A complete asymmetric synthesis of polyhydroxypiperidines

Article abstract of DOI:10.1016/S0040-4039(03)00014-5

A new general methodology for the asymmetric synthesis of polyhydroxypiperidines is described. The readily available achiral olefin 4 was transformed to 5-des(hydroxymethyl)-1-deoxynojirimycin (1) and its mannose analog 10 via regioselective aminohydroxyl

Full text of DOI:10.1016/S0040-4039(03)00014-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1567–1569
A complete asymmetric synthesis of polyhydroxypiperidines
Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, 6900 N. Loop 1604 West, San Antonio, TX 78249, USA
Received 17 December 2002; accepted 30 December 2002
Abstract—A new general methodology for the asymmetric synthesis of polyhydroxypiperidines is described. The readily available
achiral olefin 4 was transformed to 5-des(hydroxymethyl)-1-deoxynojirimycin (1) and its mannose analog 10 via regioselective
aminohydroxylation (AA), ring-closing metathesis (RCM), and diastereoselective dihydroxylation reactions. Thus, the developed
methodology made it possible to install all stereocenters in 1 and 10 in a highly stereocontrolled fashion. © 2003 Elsevier Science
Ltd. All rights reserved.
In recent years polyhydroxypiperidines such as 5-
des(hydroxymethyl)-1-deoxynojirimycin (1), 2, and
isofagomine (3) have drawn much attention among
(bio)chemists (Fig. 1).1 Such intense interest stems from
the fact that these compounds are potent inhibitors of
glycosidases that have been suggested to be implicated
in various diseases including diabetes,2 cancer,3 and
viral infection,4 and further drugs for treating these
diseases can be developed based on polyhydroxypipe-
ridine structures.
duce the required six-membered ring and vicinal diol
functionality respectively (Fig. 2)
As shown in Scheme 1, the achiral olefin 4 was a
starting point of our synthesis. The olefin 4 was
designed as a substrate for the regioselective aminohy-
droxylation reaction from the consideration that aryl-
aryl stacking interaction between the p-methoxyphenyl
group of 4 and the AA catalyst could increase enan-
tioselectivity of the AA reaction,10 and the AA reaction
of terminal olefins has been observed to occur in such a
way that a nitrogen atom predominantly adds to the
terminal carbon of the olefins.11 Thus, the osmium
Among polyhydroxypiperidines, of particular interest
are 5-des(hydroxymethyl)-1-deoxynojirimycin (1) and
its stereoisomers. Because they are potent glycosidase
inhibitors, and moreover, have been used as convenient
intermediates for the asymmetric synthesis of 2, 3, and
their stereoisomers.5 Since the first synthesis by Ganem,
a number of methodologies have been developed for
the asymmetric synthesis of 1 and its stereoisomers.5,6
However, all reported methodologies required chiral
starting materials and/or lengthy synthetic routes.
Herein we wish to report a complete asymmetric syn-
thesis of 1 and the mannose analog 10 starting from the
readily available achiral olefin 4.
Figure 1.
The developed strategy utilizes the regioselective amino-
hydroxylation (AA) reaction7 of olefins, which installs
the vicinal aminoalcohol functionality in the targets. In
addition, the ring-closing metathesis8 and diastereose-
lective dihydroxylation reactions9 will be used to intro-
Keywords: polyhydroxypiperidine; regioselective aminohydroxylation;
ring-closing metathesis.
* Tel.: +1-210-458-4958; fax: +1-210-458-4958; e-mail: hhan@utsa.edu
Figure 2. Retrosynthetic analysis.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00014-5

1568
H. Han / Tetrahedron Letters 44 (2003) 1567–1569
transformed 5 to 6. Initial terminal olefination reactions
of the aldehyde 6 with methyltriphenylphosphonium
bromide under the various reaction conditions suffered
from a poor reaction yield, and thus the modified
Horner–Wadsworth–Emmons olefination16 was used to
produce the RCM precursor 7 in 89% yield. The RCM
reaction of the diene 7 required using the second gener-
ation Grubbs’ catalyst.17 Several attempts using the
Grubbs’ catalyst proved unsuccessful generating a com-
plex reaction mixture and/or an unidentifiable product.
Dihydroxylation of the cyclic olefin 8 under the Upjohn
conditions cleanly proceeded to furnish 9 in a highly
diastereoselective manner (exclusive anti-addition),
which upon acidic hydrolysis turned into the mannose
analog 10·HCl.18
5-Des(hydroxymethyl)-1-deoxynojirimycin (1) was syn-
thesized by applying cyclic sulfate chemistry19 to the
diol 9. Thus, treatment of 9 with thionyl chloride
followed by oxidation of the resulting cyclic sulfite
using RuCl3 and NaIO4 secured the cyclic sulfate 11.
Ring opening reaction of 11 by sodium benzoate and a
final acidic hydrolysis were performed in one pot with-
out the isolation of the intermediate 12 to generate
5-des(hydroxymethyl)-1-deoxynojirimycin (1) as a HCl
salt.18 Ring opening reaction of the cyclic sulfate took
place predominantly (in 9:1 ratio) at C-3, since both
trans-diaxial ring opening rule20 and steric congestion
at C-4 favored ring opening at C-3.
In summary, 5-des(hydroxymethyl)-1-deoxynojirimycin
(1) and the mannose analog 10 were synthesized as HCl
salts from the common olefin 4 via regioselective
aminohydroxylation, ring-closing metathesis, and dihy-
droxylation reactions in a highly stereoselective man-
ner. Extension of this methodology to the asymmetric
synthesis of the remaining other isomers as well as
isofagomine and its stereoisomers is currently under
investigation. Furthermore, the developed strategy
should provide a general solution for the asymmetric
synthesis of these classes of iminosugars.
Scheme 1. Reagents and conditions: (a) (DHQD)2PHAL (6
mol%), potassium osmate (5 mol%), LiOH, AcNHBr, tert-
BuOH–H2O 1:1, 4°C, 63%; (b) MOMBr, DIPEA, CH2Cl2,
86%; (c) (Boc)2O, THF, reflux then LiOH, 85%; (d) allyl
bromide, KH, THF, 97%; (e) CAN, MeCN–H2O 4:1, 0°C,
73%; (f) oxalyl chloride, DMSO, CH2Cl2, −50°C, then TEA,
73%; (g) triethyl phosphonoacetate, LiBr, DBU, THF, 88%;
(h) second generation Grubbs’ catalyst, CH2Cl2, 89%; (i)
OsO4, NMO, MeCN–H2O 1:1, 98%; (j) 6N HCl, 80°C, 94%;
(k) SOCl2, Et3N then NaIO4, RuCl3, MeCN–CH2Cl2–H2O
1:1:1, 88%; (l) NaOBz, DMF, 105°C then (j), 90%.
Acknowledgements
Financial support from National Institute of Health
(GM 08194) and The Welch Foundation (AX-1534) is
gratefully acknowledged.
catalyzed AA reaction of 4 gave the aminoalcohol 5 in
9:1 regioselectivity as determined by the 1H NMR
spectrum of the crude products. Analytically pure 5 was
obtained by a single recrystallization of the column
purified mixture of two regioisomers from ethyl acetate.
After a MOM protection reaction, the N-acetyl group
of 5 was converted to the Boc group,12 because the
N-acetyl group not only complicated the NMR spec-
trum of the subsequent reaction products due to the
amide resonance, but also caused a poor reaction yield
in the dihydroxylation reaction of N-acetylated 8.13
Then, a reaction sequence of N-allylation, deprotection
of the PMP group by cerric ammonium nitrate
(CAN),14 and Swern oxidation15 of the resulting alcohol
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