An expeditious synthesis of isofagomine

Article abstract of DOI:10.1071/CH07016

An expeditious synthesis of isofagomine, from d-arabinose, is reported. CSIRO 2007.

Full text of DOI:10.1071/CH07016

Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 211–213
An Expeditious Synthesis of Isofagomine
Ethan D. Goddard-BorgerA and Robert V. StickA,B
AChemistry M313, School of Biomedical, Biomolecular and Chemical Sciences,
University of Western Australia, Crawley WA 6009, Australia.
BCorresponding author. Email: rvs@chem.uwa.edu.au
An expeditious synthesis of isofagomine, from d-arabinose, is reported.
Manuscript received: 22 January 2007.
Final version: 9 February 2007.
Isofagomine 1 (Scheme 1), a prominent member of the aza sugar
family, was proposed and first synthesized by Lundt, Bols, and
co-workers in 1994.[1] Subsequently, the molecule attracted con-
siderable synthetic attention[2] owing to its strong inhibition of a
range of enzymes that hydrolyze, in particular, the β-glycosidic
linkage. One of the most expeditious syntheses of 1 starts from
benzyl α-l-xylopyranoside and introduces the required nitrogen
and extra carbon atom in the form of the nitrile 2.[2] This synthe-
sis very closely follows our route to isofagomine, starting with
benzyl β-l-xylopyranoside;[3] we have recently reported some
improvements to our original synthesis of 1, as well as related
routes to other aza sugars.[4]
It seemed to us, given the importance and general need,
including our own, for access to good amounts of isofagomine,
that the time was ripe for developing a cheap and easy route
to 1. Undoubtedly the route offered by Fan and co-workers[2]
(Scheme 1) was the way to proceed but, like our own synthesis,[3]
it suffers from the expense of l-xylose, an inefficient isopropy-
lidenation step and the poor-yielding preparation of benzyl α-l-
xylopyranoside.[5] Therefore we decided to start our synthesis of
OBn
OBn
O
OH
O
O
HO
OH
HO
HO
NH
O
OH
NC
2
1
Scheme 1.
OBn
O
OBn
OBn
(a)
(b)
(c)
O
O
O
OH
OH
4
O
OH
OH
HO
HO
AcO
3
4
OBn
OBn
O
OBn
O
(d)
(e)
O
O
O
4-O2NC6H4COO
O
HO
O
ImSO2O
O
O
5
6
7
(f)
(g)
2
1
Scheme 2. (a) (i) MeC(OEt)3, CSA, CH2Cl2, (ii) Et3N, (iii) AcOH, H2O, 87%. (b) (i) CH2C(OMe)Me, CSA, CH2Cl2, (ii)
NaOH, MeOH, 94%. (c) 4-O2NC6H4CO2H, DEAD, PPh3, PhMe, 80%. (d) Et3N, MeOH, 92%. (e) SO2Cl2, ImH, C5H5N, 94%.
(f) KCN, DMF, 76%. (g) Pd(OH)2/C, conc. HCl, MeOH, 81%.
© CSIRO 2007
10.1071/CH07016
0004-9425/07/030211

212
E. D. Goddard-Borger and R. V. Stick
1 from inexpensive and readily available d-arabinose, necessitat-
ing the replacement of the hydroxyl group at C4 with the required
nitrile, and with retention of configuration; our synthesis is out-
lined in Scheme 2. Such conversions of d-arabinopyranosides
into l-xylopyranosides have ample precedent.[6]
4
(19.6 g, 70.0 mmol), PPh3 (50.5 g, 192 mmol), and
4-O2NC6H4CO2H (32.2 g, 192 mmol) in dry PhMe (175 mL)
at 0◦C. The resulting mixture was warmed and stirred (40◦C,
12 h). The dark mixture was concentrated and rapid silica gel
filtration (EtOAc/petrol/Et3N, 5:94:1 then 10:89:1) gave the
4-nitrobenzoate 5 as pale yellow needles (24.0 g, 80%). mp 104–
105◦C (EtOAc/petrol). [α]D −38.0◦ (MeCN). δH (600 MHz,
CD3CN) 1.41 (6H, 2s, CH3), 3.57 (dd, J4,5 10.7, J5,5 11.2, H5),
3.68 (dd, J1,2 3.1, J2,3 9.6, H2), 3.97 (dd, J4,5 5.5, H5), 4.27
(dd, J3,4 9.9, H3), 4.61, 4.81 (ABq, J 12.0, CH2Ph), 5.28 (d,
H1), 5.32 (ddd, H4), 7.32–7.44 (m, Ph), 8.16–8.29 (4H, m, Ar).
δC (150.9 MHz, CD3CN) 26.8, 27.0 (2C, CH3), 60.3 (C5), 70.5
(CH2Ph), 73.3, 74.8, 76.8 (C2,3,4), 97.3 (C1), 111.6 [C(CH3)2],
124.7–151.9 (Ar, Ph), 164.7 (C=O). m/z 430.1477; [M + H]+
requires 430.1502.
Benzyl β-d-arabinopyranoside[7] was converted into the diol
3 using standard orthoester chemistry and thence the alcohol
4, the configuration of which at C4 was easily inverted by
Mitsunobu chemistry, providing the ester 5; a simple trans-
esterification process then gave the known alcohol 6.[2] We then
found it convenient to avoid the formation of an expensive tri-
flate from the alcohol 6;[2] instead, the imidazylate 7 allowed for
the formation of the nitrile 2. The described reductive amination
then converted 2 into isofagomine 1.[2]
A gram of isofagomine can now be prepared from
d-arabinose, in an overall yield of 30%, in about eight days.
Benzyl 2,3-O-Isopropylidene-α-L-xylopyranoside 6
Experimental
Triethylamine (10 mL) was added to the 4-nitrobenzoate 5
(21.5 g) in MeOH (250 mL), and the mixture stirred (40◦C,
30 min). The solution was concentrated and flash chromatog-
raphy (EtOAc/petrol/Et3N, 25:74:1) gave the alcohol 6 as a
colourless oil (12.9 g, 92%). [α]D −115◦ (MeOH; lit.[2] −119.0◦
Generalexperimentalprocedureshavebeendescribedrecently.[8]
Benzyl 4-O-Acetyl-β-D-arabinoside 3
Camphor-10-sulfonic acid (580 mg, 2.50 mmol) was added
to benzyl β-d-arabinopyranoside[7] (21.6 g, 90 mmol) and tri-
ethyl orthoacetate (33.0 mL, 180 mmol) in CH2Cl2 (350 mL)
and the mixture stirred (30◦C, 2 h). Triethylamine (5 mL) was
added before the solution was washed with water, dried over
MgSO4, filtered, and concentrated. The residue was dissolved in
AcOH/H2O(9:1, 200 mL)andthesolutionstirred(15 min). Con-
centration of the mixture, co-evaporation with PhMe, and recrys-
tallization gave the diol 3 as colourless needles (22.1 g, 87%). mp
95.0–95.5◦C (Et2O/petrol). [α]D −213◦. δH (600 MHz) 1.94–
2.67 (2H, br m, OH), 2.14 (s, CH3), 3.75 (dd, J4,5 2.1, J5,5 13.0,
H5), 3.84 (dd, J1,2 3.8, J2,3 9.8, H2), 3.86 (dd, J4,5 1.4, H5), 3.96
(dd, J3,4 3.6, H3), 4.54, 4.76 (ABq, J 11.7, CH2Ph), 5.02 (d, H1),
5.15 (ddd, H4), 7.28–7.41 (m, Ph). δC (150.9 MHz) 21.2 (CH3),
61.1 (C5), 69.2, 70.0, 71.4 (C2,3,4), 70.1 (CH2Ph), 98.0 (C1),
128.2, 128.3, 128.8, 136.9 (Ph), 171.1 (C=O). m/z 283.1179;
[M + H]+ requires 283.1182.
1
(MeOH)). The H and 13C NMR spectra were consistent with
those previously reported.[2]
Benzyl 4-O-(Imidazolyl-1-sulfonyl)-2,3-O-
isopropylidene-α-L-xylopyranoside 7
Sulfuryl chloride (2.41 mL, 30.0 mmol) in CH2Cl2 (10 mL)
was added dropwise to the alcohol 6 (7.01 g, 25.0 mmol) and
pyridine (4.85 mL, 60.0 mmol) in CH2Cl2 (100 mL) at −35◦C
and the mixture stirred (1 h). Imidazole (7.49 g, 110 mmol) was
added, the mixture allowed to warm to room temperature, and
stirred (16 h). The solution was diluted (CH2Cl2), washed with
water, dried over MgSO4, filtered, and concentrated.The residue
was subjected to flash chromatography (EtOAc/petrol/Et3N,
15:84:1) to give the imidazylate 7 as colourless needles (9.64 g,
94%). mp 80–81◦C (Et2O/petrol). [α]D −115◦ (MeCN). δH
(600 MHz, CD3CN) 1.29, 1.32 (6H, 2s, CH3), 3.52 (dd, J4,5
9.9, J5,5 11.3, H5), 3.53 (dd, J1,2 3.1, J2,3 9.5, H2), 3.71 (dd,
J4,5 5.6, H5), 4.00 (dd, J3,4 9.6, H3), 4.56, 4.74 (ABq, J 12.0,
CH2Ph), 4.93 (ddd, H4), 5.21 (d, H1), 7.13–7.14 (1H, m, Im),
7.30–7.41 (m, Ph), 7.47–7.48 (1H, m, Im), 8.03–8.04 (1H,
m, Im). δC (150.9 MHz, CD3CN) 26.5, 26.7 (2C, CH3), 59.8
(C5), 70.7 (CH2Ph), 74.2, 76.3, 82.3 (C2,3,4), 96.9 (C1), 112.0
[C(CH3)2], 119.3–138.5 (Im, Ph). m/z 411.1226; [M + H]+
requires 411.1226.
Benzyl 2,3-O-Isopropylidene-β-D-arabinopyranoside 4
Camphor-10-sulfonic acid (116 mg, 0.50 mmol) was added to
the diol 3 (21.2 g, 75.0 mmol) and 2-methoxypropene (12.9 mL,
135 mmol) in CH2Cl2 (200 mL), and the mixture stirred
(30 min). Triethylamine (1 mL) was added and the solution
stirred; saturated methanolic NaOH (30 mL) was added, and
the solution again stirred (10 min). The solution was diluted
(CH2Cl2), washed with water, dried over MgSO4, filtered, and
concentratedtogivethecrudeacetonide4asapaleyellowoilthat
was sufficiently pure for the next step of the synthesis. Purifi-
cation by flash chromatography (EtOAc/petrol/Et3N, 25:74:1)
gave the alcohol 4 as a colourless oil (19.8 g, 94%). [α]D −255◦
(MeCN). δH (600 MHz, CD3CN) 1.37, 1.38 (6H, 2s, CH3), 3.14
(br s, OH), 3.60 (dd, J4,5 1.7, J5,5 12.6, H5), 3.70 (dd, J4,5 1.6,
H5), 3.94–4.00 (m, H2,3), 4.20 (ddd, J3,4 2.9, H4), 4.55, 4.75
(ABq, J 12.0, CH2Ph), 5.26 (d, J1,2 2.8, H1), 7.27–7.42 (m,
Ph). δC (150.9 MHz, CD3CN) 27.0 (CH3), 65.2 (C5), 68.8, 72.2,
74.3 (C2,3,4), 70.2 (CH2Ph), 98.8 (C1), 110.0 [C(CH3)2], 128.6,
129.4, 139.0 (Ph). m/z 281.1383; [M + H]+ requires 281.1389.
Benzyl 4-C-Cyano-4-deoxy-2,3-O-isopropylidene-
β-D-arabinoside 2
Potassium cyanide (6.3 g, 96 mmol) was added to the imidazy-
late 7 (4.9 g, 12 mmol) in DMF (150 mL) and the mixture
stirred (50◦C, 48 h). The mixture was then concentrated, diluted
(CH2Cl2), washed with water, dried over MgSO4, filtered, and
concentrated. The residue was subjected to flash chromatog-
raphy (EtOAc/petrol/Et3N, 5:94:1) to give the nitrile 2 as a
colourless oil (2.6 g, 76%). [α]D −198◦ (MeOH; lit.[2] −204.6◦
1
(MeOH)). The H and 13C NMR spectra were consistent with
those previously reported.[2]
Benzyl 2,3-O-Isopropylidene-4-O-
(4-nitrobenzoyl)-α-L-xyloside 5
Acknowledgments
Diethyl azodicarboxylate (30.6 mL, 196 mmol) in dry PhMe
(25 mL) was added dropwise with stirring to the alcohol
E.D.G.-B. thanks the University of WesternAustralia for a Hackett postgrad-
uate scholarship.

Expeditious Synthesis of Isofagomine
213
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