), 3.35 (d, J_6b,6a= 7.1 Hz, 1 H, 6b-H), 1.59 (s, 3 H, 1-H), 1.45,

1.29 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃,

20 °C): δ = 112.1 [C(CH₃)₂], 107.3 (C-2), 82.7 (C-3), 80.8 (C-4),

78.1 (C-5), 64.5 (C-6), 26.2, 25.5 [C(CH₃)₂], 14.0 (C-1) ppm.

5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-L-lyxono-1,4-lact-

one (35): tert-Butyldimethylsilyl chloride (2.4 g, 15.9 mmol) was

added to a solution of lactone 11 (2.0 g, 10.6 mmol) in pyridine

(20 mL) at room temp. The reaction mixture was stirred for 16 h,

after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated

the complete consumption of the starting material (R_f= 0.11) and

the formation of a major product (R_f= 0.71). The reaction mixture

was diluted with ethyl acetate (150 mL) and washed with hydro-

chloric acid (2 m aq.; 3ϫ 40 mL). The organic phase was dried

(MgSO₄), filtered, and concentrated in vacuo. The crude residue

was purified by flash chromatography (49:1 to 9:1, cyclohexane/

ethyl acetate) to give silyl ether 35 (3.13 g, 97%) as a white crystal-

line solid. HRMS (ESI): calcd. for [C₁₄H₂₆O₅Si + Na]⁺325.1442;

found 325.1438, m.p. 85–87 °C [for the enantiomer: ref.^[52]m.p. 90–

91 °C]. [α]²_D⁰= –39.6 (c = 1.37, CHCl₃) [for the enantiomer: ref.^[52]

= 4.08, CHCl ). IR (film): ν = 3500, 1365, 1177 cm^–1. ¹H NMR

˜

3

(400 MHz, CDCl₃, 20 °C): δ = 7.81–7.75 (m, 4 H, H^A-Ar, H^B-Ar),

7.36–7.31 (m, 4 H, H^A-Ar, H^B-Ar), 4.68 (dd, J_4,3= 6.7, J_4,5

=

4.0 Hz, 1 H, 4^B-H), 4.64 (br. d, J_4,3= 5.7 Hz, 1 H, 4^A-H), 4.42 (d,

J_3,4= 5.7 Hz, 1 H, 3^A-H), 4.41 (d, J_3,4= 6.7 Hz, 1 H, 3^B-H), 4.24

(br. a-t, J_5,6= J_5,6a= 6.6 Hz, 1 H, 5^A-H), 4.19–4.03 (m, 5 H, 5^B-H,

[α]²_D⁰= +54.9 (c = 1.03, CHCl )]. IR (film): ν = 1773 cm^–1. ¹H

˜

3

NMR (400 MHz, CDCl₃, 20 °C): δ = 4.80 (br. s, 2 H, 2-H, 3-H),

2

4.51 (a-t, J_4,5a= J_4,5b= 6.8 Hz, 1 H, 4-H), 3.98 (dd, J_5a,5b= 10.6,

B

6a^A-H, 6a^B-H, 6b^A-H, 6b^B-H), 2.54 (s, 3 H, CH₃6-O-Ts), 2.45 (s,

2

J_5a,4= 6.3 Hz, 1 H, 5a-H), 3.93 (dd, J_5b,5a= 10.6, J_5b,4= 7.3 Hz,

A

3 H, CH₃6-O-Ts), 1.57, 1.40 [2 s, 2ϫ 3 H, C(CH₃)₂^B], 1.48 (s,

1 H, 5b-H), 1.46, 1.38 [2 s, 2 ϫ 3 H, C(CH₃)₂], 0.90 [s, 9 H,

SiC(CH₃)₃], 0.09 [s, 6 H, Si(CH₃)₂] ppm. ¹³C NMR (100 MHz,

CDCl₃, 20 °C): δ = 173.9 (C-1), 114.2 [C(CH₃)₂], 79.5 (C-4), 76.2,

75.9 (C-2, C-3), 61.0 (C-5), 26.9, 26.0 [C(CH₃)₂], 25.9 [SiC(CH₃)₃],

18.5 [SiC(CH₃)₃], –5.2, –5.4 [Si(CH₃)₂] ppm. MS (ESI): m/z (%) =

325 (10) [M + Na]⁺, 357 (100) [M + MeOH + Na]⁺.

3 H, 1^A-H), 1.45, 1.30 [2 s, 2ϫ 3 H, C(CH₃)₂^A], 1.36 (s, 3 H, 1^B-H)

ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 145.2 (C^A-p 6-O-

Ts, C^B-p 6-O-Ts), 132.9 (C^A-i 6-O-Ts), 132.5 (C^B-i 6-O-Ts), 130.0,

128.2 (C^A-Ar, C^B-Ar), 116.1 [C(CH₃)₂^B], 113.1 [C(CH₃)₂^A], 107.7

(C-2^A), 102.3 (C-2^B), 85.7 (C-3^A), 83.9 (C-3^B), 83.0 (C-5^A), 82.5 (C-

4^A), 81.0 (C-4^B), 78.9 (C-5^B), 70.4 (C-6^A), 69.1 (C-6^B), 26.6, 25.9

[C(CH₃)₂^B], 26.6, 25.3 [C(CH₃)₂^A], 25.0 (C-1^B), 22.9 (C-1^A), 21.8

6-O-tert-Butyldimethylsilyl-1-deoxy-3,4-O-isopropylidene-L-tagato-

A

B

furanose (36): Methyllithium (1.6 m in Et₂O; 7.8 mL, 12.4 mmol)

was added dropwise to a solution of lactone 35 (3.13 g, 10.4 mmol)

in THF (40 mL) at –78 °C. The reaction mixture was stirred for

4 h, after which TLC analysis (5:1, cyclohexane/ethyl acetate) indi-

cated the complete consumption of the starting material (R_f= 0.40)

and the formation of a major product (R_f= 0.38). Water (30 mL)

and ethyl acetate (200 mL) were added slowly, and the mixture was

stirred vigorously at room temp. The phases were separated, and

the aqueous layer was extracted with ethyl acetate (3ϫ 100 mL).

The organic fractions were combined, dried (MgSO₄), filtered, and

concentrated in vacuo. The crude residue was purified by flash

chromatography (49:1 to 9:1, cyclohexane/ethyl acetate) to give lac-

tols 36 (2.73 g, 83%) as a white crystalline solid, as a 4.1:1 (A:B)

anomeric mixture. HRMS (ESI): calcd. for [C₁₅H₃₀O₅Si + Na]⁺

341.1755; found 341.1755, m.p. 66–72 °C. [α]²_D⁰= –8.1 (c = 1.32,

(CH₃6-O-Ts, CH₃6-O-Ts) ppm. MS (ESI): m/z (%) = 381 (100)

[M + Na]⁺.

2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-2-N-(4-methoxybenz-

yl)-2-C-methyl-

O-isopropylidene-

D

-altrononitrile (33) and 2,6-Anhydro-1-deoxy-3,4-

-psicofuranose (34): See General Procedure. 4-

D

Methoxybenzylamine (0.18 mL, 1.40 mmol), potassium cyanide

(91 mg, 1.40 mmol), and tosylate 32 (200 mg, 0.56 mmol) at room

temp. for 1 d, and at 40 °C for 2 d, gave α-iminonitrile 33 (R_f=

0.47; 26 mg, 14%) as a yellow oil, and anhydro compound 34 (R_f

= 0.68; 54 mg, 51%) as a volatile, white crystalline solid.

Data for α-iminonitrile 33: HRMS (ESI): calcd. for [C₁₈H₂₄N₂O₄

+ Na]⁺355.1628; found 355.1626. [α]²_D⁰= –12.9 (c = 0.89, CHCl₃).

IR (film): ν = 3460, 2221 cm^{–1 1}H NMR (500 MHz, CDCl₃,

.

˜

20 °C): δ = 7.18 (d, J = 8.5 Hz, 2 H, H-Ar), 6.86 (d, J = 8.5 Hz,

2 H, H-Ar), 4.50 (a-t, J_4,3= J_4,5= 5.2 Hz, 1 H, 4-H), 3.99 (d, ²J_gem

= 13.2 Hz, 1 H, CHa 2-N-PMB), 3.88 (d, J_3,4= 5.7 Hz, 1 H, 3-H),

3.80 (s, 3 H, CH₃2-N-PMB), 3.83–3.78 (m, 1 H, 5-H), 3.17 (d,

²J_gem= 13.2 Hz, 1 H, CHb 2-N-PMB), 2.78 (dd, ²J_6a,6b= 11.9, J_6a,5

CHCl ). IR (film): ν = 3430 cm^–1. ¹H NMR (400 MHz, CDCl₃,

˜

3

20 °C): δ = 4.77 (dd, J_4,3= 5.8, J_4,5= 3.8 Hz, 1 H, 4^A-H), 4.72 (dd,

J_4,3= 6.1, J_4,5= 3.5 Hz, 1 H, 4^B-H), 4.43 (d, J_3,4= 5.8 Hz, 1 H,

3^A-H), 4.25 (d, J_3,4= 6.1 Hz, 1 H, 3^B-H), 4.16 (a-td, J_5,6a= J_5,6b

=

2

6.4, J_5,4= 4.0 Hz, 1 H, 5^A-H), 3.93 (dd, J_6a,6b= 10.6, J_6a,5

2

= 6.0 Hz, 1 H, 6a-H), 2.48 (a-t, J_6b,6a= J_6b,5= 11.7 Hz, 1 H, 6b-

2

5.6 Hz, 1 H, 6a^A-H), 3.90 (dd, J_6a,6b= 10.6, J_6a,5= 7.1 Hz, 1 H,

6a^B-H), 3.78 (a-dd, ²J = 10.6, J = 6.6 Hz, 2 H, 6b^A-H, 6b^B-H), 3.66

(ddd, J_5,6a= 7.1, J_5,6b= 5.3, J_5,4= 3.8 Hz, 1 H, 5^B-H), 1.52, 1.35

[2 s, 2ϫ 3 H, C(CH₃)₂^B], 1.51 (s, 3 H, 1^A-H), 1.38 (s, 3 H, 1^B-H),

1.44, 1.30 [2 s, 2ϫ 3 H, C(CH₃)₂^A], 0.90 [s, 9 H, SiC(CH₃)₃^A], 0.89

[s, 9 H, SiC(CH₃)₃^B], 0.08 [s, 6 H, Si(CH₃)₂^A], 0.06 [s, 6 H,

Si(CH₃)₂^B] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 112.8

[C(CH₃)₂^B], 112.6 [C(CH₃)₂^A], 105.3 (C-2^A), 102.3 (C-2^B), 85.5 (C-

3^A), 82.4 (C-3^B), 80.7 (C-4^A), 79.9 (C-5^A), 79.9 (C-4^B), 77.0 (C-5^B),

61.6 (C-6^A), 61.0 (C-6^B), 26.3 [SiC(CH₃)₃^B], 26.1 [SiC(CH₃)₃^A],

H), 1.77, 1.41 [2 s, 2ϫ 3 H, C(CH₃)₂], 1.68 (s, 3 H, 2-CH₃) ppm.

¹³C NMR (125 MHz, CDCl₃, 20 °C): δ = 159.2 (C-p 2-N-PMB),

129.9 (C-Ar), 129.7 (C-i 2-N-PMB), 119.3 (CN), 114.1 (C-Ar),

111.4 [C(CH₃)₂], 80.4 (C-3), 74.1 (C-4), 65.6 (C-5), 62.9 (C-2), 55.5

(CH₃2-N-PMB), 53.4 (CH₂2-N-PMB), 49.2 (C-6), 26.1, 25.5

[C(CH₃)₂], 25.7 (2-CH₃) ppm. MS (ESI): m/z = 371 (12) [M +

K]⁺, 355 (100) [M + Na]⁺.

Selected Data for 34: M.p. 102–104 °C [ref.^[51]m.p. 105–106 °C

(hexane)]. [α]²_D⁰= –65.4 (c = 1.1, CHCl₃)] (c = 1.13, CHCl₃) [ref.^[51]

[α]_D= –78.1. ¹H NMR (400 MHz, CDCl₃, 20 °C): δ = 4.58 (d, J_5,6a26.0, 25.0 [C(CH₃)₂^A], 26.1, 24.9 [C(CH₃)₂^B], 22.8 (C-1^A), 22.2 (C-

= 4.0 Hz, 1 H, 5-H), 4.38 (d, J_4,3= 5.5 Hz, 1 H, 4-H), 4.10 (d, J_3,4

1^B), 18.7 [SiC(CH₃)₃^A], 18.5 [SiC(CH₃)₃^B], –5.1 (SiCH₃^A), –5.2

Eur. J. Org. Chem. 2014, 2053–2069

www.eurjoc.org

2065

B. J. Ayers, G. W. J. Fleet

FULL PAPER

2

(SiCH₃^A, SiCH₃^B), –5.3 (SiCH₃^B) ppm. MS (ESI): m/z (%) = 341

CH₃2-N-PMB), 3.17 (d, J_gem= 12.6 Hz, 1 H, CHb 2-N-PMB),

2.88 (dd, ²J_6a,6b= 13.5, J_6a,5= 1.8 Hz, 1 H, 6a-H), 2.74 (dd, ²J_6b,6a

= 13.5, J_6b,5= 2.4 Hz, 1 H, 6b-H), 2.25 (br. d, J_OH,5= 7.3 Hz, 1 H,

5-OH), 1.74, 1.38 [2 s, 2ϫ 3 H, C(CH₃)₂], 1.73 (s, 3 H, 2-CH₃) ppm.

¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 159.3 (C-p 2-N-PMB),

130.2 (C-Ar), 129.3 (C-i 2-N-PMB), 119.0 (CN), 114.4 (C-Ar),

111.1 [C(CH₃)₂], 78.1 (C-3), 76.0 (C-4), 64.7 (C-5), 63.4 (C-2), 55.4

(CH₃2-N-PMB), 53.3 (CH₂2-N-PMB), 49.4 (C-6), 26.1 [C(CH)₃],

25.6 [2-CH₃, C(CH)₃] ppm. MS (ESI): m/z (%) = 371 (25) [M +

K]⁺, 355 (100) [M + Na]⁺.

(100) [M + Na]⁺.

1-Deoxy-3,4-O-isopropylidene-L-tagatofuranose (37): Tetra-n-butyl-

ammonium fluoride (1 m in THF; 11.0 mL, 11.0 mmol) was added

dropwise to a solution of silyl ethers 36 (2.68 g, 8.41 mmol) at room

temp. The reaction mixture was stirred for 18 h, after which TLC

analysis (5:1, cyclohexane/ethyl acetate) indicated the complete

consumption of the starting materials (R_f= 0.38) and the forma-

tion of a major product (baseline). The reaction mixture was con-

centrated in vacuo. The crude residue was purified by flash

chromatography (3:1:0 to 0:9:1, cyclohexane/ethyl acetate/meth-

anol) to give lactol 37 (1.60 g, 93%) as a white crystalline solid, as a

single anomer. HRMS (ESI): calcd. for [C₉H₁₆O₅+ Na]⁺227.0890;

5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-2-C-methyl-D-rib-

ono-1,4-lactone (40): tert-Butyldimethylsilyl chloride (2.8 g,

18.5 mmol) was added in one portion to a solution of lactone 17

(2.5 g, 12.4 mmol) at room temp. The reaction mixture was stirred

found 227.0895, m.p. 130–131 °C. [α]²_D⁰= –19.0 (c = 1.55, CHCl₃).

IR (film): ν = 3359 cm^–1. H NMR (400 MHz, CD OD, 20 °C): δ for 17 h, after which TLC analysis (1:1, cyclohexane/ethyl acetate)

1

˜

3

= 4.79 (dd, J_4,3= 5.8, J_4,5= 3.9 Hz, 1 H, 4-H), 4.36 (d, J_3,4

=

indicated the complete consumption of the starting material (R_f=

0.53) and the formation of a major product (R_f= 0.91). The reac-

tion mixture was diluted with ethyl acetate (150 mL) and washed

with hydrochloric acid (2 m aq.; 3ϫ 50 mL). The organic phase

was dried (MgSO₄), filtered, and concentrated in vacuo. The crude

residue was purified by flash chromatography (19:1 to 9:1, cyclo-

hexane/ethyl acetate) to give silyl ether 40 (3.56 g, 91%) as a white

crystalline solid. HRMS (ESI): calcd. for [C₁₅H₂₈O₅Si + Na]⁺

339.1598; found 339.1596, m.p. 50–52 °C. [α]²_D⁵= –19.5 (c = 1.49,

5.8 Hz, 1 H, 3-H), 4.12 (ddd, J_5,6b= 6.8, J_5,6a= 5.1, J_5,4= 3.9 Hz,

2

1 H, 5-H), 3.80 (dd, J_6a,6b= 11.4, J_6a,5= 5.1 Hz, 1 H, 6a-H), 3.68

2

(dd, J_6b,6a= 11.4, J_6b,5= 6.8 Hz, 1 H, 6b-H), 1.42 (s, 3 H, 1-H),

1.41, 1.30 [2 s, 2 ϫ 3 H, C(CH₃)₂] ppm. ¹³C NMR (100 MHz,

CD₃OD, 20 °C): δ = 113.5 [C(CH₃)₂], 105.8 (C-2), 87.2 (C-3), 82.0

(C-4), 80.4 (C-5), 61.3 (C-6), 26.4, 24.9 [C(CH₃)₂], 22.2 (C-1) ppm.

MS (ESI): m/z (%) = 227 (100) [M + Na]⁺.

1-Deoxy-3,4-O-isopropylidene-6-O-p-tolylsulfonyl-L-tagatofuranose

CHCl ). IR (film): ν = 1787 cm^–1. ¹H NMR (400 MHz, CDCl₃,

˜

3

(38): A solution of p-toluenesulfonyl chloride (1.5 g, 7.84 mmol) in

pyridine (2 mL) was added dropwise to a solution of lactol 37

(800 mg, 3.92 mmol) in pyridine (8 mL) at 0 °C. After 30 min, the

reaction mixture was warmed to room temp. and stirred for a fur-

ther 16 h, after which TLC analysis (5:1, toluene/acetone) indicated

the complete consumption of the starting material (R_f= 0.09) and

the formation of a major product (R_f= 0.56). The reaction mixture

was diluted with ethyl acetate (200 mL) and washed with hydro-

chloric acid (2 m aq.; 3ϫ 30 mL). The organic phase was dried

(MgSO₄), filtered, and concentrated in vacuo. The crude residue

was purified by flash chromatography (19:1 to 7:3, cyclohexane/

20 °C): δ = 4.50 (s, 1 H, 3-H), 4.48 (a-t, J_4,5a= J_4,5b= 2.3 Hz, 1 H,

4-H), 3.91 (dd, J_5a,5b= 11.6, J_5a,4= 3.0 Hz, 1 H, 5a-H), 3.84 (dd,

2

²J_5b,5a= 11.6, J_5b,4= 1.8 Hz, 1 H, 5b-H), 1.63 (s, 3 H, 2-CH₃), 1.44,

1.42 [2 s, 2ϫ 3 H, C(CH₃)₂], 0.89 [s, 9 H, SiC(CH₃)₃], 0.08, 0.07 [2

s, 6 H, Si(CH₃)₂] ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ =

176.3 (C-1), 113.0 [C(CH₃)₂], 83.3 (C-4), 82.9 (C-2), 82.8 (C-3), 63.4

(C-5), 27.0, 27.0 [C(CH₃)₂], 26.1 [SiC(CH₃)₃], 20.1 (2-CH₃), 18.8

[SiC(CH₃)₃], –5.2, –5.5 [Si(CH₃)₂] ppm. MS (ESI): m/z (%) = 339

(100) [M + Na]⁺, 334 (75) [M + NH₄]⁺.

6-O-tert-Butyldimethylsilyl-1-deoxy-3,4-O-isopropylidene-3-C-

ethyl acetate) to give tosylate 38 (1.22 g, 87%) as a white crystalline methyl-D-psicofuranose (41): Methyllithium (1.6 m in Et₂O; 6.5 mL,

solid, as a single anomer. HRMS (ESI): calcd. for [C₁₆H₂₂O₇S +

10.4 mmol) was added dropwise to a solution of lactone 40 (3.0 g,

9.48 mmol) in THF (30 mL) at –78 °C. The reaction mixture was

Na]⁺381.0978; found 381.0975, m.p. 90–92 °C. [α]²_D⁰= –4.6 (c =

2.05, CHCl ). IR (film): ν = 3489, 1364, 1177 cm^{–1 1}H NMR stirred for 4 h, after which TLC analysis (5:1, cyclohexane/ethyl

.

˜

3

(400 MHz, CDCl₃, 20 °C): δ = 7.80 (d, 2 H, H-Ar), 7.33 (d, 2 H,

H-Ar), 4.73 (dd, J_4,3= 5.8, J_4,5= 3.8 Hz, 1 H, 4-H), 4.40 (d, J_3,4

5.8 Hz, 1 H, 3-H), 4.28 (dd, J_6a,6b= 11.4, J_6a,5= 3.8 Hz, 1 H, 6a- Water (30 mL) and ethyl acetate (75 mL) were added slowly, and

acetate) indicated the complete consumption of the starting mate-

rial (R_f= 0.73) and the formation of a major product (R_f= 0.81).

=

2

H), 4.27 (dt, J_5,6b= 8.3, J_5,4= J_5,6a= 3.8 Hz, 1 H, 5-H), 4.14 (dd,

the resulting biphasic mixture was warmed to room temp. The

phases were separated, and the aqueous layer was extracted with

²J_6b,6a= 11.4, J_6b,5= 8.3 Hz, 1 H, 6b-H), 2.44 (s, 3 H, CH₃6-O-

Ts), 1.46 (s, 3 H, 1-H), 1.34, 1.25 [2 s, 2ϫ 3 H, C(CH₃)₂] ppm. ¹³C ethyl acetate (3ϫ 75 mL). The organic fractions were combined,

NMR (100 MHz, CDCl₃, 20 °C): δ = 145.0 (C-p 6-O-Ts), 132.9 (C- dried (MgSO₄), filtered, and concentrated in vacuo. The crude resi-

i 6-O-Ts), 129.9 (C-Ar), 128.3 (C-Ar), 113.0 [C(CH₃)₂], 105.7 (C-

due was purified by flash chromatography (19:1 to 9:1, cyclohex-

2), 85.3 (C-3), 80.5 (C-4), 76.5 (C-5), 68.3 (C-6), 26.1, 24.8 ane/ethyl acetate) to give lactol 41 (2.20 g, 70%) as a colourless oil,

[C(CH₃)₂], 22.4 (C-1), 21.8 (CH₃6-O-Ts) ppm. MS (ESI): m/z (%)

as a single anomer. HRMS (ESI): calcd. for [C₁₆H₃₂O₅Si + Na]⁺

= 381 (100) [M + Na]⁺.

355.1911; found 355.1911. [α]²_D⁵= +4.5 (c = 3.79, CHCl₃). IR (film):

ν = 3398 cm^–1. ¹H NMR (400 MHz, CDCl₃, 20 °C): δ = 4.97 (s,

˜

2,6-Dideoxy-2,6-imino-3,4-O-isopropylidene-2-N-(4-methoxybenz-

yl)-2-C-methyl-L-galactononitrile (39): See General Procedure. 4-

1 H, 3-H), 4.48 (d, J_4,5= 1.3 Hz, 1 H, 4-H), 4.15 (a-q, J_5,4= J_5,6a

2

= J_5,6b= 1.5 Hz, 1 H, 5-H), 3.78 (dd, J_6a,6b= 11.1, J_6a,5= 1.5 Hz,

Methoxybenzylamine (0.18 mL, 1.40 mmol), potassium cyanide

(91 mg, 1.40 mmol), and tosylate 38 (201 mg, 0.56 mmol) at 65 °C

for 2 d gave recovered starting material 38 (69 mg, 34%) and α-

iminonitrile 39 (25 mg, 13%; 20% b.r.s.m.) as a yellow oil. HRMS

(ESI): calcd. for [C₁₈H₂₄N₂O₄+ Na]⁺355.1628; found 355.1622.

1 H, 6a-H), 3.73 (dd, ²J_6b,6a= 11.1, J_6b,5= 1.8 Hz, 1 H, 6b-H), 1.47

(s, 3 H, 1-H), 1.45, 1.43 [2 s, 2ϫ 3 H, C(CH₃)₂], 1.42 (s, 3 H, 3-

CH₃), 0.92 [s, 9 H, SiC(CH₃)₃], 0.13 [s, 6 H, Si(CH₃)₂] ppm. ¹³C

NMR (100 MHz, CDCl₃, 20 °C): δ = 112.9 [C(CH₃)₂], 107.6 (C-2),

93.5 (C-3), 87.6 (C-4), 85.0 (C-5), 65.2 (C-6), 29.1, 27.9 [C(CH₃)₂],

25.9 [SiC(CH₃)₃], 20.8 (C-1), 20.6 (3-CH₃), 18.5 [SiC(CH₃)₃], –5.8

[Si(CH₃)₂] ppm. MS (ESI): m/z (%) = 355 (100) [M + Na]⁺.

[α]²_D⁰= +34.1 (c = 1.13, CHCl ). IR (film): ν = 3478, 2230 cm^–1. ¹H

˜

3

NMR (400 MHz, CDCl₃, 20 °C): δ = 7.19 (d, J = 8.6 Hz, 2 H, H-

Ar), 6.88 (d, J = 8.6 Hz, 2 H, H-Ar), 4.26 (dd, J_4,3= 5.6, J_4,5

1.3 Hz, 1 H, 4-H), 4.05 (d, J_gem= 12.6 Hz, 1 H, CHa 2-N-PMB),

3.96 (d, J_3,4= 5.6 Hz, 1 H, 3-H), 3.92 (br. s, 1 H, 5-H), 3.80 (s, 3 H,

=

2

1-Deoxy-3,4-O-isopropylidene-3-C-methyl-D-psicofuranose (42) and

2,6-Anhydro-1-deoxy-3,4-O-isopropylidene-3-C-methyl-

D

-psicofur-

2066

www.eurjoc.org

Eur. J. Org. Chem. 2014, 2053–2069

One-Pot Iminosugar Synthesis

anose (43): Tetra-n-butylammonium fluoride (1 m in THF; 7.2 mL,

7.2 mmol) was added dropwise to a solution of lactol 41 (1.82 g,

5.47 mmol) at room temp. The reaction mixture was stirred for 2 h,

after which TLC analysis (1:1, cyclohexane/ethyl acetate) indicated

the complete consumption of the starting material (R_f= 0.91) and

the formation of major (R_f= 0.34) and minor (R_f= 0.95) products.

The reaction mixture was concentrated in vacuo. The crude residue

was purified by flash chromatography (3:1:0 to 0:9:1, cyclohexane/

ethyl acetate/methanol) to give lactols 42 (R_f= 0.34, 1.02 g, 85%)

as a colourless oil, as a 1:1 (A:B) mixture of anomers, and 2,6-

anhydro compound 43 (R_f= 0.95, 55 mg, 5%) as a volatile, white

crystalline solid.

O-Ts), 132.9 (C^A-i 6-O-Ts), 132.6 (C^B-i 6-O-Ts), 130.0 (C^B-Ar),

130.0 (C^A-Ar), 128.2 (C^A-Ar), 128.1 (C^B-Ar), 115.8 [C(CH₃)₂^B],

113.4 [C(CH₃)₂^A], 108.4 (C-2^A), 104.2 (C-2^B), 92.1 (C-3^A), 89.8 (C-

3^B), 88.2 (C-4^A), 86.6 (C-4^B), 81.4 (C-5^A), 77.6 (C-5^B), 70.6 (C-6^A),

69.1 (C-6^B), 28.9, 27.8 [C(CH₃)₂^A], 27.0, 26.2 [C(CH₃)₂^B], 22.8 (C-

1^B), 22.5 (C-1^A), 21.8 (CH₃^A6-O-Ts, CH₃^B6-O-Ts), 21.3 (3-CH₃^B),

20.4 (3-CH₃^A) ppm. MS (ESI): m/z (%) = 395 (100) [M + Na]⁺.

2,6-Anhydro-1-deoxy-3,4-O-isopropylidene-3-C-methyl-D-psicofur-

anose (43): See General Procedure. 4-Methoxybenzylamine

(0.17 mL, 1.32 mmol), potassium cyanide (86 mg, 1.32 mmol), and

tosylate 44 (197 mg, 0.53 mmol) at 45 °C for 2 d gave anhydro com-

pound 43 (74 mg, 70%) as a volatile, white crystalline solid.

Data for lactols 42: HRMS (ESI): calcd. for [C₁₀H₁₈O₅+ Na]⁺

241.1046; found 241.1041. [α]²_D⁵= –53.1 (c = 1.92, CHCl₃). IR

5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-3-C-methyl-L-

(film): ν = 3286 cm^–1. ¹H NMR (400 MHz, CDCl , 20 °C): δ = 4.57

lyxono-1,4-lactone (46): tert-Butyldimethylsilyl chloride (1.32 g,

8.75 mmol) was added to a solution of lactone 22 (1.18 g,

5.84 mmol) in pyridine (6 mL) at room temp. The reaction mixture

was stirred for 16 h, after which TLC analysis (1:1, cyclohexane/

ethyl acetate) indicated the complete consumption of the starting

material (R_f= 0.20) and the formation of a major product (R_f=

0.88). The reaction mixture was diluted with ethyl acetate (150 mL)

and washed with hydrochloric acid (2 m aq.; 40 mL). The organic

phase was dried (MgSO₄), filtered, and concentrated in vacuo. The

crude residue was purified by flash chromatography (39:1 to 9:1,

cyclohexane/ethyl acetate) to give silyl ether 46 (1.78 g, 97%) as a

white crystalline solid. HRMS (ESI): calcd. for [C₁₅H₂₈O₅Si +

Na]⁺339.1598; found 339.1592, m.p. 46–48 °C. [α]²_D⁰= –41.1 (c =

˜

3

(d, J_4,5= 1.2 Hz, 1 H, 4^B-H), 4.48 (br. d, J_5,6a= 4.0 Hz, 1 H, 5^A-

H), 4.18–4.17 (m, 1 H, 5^B-H), 4.01 (br. s, 1 H, 4^A-H), 3.82–3.68 (m,

2 H, 6a^B-H, 6b^B-H), 3.56 (dd, J_6a,6b= 9.8, J_6a,5= 4.3 Hz, 1 H,

2

6a^A-H), 3.33 (d, J_6b,6a= 9.8 Hz, 1 H, 6b^A-H), 1.52 (s, 3 H, 3-

2

CH₃^B), 1.50 (s, 3 H, 3-CH₃^A), 1.46 [s, 3 H, C(CH₃)^B], 1.45 [s, 6 H,

1^B-H, C(CH₃)^A], 1.43 [s, 3 H, C(CH₃)^B], 1.40 [s, 3 H, C(CH₃)^A],

1.37 (s, 3 H, 1^A-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ =

112.9 [C(CH₃)₂^A], 112.4 [C(CH₃)₂^B], 109.3 (C-2^B), 107.7 (C-2^A),

93.0 (C-3^A), 89.7 (C-3^B), 87.6 (C-4^B), 86.0 (C-4^A), 85.4 (C-5^B), 78.5

(C-5^A), 63.8 (C-6^A), 63.8 (C-6^B), 28.8, 27.8 [C(CH₃)₂^B], 27.9, 27.2

[C(CH₃)₂^A], 22.9 (3-CH₃^B) 21.9 (3-CH₃^A), 20.4 (C-1^B), 19.8 (C-1^A)

ppm. MS (ESI): m/z (%) = 217 (100) [M – H]^–.

2.38, CHCl ). IR (film): ν = 1789 cm^{–1 1}H NMR (400 MHz,

.

˜

3

Selected Data for 2,6-anhydro compound 43: M.p. 44–46 °C [sub-

limes]. [α]²_D⁵= –15.1 (c = 1.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃,

CDCl₃, 20 °C): δ = 4.42 (a-td, J_4,5a= J_4,5b= 6.2, J_4,3= 3.3 Hz,

1 H, 4-H), 4.39 (d, J_3,4= 3.3 Hz, 1 H, 3-H), 3.95 (dd, ²J_5a,5b= 10.9,

20 °C): δ = 4.46 (d, J_5,6a= 4.3 Hz, 1 H, 5-H), 4.00 (s, 1 H, 4-H),

2

J_5a,4= 5.8 Hz, 1 H, 5a-H), 3.93 (dd, J_5b,5a= 10.9, J_5b,4= 6.6 Hz,

2

3.54 (dd, ²J_6a,6b= 7.3, J_6a,5= 4.3 Hz, 1 H, 6a-H), 3.32 (d, J_6b,6a

=

1 H, 5b-H), 1.54 (s, 3 H, 2-CH₃), 1.42, 1.38 [2 s, 2 ϫ 3 H,

7.3 Hz, 1 H, 6b-H), 1.51 (s, 3 H, 1-H), 1.42, 1.36 [2 s, 2ϫ 3 H,

C(CH₃)₂], 1.39 (s, 3 H, 3-CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃,

20 °C): δ = 112.4 [C(CH₃)₂], 109.3 (C-2), 89.7 (C-3), 86.1 (C-4),

78.5 (C-5), 63.8 (C-6), 27.9, 27.2 [C(CH₃)₂], 19.8 (3-CH₃), 12.4 (C-

1) ppm.

C(CH₃)₂], 0.90 [s, 9 H, SiC(CH₃)₃], 0.09 [s, 6 H, Si(CH₃)₂] ppm. ¹³

C

NMR (100 MHz, CDCl₃, 20 °C): δ = 176.5 (C-1), 113.1

[C(CH₃)₂], 83.0 (C-2), 80.5 (C-3), 78.5 (C-4), 61.0 (C-5), 27.0, 26.8

[C(CH₃)₂], 25.9 [SiC(CH₃)₃], 18.4 [SiC(CH₃)₃], 18.2 (2-CH₃), –5.2,

–5.4 [Si(CH₃)₂] ppm. MS (ESI): m/z (%) = 339 (100) [M + Na]⁺.

1-Deoxy-3,4-O-isopropylidene-3-C-methyl-6-O-p-tolylsulfonyl-

psicofuranose (44) and 2,6-Anhydro-1-deoxy-3,4-O-isopropylidene-3-

C-methyl- -psicofuranose (43): A solution of p-toluenesulfonyl

D-

6-O-tert-Butyldimethylsilyl-1-deoxy-3,4-O-isopropylidene-3-C-

methyl-L-tagatofuranose (47): Methyllithium (1.6 m in Et₂O;

D

4.1 mL, 6.52 mmol) was added dropwise to a solution of lactone

46 (1.72 g, 5.43 mmol) in THF (17 mL) at –78 °C. The reaction

mixture was stirred for 2.5 h, after which TLC analysis (5:1, cyclo-

hexane/ethyl acetate) indicated the complete consumption of the

starting material (R_f= 0.48) and the formation of a major product

(R_f= 0.47). Water (15 mL) and ethyl acetate (100 mL) were added

slowly, and the vigorously stirred, biphasic mixture was warmed to

room temp. The phases were separated, and the aqueous layer was

extracted with ethyl acetate (3ϫ 75 mL). The organic fractions

were combined, dried (MgSO₄), filtered, and concentrated in

vacuo. The crude residue was purified by flash chromatography

(39:1 to 9:1, cyclohexane/ethyl acetate) to give lactols 47 (1.62 g,

90%) as a white crystalline solid, as a 2.4:1 (A:B) mixture of ano-

mers. HRMS (ESI): calcd. for [C₁₆H₃₂O₅Si + Na]⁺355.1911; found

355.1906, m.p. 78–80 °C. [α]²_D⁰= +1.9 (c = 1.35, CHCl₃). IR (film):

chloride (890 mg, 4.67 mmol) in pyridine (2 mL) was added drop-

wise to a solution of lactols 42 (510 mg, 2.34 mmol) in pyridine

(4 mL) at –30 °C. After 30 min, the reaction mixture was warmed

to 0 °C, and after a further 1 h, it was warmed to room temp. After

19 h at room temp., TLC analysis (5:1, toluene/acetone) indicated

the complete consumption of the starting materials (R_f= 0.20) and

the formation of a major product (R_f= 0.60) and a minor product

(R_f= 0.64). The reaction mixture was diluted with ethyl acetate

(100 mL) and washed with hydrochloric acid (2 m aq.; 3ϫ 25 mL).

The organic phase was dried (MgSO₄), filtered, and concentrated

in vacuo. The crude residue was purified by flash chromatography

(99:1 to 9:1, toluene/acetone) to give tosylates 44 (660 mg, 76%) as

a white, waxy solid, as a 2:1 (A:B) ratio of anomers, and 2,6-anhy-

dro compound 43 (28 mg, 6%) as a volatile, white crystalline solid.

Data for tosylates 44: HRMS (ESI): calcd. for [C₁₇H₂₄O₇S + Na]⁺

395.1135; found 395.1131, m.p. 92–94 °C. [α]²_D⁵= +13.7 (c = 3.12,

ν = 3455 cm^–1. ¹H NMR (400 MHz, CDCl₃, 20 °C): δ = 4.39 (d,

˜

J_4,5= 3.5 Hz, 1 H, 4^A-H), 4.36 (d, J_4,5= 3.3 Hz, 1 H, 4^B-H), 4.15

CHCl ). IR (film): ν = 3487, 1369, 1190 cm^–1. ¹H NMR (400 MHz, (a-td, J_5,6a= J_5,6b= 6.0, J_5,4= 3.5 Hz, 1 H, 5^A-H), 3.93 (dd, ²J_6a,6b

˜

3

CDCl₃, 20 °C): δ = 7.81–7.77 (m, 4 H, H^A-Ar, H^B-Ar), 7.36–7.34

(m, 4 H, H^A-Ar, H^B-Ar), 4.32–4.31 (m, 1 H, 4^B-H), 4.27–4.09 (m,

7 H, 4^A-H, 5^A-H, 5^B-H, 6a^A-H, 6a^B-H, 6b^A-H, 6b^B-H), 2.44 (s, 6 H,

= 10.4, J_6a,5= 5.7 Hz, 1 H, 6a^A-H), 3.90 (dd, J_6a,6b= 9.8, J_6a,5

=

2

7.3 Hz, 1 H, 6a^B-H), 3.80 (dd, J_6b,6a= 10.4, J_6b,5= 6.3 Hz, 1 H,

2

6b^A-H), 3.79 (dd, J_6b,6a= 9.8, J_6b,5= 5.3 Hz, 1 H, 6b^B-H), 3.64

2

CH₃6-O-Ts, CH₃6-O-Ts), 1.54 (s, 3 H, CH₃^B), 1.43–1.38 (m,

(ddd, J_5,6a= 7.3, J_5,6b= 5.3, J_5,4= 3.3 Hz, 1 H, 5^B-H), 1.50, 1.47

A

B

18 H, CH₃^A, CH₃^B), 1.28 (s, 3 H, CH₃^B) ppm. ¹³C NMR [2 s, 2ϫ 3 H, C(CH₃)₂^B], 1.47 (s, 6 H, 3-CH₃^A, 3-CH₃^B), 1.44 (s,

(100 MHz, CDCl₃, 20 °C): δ = 145.3 (C^B-p 6-O-Ts), 145.1 (C^A-p 6-

3 H, 1^A-H), 1.43, 1.40 [2 s, 2ϫ 3 H, C(CH₃)₂^A], 1.34 (s, 3 H, 1^B-

Eur. J. Org. Chem. 2014, 2053–2069

www.eurjoc.org

2067

B. J. Ayers, G. W. J. Fleet

FULL PAPER

H), 0.90 [s, 9 H, SiC(CH₃)₃^A], 0.90 [s, 9 H, SiC(CH₃)₃^B], 0.08 [s,

6 H, Si(CH₃)₂^A], 0.06 [s, 6 H, Si(CH₃)₂^B] ppm. ¹³C NMR

(100 MHz, CDCl₃, 20 °C): δ = 112.9 [C(CH₃)₂^B], 112.8 [C(CH₃)₂^A],

106.4 (C-2^A), 104.2 (C-2^B), 92.2 (C-3^A), 89.0 (C-3^B), 86.8 (C-4^A),

85.8 (C-4^B), 79.0 (C-5^A), 76.1 (C-5^B), 61.4 (C-6^A), 60.9 (C-6^B), 27.9,

27.4 [C(CH₃)₂^A], 27.2, 25.9 [C(CH₃)₂^B], 26.2 [SiC(CH₃)₃^A], 26.1

[SiC(CH₃)₃^B], 22.7 (3-CH₃^A), 21.0 (3-CH₃^B), 20.7 (C-1^A), 20.3 (C-

1^B), 18.7 [SiC(CH₃)₃^A], 18.5, [SiC(CH₃)₃^B], –5.1, –5.3 [Si(CH₃)₂^A],

–5.1 [Si(CH₃)₂^B] ppm. MS (ESI): m/z (%) = 355 (100) [M + Na]⁺.

Acknowledgments

This work was supported by the Newton Abraham Research Fund

(grant to B. J. A.) and the Leverhulme Trust (grant to G. W. J. F.).

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1-Deoxy-3,4-O-isopropylidene-3-C-methyl-

L-tagatofuranose/1-de-

oxy-3,4-O-isopropylidene-3-C-methyl- -tagatopyranose (48): Tetra-

L

n-butylammonium fluoride (1 m in THF; 6.2 mL, 6.2 mmol) was

added dropwise to a solution of lactols 47 (1.59 g, 4.78 mmol) at

room temp. The reaction mixture was stirred for 2.5 h, after which

TLC analysis (5:1, cyclohexane/ethyl acetate) indicated the com-

plete consumption of the starting materials (R_f= 0.52) and the

formation of a major product (baseline). The reaction mixture was

concentrated in vacuo to give crude lactols 48 as a white crystalline

solid, which was used without further purification. Partial data for

the mixture of lactols 48: HRMS (ESI): calcd. for [C₁₀H₁₈O₅S +

Na]⁺241.1046; found 241.1051, m.p. 100–102 °C. [α]²_D⁰= –16.8 (c

[4]

[5]

[6]

[7]

[8] T. Takatsu, M. Takahashi, Y. Kawase, R. Enokita, T. Okazaki,

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shita, M. Nakajima, K. Tanzawa, J. Antibiot. 1996, 49, 54–60.

= 1.33, CHCl ). IR (film): ν = 3448 cm^–1. MS (ESI): m/z (%) = 241

˜

3

(100) [M + Na]⁺.

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tagatofuranose (49): solution of p-toluenesulfonyl chloride

A

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B. P. Bashyal, H. F. Chow, L. E. Fellows, G. W. J. Fleet, Tetra-

hedron 1987, 43, 415–422.

G. W. J. Fleet, P. W. Smith, Tetrahedron 1987, 43, 971–978.

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(699 mg, 3.67 mmol) in pyridine (1 mL) was added dropwise to a

solution of crude lactols 48 (400 mg, 1.83 mmol) in pyridine (4 mL)

at –30 °C. After 30 min, the reaction mixture was warmed to 0 °C

and stirred for 1 h, and then it was allowed to warm to room temp.

The reaction mixture was stirred for a further 22 h, after which

TLC analysis (5:1, cyclohexane/ethyl acetate) indicated the com-

plete consumption of the starting materials (baseline) and the for-

mation of a major product (R_f= 0.30). The reaction mixture was

diluted with ethyl acetate (50 mL) and washed with hydrochloric

acid (2 m aq.; 15 mL). The aqueous phase was extracted with ethyl

acetate (3ϫ 30 mL). The organic fractions were combined, dried

(MgSO₄), filtered, and concentrated in vacuo. The crude residue

was purified by flash chromatography (9:1 to 7:3, cyclohexane/ethyl

acetate) to give tosylates 49 (678 mg, 89% over two steps) as a

colourless, viscous oil, as a 3.3:1 (A:B) ratio of anomers. HRMS

(ESI): calcd. for [C₁₇H₂₄O₇S + Na]⁺395.1135; found 395.1134.

[11]

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[16]

[17]

[18]

[19]

[α]²_D⁰= –1.3 (c = 1.24, CHCl ). IR (film): ν = 3500, 1364, 1176 cm^–1.

˜

3

¹H NMR (400 MHz, CDCl₃, 20 °C): δ = 7.80 (d, J = 8.3 Hz, 4 H,

H^A-Ar, H^B-Ar), 7.34 (d, J = 8.3 Hz, 4 H, H^A-Ar, H^B-Ar), 4.36–

4.35 (m, 2 H, 4^A-H, 4^B-H), 4.30–4.23 (m, 3 H, 5^A-H, 6a^A-H, 6a^B-

[20]

[21]

[22]

[23]

2

H), 4.15 (dd, J_6b,6a= 11.6, J_6b,5= 8.3 Hz, 1 H, 6b^A-H), 4.13 (dd,

²J_6b,6a= 11.6, J_6b,5= 3.5 Hz, 1 H, 6b^B-H), 3.82 (a-td, J_5,4= J_5,6a

= 6.1, J_5,6b= 3.5 Hz, 1 H, 5^B-H), 2.44 (s, 6 H, CH₃^A6-O-Ts, CH₃

B

6-O-Ts), 1.44 (s, 3 H, 3-CH₃^A), 1.41 (s, 3 H, 1^A-H), 1.41 [s, 3 H,

C(CH₃)^B], 1.38 [s, 6 H, 1^B-H, C(CH₃)^B], 1.34 [s, 3 H, C(CH₃)^A],

1.30, 1.30 [2 s, 2ϫ 3 H, 3-CH₃^B, C(CH₃)^A] ppm. ¹³C NMR

(100 MHz, CDCl₃, 20 °C): δ = 144.9 (C^A-p 6-O-Ts, C^B-p 6-O-Ts),

132.9 (C^A-i 6-O-Ts, C^B-i 6-O-Ts), 129.9 (C^A-Ar, C^B-Ar), 128.3,

128.3 (C^A-Ar, C^B-Ar), 113.4 [C(CH₃)₂^B, C(CH₃)₂^A], 106.8 (C-2^A),

104.9 (C-2^B), 99.7 (C-3^A), 92.4 (C-3^B), 86.5 (C-4^A), 85.5 (C-4^B),

75.6 (C-5^A), 73.0 (C-5^B), 68.2 (C-6^A), 67.6 (C-6^B), 27.8, 27.3

[24]

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A

[C(CH₃)₂^A], 27.1, 27.1 [C(CH₃)₂^B], 22.3 (C-1^A), 21.8 (CH₃6-O-

B

Ts, CH₃6-O-Ts), 20.9 (C-1^B), 20.5 (3-CH₃^A), 20.3 (3-CH₃^B) ppm.

MS (ESI): m/z (%) = 395 (100) [M + Na]⁺.

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Received: November 12, 2013

Published Online: January 28, 2014

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2069

Article Doi

One-pot tandem strecker reaction and iminocyclisations: Syntheses of trihydroxypiperidine α-iminonitriles

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