Stereoselective synthesis of (-)-conduramine C-1 and (-)-conduramine D-1

Article abstract of DOI:10.1016/j.tetlet.2013.02.046

A highly stereoselective approach to aminocyclohexenetriols conduramine C-1 1 and conduramine D-1 2 has been described. Conduramines are structural units of some biologically active natural products such as (+)-lycoricidine and (+)-narciclasine. The strategy developed by us for their synthesis is general in nature to make related skeletons and also the molecules containing conduramine structural unit. The key reactions are Grignard addition on glycosylamine, ring closing metathesis (RCM), and Mitsunobu inversion.

Full text of DOI:10.1016/j.tetlet.2013.02.046

Tetrahedron Letters 54 (2013) 2329–2331
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of (ꢀ)-conduramine C-1 and (ꢀ)-conduramine D-1
⇑
Anugula Rajender, Batchu Venkateswara Rao
Organic and Biomolecular Chemistry Division, CSIR – Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective approach to aminocyclohexenetriols conduramine C-1 1 and conduramine D-1 2
has been described. Conduramines are structural units of some biologically active natural products such
as (+)-lycoricidine and (+)-narciclasine. The strategy developed by us for their synthesis is general in nat-
ure to make related skeletons and also the molecules containing conduramine structural unit. The key
reactions are Grignard addition on glycosylamine, ring closing metathesis (RCM), and Mitsunobu
inversion.
Received 22 December 2012
Revised 12 February 2013
Accepted 14 February 2013
Available online 13 March 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Aminocyclohexetriols
Conduramines
Glycosylamine
Grignard reaction
RCM
Mitsunobu inversion
Conduramines also known as aminocyclohexenetriols are the
derivatives of conduritols in which one of the OH functionality is
replaced by an amino group. Most of these conduramines are pure
synthetic analogues having significant glycosidase inhibitory activ-
ity.1 These aminocyclitols are mimics of monosaccharides and they
are structurally related to aglycon part of aminoglycosidase antibi-
otics.2 In addition, conduramines are the chiral building blocks for
variety of natural products such as (+)-lycoricidine,3a (+)-narcicla-
sine,3b (+)-valienamine,3c and some other compounds (Fig. 1).4 Be-
cause of their interesting structural features and biological activity
these molecules became an interesting target for both biologists
and chemists. In recent years many reports have been published
for their syntheses.5 However, a simple and highly efficient strat-
egy is needed for their preparation, which will help in getting these
compounds and its analogues in good quantities for biological
evaluation.
In continuation of our ongoing research program on the synthe-
sis of cyclitols,6 aminocyclitols,7 and iminosugars8 using cheaply
available carbohydrates as starting materials, herein we describe
an highly stereoselective synthesis of (ꢀ)-conduramine C-1 15j–l
and (ꢀ)-conduamine-D1 25j using Grignard addition on glycosyl-
amine (Scheme 2). This synthesis was designed based on the strat-
egy developed earlier in our group for the synthesis of chiral
amines from sugar imines.7,9
the ribofuranose 3 with vinylmagnesium bromide in dry THF at
ꢀ78 °C gave the triol 4 in 75% yield.10b,6c Oxidative cleavage of
1,2-diol in 4 using NaIO4 in THF/H2O (4:1) afforded the lactol 5
with good yield.10b,6c
Condensation of the lactol 5 in MeOH using BnNH2 under reflux
condition afforded glycosylamine. Without purification the resul-
tant glycosylamine was subjected to stereoselective Grignard addi-
tion with vinylmagnesium bromide in dry THF at ꢀ78 °C to provide
the anti amino alcohol 6 exclusively in 75% yield.7,9 Initially, we
OEt
NH2 .H3PO4
OH
OH
O
HO
HO
HO
HO
OH
NHAc
O
NH2
NH2
Conduramine
valienamine
Tamiflu
OH
OH
OH
O
OH
OH
OH
OH
O
HO
HO
HO
OH
O
N
H
OH
NH
Based on retrosynthetic analysis (Scheme 1), we have chosen
O
R
OH
OH
2,3-O-isopropylidene-D
-ribofuranose 310a as a starting material
O
for the synthesis of the key intermediate 9. Grignard addition on
Validamycin A
R = H: (+)-lycoricidine
R = OH: (+)-narciclasine
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
Figure 1. Biologically active natural products containing some conduramine or
aminocyclohexenetriol skeleton.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.046

2330
A. Rajender, B. V. Rao / Tetrahedron Letters 54 (2013) 2329–2331
NH2
HO
HO
HO
NHBoc
Cbz
BnN
O
HO
OH
O
O
2
D-ribose
O
O
O
O
NH2
OH
HO
HO
9
7
5
OH
1
Scheme 1. Retrosynthetic analysis of (ꢀ)-conduramine C-1 1 and (ꢀ)-conduramine D-1 2.
tried to protect the amino group in 6 as N-Boc derivative with
(Boc)2O and Et3N in DCM conditions but the reaction was very slow
and only about 20% conversion was observed on TLC even after
2 days. Then we decided to make it as N-Cbz derivative. When
the compound 6 was treated with benzyl chloroformate in the
presence of NaHCO3 in MeOH, the N-Cbz derivative 7 was obtained
in 90% yield. Subsequent ring closing metathesis of the diene 7
using 10 mol % Grubbs’ second generation catalyst11 in toluene un-
der reflux conditions afforded the desired amino cyclohexene moi-
ety 8 in 80% yield.
Treatment of the compound 8 with Na/Liq.NH3/THF condi-
tions12,8c gave the amino compound, which on treatment with
(Boc)2O provided the N-Boc derivative 9 in good yield. Global
deprotection of 9 with TFA in DCM gave the conduramine D-1 2,
which on acetylation under Ac2O/pyridine/DMAP conditions affor-
ded the acetyl derivative of conduramine D-1 1013a in 90% yield
(over two steps), whose analytical and physical data were in good
agreement with the reported values.5j For the synthesis of condur-
amine C-1 1, the free hydroxyl group in 9 was inverted under Mits-
unobu conditions to provide the N-Boc derivative of conduramine
C-1 11 in 80% yield (over two steps). The spectral data of com-
pound 1113b were in good accordance with the reported values.5j
Conversion of the compound 11 into conduramine C-1 1 was re-
ported by Muchowski et al. group .5j
In conclusion, we have developed a simple and highly stereose-
lective strategy for the synthesis of the conduramine C-1 and con-
duramine D-1. The overall yields of key building blocks 9 and 11
are 23.5% and 18.8%, respectively, from the cheaply available start-
ing material D-ribose. The key reactions involved in our synthesis
are highly diastereoselective Grignard addition on lactol 3 and gly-
cosylamine, ring closing metathesis, and Mitsunobu inversion.
Therefore our method has an advantage over the existing methods
and it has access for preparing analogues by choosing appropriate
sugars as starting materials.
i) BnNH2, MeOH,
OH
O
OH
O
4 Å molecular sieves, Na2SO4,
reflux, 12 h
O
OH
HO
NaIO4,
MgBr
HO
HO
THF, -78 oC, 2 h,
O
O
O
ii)
THF - H2O (4 : 1),
80%
O
O
MgBr
75%
THF, -78 oC, 3 h
5
4
3
75% over two steps
Cbz
Bn
Bn Cbz
N
NBn
NH OH
OH
Cbz-Cl, NaHCO3
Grubb's 2nd generation catalyst,
toluene, reflux, 3 h, 80%
O
O
MeOH, 0 oC - rt,
O
O
O
O
2 h, 90%
OH
8
7
6
NHBoc
NHBoc
i) TPP, DEAD,
i) Na, Liq.NH3, - 78 oC, 1 h
O
O
O
O
p-nitrobenzoic acid,
ref .5j
1
0 oC - rt, 3 h
ii) (BOC)2O, Et3N, DCM,
rt, 12 h, 78% over two steps
ii) K2CO3, MeOH,
0 oC - rt, 2 h
OH
OH
80% over two steps
11
9
i) TFA, DCM, 12 h
ii) Ac2O, pyridine,
DMAP, rt, 12 h
90% over two steps
NHAc
AcO
AcO
OAc
10
Scheme 2. Synthesis of acetyl derivative of conduramine D-1 10 and N-Boc derivative of conduramine C-1 11.

A. Rajender, B. V. Rao / Tetrahedron Letters 54 (2013) 2329–2331
2331
Muchowski, J. M.; Wu, Y.-L. J. Org. Chem. 1998, 63, 3235–3250; (k) Johnson, C.
R.; Ple, P. A.; Su, L.; Heeg, M. J.; Adams, J. P. Synlett 1992, 388–390; (l) Allemann,
S.; Vogel, P. Helv. Chim. Acta 1994, 77, 1–9.
Acknowledgments
A.R. thanks UGC (New Delhi) for fellowship and we would like
to thank Director, CSIR-IICT for the constant support and
encouragement.
6. (a) Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5103–5105; (b) Mishra,
G. P.; Ramana, G. V.; Rao, B. V. Chem. Commun. 2008, 29, 3423–3425; (c)
Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2006, 47, 4413–4441; (d) Ramana, G.
V.; Rao, B. V. Tetrahedron Lett. 2005, 46, 3049–3051; (e) Rao, J. P.; Rao, B. V.
Tetrahedron: Asymmetry 2010, 21, 930–935; (f) Mishra, G. P.; Rao, B. V.
Tetrahedron: Asymmetry 2012, 22, 812–817; (g) Rao, J. P.; Muniraju, C. H.; Rao,
B. V. Tetrahedron: Asymmetry 2012, 23, 86–92.
Supplementary data
7. (a) Rao, J. P.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron Lett. 2010, 51, 3083–3087;
(b) Rajender, A.; Rao, J. P.; Rao, B. V. Tetrahedron: Asymmetry 2011, 22, 1306–
1311.
Supplementary data (experimental procedure and spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.02.046.
8. (a) Reddy, J. S.; Rao, B. V. J. Org. Chem. 2007, 72, 2224–2227; (b) Madhan, A.;
Rao, B. V. Tetrahedron Lett. 2003, 44, 5641–5643; (c) Chandrasekhar, B.;
Madhan, A.; Rao, B. V. Tetrahedron 2007, 63, 8746–8751; (d) Chandrasekhar, B.;
Rao, B. V.; Rao, K. V. M.; Jagadeesh, B. Tetrahedron: Asymmetry 2009, 20, 1217–
1223; (e) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915–917; (f) Kumar,
A. S.; Haritha, B.; Rao, B. V. Tetrahedron Lett. 2003, 44, 4261–4263; (g)
Jagadeesh, Y.; Reddy, J. S.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron 2010, 66,
1202–1207; (h) Chandrasekhar, B.; Rao, J. P.; Rao, B. V.; Naresh, P. Tetrahedron
Lett. 2011, 52, 5921–5925; (i) Reddy, K. S.; Rao, B. V.; Raju, S. S. Tetrahedron:
Asymmetry 2011, 22, 662–668; (j) Jagadeesh, Y.; Ramakrishna, K.; Rao, B. V.
Tetrahedron: Asymmetry 2012, 23, 702–967.
References and notes
1. (a) Posternack, T. The Cyclitols; Holden-Day Inc.: San Francisco, 1965. pp 211–
212; (b) Balci, M.; Sütbeyaz, Y.; Secüen, H. Tetrahedron 1990, 46, 3715–3742;
(c) Paul, B. J.; Willis, J.; Martinot, T. A.; Ghiviriga, I.; Abboud, K. A.; Hudlicky, T. J.
Am. Chem. Soc. 2002, 124, 10416–10426; (d) Lysek, R.; Vogel, P. Tetrahedron
2006, 62, 2733–2766; (e) Lysek, R.; Schütz, C.; Vogel, P. Bioorg. Med. Chem. Lett.
2005, 15, 3071–3075.
2. (a) Chen, X.; Fan, Y.; Zheng, Y.; Shen, Y. Chem. Rev. 2003, 103, 1955–1977; (b)
Mahmud, T. Nat. Prod. Rep. 2003, 20, 137–166; (c) Kameda, Y.; Asano, N.;
Teranoshi, M.; Amatsui, K. J. Antibiot. 1980, 33, 1573–1574.
3. (a) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694–9696; (b) Elango,
S.; Yan, T.-H. J. Org. Chem. 2002, 67, 6954–6959; (c) Ogawa, S.; Kanto, M. Curr.
Top. Med. Chem. 2009, 9, 58–75; (d) Chang, Y.-K.; Lo, H.-J.; Yan, T.-H. Org. Lett.
2009, 11, 4278–4281.
4. (a) Pandey, G.; Balakrishnan, M. J. Org. Chem. 2008, 73, 8128–8131; (b) Alegret,
C.; Benet-Buchholz, J.; Riera, A. Org. Lett. 2006, 8, 3069–3072; (c) Pandey, G.;
Kumar, R.; Banerjee, P.; Puranik, V. G. Eur. J. Org. Chem. 2011, 4571–4587; (d)
Afarinkia, K.; Ndibwami, A. Synthesis 2007, 1940–1947; (f) Hudlicky, T.; Reed, J.
W. S. Synlett 2009, 685–703; (e) Shih, T.-L.; Yang, S.-Y. Molecules 2012, 17,
4498–4507; (f) Magano, J. Chem. Rev. 2009, 109, 4398–4438.
5. For the recent articles and reviews for conduramines and their derivatives, see:
(a) Ghosal, P.; Shaw, A. K. J. Org. Chem. 2012, 77, 7627–7632; (b) Norsikian, S.;
Soule, J.-F.; Cannillo, A.; Guillot, R.; Dau, M.-E. T. H.; Beau, J.-M. Org. Lett. 2012,
14, 544–547; (c) Duchek, J.; Adams, D. R.; Hudlicky, T. Chem. Rev. 2011, 111,
4223–4258; (d) Jana, C. K.; Grimme, S.; Studer, A. Chem. Eur. J. 2009, 15, 9078–
9084; (e) Chappell, D.; Drew, M. G. B.; Gibson, S.; Harwood, L. M.; Russell, A. T.
Synlett 2010, 517–520; (f) Lu, P.-H.; Yang, C.-S.; Devendar, B.; Liao, C.-C. Org.
Lett. 2010, 12, 2642–2645; (g) Trost, B. M.; Malhotra, S.; Olson, D. E.; Maruniak,
A.; Bois, J. D. J. Am. Chem. Soc. 2009, 131, 4190–4191; (h) Pandey, G.; Tiwari, K.
N.; Puranik, V. G. Org. Lett. 2008, 10, 3611–3614; (i) Bellomo, A.; Giacomini, C.;
Brena, B.; Seoane, G.; Gonzalez, D. Synth. Commun. 2007, 37, 3509–3518. and
for the synthesis of conduramine C-1 and D-1 see; (j) Leung-Toung, R.; Liu, Y.;
9. Rao, G. S.; Rao, B. V. Tetrahedron Lett. 2011, 52, 4861–4864.
10. (a) Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95–101; (b) Moon, H. R.;
Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron: Asymmetry 2002, 13, 1189–1193.
11. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956; (b)
Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim, Germany, 2003;
(c) Grubbs, R. H.; Trnka, T. M. In Ruthenium in Organic Synthesis; Murahashi, S. I.,
Ed.; Wiley-VCH: Weinheim, Germany, 2004; pp 153–178. Chapter 6; (c)
Sambasivarao, K.; Dipak, M. K. Tetrahedron 2012, 68, 397–421.
12. Sifferd, R. H.; du Vigneaud, V. J. Biol. Chem. 1935, 108, 753–755.
13. (a) Spectral data of the compound 10: mp: 140–143 °C; {for racemate of 10 lit.5j
mp: 147–148 °C}; ½a2D6ꢁ ¼ þ14:13 (c 1.0, CHCl3) IR (neat)
mmax: 3387, 2922,
2852, 1743, 1657, 1535, 1373, 1229, 1037 cmꢀ1 1H NMR (500 MHz, CDCl3): d
;
5.88 (m, 1H), 5.82–5.67 (m, 2H), 5.63–5.48 (m, 2H), 5.23 (dd, 1H, J = 1.9 and
5.7 Hz), 5.02 (m, 1H), 2.14 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 169.7, 169.5, 169.3, 169.2, 128.6, 126.2, 68.8, 66.9,
66.6, 44.6, 23.2, 20.8, 20.6; ESIMS (m/z): 336 [M+Na]+; HRMS (ESI) [M+Na]+:
Anal. Calcd for C14H19O7NNa 336.10537. Found: 336.10653.
(b) Spectral data of the compound 11: mp: 105–107 °C; {lit.5j mp: 104–106 °C};
½
a2D6ꢁ ¼ ꢀ58:2 (c 0.35, CHCl3) {lit.5j ½aD26ꢁof 11 ¼ ꢀ56:0 (c 0.47, CHCl3)}; IR (neat)
m
max: 3449, 2980, 2926, 1689, 1371, 1167 cmꢀ1 1H NMR (500 MHz, CDCl3): d
;
6.05 (m, 1H), 5.85 (m, 1H), 5.21 (br d, 1H, J = 8.3 Hz), 4.62–4.51 (m, 2H), 4.42
(m, 1H), 4.26 (m, 1H), 1.86 (br s, 1H), 1.47 (s, 9H), 1.35 (s, 3H), 1.34 (s, 3H); 13
C
NMR (75 MHz, CDCl3): d 155.5, 134.8, 128.8, 108.6, 79.7, 77.8, 75.1, 65.2, 46.8,
28.3, 26.1, 24.4; ESIMS (m/z): 308 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd
for C14H23O5NNa 308.14684. Found: 308.14720.