Asymmetric syntheses of the methyl glycosides of 2-deoxy-2-aminohexoses: D-allosamine, D-mannosamine, D-idosamine and D-talosamine

Article abstract of DOI:10.1016/j.tet.2014.06.019

A range of the methyl glycosides of 2-deoxy-2-aminohexoses, comprising D-allosamine, D-mannosamine, D-idosamine and D-talosamine, were prepared from the corresponding D-aldopentoses via a seven step synthetic sequence. The doubly diastereoselective conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide and in situ enolate oxidation with the requisite antipode of camphorsulfonyloxaziridine (CSO) was used as the key, stereodefining step. Sequential reduction of the resultant α-hydroxy-β-amino esters and oxidative cleavage of the C(1)–C(2) diol unit furnished the corresponding α-amino aldehydes. Subsequent N- and O-deprotection gave the target compounds (as mixtures of anomers) in good yield and high diastereoisomeric purity.

Full text of DOI:10.1016/j.tet.2014.06.019

Accepted Manuscript
Asymmetric syntheses of the methyl glycosides of 2-deoxy-2-aminohexoses: D-
allosamine, D-mannosamine, D-idosamine and D-talosamine
Stephen G. Davies, Ai. M. Fletcher, Emma M. Foster, James A. Lee, Paul M. Roberts,
James E. Thomson, Michael A. Waul
PII:
S0040-4020(14)00865-5
10.1016/j.tet.2014.06.019
TET 25684
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 January 2014
Revised Date: 13 March 2014
Accepted Date: 3 June 2014
Please cite this article as: Davies SG, Fletcher AM, Foster EM, Lee JA, Roberts PM, Thomson JE, Waul
MA, Asymmetric syntheses of the methyl glycosides of 2-deoxy-2-aminohexoses: D-allosamine, D-
mannosamine, D-idosamine and D-talosamine, Tetrahedron (2014), doi: 10.1016/j.tet.2014.06.019.
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ACCEPTED MANUSCRIPT
Asymmetric syntheses of the methyl glycosides of 2-deoxy-2-aminohexoses: D-allosamine, D-
mannosamine, D-idosamine and D-talosamine
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Stephen G. Davies,* Ai. M. Fletcher, Emma M. Foster, James A. Lee, Paul M. Roberts, James E. Thomson
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and Michael A. Waul
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Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
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OX1 3TA, U.K.
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E-mail: steve.davies@chem.ox.ac.uk

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Asymmetric syntheses of the methyl glycosides of 2-deoxy-2-aminohexoses: D-allosamine, D-
mannosamine, D-idosamine and D-talosamine
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Stephen G. Davies,* Ai. M. Fletcher, Emma M. Foster, James A. Lee, Paul M. Roberts, James E. Thomson
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and Michael A. Waul
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Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
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OX1 3TA, U.K.
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E-mail: steve.davies@chem.ox.ac.uk
Abstract
A range of the methyl glycosides of 2-deoxy-2-aminohexoses, comprising D-allosamine, D-mannosamine, D-
idosamine and D-talosamine, were prepared from the corresponding D-aldopentoses via a seven step
synthetic sequence. The doubly diastereoselective conjugate additions of the requisite antipode of lithium N-
benzyl-N-(α-methylbenzyl)amide and in situ enolate oxidation with the requisite antipode of
camphorsulfonyloxaziridine (CSO) was used as the key, stereodefining step. Sequential reduction of the
resultant α-hydroxy-β-amino esters and oxidative cleavage of the C(1)–C(2) diol unit furnished the
corresponding α-amino aldehydes. Subsequent N- and O-deprotection gave the target compounds (as
mixtures of anomers) in good yield and high diastereoisomeric purity.
Key words: aminosugars, 2-deoxy-2-aminohexoses, lithium amide, conjugate addition, asymmetric
synthesis
Dedicated to the memory of Professor Sandy McKillop.
1. Introduction
Aminosugars are defined as “monosaccharides having one alcoholic hydroxyl group replaced by an amino
group”; however, this category excludes glycosylamines [where such replacement occurs at the C(1)-
position] and iminosugars [in which the endocyclic oxygen atom has been replaced by a nitrogen atom].1
Aminosugars are ubiquitous in nature, occurring in plants, mammals, invertebrates and microorganisms,2
and a great variety of aminosugars have been isolated from natural sources.3 The class of aminosugars has
been known for over one hundred and ninety years;4 however, the intense fascination with these compounds
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within the scientific community is relatively recent, and was initiated by the 1946 discovery of 2-deoxy-2-
(N-methylamino)-L-glucosamine as a component in the antibiotic streptomycin.5 Aminosugars play many
important physiological roles, and a large assortment of biosynthetic materials contain aminosugar
components. For example, nucleoside and aminoglycoside antibiotics,6 chitin (exoskeletal material of
Crustacea),7 bacterial glycolipids,8 serum mucoproteins (blood group antigen determinants),9
anticoagulants,10 and biopolymers responsible for cell recognition, differentiation and protection11 all
possess aminosugar residues. Aminosugars undergo biochemical reactions not only intracellularly, but also
at the cell surface and within the extracellular matrix.12 Due to this wide and varied biological activity,
aminosugars have been targeted and extensively tested as causative agents and potential therapeutics for
various diseases and medical conditions. Aminosugars have thus been linked to the pathogenesis of
leukaemia,13 liver abscesses,14 and bacterial sepsis.15 On the other hand, these compounds are used in the
treatment of viral infections,16 mycoses,17 and colon, stomach, and liver cancers.18 The well recognised
biological importance of aminosugars has stimulated significant efforts towards the synthesis of this class of
compounds.19,20 Traditionally, aminosugars have been synthesised through multi-step transformations of
other relatively inexpensive and readily available carbohydrates.21 However, recent interest has increasingly
focused on non-carbohydrate precursors as well.22
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As part of our ongoing research programme concerning the asymmetric synthesis of enantiopure pyrrolidines
and piperidines,23 including iminosugars,24 we have previously established the doubly diastereoselective25
“matched” and “mismatched” pairings of chiral reagent and chiral substrate upon conjugate addition26 of
either antipode of lithium N-benzyl-N-(α-methylbenzyl)amide 9 to α,β-unsaturated esters 1–4 (which were
all derived from D-aldopentoses), and employed these reactions as the key stereodefining step in the
asymmetric syntheses of two novel dihydroxyhomoprolines.27 The levels of diastereoselectivity obtained
were variable and two of these polyoxygenated substrates were found not to conform to the usual pattern of
“matching” and “mismatching” observed upon conjugate addition of either antipode of lithium N-benzyl-N-
(α-methylbenzyl)amide 9 to chiral α,β-unsaturated esters,28 although in each case diastereoisomerically pure
(>99:1 dr) samples of the resultant β-amino esters were isolated after purification. The lithium amide
conjugate addition reactions to α,-unsaturated esters 1 and 2 conformed to the predicted outcomes in that
the doubly diastereoselective “matched” reactions had proceeded with the same sense, and with an enhanced
level, of diastereocontrol as those suggested by the substrate control experiments (upon conjugate addition of
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an achiral lithium amide viz. lithium N-isopropyl-N-benzylamide), resulting in the preferential formation of
the corresponding 3,4-anti--amino ester products 5 and 6, respectively. In contrast to this, in the case of the
D-lyxose derived α,β-unsaturated ester 4, an erosion in diastereoselectivity was observed for the conjugate
addition reactions of both antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide 9 compared with the
analogous reaction with lithium N-isopropyl-N-benzylamide. Furthermore, in the case of 3, the “empirically
matched” conjugate addition reaction of (S)-9 had proceeded to give the 3,4-syn--amino ester 7
preferentially, whilst the substrate control experiment had indicated preferential attack on the opposing face
of the α,-unsaturated ester 3, giving a 3,4-anti--amino ester as the major product (Scheme 1).
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Scheme 1. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(α-methylbenzyl)amide (R)-9, THF, –78 °C, 2 h; (ii) lithium (S)-
N-benzyl-N-(α-methylbenzyl)amide (S)-9, THF, –78 °C, 2 h. [a 8% conversion to the corresponding β,γ-unsaturated ester was also
observed; b an 86:14 mixture of 8 (>99:1 dr) and the corresponding β,γ-unsaturated ester was isolated].
It was envisaged that our diastereoselective aminohydroxylation procedure26,29,30 could be combined with
this doubly diastereoselective conjugate addition methodology in the synthesis of a range of 2-deoxy-2-
aminohexoses: oxidation of the intermediate lithium (Z)-β-amino enolates,31 formed upon conjugate addition
of either lithium amide reagent (R)-9 or (S)-9 to ,β-unsaturated esters 1–4, with the requisite antipode of
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camphorsulfonyloxaziridine (CSO) 10 would give the corresponding -hydroxy-β-amino esters 11, and
subsequent reduction followed by oxidative cleavage of the resultant 1,2-diols 12 would produce the
corresponding α-amino aldehydes 13, which constitute protected forms of the target 2-deoxy-2-
aminohexoses (Fig. 1). Upon application of this procedure in the aminohydroxylation of achiral ,β-
unsaturated esters,26 we have observed that the combinations of lithium amide (R)-9 and (–)-CSO 10, and
(S)-9 and (+)-CSO 10, offer marginally better levels of diastereoselectivity, although any combination of 9
and 10 yields the corresponding 2,3-anti-configured -hydroxy-β-amino ester with reasonably high
diastereoselectivity.
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Figure 1. Proposed synthesis of protected 2-deoxy-2-aminohexoses 13.
2. Results and discussion
2.1. Asymmetric synthesis of D-allosamine
The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide (R)-9 to the D-ribose derived α,β-
unsaturated ester 1 followed by in situ oxidation of the resultant lithium (Z)-β-amino enolate31 with
(–)-CSO 10 gave α-hydroxy-β-amino ester 14 (>99:1 dr) and the known β-amino ester 527 (>99:1 dr) in a
90:10 ratio. After chromatographic purification of the crude reaction mixture 14 was isolated in 76% yield
and >99:1 dr (Scheme 2). In the corresponding reaction with (+)-CSO, an 85:15 mixture of 14 and 5 was
produced, from which 14 was isolated in 53% yield and >99:1 dr. The stereochemical outcomes of these
reactions were initially assigned by analogy to the established outcomes observed upon aminohydroxylation
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of achiral α,β-unsaturated esters26 using this protocol, and was later confirmed unambiguously by single
crystal X-ray diffraction analysis of a derivative of 14.
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Scheme 2. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(α-methylbenzyl)amide (R)-9, THF, –78 °C, 2 h, then (–)-CSO
19 10, –78 °C to rt, 12 h.
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Reduction of the ester moiety within 14 upon treatment with LiAlH4 gave diol 15 which was isolated in 88%
yield and >99:1 dr (Scheme 3). The relative configuration within 15 was assigned unambiguously by single
crystal X-ray diffraction analysis,32 and the absolute (2R,3S,4S,5S,6R,αR)-configuration within 15 was
assigned relative to the known configurations of the D-ribose derived dioxolane units and the α-
methylbenzyl fragment (Fig. 2); this analysis also secured the assigned configuration within α-hydroxy-β-
amino ester 14. Treatment of 15 with NaIO4 effected cleavage of the 1,2-diol unit within 15 to give aldehyde
16 in 66% yield and >99:1 dr, then deprotection of the dioxolane units with HCl in MeOH was followed by
in situ cyclisation to give an 82:18 mixture of 2-aminofuranose anomers 17 and 18, respectively, which was
isolated in 43% combined yield. Further chromatographic purification provided an analytically pure (>99:1
dr) sample of 17 in 28% yield from 16 (Scheme 3).33 The regio- and stereochemistries within both 17 and 18
were assigned by 1H NMR NOE and 1H–13C NMR HMBC spectroscopic analyses.
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Scheme 3. Reagents and conditions: (i) LiAlH4, THF, 0 °C to rt, 16 h; (ii) NaIO4, MeOH, rt, 24 h; (iii) HCl in MeOH, 50 °C, 24 h;
(iv) further purification of an aliquot.
Figure 2. X-ray crystal structure of (2R,3S,4S,5S,6R,αR)-15 (selected H atoms are omitted for clarity).
Further protecting group manipulation of the sample of 17 (>99:1 dr) produced a range of derivatives 19–22.
First, acetylation of the C(3)-, C(5)- and C(6)-hydroxyl groups within 17 gave 19 in 91% yield and >99:1 dr.
Hydrogenolytic N-debenzylation of 19 produced a mixture compounds 20 [in which the C(3)-O-acetyl group
had partially migrated onto the C(2)-amino substituent];34 the composition of this mixture was confirmed
upon treatment with Ac2O which gave only 22 in 85% yield (from 19) and >99:1 dr, and also upon
hydrolysis of the mixture with KOH which gave only 21 in 84% yield (from 19) and >99:1 dr. Methyl
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glycoside 21 was also produced directly from 17 upon hydrogenolysis in the presence of Pearlman’s catalyst
[Pd(OH)2/C], and was isolated in quantitative yield and >99:1 dr after purification (Scheme 4). In each case,
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1H NMR NOE and H–13C NMR HMBC spectroscopic analyses of 19, 21 and 22 confirmed the assigned
regio- and stereochemistries: the 1H NMR 3J1,2 coupling constants for all the α-anomers in this series were in
the range of 1.5–2.5 Hz, while all corresponding β-anomers possessed 3J1,2 values of 4.7 Hz. Thus, it would
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appear that H NMR J1,2 coupling constants are diagnostic of the relative configuration between the C(1)
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and C(2) stereocentres within this series.
Scheme 4. Reagents and conditions: (i) Ac2O, DMAP, pyridine, rt, 12 h; (ii) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 18 h; (iii) KOH
(1.0 M aq), MeOH/H2O (1:1), rt, 4 h.
2.2. Asymmetric synthesis of D-mannosamine
For the D-arabinose derived α,β-unsaturated ester 2, conjugate addition of lithium (S)-N-benzyl-N-(α-
methylbenzyl)amide (S)-9 followed by in situ oxidation of the resultant lithium (Z)-β-amino enolate31 with
(+)-CSO 10 gave an 18:52:30 mixture of the known β-amino ester 627 (>99:1 dr), and α-hydroxy-β-amino
esters 23 and 24, respectively. After chromatographic purification, 6 was isolated in 10% yield and >99:1 dr,
and a 60:40 mixture of 23 and 24 was isolated in 82% combined yield; further purification of an aliquot of
this mixture allowed the isolation of an analytically pure sample of 23 in 39% yield (from 2) and >99:1 dr
(Scheme 5).35
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Scheme 5. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(α-methylbenzyl)amide (S)-9, THF, –78 °C, 2 h, then (+)-CSO 10,
–78 °C to rt, 12 h; (ii) further purification of an aliquot. [a a 20:80 mixture of 23 and 24, respectively, was also isolated in 25%
combined yield].
Reduction of 23 with LiAlH4 gave diol 25 which was isolated in 92% yield and >99:1 dr (Scheme 6). The
relative configuration within 25 was established by single crystal X-ray diffraction analysis of its C(2)-
epimer 2932 (which was obtained in >99:1 dr upon reduction of the 60:40 mixture of 23 and 24, respectively,
with LiAlH4 followed by recrystallisation to give 29); the absolute (2R,3R,4R,5S,6R,αS)- and
(2S,3R,4R,5S,6R,αS)-configurations within 25 and 29, respectively, were in each case assigned relative to the
known configurations of the D-arabinose derived dioxolane units and the α-methylbenzyl fragment (Fig. 3).
This analysis therefore also secured the configurations within both 23 and 24.36 Oxidative cleavage of the
C(1)–C(2) bond within 25 gave aldehyde 26 in 76% yield and >99:1 dr, and subsequent acid-mediated
deprotection of the dioxolane units gave an 80:20 mixture of 2-aminofuranose anomers 27 and 28,
respectively, which was isolated in 68% combined yield. Further chromatographic purification of an aliquot
provided an analytically pure (>99:1 dr) sample of the minor diastereoisomer 28 in 7% yield (from 26), and
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regioselectivity of cyclisation and the configurations at C(1) within both 27 and 28 to be established.
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Scheme 6. Reagents and conditions: (i) LiAlH4, THF, 0 °C to rt, 16 h; (ii) NaIO4, MeOH, rt, 24 h; (iii) HCl in MeOH, 50 °C, 24 h;
(iv) further purification of an aliquot. [a a 65:35 mixture of 27 and 28, respectively, was also isolated in 16% combined yield].
Figure 3. X-ray crystal structure of (2S,3R,4R,5S,6R,αS)-29 (selected H atoms are omitted for clarity).
Removal of the N-benzyl and N-α-methylbenzyl protecting groups within 28 was achieved by
hydrogenolysis in the presence of Pearlman’s catalyst [Pd(OH)2/C] which gave methyl glycoside 30 in
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quantitative yield and >99:1 dr, after chromatographic purification (Scheme 7). Again both H NMR NOE
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configuration at C(1) within 30 to be confirmed.
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Scheme 7. Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 18 h.
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2.3. Asymmetric synthesis of D-idosamine
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For the D-xylose derived α,β-unsaturated ester 3, we have shown that conjugate addition of lithium (S)-N-
benzyl-N-(α-methylbenzyl)amide (S)-9 followed by treatment of the resultant lithium (Z)-β-amino enolate
with satd aq NH4Cl gives the corresponding 3,4-syn-diastereoisomer 7 in 90:10 dr.27 Application of the
aminohydroxylation protocol to this substrate, treating the intermediate lithium (Z)-β-amino enolate with
(+)-CSO 10 gave a mixture of the known β-amino ester 7,27 and α-hydroxy-β-amino esters 31 and 32.34,37
After purification of the crude reaction mixture, 7 was isolated in 8% yield and >99:1 dr, and a 70:30
mixture of 31 and 32, respectively, was isolated in 65% combined yield; further purification of an aliquot of
this mixture allowed the isolation of an analytically pure sample of 31 in 37% yield (from 3) and >99:1 dr
(Scheme 8). In this case, single crystal X-ray diffraction analysis of 31 allowed its relative configuration to
be determined unambiguously,32 with the absolute (2S,3R,4S,5R,6R,αS)-configuration within 31 being
assigned relative to the known configurations of the D-xylose derived dioxolane units and the α-
methylbenzyl fragment (Fig. 4); this analysis also allowed the configuration within 32 to be determined.38
Scheme 8. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(α-methylbenzyl)amide (S)-9, THF, –78 °C, 2 h, then (+)-CSO 10,
55 –78 °C to rt, 12 h; (ii) further purification of an aliquot. [a a 15:85 mixture of 31 and 32, respectively, was also isolated in 12%
56 combined yield].
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Figure 4. X-ray crystal structure of (2S,3R,4S,5R,6R,αS)-31 (selected H atoms are omitted for clarity).
Reduction of the ester moiety within 31, upon treatment with LiAlH4, gave diol 33 in 88% yield and >99:1
dr, and subsequent oxidative cleavage of the 1,2-diol unit within 33 gave aldehyde 34 in 79% yield and
>99:1 dr.38 Treatment of 34 with HCl in MeOH gave an inseparable 80:20 mixture of 2-aminofuranose
anomers 35 and 36, respectively. Hydrogenolytic N-deprotection of this mixture gave an 80:20 mixture of 37
and 38, respectively, in quantitative yield (Scheme 9). The regioselectivity of cyclisation and the
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configurations at C(1) within 35–38 were established in each case by H NMR NOE and H–13C NMR
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Scheme 9. Reagents and conditions: (i) LiAlH4, THF, 0 °C to rt, 16 h; (ii) NaIO4, MeOH, rt, 24 h; (iii) HCl in MeOH, 50 °C,
24 h; (iv) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 18 h.
2.4. Asymmetric synthesis of D-talosamine
For the D-lyxose derived ,β-unsaturated ester 4, we have shown that conjugate addition of lithium (S)-N-
benzyl-N-(α-methylbenzyl)amide (S)-9 followed by treatment of the resultant lithium (Z)-β-amino enolate
with satd aq NH4Cl gives the corresponding 3,4-anti-diastereoisomer in 77:23 dr.27 Application of the
aminohydroxylation protocol to this substrate, treating the intermediate lithium (Z)-β-amino enolate with
(+)-CSO 10, gave a 5:25:70 mixture of the known β-amino esters 8 and 39,27 and -hydroxy-β-amino ester
40, respectively. After purification of the crude reaction mixture, 39 and 40 were isolated in 7 and 35%
yield, respectively, and in >99:1 dr in each case (Scheme 10).39 The relative configuration within 40 was
established unambiguously via single crystal X-ray diffraction analysis,32 and the absolute
(2S,3R,4R,5R,6R,S)-configuration within 40 was assigned by reference to the known configurations of the
D-lyxose derived dioxolane units and the -methylbenzyl fragment (Fig. 5).
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Scheme 10. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(α-methylbenzyl)amide (S)-9, THF, –78 °C, 2 h, then (+)-CSO
10, –78 °C to rt, 12 h.
Figure 5. X-ray crystal structure of (2S,3R,4R,5R,6R,S)-40 (selected H atoms are omitted for clarity).
Reduction of 40 with LiAlH4 gave 41 in 93% yield and >99:1 dr. Oxidative cleavage of the 1,2-diol unit
within 41 gave aldehyde 42 in 77% isolated yield and >99:1 dr, and treatment of 42 with HCl in MeOH
produced an 81:19 mixture of 2-aminofuranose anomers 43 and 44, respectively. After chromatographic
49 purification, the major diastereoisomer 43 was isolated in 49% yield and >99:1 dr. Subsequent
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hydrogenolytic deprotection of 43 gave 45 in quantitative yield and >99:1 dr (Scheme 11).
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Scheme 11. Reagents and conditions: (i) LiAlH4, THF, 0 °C to rt, 16 h; (ii) NaIO4, MeOH, rt, 24 h; (iii) HCl in MeOH, 50 °C,
24 h; (iv) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 18 h. [a a 33:67 mixture of 43 and 44 was isolated in 11% combined yield].
3. Conclusion
39 In conclusion, a range of D-aldopentoses were elaborated to the methyl glycosides of the corresponding 2-
40
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42
deoxy-2-aminohexoses via a seven step synthetic sequence employing the doubly diastereoselective
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44
conjugate additions of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide and in situ
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46
enolate oxidation with the requisite antipode of camphorsulfonyloxaziridine (CSO) as the key,
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stereodefining step. In each case, the empirically “matched” pairings of enantiopure lithium amide reagent 9
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and enantiopure oxidant 10 [i.e., (S)-9 and (+)-10, and (R)-9 and (–)-10] proved optimal upon
51
aminohydroxylation of the enantiopure α,β-unsaturated esters, although in one case the preferential
formation of the corresponding 2,3-syn-α-hydroxy-β-amino ester was noted. Sequential reduction of the
resultant α-hydroxy-β-amino esters and oxidative cleavage of the C(1)–C(2) diol unit furnished the
corresponding α-amino aldehydes. Subsequent N- and O-deprotection gave the target compounds which
were isolated as mixtures of anomers. The conversion of the D-aldopentose derived α-hydroxy-β-amino
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esters, produced using this methodology, into the corresponding 3-deoxy-3-aminoheptoses and 4-deoxy-4-
aminohexoses is currently underway in our laboratory and will be reported in due course.
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4. Experimental
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4.1. General Experimental
9
Reactions involving organometallic or other moisture-sensitive reagents were carried out under a nitrogen or
argon atmosphere using standard vacuum line techniques and glassware that was flame dried and cooled
under nitrogen before use. BuLi was purchased as a solution in hexanes and titrated against diphenylacetic
acid before use. Solvents were dried according to the procedure outlined by Grubbs and co-workers.40 Water
was purified by an Elix® UV-10 system. All other reagents were used as supplied (analytical or HPLC
grade) without prior purification. Organic layers were dried over MgSO4. Thin layer chromatography was
performed on aluminium plates coated with 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq. KMnO4, or 10% ethanolic phosphomolybdic acid. Flash column chromatography was
performed on Kieselgel 60 silica.
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Elemental analyses were recorded by the microanalysis service of the London Metropolitan University, U.K.
Melting points were recorded on a Gallenkamp Hot Stage apparatus. Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm cell. Specific rotations are reported in 10−1 deg
cm2 g−1 and concentrations in g/100 mL. IR spectra were recorded on a Bruker Tensor 27 FT-IR
spectrometer using an ATR module. Selected characteristic peaks are reported in cm–1. NMR spectra were
recorded on Bruker Avance spectrometers in the deuterated solvent stated. Spectra were recorded at rt. The
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1
field was locked by external referencing to the relevant deuteron resonance. H−1H COSY, H−13C HSQC,
1
and H−13C HMBC NMR spectroscopic analyses were used to establish atom connectivity. When the
diastereotopic methyl groups of acetonide functionalities could not be unambiguously assigned, the
descriptor MeCMe was employed. In the 1H and 13C NMR spectra, these descriptors are intended to convey
neither that the resonances are attributable to methyl groups that reside on the same, nor on different carbon
atoms. Low-resolution mass spectra were recorded on a VG MassLab 20–250 or a Micromass Platform 1
spectrometer. Accurate mass measurements were run on either a Bruker MicroTOF internally calibrated with
polyalanine, or a Micromass GCT instrument fitted with a Scientific Glass Instruments BPX5 column (15 m
 0.25 mm) using amyl acetate as a lock mass.
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4.2. tert-Butyl (2R,3S,4S,5S,6R,αR)-2,4,5,6,7-pentahydroxy-3-[N-benzyl-N-(α-methylbenzyl)amino]-
4,5,6,7-di-O-isopropylideneheptanoate 14
1
2
BuLi (2.5 M in hexanes, 1.20 mL, 3.00 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-
(α-methylbenzyl)amine (643 mg, 3.04 mmol, >99:1 er) in THF (3 mL) at 78 °C, the resultant solution was
stirred at 78 °C for 30 min. A solution of 127 (500 mg, 1.52 mmol, >99:1 dr) in THF (2 mL) at –78 °C was
then added dropwise and the reaction mixture was stirred at 78 °C for 2 h. (–)-CSO 10 (700 mg, 3.05
mmol) was then added and the resultant mixture was allowed to warm to rt over 12 h. The reaction mixture
was then diluted with Et2O (10 mL) and filtered. The filtrate was washed sequentially with 10% aq citric
acid (10 mL), satd aq NaHCO3 (10 mL) and brine (10 mL), then dried and concentrated in vacuo to give a
90:10 mixture of 14 and 5, respectively. Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 89:11 increased to 83:17) gave 14 as a pale yellow oil (640 mg, 76%, >99:1 dr); []2D0 +9.7 (c
1.0 in CHCl3); νmax (ATR) 3502 (O–H), 2982, 2935 (C–H), 1731 (C=O); δH (400 MHz, CDCl3) 1.14 (3H, s,
MeCMe), 1.29 (3H, s, MeCMe), 1.36 (3H, s, MeCMe), 1.42 (3H, d, J 7.1, C(α)Me), 1.45 (3H, s, MeCMe),
1.51 (9H, s, CMe3), 3.12 (1H, d, J 6.7, OH), 3.44 (1H, dd, J 7.9, 6.1, C(7)HA), 3.62 (1H, app d, J 10.1,
C(3)H), 3.73 (1H, d, J 15.9, NCHAHBPh), 3.79 (1H, dd, J 7.9, 6.6, C(7)HB), 4.14–4.23 (3H, m, C(5)H,
C(6)H, C(α)H), 4.32–4.40 (3H, m, C(2)H, C(4)H, NCHAHBPh), 7.19–7.46 (10H, m, Ph); δC (100 MHz,
CDCl3) 19.3 (C(α)Me), 24.7, 25.9, 26.3, 26.7 (2 × CMe2), 28.2 (CMe3), 50.3 (NCH2Ph), 59.7 (C(5)), 61.1
(C(α)), 65.6 (C(7)), 65.6, 70.6 (C(2), C(4)), 74.0, 74.5 (C(3), C(6)), 82.3 (CMe3), 107.3, 109.0 (2 × CMe2),
126.5, 127.4, 127.8, 128.2, 128.2, 128.8 (o,m,p-Ph), 142.3, 142.9 (i-Ph), 173.0 (C(1)); m/z (ESI+) 578
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+
([M+Na]+, 70%), 556 ([M+H]+, 100%); HRMS (ESI+) C32H45NNaO7 ([M+Na]+) requires 578.3088; found
578.3081.
4.3. (2R,3S,4S,5S,6R,αR)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-4,5,6,7-di-O-isopropylideneheptan-
1,2,4,5,6,7-hexaol 15
LiAlH4 (1.0 M in THF, 1.40 mL, 1.40 mmol) was added dropwise to a stirred solution of 14 (350 mg, 0.631
mmol, >99:1 dr) in THF (5 mL) at 0 C and the resultant mixture was allowed to warm to rt over 16 h. The
reaction mixture was quenched by cautiously adding ice, then filtered through a short plug of Celite® (eluent
Et2O, 10 mL). The filtrate was then partitioned between H2O (5 mL) and Et2O (5 mL) and the organic layer
was dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 50:50) gave 15 as a colourless viscous oil (270 mg, 88%, >99:1 dr). Further purification of an
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aliquot via recrystallisation (CH2Cl2/n-heptane) gave an analytically pure sample of 15 as a white solid
(>99:1 dr); C28H39NO6 requires C, 69.25; H, 8.1; N 2.9%; found C, 69.2; H, 7.9; N, 3.0%; mp 65–69 °C;
[]2D0 –42.3 (c 0.3 in CHCl3); νmax (ATR) 3445 (O–H), 2985, 2945 (C–H), 1739 (C=O); δH (500 MHz,
CDCl3) 1.39–1.44 (9H, m, C(α)Me, 2 × MeCMe), 1.49 (3H, s, MeCMe), 1.58 (3H, s, MeCMe), 1.85 (1H, br
s, C(1)OH), 2.80 (1H, s, C(2)OH), 3.09 (1H, app s, C(1)HA), 3.38 (1H, app s, C(1)HB), 3.62 (1H, app d, J
8.8, C(3)H), 3.83 (1H, d, J 14.2, NCHAHBPh), 3.85–3.90 (2H, m, C(2)H, C(α)H), 3.93 (1H, dd, J 8.7, 5.9,
C(7)HA), 4.10 (1H, d, J 14.2, NCHAHBPh), 4.14 (1H, dd, J 8.7, 6.2, C(7)HB), 4.24 (1H, dd, J 9.3, 7.7,
C(5)H), 4.56–4.61 (1H, m, C(6)H), 4.76 (1H, app d, J 7.7, C(4)H), 7.16–7.40 (10H, m, Ph); δC (125 MHz,
CDCl3) 11.2 (C(α)Me), 23.3, 25.4, 26.5, 27.1 (2 × CMe2), 52.1 (NCH2Ph), 54.7 (C(3)), 56.6 (C(α)), 64.9
(C(1)), 68.3 (C(7)), 70.3 (C(2)), 73.7 (C(6)), 77.8 (C(4)), 79.0 (C(5)), 108.4, 109.8 (2 × CMe2), 127.1, 127.2,
127.9, 128.4, 128.5, 129.1 (o,m,p-Ph), 140.4, 142.9 (i-Ph); m/z (ESI+) 993 ([2M+Na]+, 100%), 508
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+
([M+Na]+, 15%), 486 ([M+H]+, 80%); HRMS (ESI+) C28H40NO6 ([M+H]+) requires 486.2850; found
486.2834.
4.4. (2R,3S,4S,5R,αR)-2-[N-Benzyl-N-(α-methylbenzyl)amino]-3,4,5,6,-di-O-isopropylidene-3,4,5,6-
tetrahydroxyhexanal 16
NaIO4 (220 mg, 1.03 mmol) was added to a stirred solution of 15 (170 mg, 0.351 mmol, >99:1 dr) in MeOH
(10 mL) at rt, and the resultant mixture was left to stir at rt for 24 h. The resultant suspension was filtered
through a short plug of Celite® (eluent MeOH, 15 mL), and the filtrate was concentrated in vacuo. The
residue was diluted with Et2O (20 mL) and filtered through a short plug of Celite® (eluent Et2O, 20 mL),
then the filtrate was concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 83:17) gave 16 as a yellow oil (105 mg, 66%, >99:1 dr); []2D0 –80.6 (c 1.0 in CHCl3); νmax
(ATR) 2986, 2936 (C–H), 1731 (C=O); δH (500 MHz, CDCl3) 1.18 (3H, s, MeCMe), 1.24 (3H, s, MeCMe),
1.33 (6H, s, 2 × MeCMe), 1.38 (3H, d, J 6.9, C(α)Me), 3.87 (1H, dd, J 8.5, 5.4, C(6)HA), 4.06–4.20 (5H, m,
C(2)H, C(4)H, C(5)H, C(6)HB, C(α)H), 4.21 (1H, d, J 15.1, NCHAHBPh), 4.26 (1H, d, J 15.1, NCHAHBPh),
4.65 (1H, app d, J 6.6, C(3)H), 7.20–7.55 (10H, m, Ph), 9.60 (1H, s, C(1)H); δC (125 MHz, CDCl3) 16.9
(C(α)Me), 24.3, 25.1, 26.5, 26.7 (2 × CMe2), 52.1 (NCH2Ph), 58.4, 64.0, 73.9, 78.5 (C(2), C(4), C(5), C(α)),
68.3 (C(6)), 79.2 (C(3)), 109.1, 109.7 (2 × CMe2), 126.8, 127.0, 127.7, 128.2, 128.2, 128.3 (o,m,p-Ph),
141.4, 143.7 (i-Ph), 202.5 (C(1)); m/z (ESI+) 476 ([M+Na]+, 100%), 454 ([M+H]+, 85%); HRMS (ESI+)
+
C27H35NNaO5 ([M+Na]+) requires 476.2407; found 476.2400.
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4.5. Methyl (1R,2R,3S,4S,5R,αR)-2-deoxy-2-[N-benzyl-N-(α-methylbenzyl)amino]-β-D-allofuranose 17
A solution of HCl in MeOH (1.25 M, 35 mL) was added to 16 (840 mg, 1.85 mmol), and the resultant
mixture was heated at 50 °C for 24 h. The reaction mixture was then allowed to cool to rt, concentrated in
vacuo, and the residue was partitioned between 2.0 M aq NaOH (30 mL) and CH2Cl2 (30 mL). The aqueous
layer was extracted with CH2Cl2 (2 × 30 mL) and the combined organic extracts were dried and concentrated
in vacuo to give an 82:18 mixture of 17 and 18, respectively. Purification via flash column chromatography
(eluent CH2Cl2/MeOH, 96:4) gave an 82:18 mixture of 17 and 18, respectively, as a pale yellow oil (305 mg,
43%). Further purification of an aliquot (75 mg) via flash column chromatography (eluent CH2Cl2/MeOH,
98:2) gave 17 as a pale yellow oil (50 mg, 28%, >99:1 dr); []2D0 +19.2 (c 0.3 in CHCl3); νmax (ATR) 3323
(O–H), 2970 (C–H); δH (400 MHz, MeOH-d4) 1.45 (3H, d, J 7.1, C(α)Me), 3.03 (3H, s, OMe), 3.48–3.57
(2H, m, C(3)H, C(6)HA), 3.70–3.74 (2H, m, C(2)H, C(6)HB), 3.77–3.82 (3H, m, C(4)H, NCH2Ph), 4.09 (1H,
q, J 7.1, C(α)H), 4.28 (1H, d, J 2.5, C(1)H), 4.46 (1H, app q, J 3.3, C(5)H), 7.21–7.40 (10H, m, Ph); δC (100
MHz, MeOH-d4) 15.6 (C(α)Me), 51.5 (NCH2Ph), 54.6 (OMe), 57.4 (C(α)), 63.8 (C(6)), 65.9 (C(2)), 72.1
(C(5)), 73.7 (C(3)), 86.9 (C(4)), 106.0 (C(1)), 127.0, 127.4, 128.2, 128.2, 128.5, 128.5 (o,m,p-Ph), 140.4,
141.5 (i-Ph); m/z (ESI+) 797 ([2M+Na]+, 100%), 410 ([M+Na]+, 85%), 388 ([M+H]+, 85%); HRMS (ESI+)
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+
C22H30NO5 ([M+H]+) requires 388.2118; found 388.2111. Data for 18: δH (500 MHz, MeOH-d4) 1.49 (3H,
d, J 7.3, C(α)Me), 2.81 (3H, s, OMe), 3.58–3.60 (1H, m, C(3)H), 3.70–3.82 (5H, m, C(2)H, C(6)H2,
NCH2Ph), 4.01 (1H, app d, J 4.1, C(4)H), 4.12–4.14 (1H, m, C(α)H), 4.34 (1H, app d, J 5.4, C(5)H), 4.45–
4.47 (1H, m, C(1)H), 7.13–7.40 (10H, m, Ph); δC (125 MHz, MeOH-d4) [selected peaks] 11.9 (C(α)Me),
53.3 (NCH2Ph), 54.7 (OMe), 58.1 (C(α)), 64.4 (C(6)), 67.4 (C(2)), 72.5 (C(5)), 73.6 (C(3)), 88.3 (C(4)),
105.7 (C(1)), 128.7, 129.0, 129.0, 129.1, 129.3, 129.8 (o,m,p-Ph).
4.6. Methyl (1R,2R,3S,4S,5R,αR)-O,O,O-triacetyl-2-deoxy-2-[N-benzyl-N-(α-methylbenzyl)amino]-β-D-
allofuranose 19
Ac2O (0.12 mL, 1.3 mmol) and DMAP (5 mg) were added sequentially to a stirred solution of 17 (50 mg,
0.13 mmol, >99:1 dr) in pyridine (4 mL) at rt, and the resultant mixture was stirred at rt for 12 h. H2O (10
mL) was then added and the reaction mixture was diluted with EtOAc (10 mL). The aqueous layer was
extracted with EtOAc (3 × 5 mL) and the combined organic extracts were washed sequentially with satd aq
CuSO4 (10 mL), H2O (10 mL) and brine (10 mL), then dried and concentrated in vacuo. Purification via
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flash column chromatography (eluent 30–40 °C petrol/Et2O, 50:50) gave 19 as a colourless oil (60 mg, 91%,
>99:1 dr); []2D0 +16.4 (c 1.0 in MeOH); νmax (ATR) 3023, 2967, 2837 (C–H), 1745 (C=O); δH (500 MHz,
CDCl3) 1.43 (3H, d, J 7.0, C(α)Me), 2.08 (3H, s, COMe), 2.09 (3H, s, COMe), 2.19 (3H, s, COMe), 3.06
(3H, s, OMe), 3.82 (1H, d, J 15.3, NCHAHBPh), 3.88 (1H, d, J 15.3, NCHAHBPh), 3.94 (1H, q, J 7.0,
C(α)H), 4.02 (1H, dd, J 7.5, 1.5, C(2)H), 4.10–4.14 (1H, m, C(6)HA), 4.16 (1H, d, J 1.5, C(1)H), 4.17–4.22
(1H, m, C(4)H), 4.47 (1H, dd, J 9.7, 2.7, C(6)HB), 5.10–5.13 (1H, m, C(5)H), 5.36 (1H, dd, J 7.5, 4.3,
C(3)H), 7.26–7.47 (10H, m, Ph); δC (125 MHz, CDCl3) 17.7 (C(α)Me), 20.8, 20.9, 21.1 (3 × COMe), 51.9
(NCH2Ph), 55.4 (OMe), 57.1 (C(α)), 62.8 (C(6)), 63.0 (C(2)), 72.1 (C(5)), 74.9 (C(3)), 81.5 (C(4)), 106.7
(C(1)), 126.9, 127.3, 127.8, 128.1, 128.2, 128.4 (o,m,p-Ph), 140.3, 140.7 (i-Ph), 169.9, 170.1, 170.6 (3 ×
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+
COMe); m/z (ESI+) 536 ([M+Na]+, 60%); HRMS (ESI+) C28H35NNaO8 ([M+Na]+) requires 536.2255;
found 536.2249.
4.7. Methyl (1R,2R,3S,4S,5R)-2-deoxy-2-amino-β-D-allofuranose 21
Method A: Pd(OH)2/C (43 mg, 50% w/w) was added to a stirred solution of 17 (85 mg, 0.22 mmol, >99:1 dr)
in MeOH (5 mL) at rt. The resultant solution was degassed and saturated with H2 before being stirred at rt
under H2 (1 atm) for 18 h. The reaction mixture was then filtered through a short plug of Celite® (eluent
MeOH, 10 mL) and the filtrate was concentrated in vacuo to give 21 as a colourless oil (43 mg, quant, >99:1
dr); []2D0 –54.4 (c 2.8 in MeOH); νmax (ATR) 3355, 3300 (O–H, N–H), 2930 (C–H); δH (500 MHz, D2O)
3.35 (3H, s, OMe), 3.56 (1H, dd, J 11.7, 6.0, C(6)HA), 3.62–3.71 (3H, m, C(2)H, C(5)H, C(6)HB), 3.91 (1H,
dd, J 7.6, 4.4, C(4)H), 4.61 (1H, dd, J 6.0, 4.4, C(3)H), 5.08 (1H, d, J 2.5, C(1)H); δC (125 MHz, D2O) 55.8
(OMe), 57.1 (C(2)), 62.6 (C(6)), 69.8 (C(3)), 72.2 (C(5)), 83.8 (C(4)), 105.4 (C(1)); m/z (ESI+) 216
+
([M+Na]+, 55%), 194 ([M+H]+, 100%); HRMS (ESI+) C7H15NNaO5 ([M+Na]+) requires 216.0842; found
216.0846.
Method B – Step 1: Pd(OH)2/C (43 mg, 50% w/w) was added to a stirred solution of 19 (85 mg, 0.17 mmol,
>99:1 dr) in MeOH (5 mL) at rt. The resultant solution was degassed and saturated with H2 before being
stirred at rt under H2 (1 atm) for 18 h. The reaction mixture was then filtered through a short plug of Celite®
(eluent MeOH, 10 mL) and the filtrate was concentrated in vacuo to give a mixture of compounds 20 as a
colourless oil (52 mg).
Method B – Step 2: KOH (1.0 M aq, 1.0 mL) was added to a stirred solution of the mixture 20 (52 mg) in
MeOH/H2O (1:1, 4 mL) at rt, and the resultant mixture was stirred at rt for 4 h. The reaction mixture was
19

ACCEPTED MANUSCRIPT
filtered through a short plug of Celite® (eluent MeOH, 5 mL), then dried and concentrated in vacuo to give
21 as a colourless oil (27 mg, 84% from 19, >99:1 dr); []2D0 – 54.5 (c 1.0 in MeOH).
1
2
3
4
5
6
4.8. Methyl (1R,2R,3S,4S,5R)-N,O,O,O-tetraacetyl-2-deoxy-2-amino-β-D-allofuranose 22
7
8
9
Step 1: Pd(OH)2/C (20 mg, 50% w/w) was added to a stirred solution of 19 (40 mg, 78 μmol, >99:1 dr) in
MeOH (5 mL) at rt. The resultant solution was degassed and saturated with H2 before being stirred at rt
under H2 (1 atm) for 18 h. The reaction mixture was then filtered through a short plug of Celite® (eluent
MeOH, 10 mL) and the filtrate was concentrated in vacuo to give a mixture of compounds 20 as a colourless
oil (25 mg).
10
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19
20
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23
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65
Step 2: Ac2O (0.07 mL, 0.74 mmol) and DMAP (3 mg, 12% w/w) were added sequentially to a stirred
solution of the mixture 20 (25 mg) in pyridine (2 mL) at rt, and the resultant mixture was stirred at rt for 12
h. H2O (10 mL) was then added and the reaction mixture was diluted with EtOAc (10 mL). The aqueous
layer was extracted with EtOAc (3 × 5 mL) and the combined organic extracts were washed sequentially
with satd aq CuSO4 (10 mL), H2O (10 mL) and brine (10 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent CH2Cl2/MeOH, 90:10) gave 22 as a colourless oil (24
mg, 85% from 19, >99:1 dr); []2D0 –18.8 (c 2.0 in CHCl3); νmax (ATR) 3282 (O–H, N–H), 2937 (C–H),
1747, 1662 (C=O); δH (500 MHz, C6D6) 1.81 (3H, s, COMe), 1.82 (6H, s, 2 × COMe), 1.94 (3H, s, COMe),
3.24 (3H, s, OMe), 4.33 (1H, dd, J 12.2, 6.2, C(6)HA), 4.41 (1H, dd, J 6.3, 4.9, C(4)H), 4.72 (1H, dd, J 12.2,
3.4, C(6)HB), 4.91 (1H, d, J 2.2, C(1)H), 5.01–5.04 (1H, m, C(2)H), 5.60–5.63 (1H, m, C(5)H), 5.86 (1H,
dd, J 5.7, 4.9, C(3)H), 6.19 (1H, d, J 7.9, NH); δC (125 MHz, C6D6) 20.2, 20.3, 20.6, 22.6 (4 × COMe), 55.4
(OMe), 56.2 (C(2)), 63.0 (C(6)), 72.0 (C(5)), 73.2 (C(3)), 80.7 (C(4)), 108.4 (C(1)), 169.0, 169.6, 169.7,
+
170.1 (4 × COMe); m/z (ESI+) 384 ([M+Na]+, 100%); HRMS (ESI+) C15H23NNaO9 ([M+Na]+) requires
384.1265; found 384.1252.
4.9. tert-Butyl (2R,3R,4R,5S,6R,αS)-2,4,5,6,7-pentahydroxy-3-[N-benzyl-N-(α-methylbenzyl)amino]-
4,5,6,7-di-O-isopropylideneheptanoate 23
BuLi (1.9 M in hexanes, 19.2 mL, 36.5 mmol) was added dropwise to a stirred solution of (S)-N-benzyl-N-
(α-methylbenzyl)amine (7.70 g, 36.4 mmol, >99:1 er) in THF (40 mL) at 78 °C, and the resultant mixture
was stirred at 78 °C for 30 min. A solution of 227 (6.00 g, 18.3 mmol, >99:1 dr) in THF (20 mL) at –78 °C
was then added dropwise and the resultant mixture was stirred at 78 °C for 2 h. (+)-CSO 10 (8.39 g, 36.6
20

ACCEPTED MANUSCRIPT
mmol) was then added and the reaction mixture was allowed to warm to rt over 12 h. The reaction mixture
was then diluted with Et2O (120 mL) and filtered. The filtrate was washed sequentially with 10% aq citric
acid (120 mL), satd aq NaHCO3 (120 mL) and brine (120 mL), then dried and concentrated in vacuo to give
an 18:52:30 mixture of 6, 23 and 24, respectively. Purification via flash column chromatography (eluent 30–
40 °C petrol/Et2O/Et3N, 83:16:1) gave 6 as a white solid (1.01g, 10%, >99:1 dr);27 mp 56–60 °C; {lit.27 mp
53–58 °C}; []2D5 +22.9 (c 1.0 in CHCl3); {lit.27 []D25 +23.5 (c 1.0 in CHCl3)}; δH (400 MHz, CDCl3) 1.32
(3H, s, MeCMe), 1.36 (3H, s, MeCMe), 1.38 (6H, s, 2 × MeCMe), 1.41 (9H, s, CMe3), 1.46 (3H, d, J 6.8,
C(α)Me), 2.31 (1H, dd, J 15.4, 5.7, C(2)HA), 2.36 (1H, dd, J 15.4, 6.9, C(2)HB), 3.70 (1H, app t, J 7.5,
C(5)H), 3.73–3.80 (3H, m, C(3)H, NCH2Ph), 3.91 (1H, dd, J 8.0, 5.5, C(7)HA), 4.04–4.17 (3H, m, C(6)H,
C(7)HB, C(α)H), 4.27 (1H, dd, J 7.6, 2.5, C(4)H), 7.19–7.40 (10H, m, Ph). Further elution gave a 60:40
mixture of 23 and 24, respectively, as a pale yellow oil (8.31 g, 82%). Purification of an aliquot (540 mg) via
flash column chromatography (eluent 30–40 °C petrol/Et2O, 91:9) gave 23 as a pale yellow oil (258 mg,
39% from 2, >99:1 dr); []2D0 +25.0 (c 1.0 in CHCl3); νmax (ATR); 3485 (O–H), 2984, 2936 (C–H), 1738
(C=O); δH (400 MHz, CDCl3) 1.36 (9H, s, CMe3), 1.39 (3H, s, MeCMe), 1.43 (3H, s, MeCMe), 1.46 (6H, s,
2 × MeCMe), 1.52 (3H, d, J 7.0, C(α)Me), 3.55 (1H, dd, J 6.1, 1.2, C(3)H), 3.72 (1H, app t, J 8.2, C(5)H),
3.81 (1H, d, J 14.0, NCHAHBPh), 3.84 (1H, dd, J 8.5, 6.3, C(7)HA), 4.05–4.10 (1H, m, C(6)H), 4.12–4.20
(3H, m, C(7)HB, NCHAHBPh, C(α)H), 4.29 (1H, dd, J 6.1, 3.6, C(2)H), 4.49 (1H, dd, J 7.8, 1.2, C(4)H),
7.20–7.38 (10H, m, Ph); δC (100 MHz, CDCl3) 13.7 (C(α)Me), 25.6, 26.6, 27.0, 27.1 (2 × CMe2), 27.9
(CMe3), 51.6 (NCH2Ph), 57.0 (C(α)), 58.4 (C(3)), 67.8 (C(2)), 68.3 (C(7)), 77.8 (C(6)), 78.7 (C(5)), 80.5
(C(4)), 81.4 (CMe3), 109.8, 110.0 (2 × CMe2), 127.1, 127.2, 128.1, 128.2, 128.4, 129.1 (o,m,p-Ph), 140.1,
142.9 (i-Ph), 172.8 (C(1)); m/z (ESI+) 578 ([M+Na]+, 40%), 556 ([M+H]+, 100%); HRMS (ESI+)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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23
24
25
26
27
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31
32
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39
40
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43
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45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
+
C32H46NO7 ([M+H]+) requires 556.3269; found 556.3266. Further elution gave an 20:80 mixture of 23 and
24, respectively, as a pale yellow oil (167 mg, 25%). Data for 24: δH (400 MHz, CDCl3) 1.33 (3H, s,
MeCMe), 1.38 (6H, s, 2 × MeCMe), 1.47 (3H, s, MeCMe), 1.49 (3H, d, J 7.1, C(α)Me), 1.51 (9H, s, CMe3),
3.13 (1H, d, J 6.1, OH), 3.67–3.70 (1H, m, C(2)H), 3.78 (1H, d, J 16.0, NCHAHBPh), 3.83–3.85 (1H, m,
C(3)H), 3.86–3.93 (2H, m, C(7)H2), 4.05 (1H, q, J 7.1 C(α)H), 4.06–4.10 (1H, m, C(4)H), 4.21 (1H, d, J
16.0, NCHAHBPh), 4.38–4.45 (2H, m, C(5)H, C(6)H), 7.21–7.45 (10H, m, Ph); δC (100 MHz, CDCl3) 19.0
(C(α)Me), 25.5, 26.4, 27.2, 27.9 (2 × CMe2), 28.1 (CMe3), 52.0 (NCH2Ph), 57.5 (C(α)), 60.7 (C(3)), 64.9
(C(7)), 71.0 (C(2)), 76.6, 76.6, 79.4 (C(4)), (C(5)), (C(6)), 82.4 (CMe3), 109.2, 109.5 (2 × CMe2), 126.8,
127.3, 128.1, 128.2, 128.4, 128.5 (o,m,p-Ph), 140.4, 140.9 (i-Ph), 172.9 (C(1)).
21

ACCEPTED MANUSCRIPT
4.10. (2R,3R,4R,5S,6R,αS)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-4,5,6,7-di-O-isopropylideneheptan-
1,2,4,5,6,7-hexaol 25
1
2
3
4
5
6
7
8
LiAlH4 (1.0 M in THF, 0.60 mL, 0.60 mmol) was added dropwise to a stirred solution of 23 (150 mg, 0.270
mmol, >99:1 dr) in THF (2 mL) at 0 C and the resultant mixture was allowed to warm to rt over 16 h. The
reaction mixture was quenched by cautiously adding ice, then filtered through a short plug of Celite® (eluent
Et2O, 10 mL). The filtrate was then partitioned between H2O (5 mL) and Et2O (5 mL) and the organic layer
was dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 50:50) gave 25 as a yellow oil (120 mg, 92%, >99:1 dr); []2D0 +29.0 (c 1.0 in CHCl3); νmax
(ATR) 3446 (O–H), 2986, 2934 (C–H); δH (400 MHz, CDCl3) 1.41 (3H, s, MeCMe), 1.42 (3H, s, MeCMe),
1.43 (3H, s, MeCMe), 1.50 (3H, s, MeCMe), 1.54 (3H, d, J 6.8, C(α)Me), 3.25–3.31 (1H, m, C(1)HA), 3.26
(1H, app d, J 6.3, C(3)H), 3.44 (1H, app d, J 8.6, C(1)HB), 3.73 (1H, app t, J 8.6 C(5)H), 3.78 (1H, d, J 13.6,
NCHAHBPh), 3.92 (1H, app dd, J 9.9, 4.3, C(2)H), 3.99 (1H, dd, J 8.6, 5.8, C(7)HA), 4.09–4.14 (2H, m,
C(6)H, C(α)H), 4.23 (1H, dd, J 8.6, 6.2, C(7)HB), 4.30 (1H, d, J 13.6, NCHAHBPh) 4.52 (1H, app d, J 8.3,
C(4)H), 7.21–7.40 (10H, m, Ph); δC (100 MHz, CDCl3) 11.2 (C(α)Me), 25.9, 26.6, 26.6, 27.1 (2 × CMe2),
52.1 (NCH2Ph), 54.6 (C(3)), 55.9 (C(α)), 63.2 (C(1)), 68.4 (C(7)), 68.6 (C(2)), 78.0 (C(6)), 79.3 (C(5)), 81.6
(C(4)), 109.2, 110.2 (2 × CMe2), 127.2, 127.3, 128.1, 128.3, 128.4, 129.3 (o,m,p-Ph), 140.3, 143.4 (i-Ph);
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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60
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65
+
m/z (ESI+) 993 ([2M+Na]+, 90%), 508 ([M+Na]+, 10%), 486 ([M+H]+, 100%); HRMS (ESI+) C28H40NO6
([M+H]+) requires 486.2850; found 486.2846.
4.11. (2S,3R,4S,5R,αS)-2-[N-Benzyl-N-(α-methylbenzyl)amino]-3,4,5,6,-di-O-isopropylidene-3,4,5,6-
tetrahydroxyhexanal 26
NaIO4 (265 mg, 1.24 mmol) was added to a stirred solution of 25 (120 mg, 0.247 mmol, >99:1 dr) in MeOH
(5 mL) at rt, and the resultant mixture was left to stir at rt for 24 h. The resultant suspension was filtered
through a short plug of Celite® (eluent MeOH, 5 mL), and the filtrate was concentrated in vacuo. The residue
was diluted with Et2O (5 mL) and filtered through a short plug of Celite® (eluent Et2O, 5 mL), then the
filtrate was concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 83:17) gave 26 as a pale yellow oil (85 mg, 76%, >99:1 dr); []2D4 +48.8 (c 1.0 in CHCl3); νmax
(ATR) 2986 (C–H), 1728 (C=O); δH (400 MHz, CDCl3) 1.18 (3H, s, MeCMe), 1.33 (3H, s, MeCMe), 1.36
(3H, s, MeCMe), 1.38 (3H, s, MeCMe), 1.50 (3H, d, J 6.8, C(α)Me), 3.77 (1H, app s, C(2)H), 3.95–3.98 (1H,
22

ACCEPTED MANUSCRIPT
m, C(6)HA), 4.04–4.07 (2H, m, C(4)H, C(5)H), 4.14–4.19 (2H, m, C(6)HB, C(α)H), 4.23 (1H, d, J 14.6,
NCHAHBPh), 4.29 (1H, d, J 14.6, NCHAHBPh), 4.38–4.40 (1H, m, C(3)H), 7.23–7.56 (10H, m, Ph), 9.67
(1H, d, J 1.3, C(1)H); δC (100 MHz, CDCl3) 15.9 (C(α)Me), 25.6, 26.4, 26.8, 27.1 (2 × CMe2), 52.3
(NCH2Ph), 57.2 (C(α)), 64.6 (C(2)), 68.0 (C(6)), 77.5, 78.2 (C(4), C(5)), 82.1 (C(3)), 109.9, 110.0 (2 ×
CMe2), 127.0, 127.1, 127.8, 128.2, 128.3, 128.6 (o,m,p-Ph), 140.6, 143.2 (i-Ph), 203.1 (C(1)); m/z (ESI+)
1
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3
4
5
6
7
8
9
+
476 ([M+Na]+, 100%), 454 ([M+H]+, 50%); HRMS (ESI+) C27H35NNaO5 ([M+Na]+) requires 476.2407;
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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36
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48
49
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51
52
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61
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63
64
65
found 476.2406.
4.12. Methyl (1R,2S,3R,4S,5R,αS)-2-deoxy-2-[N-benzyl-N-(α-methylbenzyl)amino]-α-D-mannofuranose
28
A solution of HCl in MeOH (1.25 M, 85 mL) was added to 26 (2.10 g, 4.64 mmol, >99:1 dr), and the
resultant mixture was heated at 50 °C for 24 h. The reaction mixture was then allowed to cool to rt,
concentrated in vacuo, and the residue was partitioned between 2.0 M aq NaOH (60 mL) and CH2Cl2 (60
mL). The aqueous layer was extracted with CH2Cl2 (2 × 60 mL) and the combined organic extracts were
dried and concentrated in vacuo to give an 80:20 mixture of 27 and 28, respectively. Purification via flash
column chromatography (eluent CH2Cl2/MeOH, 95:5) gave an 80:20 mixture of 27 and 28, respectively, as a
pale yellow oil (1.22 g, 68%). Further purification of an aliquot (300 mg) via flash column chromatography
(eluent CH2Cl2/MeOH, 99:1) gave 28 as a pale yellow oil (33 mg, 7%, >99:1 dr); []2D0 –57.2 (c 1.0 in
CHCl3); νmax (ATR) 3463 (O–H), 2932 (C–H); δH (500 MHz, MeOH-d4) 1.49 (3H, d, J 6.9, C(α)Me), 2.73
(3H, s, OMe), 3.11 (1H, app t, J 4.1, C(2)H), 3.52 (1H, d, J 14.5, NCHAHBPh), 3.63 (1H, dd, J 11.7, 5.7,
C(6)HA), 3.80 (1H, dd, J 11.7, 2.7, C(6)HB), 3.86–3.93 (2H, m, C(4)H, C(5)H), 4.03 (1H, d, J 14.5,
NCHAHBPh), 4.39 (1H, d, J 3.8, C(1)H), 4.46 (1H, app t, J 4.0, C(3)H), 4.52 (1H, q, J 6.9, C(α)H), 7.12–
7.55 (10H, m, Ph); δC (125 MHz, MeOH-d4) 11.5 (C(α)Me), 54.5 (NCH2Ph), 54.7 (OMe), 58.0 (C(α)), 65.0
(C(6)), 68.9 (C(2)), 72.1 (C(5)), 72.5 (C(3)), 82.8 (C(4)), 105.6 (C(1)), 127.5, 127.9, 128.7, 128.9, 129.5,
129.8 (o,m,p-Ph), 142.8, 144.8 (i-Ph); m/z (ESI+) 797 ([2M+Na]+, 100%), 410 ([M+Na]+, 80%), 388
([M+H]+, 90%); HRMS (ESI+) C22H30NO5 ([M+H]+) requires 388.2118; found 388.2115. Further elution
+
gave a 65:35 mixture of 27 and 28, respectively, as a pale yellow oil (70 mg, 16%). Data for 27: δH (500
MHz, MeOH-d4) 1.48 (3H, d, J 6.9, C(α)Me), 3.02 (3H, s, OMe), 3.46 (1H, app t, J 4.6, C(2)H), 3.57 (1H,
dd, J 11.5, 6.2, C(6)HA), 3.74 (1H, d, J 15.3, NCHAHBPh), 3.76 (1H, dd, J 11.5, 3.2, C(6)HB), 3.86–3.94
(2H, m, C(4)H, C(5)H) overlapping 3.94 (1H, d, J 15.3, NCHAHBPh), 4.27 (1H, q, J 6.9, C(α)H), 4.42 (1H,
23

ACCEPTED MANUSCRIPT
dd, J 4.7, 2.5, C(3)H), 4.62 (1H, d, J 4.4, C(1)H), 7.11–7.55 (10H, m, Ph); δC (125 MHz, MeOH-d4) 13.1
(C(α)Me), 52.7 (NCH2Ph), 55.7 (OMe), 58.9 (C(α)), 65.1 (C(6)), 70.9 (C(5)), 71.4 (C(2)), 73.3 (C(3)), 81.0
(C(4)), 106.8 (C(1)), 127.6, 128.0, 128.7, 129.0, 129.2, 129.6 (o,m,p-Ph), 142.7, 144.2 (i-Ph).
1
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7
8
9
4.13. (2S,3R,4R,5S,6R,αS)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-4,5,6,7-di-O-isopropylideneheptan-
1,2,4,5,6,7-hexaol 29
10
11
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29
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65
LiAlH4 (1.0 M in THF, 31.7 mL, 31.7 mmol) was added dropwise to a stirred solution of a 60:40 mixture of
23 and 24, respectively, (8.00 g, 14.4 mmol) in THF (50 mL) at 0 C and the resultant mixture was allowed
to warm to rt over 16 h. The reaction mixture was quenched by cautiously adding ice, then filtered through a
short plug of Celite® (eluent Et2O, 100 mL). The filtrate was then partitioned between H2O (50 mL) and
Et2O (50 mL) and the organic layer was dried and concentrated in vacuo to give a 60:40 mixture of 25 and
29, respectively (6.93 g). Purification of an aliquot via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 50:50) and recrystallisation (CHCl3/n-heptane) gave an analytically pure sample of 29 as a
white solid; mp 92–93 °C; []2D0 +24.8 (c 0.8 in CHCl3); νmax (ATR) 3460 (O–H), 2984, 2933 (C–H); δH (500
MHz, MeOH-d4) 1.43 (3H, s, MeCMe), 1.44 (3H, s, MeCMe), 1.45 (3H, s, MeCMe), 1.46 (3H, s, MeCMe),
1.51 (3H, d, J 6.9, C(α)Me), 2.79 (1H, dd, J 11.3, 8.4, C(1)HA), 3.22 (1H, dd, J 8.8, 1.0, C(3)H), 3.51 (1H,
dd, J 11.3, 3.5, C(1)HB), 3.88 (1H, d, J 14.2, NCHAHBPh), 3.91–3.94 (1H, m, C(7)HA), 3.98–4.04 (2H, m,
C(2)H, C(α)H), 4.10–4.18 (3H, m, NCHAHBPh, C(6)H, C(7)HB), 4.38 (1H, app t, J 8.2, C(5)H), 4.46 (1H,
dd, J 8.2, 1.0, C(4)H), 7.22–7.38 (10H, m, Ph); δC (125 MHz, MeOH-d4) 13.6 (C(α)Me), 26.1, 27.2, 27.4,
27.5 (2 × CMe2), 53.1 (NCH2Ph), 57.8, 57.9 (C(3), (C(α)), 67.1 (C(1)), 68.9 (C(7)), 71.8 (C(2)), 79.5 (C(6)),
80.7 (C(5)), 82.7 (C(4)), 110.3, 111.1 (2 × CMe2), 128.1, 128.3, 129.0, 129.3, 129.6, 130.3 (o,m,p-Ph),
+
142.1, 145.0 (i-Ph); m/z (ESI+) 486 ([M+H]+, 100%); HRMS (ESI+) C28H40NO6 ([M+H]+) requires
486.2850; found 486.2847.
4.14. Methyl (1R,2S,3R,4S,5R)-2-deoxy-2-amino-β-D-mannofuranose 30
Pd(OH)2/C (7 mg, 50% w/w) was added to a stirred solution of 28 (14 mg, 36 μmol, >99:1 dr) in MeOH (1
mL) at rt. The resultant solution was degassed and saturated with H2 before being stirred at rt under H2 (1
atm) for 18 h. The reaction mixture was then filtered through a short plug of Celite® (eluent MeOH) and the
filtrate was concentrated in vacuo to give 30 as a colourless oil (7 mg, quant, >99:1 dr);41 []D20 –41.3 (c 0.4
in CHCl3); νmax (ATR) 3372 (O–H, N–H), 2923 (C–H); δH (500 MHz, MeOH-d4) 3.29 (1H, app t, J 5.0,
24

ACCEPTED MANUSCRIPT
C(2)H), 3.37 (3H, s, OMe), 3.67 (1H, dd, J 11.4, 5.7, C(6)HA), 3.83 (1H, dd, J 11.4, 2.8, C(6)HB), 3.89 (1H,
ddd, J 8.8, 5.7, 2.8, C(5)H), 3.94 (1H, dd, J 8.8, 4.1, C(4)H), 4.15 (1H, dd, J 5.0, 4.1, C(3)H), 4.76 (1H, d, J
4.7, C(1)H); δC (125 MHz, MeOH-d4) 55.8 (OMe), 58.2 (C(2)), 65.0 (C(6)), 72.1 (C(5)), 72.5 (C(3)), 82.6
1
2
3
4
5
6
7
8
+
(C(4)), 105.2 (C(1)); m/z (ESI+) 216 ([M+Na]+, 40%), 194 ([M+H]+, 50%); HRMS (ESI+) C7H15NNaO5
([M+Na]+) requires 216.0842; found 216.0843.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
4.15. tert-Butyl (2S,3R,4S,5R,6R,αS)-2,4,5,6,7-pentahydroxy-3-[N-benzyl-N-(α-methylbenzyl)amino]-
4,5,6,7-di-O-isopropylideneheptanoate 31
BuLi (1.7 M in hexanes, 53.8 mL, 91.5 mmol) was added dropwise to a stirred solution of (S)-N-benzyl-N-
(α-methylbenzyl)amine (19.6 g, 92.8 mmol, >99:1 er) in THF (100 mL) at 78 °C, and the resultant solution
was stirred at 78 °C for 30 min. A solution of 327 (15.2 g, 46.3 mmol, >99:1 dr) in THF (50 mL) at –78 °C
was then added dropwise and the reaction mixture was stirred at 78 °C for 2 h. (+)-CSO 10 (21.2 g, 92.4
mmol) was then added and the resultant mixture was allowed to warm to rt over 12 h. The reaction mixture
was then diluted with Et2O (250 mL) and filtered. The filtrate was washed sequentially with 10% aq citric
acid (200 mL), satd aq NaHCO3 (200 mL) and brine (200 mL), then dried and concentrated in vacuo to give
a mixture of 7, 31 and 32. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O,
83:17) gave 7 as a pale yellow oil (2.02 g, 8%, >99:1 dr);27 []D25 +5.0 (c 1.0 in CHCl3); {lit.27 []D25 +4.7 (c
1.0 in CHCl3)}; δH (400 MHz, CDCl3) 1.27 (3H, s, MeCMe), 1.29 (3H, d, J 7.2, C(α)Me), 1.32 (3H, s,
MeCMe), 1.36 (3H, s, MeCMe), 1.43 (3H, s, MeCMe), 1.44 (9H, s, CMe3), 1.91 (1H, dd, J 15.2, 2.4,
C(2)HA), 2.49 (1H, dd, J 15.2, 10.8, C(2)HB), 3.36 (1H, dt, J 10.8, 2.4, C(3)H), 3.52 (1H, d, J 15.4,
NCHAHBPh), 3.72–3.86 (3H, m, C(α)H, C(6)H, C(7)HA), 3.99 (1H, dd, J 7.5, 6.1, C(7)HB), 4.03 (1H, dd, J
8.2, 2.4, C(4)H), 4.37–4.42 (2H, m, C(5)H, NCHAHBPh), 7.24–7.39 (8H, m, Ph), 7.50–7.52 (2H, m, Ph).
Further elution gave a 70:30 mixture of 31 and 32, respectively, as a yellow oil (16.8 g, 65%). Purification of
an aliquot (2.13 g) via flash column chromatography (eluent 30–40 °C petrol/Et2O, 91:9) gave 31 as a white
solid (1.20 g, 37%, >99:1 dr); mp 65–70 °C; []2D0 +17.0 (c 0.5 in CHCl3); νmax (ATR) 3524 (O–H), 2984,
2934 (C–H), 1731 (C=O); δH (400 MHz, CDCl3) 1.25 (3H, d, J 7.0, C(α)Me), 1.29 (6H, s, 2 × MeCMe), 1.33
(3H, s, MeCMe), 1.36 (3H, s, MeCMe), 1.50 (9H, s, CMe3), 3.24 (1H, d, J 8.6, OH), 3.31 (1H, app s,
C(3)H), 3.41 (1H, app t, J 6.8, C(6)H), 3.80–3.91 (3H, m, C(7)H2, NCHAHBPh), 4.03 (1H, q, J 7.0, C(α)H),
4.09 (1H, dd, J 8.5, 1.9, C(4)H), 4.16 (1H, dd, J 8.6, 1.3, C(2)H), 4.28 (1H, dd, J 8.5, 1.7, C(5)H), 4.88 (1H,
d, J 15.4, NCHAHBPh), 7.22–7.52 (10H, m, Ph); δC (100 MHz, CDCl3) 21.2 (C(α)Me), 26.0, 26.0, 26.1, 27.0
25

ACCEPTED MANUSCRIPT
(2 × CMe2), 28.0 (CMe3), 54.3 (NCH2Ph), 56.3 (C(3)), 59.8 (C(α)), 66.0 (C(7)), 72.3 (C(2)), 73.5 (C(6)),
75.9 (C(5)), 77.9 (C(4)), 82.6 (CMe3), 109.3, 109.5 (2 × CMe2), 126.3, 127.4, 127.9, 128.2, 128.2, 128.4
(o,m,p-Ph), 142.8, 142.8 (i-Ph), 173.3 (C(1)); m/z (ESI+) 578 ([M+Na]+, 40%), 556 ([M+H]+, 100%); HRMS
1
2
3
4
5
+
(ESI+) C32H45NNaO7 ([M+Na]+) requires 578.3088; found 578.3086. Further elution gave a 15:85 mixture
6
7
8
9
of 31 and 32, respectively, as a yellow oil (392 mg, 12%). Data for 32: δH (400 MHz, CDCl3) [selected
peaks] 1.38 (3H, s, MeCMe), 1.40 (3H, s, MeCMe), 1.41 (3H, s, MeCMe), 1.44 (3H, s, MeCMe), 1.49 (9H,
s, CMe3), 3.09 (1H, d, J 4.1, OH), 3.82–3.88 (1H, m, C(7)HA), 4.01–4.04 (1H, m, C(7)HB), 4.27 (1H, dd, J
4.1, 2.7, C(2)H), 7.21–7.51 (10H, m, Ph); δC (100 MHz, CDCl3) [selected peaks] 21.1 (C(α)Me), 25.7, 26.2,
27.0, 27.4 (2 × CMe2), 28.0 (CMe3), 65.9 (C(7)), 70.2 (C(2)), 82.9 (CMe3), 108.7, 109.4 (2 × CMe2), 126.3,
127.4, 127.9, 128.2, 128.2, 128.3 (o,m,p-Ph), 142.8 (i-Ph), 174.0 (C(1)).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
4.16. (2S,3R,4S,5R,6R,αS)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-4,5,6,7-di-O-isopropylideneheptan-
1,2,4,5,6,7-hexaol 33
LiAlH4 (1.0 M in THF, 0.50 mL, 0.50 mmol) was added dropwise to a stirred solution of 31 (130 mg, 234
μmol, >99:1 dr) in THF (2 mL) at 0 C and the resultant mixture was allowed to warm to rt over 16 h. The
reaction mixture was quenched by cautiously adding ice, then filtered through a short plug of Celite® (eluent
Et2O, 10 mL). The filtrate was then partitioned between H2O (5 mL) and Et2O (5 mL) and the organic layer
was dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 50:50) gave 33 as a pale yellow oil (100 mg, 88%, >99:1 dr); []2D5 –21.4 (c 1.0 in CHCl3); νmax
(ATR) 3451 (O–H), 2986, 2932 (C–H); δH (400 MHz, CDCl3) 1.32–1.34 (6H, m, C(α)Me, MeCMe), 1.36
(3H, s, MeCMe), 1.37 (3H, s, MeCMe), 1.41 (3H, s, MeCMe), 2.92 (1H, app d, J 4.0, C(3)H), 3.42 (2H, app
d, J 5.6, C(1)H2), 3.58 (1H, app t, J 7.2, C(6)H), 3.70 (1H, dd, J 9.6, 5.1, C(2)H), 3.77 (1H, app t, J 7.8,
C(7)HA), 3.88 (1H, d, J 14.7, NCHAHBPh), 3.88–3.92 (1H, m, C(7)HB), 4.12 (1H, q, J 6.7, C(α)H), 4.35–
4.37 (2H, m, C(4)H, C(5)H), 4.54 (1H, d, J 14.7, NCHAHBPh), 7.25–7.47 (10H, m, Ph); δC (100 MHz,
CDCl3) 20.7 (C(α)Me), 25.7, 26.1, 26.3, 27.1 (2 × CMe2), 53.6 (NCH2Ph), 55.9 (C(3)), 58.9 (C(α)), 65.2
(C(1)), 66.0 (C(7)), 71.7 (C(2)), 73.9 (C(6)), 76.2, 77.9 (C(4), C(5)), 109.1, 109.4 (2 × CMe2), 126.7, 127.4,
127.9, 128.3, 128.4, 128.5 (o,m,p-Ph), 141.7, 143.4 (i-Ph); m/z (ESI+) 993 ([2M+Na]+, 90%), 508 ([M+Na]+,
+
30%), 486 ([M+H]+, 100%); HRMS (ESI+) C28H40NO6 ([M+H]+) requires 486.2850; found 486.2850.
26

ACCEPTED MANUSCRIPT
4.17. (2S,3S,4R,5R,αS)-2-[N-Benzyl-N-(α-methylbenzyl)amino]-3,4,5,6,-di-O-isopropylidene-3,4,5,6-
tetrahydroxyhexanal 34
1
2
NaIO4 (220 mg, 1.03 mmol) was added to a stirred solution of 33 (100 mg, 0.206 mmol) in MeOH (5 mL) at
rt, and the resultant mixture was left to stir at rt for 24 h. The resultant suspension was filtered through a
short plug of Celite® (eluent MeOH, 5 mL), and the filtrate was concentrated in vacuo. The residue was
dissolved in Et2O (5 mL) and filtered through a short plug of Celite® (eluent Et2O, 5 mL), then the filtrate
was concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O,
83:17) gave 34 as a yellow oil (74 mg, 79%, >99:1 dr); []2D5 –60.6 (c 1.0 in CHCl3); νmax (ATR) 2986, 2935
(C–H), 1723 (C=O); δH (400 MHz, CDCl3) 1.26 (3H, s, MeCMe), 1.37–1.40 (9H, m, C(α)Me, 2 × MeCMe),
1.43 (3H, s, MeCMe), 3.52 (1H, d, J 4.0, C(2)H), 3.85–3.94 (2H, m, C(5)H, C(6)HA), 3.99 (1H, dd, J 6.8,
5.8, C(6)HB), 4.16 (1H, q, J 7.0, C(α)H), 4.23 (1H, d, J 14.8, NCHAHBPh), 4.27 (1H, dd, J 8.2, 2.7, C(4)H),
4.43 (1H, d, J 14.8, NCHAHBPh), 4.62 (1H, dd, J 8.2, 4.0, C(3)H), 7.25–7.48 (10H, m, Ph), 9.34 (1H, s,
C(1)H); δC (100 MHz, CDCl3) 19.9 (C(α)Me), 25.7, 26.1, 26.4, 27.1 (2 × CMe2), 54.1 (NCH2Ph), 59.2
(C(α)), 65.3 (C(2)), 66.0 (C(6)), 74.1 (C(5)), 76.2 (C(3)), 76.4 (C(4)), 109.4, 109.5 (2 × CMe2), 126.9, 127.7,
127.8, 128.0, 128.4, 128.6 (o,m,p-Ph), 141.0, 142.5 (i-Ph), 202.8 (C(1)); m/z (ESI+) 486 ([M+MeOH+H]+,
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
+
100%), 476 ([M+Na]+, 30%), 454 ([M+H]+, 5%); HRMS (ESI+) C28H40NO6 ([M+MeOH+H]+) requires
486.2850; found 486.2850.
4.18. Methyl (1R,2S,3S,4R,5R,αS)-2-deoxy-2-[N-benzyl-N-(α-methylbenzyl)amino]-β-D-idofuranose 35
and methyl (1S,2S,3S,4R,5R,αS)-2-deoxy-2-[N-benzyl-N-(α-methylbenzyl)amino]-α-D-idofuranose 36
A solution of HCl in MeOH (1.25 M, 25 mL) was added to 34 (800 mg, 1.77 mmol, >99:1 dr), and the
resultant mixture was heated at 50 °C for 24 h. The reaction mixture was then allowed to cool to rt,
concentrated in vacuo, and the residue was partitioned between 2.0 M aq NaOH (30 mL) and CH2Cl2 (30
mL). The aqueous layer was extracted with CH2Cl2 (2 × 30 mL) and the combined organic extracts were
dried and concentrated in vacuo to give an 80:20 mixture of 35 and 36, respectively. Purification via flash
column chromatography (eluent CH2Cl2/MeOH, 90:10) gave an 80:20 mixture of 35 and 36, respectively, as
a pale yellow oil (460 mg, 67%). Data for mixture: νmax (ATR) 3400 (O–H), 2950 (C–H); m/z (ESI+) 410
+
([M+Na]+, 40%), 388 ([M+H]+, 100%); HRMS (ESI+) C22H30NO5 ([M+H]+) requires 388.2118; found
388.2108. Data for 35: δH (500 MHz, MeOH-d4) 1.45 (3H, d, J 6.9, C(α)Me), 3.24 (3H, s, OMe), 3.30 (1H,
dd, J 6.6, 5.0, C(2)H), 3.60–3.64 (2H, m, C(6)H2), 3.88–3.92 (1H, m, C(5)H), 3.99 (1H, d, J 14.5,
27

ACCEPTED MANUSCRIPT
NCHAHBPh), 3.99 (1H, q, J 6.9, C(α)H), 4.02 (1H, dd, J 6.9, 3.8, C(4)H), 4.09 (1H, d, J 14.5, NCHAHBPh),
4.36 (1H, d, J 5.0, C(1)H), 4.53 (1H, app t, J 6.8, C(3)H), 7.20–7.51 (10H, m, Ph); δC (125 MHz, MeOH-d4)
16.1 (C(α)Me), 53.7 (NCH2Ph), 55.3 (OMe), 57.9 (C(α)), 64.1 (C(6)), 69.7 (C(2)), 72.2 (C(5)), 72.4 (C(3)),
78.5 (C(4)), 105.1 (C(1)), 127.6, 127.7, 129.0, 129.0, 129.2, 129.6 (o,m,p-Ph), 143.6, 145.7 (i-Ph). Data for
36: δH (500 MHz, MeOH-d4) 1.43 (3H, d, J 6.6, C(α)Me), 3.06 (1H, app d, J 3.5, C(2)H), 3.24 (3H, s, OMe),
3.35–3.38 (2H, m, C(6)H2), 3.75 (1H, d, J 14.8, NCHAHBPh), 3.88–3.92 (2H, m, NCHAHBPh, C(α)H), 4.24–
4.26 (1H, m, C(5)H), 4.28 (1H, app t, J 4.3, C(3)H), 4.45 (1H, app d, J 4.7, C(4)H), 4.75 (1H, app s, C(1)H),
7.20–7.51 (10H, m, Ph); δC (125 MHz, MeOH-d4) 16.5 (C(α)Me), 51.9 (NCH2Ph), 55.3 (OMe), 57.9 (C(α)),
63.3 (C(6)), 69.9 (C(2)), 73.5 (C(5)), 75.4 (C(3)), 79.5 (C(4)), 105.4 (C(1)), 127.8, 128.1, 129.1, 129.1,
129.2, 129.3 (o,m,p-Ph), 142.5, 143.7 (i-Ph).
1
2
3
4
5
6
7
8
9
10
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13
14
15
16
17
18
19
20
21
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27
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
4.19. Methyl (1R,2S,3S,4R,5R)-2-deoxy-2-amino-β-D-idofuranose 37 and methyl (1S,2S,3S,4R,5R)-2-
deoxy-2-amino-α-D-idofuranose 38
Pd(OH)2/C (25 mg, 50% w/w) was added to a stirred solution of an 80:20 mixture of 35 and 36 (50 mg,
0.013 mmol) in MeOH (5 mL) at rt. The resultant solution was degassed and saturated with H2 before being
stirred at rt under H2 (1 atm) for 18 h. The reaction mixture was then filtered through a short plug of Celite®
(eluent MeOH, 40 mL) and the filtrate was concentrated in vacuo to give an 80:20 mixture of 37 and 38,
respectively, as a colourless oil (25 mg, quant). Data for mixture: νmax (ATR) 3370, 3315 (O–H, N–H), 2935
+
(C–H); m/z (ESI+) 216 ([M+Na]+, 100%), 194 ([M+H]+, 50%); HRMS (ESI+) C7H15NNaO5 ([M+Na]+)
requires 216.0842; found 216.0838. Data for 37: δH (500 MHz, MeOH-d4) 3.35–3.36 (1H, m, C(2)H), 3.43
(3H, s, OMe), 3.61–3.72 (2H, m, C(6)H2), 3.92 (1H, app dd, J 10.9, 5.4, C(5)H), 4.03 (1H, dd, J 5.3, 2.4,
C(3)H), 4.24 (1H, dd, J 10.9, 5.3, C(4)H), 4.74 (1H, d, J 1.3, C(1)H); δC (125 MHz, MeOH-d4) 55.9 (OMe),
64.5 (C(6)), 65.3 (C(2)), 71.3 (C(5)), 78.6 (C(3)), 83.0 (C(4)), 111.2 (C(1)). Data for 38: δH (500 MHz,
MeOH-d4) 2.82 (1H, app t, J 3.4, C(2)H), 3.44 (3H, s, OMe), 3.61–3.72 (2H, m, C(3)H, C(4)H), 3.74–3.83
(2H, m, C(6)H2), 4.05–4.08 (1H, m, C(5)H), 4.63 (1H, d, J 2.8, C(1)H); δC (125 MHz, MeOH-d4) 54.5
(C(2)), 55.8 (OMe), 62.6 (C(6)), 70.1 (C(5)), 70.3, 72.7 (C(3), C(4)), 104.1 (C(1)).
28