Diastereoselective nitrenium ion-mediated cyclofunctionalization: Total synthesis of (+)-castanospermine

Article abstract of DOI:10.1021/ol102371x

The asymmetric total synthesis of the α-glucosidase inhibitor (+)-castanospermine is reported. The central theme in our approach to this polyhydroxylated alkaloid is the simultaneous generation of the piperidine ring and the C-1/8a erythro stereodiad thro

Full text of DOI:10.1021/ol102371x

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5330-5333
Diastereoselective Nitrenium
Ion-Mediated Cyclofunctionalization:
Total Synthesis of (+)-Castanospermine
Edward G. Bowen and Duncan J. Wardrop*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061, United States
wardropd@uic.edu
Received October 1, 2010
ABSTRACT
The asymmetric total synthesis of the r-glucosidase inhibitor (+)-castanospermine is reported. The central theme in our approach to this
polyhydroxylated alkaloid is the simultaneous generation of the piperidine ring and the C-1/8a erythro stereodiad through the diastereoselective,
oxamidation of an unsaturated O-alkyl hydroxamate. This process is believed to proceed sequentially via singlet acylnitrenium and aziridinium
ion intermediates.
(+)-Castanospermine (1), a polyhydroxylated indolizidine
alkaloid originally isolated from the seeds of the Moreton
Scheme 1. Retrosynthetic Analysis of Castanospermine (1)
Bay chestnut tree (Castanospermum australe),1 displays a
prestigious range of biological activities which stem from
its role as a glycosidase inhibitor (Scheme 1).2 Compound
1’s ability to inhibit endoplasmic reticulum (ER) glucosidase
I is of particular significance since this leads to the abrogation
of normal glycoprotein trafficking,3 a process critical to a
host of cellular functions as well as the coat protein
biogenesis of enveloped viruses.4 From a drug-development
standpoint, compound 1 has elicited considerable interest
(1) (a) Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.;
Pryce, R. J.; Arnold, E.; Clardy, J. Phytochemistry 1981, 4, 811. (b) Nash,
R. J.; Fellows, L. E.; Dring, J. V.; Stirton, C. H.; Carter, D.; Hegarty, M. P.;
Bell, E. A. Phytochemistry 1988, 5, 1403.
since it displays activity against several human viral patho-
gens, including HCV, parainfluenza, dengue virus, HSV-2,
and HIV-1.5 Most recently, castanospermine has also been
found to inhibit the Rho/Ras-glycosylating action of Clostrid-
ium difficile toxin B,6 which is the major virulence factor of
this Gram-positive bacteria and the causative agent of
(2) (a) Saul, R.; Chambers, J. P.; Molyneux, R. J.; Elbein, A. D. Arch.
Biochem. Biophys. 1983, 221, 593 (ꢀ-glucosidase, ꢀ-glucocerebrosidase,
ꢀ-xylosidase). (b) Trugnan, G.; Rousset, M.; Zweibaum, A. FEBS Lett. 1986,
195, 28 (sucrase). (c) Campbell, B. C.; Molyneux, R. J.; Jones, K. C.
J. Chem. Ecol. 1987, 13, 1759 (disaccharidases). (h) Scofield, A. M.;
Rossiter, J. T.; Witham, P.; Kite, G. C.; Nash, R. J.; Fellows, L. E.
Phytochemistry 1990, 29, 107 (thioglucosidase). (i) Valaitis, A. P.; Bowers,
D. F. Insect Biochem. Mol. Biol. 1993, 23, 599 (trehalase).
10.1021/ol102371x  2010 American Chemical Society
Published on Web 10/21/2010

antibiotic-associated pseudomembranous colitis, a leading
cause of infectious diarrhea in hospitals worldwide.7
Given the biological activity of castanospermine, it is
understandable that almost 30 years after its initial isolation
this alkaloid remains a relevant and popular synthetic
target.8,9 That minor structural/stereochemical alterations to
1 lead to dramatic alterations in glycosidase selectivity only
adds further impetus to the development of new synthetic
routes to this natural product.10 In light our of our ongoing
interest in the synthesis of R-glucosidase inhibitors11,12 and
having recently reported a versatile oxamidation method for
the preparation of R-hydroxyalkyl lactams involving the
intramolecular addition of acylnitrenium ions to alkenes,13
we were prompted to consider whether this methodology
might be gainfully employed in the enantioselective prepara-
tion of (+)-castanospermine. Herein, we report the successful
implementation of this idea through the use of a substrate-
controlled nitrenium ion oxamidation reaction.
closure (Scheme 1). In turn, this compound would be
accessed through the cyclization of the nitrenium ion
generated upon the oxidation of methyl D-gluco-hydroxamate
6. Since singlet nitrenium ions are known to undergo
concerted addition to alkenes,14 this reaction would generate
bicyclic aziridinium ion 3, which upon concerted, regiose-
lective ion-pair collapse at the external (R) position15 and
hydrolysis of the resulting triflouroacetate ester adduct would
provide δ-lactam 2 and thereby establish the C-1/8a erythro
stereodiad of the natural product. Regarding the diastereo-
selectivity of the addition process, we anticipated that
cyclization of the nitrenium ion generated from 6 would
preferentially proceed via a transition state resembling
pseudochair 4, thereby avoiding the 1,3-allylic strain16
present in boatlike conformer 5.17
Our initial route toward (+)-castanospermine (1) com-
menced from tribenzyl D-glucono-δ-lactone (7),18 which
underwent ring opening with the methoxylamine in the
presence of Me3Al19 to provide O-methyl hydroxamate 8 in
excellent yield (Scheme 2). Chemoselective oxidation of the
From a reterosynthetic perspective, we envisioned that the
indolizidine ring of 1 could be generated from R-hydroxy-
alkyl lactam 2 through a sequence of reduction and ring
(3) (a) Gloster, T.; Meloncelli, P.; Stick, R.; Zechel, D.; Vasella, A.;
Davies, G. J. Am. Chem. Soc. 2007, 129, 2345. (b) Pan, Y. T.; Hori, H.;
Saul, R.; Sanford, B. A.; Molyneux, R. J.; Elbein, A. D. Biochemistry 1983,
22, 3975. (c) Sasak, V. W.; Ordovas, J. M.; Elbein, A. D.; Berninger, R. W.
Biochem. J. 1985, 232, 759. (d) Ellmers, B. R.; Rhinehart, B. L.; Robinson,
K. M. Biochem. Pharmacol. 1987, 36, 2381. (e) Foddy, L.; Hughes, R. C.
Eur. J. Pharmacol. 1988, 175, 291.
Scheme 2. Initial Route to (+)-Castanospermine (1)
(4) (a) Gloster, T. M.; Davies, G. J. Org. Biomol. Chem. 2010, 8, 305.
(b) Winchester, B. G. Tetrahedron: Asymmetry 2009, 20, 645.
(5) (a) Durantel, D. Curr. Opin. InVest. Drugs 2009, 10, 860 (HCV).
(b) Tanaka, Y.; Kato, J.; Kohara, M.; Galinski, M. AntiViral Res. 2006, 72,
1 (parainfluenza). (c) Whitby, K.; Pierson, T.; Geiss, B.; Lane, K.; Engle,
M.; Zhou, Y.; Doms, R.; Diamond, M. J. Virol. 2005, 79, 8698 (dengue
virus). (d) Whitby, K.; Taylor, D.; Patel, D.; Ahmed, P.; Tyms, A. AntiViral
Chem. Chemother. 2004, 15, 141 (bovine viral diarrhea virus/HCV). (e)
Ahmed, S. P.; Nash, R.; Bridges, C.; Taylor, D.; Kang, M.; Porter, E.; Tyms,
A. Biochem. Biophys. Res. Commun. 1995, 208, 267 (HSV-2). (f) Bridges,
C.; Brennan, T.; Taylor, D.; McPherson, M.; Tyms, A. AntiViral Res. 1994,
25, 169 (HIV-1).
(6) Jank, T.; Ziegler, M. O.; Schulz, G. E.; Aktories, K. FEBS Lett.
2008, 582, 2277.
(7) Lyras, D.; O’Connor, J.; Howarth, P.; Sambol, S.; Carter, G.;
Phumoonna, T.; Poon, R.; Adams, V.; Vedantam, G.; Johnson, S.; Gerding,
D.; Rood, J. Nature 2009, 458, 1176.
(8) For recent syntheses of castanospermine, see: (a) Liu, G.; Wu, T. J.;
Ruan, Y. P.; Huang, P. Q. Chem.sEur. J. 2010, 16, 5755. (b) Jensen, T.;
Mikkelsen, M.; Lauritsen, A.; Andresen, T. L.; Gotfredsen, C. H.; Madsen,
R. J. Org. Chem. 2009, 74, 8886. (c) Ceccon, J.; Danoun, G.; Greene, A. E.;
Poisson, J. F. Org. Biomol. Chem. 2009, 7, 2029. (d) Machan, T.; Davis,
A. S.; Liawruangrath, B.; Pyne, S. G. Tetrahedron 2008, 64, 2725. (e)
Karanjule, N. S.; Markad, S. D.; Shinde, V. S.; Dhavale, D. D. J. Org.
Chem. 2006, 71, 4667. (f) Zhao, Z. M.; Song, L.; Mariano, P. S. Tetrahedron
primary alcohol, using TEMPO and trichloroisocyanuric acid
(TCICA),20 now generated unstable aldehyde 9.21 Exposure
of this substrate to the ylide generated from 3-(tert-
butyldimethylsilyloxy)propyl phosphonium bromide and KH-
2005, 61, 8888. (g) Cronin, L.; Murphy, P. V. Org. Lett. 2005, 7, 2691
.
(9) For a review of recent total syntheses of castanospermine and related
R-glucosidase inhibitors, see: (a) Wardrop, D. J.; Waidyarachchi, S. L. Nat.
Prod. Rep. 2010, 27, 1413. For a review of earlier syntheses of castano-
spermine, see: (b) Lo´pez, M. D.; Cobo, J.; Nogueras, M. Curr. Org. Chem.
2008, 12, 718
.
(10) For bioactive analogues of castanospermine, see: (a) Louvel, J.;
Botuha, C.; Chemla, F.; Demont, E.; Ferreira, F.; Pe´rez-Luna, A. Eur. J.
Org. Chem. 2010, 2921. (b) Pluvinage, B.; Ghinet, M. G.; Brzezinski, R.;
Boraston, A. B.; Stubbs, K. A. Org. Biomol. Chem. 2009, 7, 4169. (c)
Aguilar-Moncayo, M.; Mellet, C. O.; Ferna´ndez, J. M. G.; Garcia-Moreno,
M. I. J. Org. Chem. 2009, 74, 3595. (d) Aguilar-Moncayo, M.; Gloster,
T. M.; Turkenburg, J. P.; Garcia-Moreno, M. I.; Mellet, C. O.; Davies,
G. J.; Ferna´ndez, J. M. G. Org. Biomol. Chem. 2009, 7, 2738. (e) Benltifa,
M.; Garcia Moreno, M. I.; Ortiz Mellet, C.; Garcia Ferna´ndez, J. M.;
Wadouachi, A. Bioorg. Med. Chem. Lett. 2008, 18, 2805.
(14) (a) Rudchenko, V. F.; Ignatov, S. M.; Kostyanovsky, R. G. Chem.
Commun. 1990, 261. (b) Vedejs, E.; Sano, H. Tetrahedron Lett. 1992, 33,
3261. (c) Hoffman, R. V.; Christophe, N. B. J. Org. Chem. 1988, 53, 4769.
(15) For regioselective ring opening of a 1-azabicyclo[4.1.0]heptane-based
aziridinium ion, see: (a) D’hooghe, M. D.; Vanlangendonck, T.; Tsˇrnroos,
K. W.; De Kimpe, N. J. Org. Chem. 2006, 71, 4678. (b) Ref 13.
(16) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(17) For a related conformational analysis made in reference to an
intramolecular Huisgen alkene-azide cycloaddition, see: Zhou, Y.; Murphy,
P. V. Org. Lett. 2008, 10, 3777.
(11) Bowen, E. G.; Wardrop, D. J. J. Am. Chem. Soc. 2009, 131, 6062
(12) See ref 9a.
(13) Wardrop, D. J.; Bowen, E. G.; Forslund, R. E.; Sussman, A. D.;
Weerasekera, S. L. J. Am. Chem. Soc. 2010, 132, 1188.
.
(18) Lo´pez, R.; Ferna´ndez-Mayorala, A. J. Org. Chem. 1994, 59, 737.
(19) (a) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J. Am. Chem.
Soc. 2000, 122, 2995. (b) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron
Lett. 1977, 18, 4171.
Org. Lett., Vol. 12, No. 22, 2010
5331

MDS22 provided 10 in poor yield. Inefficiencies of prepa-
ration notwithstanding, we proceeded to investigate the key
cyclization step using this substrate.
Scheme 3
.
Second-Generation Route to (+)-Castanospermine
(1)
Upon exposure to phenyliodine bis(triflouroacetate) (PIFA)
and trifluoroacetic acid in CH2Cl2, hydroxamate 10 under-
went slow cyclization to form a mixture of products which
following in situ ammonolysis of the trifluoroacetate adducts
were separated by flash chromatography to provide com-
pounds 11 and 13 and their desilyated counterparts 12 and
14. The unanticipated formation of 1,4-oxazepan-3-ones 13
and 14 presumably arises from competitive interception of
the nitrenium ion intermediate by the C-3 benzyl ether in
10.23 More encouragingly, oxamidation products 11 and 12
were isolated as single diastereomers, which NOSEY experi-
ments indicated were of the desired stereochemistry at C-6.
In light of the involvement of the C-3 O-protecting group
during cyclization and the inefficiency of the preceding
Wittig reaction, a number of alterations to our synthetic plan
were clearly mandated. Accordingly, we decided to evaluate
alternative protecting groups that would not irreversibly trap
the putative N-acylnitrenium ion. To impede loss of the TBS
silyl ether under the acidic reaction conditions, a TIPS
protecting group was chosen as a more robust surrogate.
Our plan thus amended, the second-generation, and
ultimately successful, route to (+)-castanospermine com-
menced from R-D-xylopyranoside 15,24 which through
reductive etherification of the corresponding (bis)trimethyl-
silyl ether using benzaldehyde25 was converted to dibenzyl
ether 16 (Scheme 3). While direct deallylation of 16 proved
to be unexpectedly challenging and failed with a number of
reagents, a stepwise approach to this task ultimately proved
successful. Thus, exposure of 16 to catalytic HRh(PPh3)3 in
THF provided the corresponding enol ether which without
isolation was hydrolyzed with HgCl2-HgO to afford a
mixture of lactol anomers in good overall yield.26 Conversion
of these products to lactone 17 while sluggish with PDC or
PCC proceeded with high efficiency under the Albright-
Goldman conditions (DMSO, Ac2O).27
treatment of the aldehyde with the ylide generated from (3-
isopropylsiloxy)propyltriphenylphosphonium bromide28 then
provided 18 in high overall yield. Chemoselective saponi-
fication of the methyl ester was now accomplished by the
treatment of 18 with aqueous KOH (0.1 M, 3 equiv) in THF
and MeOH. Formation of oxamidation substrate 19 was then
accomplished by conversion of 18 to the corresponding
mixed anhydride, which was treated with methoxylamine
hydrochloride.
Disappointingly, exposure of compound 19 to PIFA in the
presence of trifluoroacetic acid at room temperature failed
to effect cyclization and instead generated an intractable
mixture of products.29 Fortunately, performing this reaction
at higher temperature, accomplished by adding 19 to a
solution of PIFA and trifluoroacetic acid in CHCl3 at reflux,
rapidly afforded 20, which was isolated as a single diaste-
reoisomer after in situ ammonolysis of the trifluoroacetate
adduct. That 19 does not undergo cyclization at ambient
temperature, in contrast to compound 10, may reflect a
decrease in the stability of the intermediate nitrenium ion,
which in this case could be destabilized by the presence of
a more electron-withdrawing, R-acyloxy substituent. This
interpretation is consistent with our current belief that
In preparation for installation of the pendant alkene,
methanolysis of 17 in the presence of camphorsulfonic acid
provided the corresponding δ-hydroxy ester in high yield.
Addition of a phosphate buffer (pH 7) prior to workup, to
prevent transesterification to 17, was found to be a prereq-
uisite for the success of this reaction. Oxidation of the
primary alcohol, again using TEMPO and TCICA, and
(20) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3,
3041.
(21) Upon standing for 12 h at room temperature, compound 9 underwent
cyclization to form a mixture of cyclic carbinolamine diastereomers.
(22) Glebocka, A.; Sicinski, R.; Plum, L.; Clagett-Dame, M.; Deluca,
H. J. Med. Chem. 2006, 49, 2909.
(23) Kikugawa, Y.; Shimado, M.; Matsumoto, K. Heterocycles 1994,
37, 293.
(24) Prepared in two steps, from D-xylose: Rosenberg, H.; Riley, A.;
Marwood, R.; Correa, V.; Taylor, C.; Potter, B. Carbohydr. Res. 2001, 332,
53.
(28) For details of preparation, see Supporting Information and: Clayden,
J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem. Soc. 2005, 127, 2412.
(29) Oxidation of O-alkyl hydroxamates can also lead to the formation
of thermally unstable N,N′-dialkoxy-N,N′-diacylhydrazines: (a) De Almeida,
M. V.; Barton, D. H. R.; Bytheway, I.; Ferreira, J. A.; Hall, M. B.; Liu,
W.; Taylor, D. K.; Thomson, L. J. Am. Chem. Soc. 1995, 117, 4870. (b)
Cooley, J. H.; Mosher, M. W.; Khan, M. A. J. Am. Chem. Soc. 1968, 90,
1867. (c) Crawford, R. J.; Raap, R. J. Org. Chem. 1963, 28, 2419.
(25) Hatakeyama, S.; Mori, H.; Kitano, K.; Yamada, H.; Nishizawa,
M. Tetrahedron Lett. 1994, 35, 4367.
(26) (a) Boons, G.; Burton, A.; Isles, S. Chem. Commun. 1996, 141.
(b) Uma, R.; Davies, M.; Cre´visy, C.; Gre´e, R. Eur. J. Org. Chem. 2001,
3141. (c) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1973, 38, 3224.
(27) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1965, 87, 4214.
5332
Org. Lett., Vol. 12, No. 22, 2010

formation of this N-electrophile is rate limiting and may
occur from an N-methoxy-N-trifluoroacetoxy, or anomeric,
amide.30
Scheme 4. Total Synthesis of (+)-Castanospermine (1)
As with piperidinones 11 and 12, a 2D NOESY experiment
conducted upon 21 revealed a correlation between H-4 and
H-6, which together with the absence of interactions between
H-3 and H-5 is diagnostic of a half-chair conformation31 and
confirms the relative stereochemistry at C-6 (Scheme 3).
Treatment of compound 21 with Mo(CO)6 in aqueous
acetonitrile now cleaved the N-O bond and provided the
corresponding NH-lactam,32 which was reduced with borane
to yield piperidine 22. Removal of the TIPS ether, using
TBAF in THF, then provided the corresponding amino-2,4-
diol in excellent yield. Selective bromination of this primary
alcohol and in situ cyclization to indolizidine 23 was now
accomplished by recourse to Appel’s conditions.33 Reflecting
the relatively hindered environment at the C-2 position,
saponification of the pivalate ester now proceeded slowly at
room temperature to provide the 6,7-di-O-benzyl ether of
castanospermine, albeit in high yield. With the C-1a stereo-
center now constrained within the indolizidine ring system,
unambiguous assignment of stereochemistry was possible
through a NOSEY experiment (Scheme 4). Finally, removal
of the benzyl ethers, via hydrogenolysis in the presence of
In conclusion, we have developed a 15-step synthesis of
(+)-castanospermine (1) in which the C-1/8a stereodiad is
established through the diastereoselective oxamidation of an
unsaturated O-alkyl hydroxamate. That this process was
found to be stereospecific with respect to alkene geometry
supports our current belief that the oxamidation proceeds
via the concerted ring opening of a bicyclic aziridinium ion
formed upon the addition of a singlet nitrenium ion to the
pendant alkene. Extension of this valuable methodology to
the preparation of other azasugars is now in progress.
1
PdCl2, provided (+)-castanospermine (1). The H and 13C
NMR spectral data obtained from this material were identical
to those reported for the natural product. In addition, the
optical rotation of synthetic 1 ([R]24D -86.0; c 0.1, MeOH)
closely matched that of the natural product ([R]25D -87.2; c
2.1, MeOH).34
Acknowledgment. We thank the National Institutes of
Health (GM-67176) and the University of Illinois at Chicago
for financial support of this work.
(30) (a) Glover, S. A. AdV. Phys. Org. Chem. 2008, 42, 35. (b) Glover,
S. A.; Rauk, A. J. Chem. Soc., Perkin Trans. 2 2002, 1740. (c) Glover,
S. A.; Hammond, G. P. J. Org. Chem. 1998, 63, 9684.
(31) Boudreault, N.; Ball, R. G.; Bayly, C.; Bernstein, M. A.; Leblanc,
Y. Tetrahedron 1994, 50, 7947.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(32) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351.
(33) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801.
(34) Scheider, M. J.; Ungemach, F. S.; Broquist, H. P.; Harris, T. M.
Tetrahedron 1983, 39, 29.
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