A synthesis of 2-epi-fagomine using gold(I)-catalysed allene cyclisation

Article abstract of DOI:10.1016/j.tetlet.2011.03.130

A synthesis of 2-epi-fagomine via a highly stereoselective gold(I)-catalysed allene cyclisation is described. The stereochemical outcome of the cyclisation is opposite to that observed in previous studies. In contrast, gold(III)-catalysed cyclisation is i

Full text of DOI:10.1016/j.tetlet.2011.03.130

Tetrahedron Letters 52 (2011) 2969–2971
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Tetrahedron Letters
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A synthesis of 2-epi-fagomine using gold(I)-catalysed allene cyclisation
⇑
Roderick W. Bates , Pearly Shuyi Ng
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of 2-epi-fagomine via a highly stereoselective gold(I)-catalysed allene cyclisation is described.
The stereochemical outcome of the cyclisation is opposite to that observed in previous studies. In con-
trast, gold(III)-catalysed cyclisation is inefficient and gives rise to double cyclisation by-products.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 February 2011
Revised 10 March 2011
Accepted 25 March 2011
Available online 1 April 2011
Keywords:
Piperidine
Aza-sugar
Allene
Gold
Interest in the synthesis of aza-sugars continues due to their
biological properties, specifically their potential as glycosidase
inhibitors and anti-cancer and anti-viral applications.1 Fagomine
(1) and its diastereoisomers, such as 2-epi-fagomine (2),2 form a
group of aza-sugars and have been the subject of several
syntheses.3
of the alkyne.9 Sonogashira coupling with trimethylsilylacetylene
gave the enyne 8. Caddick et al. have shown that efficient asym-
metric dihydroxylation of such enynes using the Sharpless system
only proceeds efficiently if the alcohol is protected as its para-
methoxylphenyl ether.10 This protecting group was introduced
using a Mitsunobu reaction. Asymmetric dihydroxylation of ether
9 using AD-mix-b as the chiral oxidant in the presence of methane-
sulfonamide then proceeded to give the diol 10 in 86% yield and
97% ee (determined by chiral HPLC). Desilylation and Searles–Crab-
bé homologation introduced the allene moiety. The nucleophilic
nitrogen group was then installed by a sequence involving double
TBS protection, oxidative removal of the PMP group with ceric
ammonium nitrate,11 mesylation, displacement of the mesylate
by azide, reduction and carbamate formation. It should be noted
that formation of the bis-TBS ether 12 required the use of TBS-tri-
flate. With TBS-chloride, the monoprotected compound was
formed. PMP removal requires carefully defined conditions: drop-
wise addition of ceric ammonium nitrate solution to a solution of
the PMP ether 12 and pyridine, otherwise partial desilylation was
OH
OH
OH
OH
OH
OH
N
H
N
H
2
1
Recently, we reported a synthesis of Pyne’s swainsonine precur-
sor 54 employing a highly diastereoselective gold-catalysed allene
cyclisation,5 with the resulting pendant vinyl group being em-
ployed to form the pyrrolidine ring through RCM (Scheme 1).6 It
occurred to us that oxidative cleavage of this group would generate
a hydroxymethyl substituent. If the substrate for cyclisation in-
cluded a second protected alcohol, this would lead to the fagomine
family. In this Letter, we report the realisation of this idea to obtain
2-epi-fagomine (2).
OTBS
•
OTBS
AuCl3, CaCO3
t-BocHN
N
4
3
t-Boc
Our intention was to introduce the 1,2-diol by asymmetric
dihydroxylation7 and the allene via Searles–Crabbé homologation
(Scheme 2).8 The vinyl bromide 7 was prepared from 3-butyn-1-
ol by terminal bromination followed by selective trans-reduction
OTBS
OTBS
H
H
N
OH
N
5
6
OH
⇑
Corresponding author.
E-mail address: roderick@ntu.edu.sg (R.W. Bates).
Scheme 1. Swainsonine formal synthesis.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.130

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R. W. Bates, P. Shuyi Ng / Tetrahedron Letters 52 (2011) 2969–2971
SiMe3
1. NBS, AgNO3
2. AlCl3, LiAlH4
(Ph3P)2PdCl2, CuI,
Et3N, THF
Br
66%
70%
7
HO
HO
SiMe3
SiMe3
MeOC6H4OH
PPh3, DIAD
63%
HO
8
PMPO
9
AD mix-β
MeSO2NH2
aq. t-BuOH
OH
SiMe3
1. MeOH, K2CO3
2. (CH2O)n, Cy2NH, CuBr
86%
OH
10 97% ee
75%
PMPO
OH
OTBS
OTBS
OH
TBSOTf
2,6-lutidine
86%
PMPO
•
X
•
11
12 X = OPMP
Ce(NH4)2(NO3)6
py, aq. MeCN
81%
13 X = OH
1. MsCl, Et3N
2. NaN3
Figure 1. X-ray structure of oxazolidinone 17.
66%
14 X = N3
by attack of the Boc carbonyl group with loss of the t-butyl group,
followed by formation of the exocyclic alkene with net reduction of
gold. This process may be compared to the double cyclisation of ur-
eas reported by Widenhoefer13 which, however, occurs with a
gold(I) catalyst and proceeds with ultimate protonolysis of an sp3
carbon–gold bond to give a methyl substituent. The formation of
exo-alkylidene oxazolidinones by the gold-catalysed cyclisation
of Boc-containing alkyne derivatives has been reported.14
1. Ph3P, H 2O
98%
2. Boc2O, i-Pr2NEt
15 X = NHt-Boc
Scheme 2. Allene synthesis.
observed. Further, it was important to introduce the azide after al-
lene formation. When the order of these reactions was altered, it
was found that the intramolecular cycloaddition of the azide to
the alkyne became significant.
In contrast, the use of Ph3PAuSbF6, generated in situ by treat-
ment of Ph3PAuCl with AgSbF6 delivered the expected cyclisation
product 16 in good yield (85%) as a single stereoisomer without
formation of 17.15 Oxidative cleavage of the alkene (ozonolysis
with a sodium borohydride work-up) followed by deprotection
(HCl in 1,4-dioxane/methanol) gave a material that was found to
be epi-fagomine (2), rather than fagomine (1), as was evident from
inspection of the 1H and 13C NMR spectra of both the hydrochloride
salt and the free base, generated by use of Amberlyst A26 (OH)
(Scheme 4).16 This indicates that the cyclisation proceeds with
the opposite sense of stereoselectivity as that of the cyclisation
employed in our swainsonine synthesis, delivering the vinyl group
cis to the nearest siloxy group. It is, therefore, likely that the mol-
ecule adopts a different conformation 18 during cyclisation, possi-
bly with the two ether groups trans-diaxial, as observed in the X-
ray structure of 17, which might be due to dipolar effects. Asano
and co-workers,2 on the basis of NOE results, proposed a similar
diaxial relationship for the two hydroxy groups in 3,4-di-epi-fago-
mine, while higher than expected proportions of the diaxial con-
former in cyclohexanes with multiple electronegative
substituents has been noted.17
With the desired allene 15 in hand, we submitted it to the cyc-
lisation conditions, AuCl3 and CaCO3 in CH2Cl2–CH3CN, which we
had previously employed in our swainsonine formal synthesis.
While a cyclised product 16 was obtained with complete stereose-
lectivity, the yield was poor (40%) and a by-product was also iso-
lated (Scheme 3). The by-product was assigned the gross
structure 17 by analysis of the 1H and 13C NMR data. X-ray crystal-
lography (Fig. 1) confirmed this assignment and showed the 2,3-
cis-stereochemistry.12 It may be noted that the by-product 17 does
not arise from cyclisation of the desired vinyl compound 16, as no
reaction was observed on re-exposure of 16 to the reaction condi-
tions. We speculate that cyclisation occurs at the vinyl gold stage
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
+
N
t-BocHN
•
N
t-Boc
O
O
The optical rotation of our material was found to be ꢀ10.6 (c
0.32, H2O). This is opposite to the value reported by Takahata3e
for synthetic 3,4-di-epi-fagomine (+13.4), which is the enantiomer
15
16
40%
17
7%
AuCl3, CaCO3
85%
0%
Ph3PAuCl, AgSbF6,
CaCO3
1. O3; NaBH4
2. HCl, MeOH,
dioxane
OTBS
OTBS
OH
OH
OH
TBSO
3. amberlyst A26
N
t-Boc
16
N
H
•
53%
NH
t-Boc
18
TBSO
2
Scheme 3. Allene cyclisation.
Scheme 4. 2-epi-Fagomine synthesis.

R. W. Bates, P. Shuyi Ng / Tetrahedron Letters 52 (2011) 2969–2971
2971
5. For reviews of the use of gold, see: Hashmi, A. S. K.; Bührle, M. Aldrichim. Acta
2010, 43, 27; Fürstner, A. Chem. Soc. Rev. 2009, 39, 3208; Arcadi, A. Chem. Rev.
2009, 108, 3266; Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239; Patil, N.
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6. Bates, R. W.; Dewey, M. R. Org. Lett. 2009, 11, 3706; For the first use of AuCl3 in
allene cyclisation, see: Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285.
of 2-epi-fagomine. Asano reported a value of ꢀ8.7 for the material
isolated from the seeds of Xanthocercis zambesiaca.2 Thus, Asano’s
material is likely to be 2-epi-fagomine.
We have achieved a novel synthesis of 2-epi-fagomine (2)
employing an efficient and highly stereoselective gold-catalysed
cyclisation. Work on adapting this method to the synthesis of fago-
mine itself by manipulation of the protecting groups is in hand.
7. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
8. Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbé, P. J. Chem. Soc.,
Perkin Trans. 1 1984, 747.
Acknowledgements
9. Yadav, J. S.; Reddy, E. J. Biosci., Biotechnol., Biochem. 2000, 64, 1726.
10. Caddick, S.; Shanmugathasan, S.; Brasseur, D.; Delisser, V. M. Tetrahedron Lett.
1997, 38, 5735.
11. Masaki, Y.; Yoshizawa, K.; Itoh, A. Tetrahedron Lett. 1996, 37, 9321.
12. Details have been deposited with the Cambridge Crystallographic Data Centre
and may be obtained at http://www.ccdc.cam.ac.uk CCDC deposition number:
810676.
We thank the Singapore Ministry of Education Academic Re-
search Fund Tier 2 (Grant T206B1220RS) and Nanyang Technolog-
ical University for generous support of this work. P.S.N. would like
to thank Forma Therapeutics for financial support.
References and notes
13. Li, H.; Widenhoefer, R. A. Org. Lett. 2009, 11, 2671.
14. Robles-Machin, R.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2006, 71, 5023; Buzas,
A.; Gagosz, F. Synlett 2006, 2727.
15. Procedure for piperidine 16: CaCO3 (16.7 mg, 0.166 mmol), Ph3PAuCl (4.9 mg,
1. Iminosugars: From Synthesis to Therapeutic Applications; Compain, P., Martin, O.
R., Eds.; Wiley-Interscience: New York, 2007; Afarinkia, K.; Bahar, A.
Tetrahedron: Asymmetry 2005, 16, 1235; Asano, N. Glycobiology 2003, 13, 93R.
2. For the isolation of fagomine and its diastereoisomers, see: Kato, A.; Asano, N.;
Kizu, H.; Matsui, K.; Watson, A. A.; Nash, R. J. J. Nat. Prod. 1997, 60, 312. and
references therein.
3. (a) Bartali, L.; Casini, A.; Guarana, A.; Occhiato, E. G.; Scarpi, D. Eur. J. Org. Chem.
2010, 5831; (b) Bartali, L.; Scarpi, D.; Guarna, A.; Prandi, C.; Occhiato, E. G.
Synlett 2009, 913; (c) Yokoyama, H.; Ejiri, H.; Miyazawa, M.; Yamaguchi, S.;
Hirai, Y. Tetrahedron: Asymmetry 2007, 18, 852; (d) Castillo, J. A.; Calveras, J.;
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Joglar, J.; Clapés, P. Org. Lett. 2006, 8, 6067; (e) Takahata, H.; Banba, Y.; Ouchi,
H.; Nemoto, H.; Kato, A.; Adachi, I. J. Org. Chem. 2003, 68, 3603; (f) Désiré, J.;
Dransfield, P. J.; Gore, P. M.; Shipman, M. Synlett 2001, 1329; (g) Banba, Y.; Abe,
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Fleet, G. W. J.; Smith, P. W. Tetrahedron Lett. 1985, 26, 1469.
9.98 lmol) and AgSbF6 (3.4 mg, 9.98 lmol) were added to a solution of allene
15 (78.5 mg, 0.166 mmol) in dry CH2Cl2 (1.6 mL). The mixture was stirred at
room temperature for 8 h in the absence of light. The reaction mixture was
filtered through a plug of Celite and washed with CH2Cl2 (5 mL). The filtrate
was concentrated to give a colourless oil. The crude material was purified by
silica gel chromatography (100% hexane to 4% EtOAc/hexane) to yield 16
(67 mg, 85%) as a colourless oil.
16. Data for 2-epi-fagomine (2): ½a D21
ꢁ
ꢀ10.6 (c 0.32, H2O) [Lit3e a 2D5
½ ꢁ +13.4 (c 0.32,
H2O); Lit2
½
a 2D5
ꢁ
ꢀ8.7 (c 0.3, H2O)]; 1H NMR (400 MHz, D2O) d 1.51–1.58 (m, 1H),
1.89–1.98 (m, 1H), 2.79–2.82 (m, 2H), 3.04 (dt, J = 6.8, 2.8 Hz, 1H), 3.64 (br s,
1H), 3.66 (br s, 1H), 3.68 (dd, J = 4.8, 2.8 Hz, 1H), 3.89 (dt, J = 4.8, 3.6 Hz, 1H);
13C NMR (100 MHz, D2O) d 28.1, 38.6, 55.3, 60.1, 67.9, 68.9. For spectroscopic
data for 2-epi-fagomine or 3,4-di-epi-fagomine, see Ref. 2,3e.
17. Lemieux, R. U.; Lown, J. W. Can. J. Chem. 1964, 42, 893; de Angelis, S.; Batsanov,
A.; Norman, T. J.; Parker, D.; Senanyake, K.; Vepsalainen, J. J. Chem. Soc., Chem.
Commun. 1995, 2361.
4. Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774.