A common approach to the total synthesis of l-1-deoxyallonojirimycin, l-homo-1-deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine A5

Article abstract of DOI:10.1016/j.tetlet.2016.03.025

A common strategy for the synthesis of polyhydroxylated piperidines l-1-deoxyallonojirimycin, l-homo-1-deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine A₅ from the readily available d-ribose as a starting material has been describ

Full text of DOI:10.1016/j.tetlet.2016.03.025

Accepted Manuscript
A common approach to the total synthesis of L-1-deoxyallonojirimycin, L-ho-
mo-1-deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine A5
Chinthala Muniraju, Maddimsetti Venkateswara Rao, Anugula Rajender,
Batchu Venkateswara Rao
PII:
S0040-4039(16)30248-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.025
TETL 47413
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 February 2016
7 March 2016
8 March 2016
Please cite this article as: Muniraju, C., Rao, M.V., Rajender, A., Rao, B.V., A common approach to the total
synthesis of L-1-deoxyallonojirimycin, L-homo-1-deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine
A5, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.025
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
A common approach to the total synthesis of L-1-deoxyallonojirimycin, L-homo-1-
deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine A5
Chinthala Muniraju, Maddimsetti Venkateswara Rao, Anugula Rajender, and Batchu Venkateswara Rao
Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A common strategy for the synthesis of polyhydroxylated piperidines L-1-
deoxyallonojirimycin, L-homo-1-deoxyazaallose and triacetyl derivative of 5-epi
hyacinthacine A5 from the readily available D-ribose as a starting material has
been described.
Available online
Keywords:
Imine Formation
Grignard addition
Cyclisation
2009 Elsevier Ltd. All rights reserved.
Cross metathesis
Total synthesis
1
Polyhydroxylated piperdines and pyrrolidines are well known
in nature as mimics of monosaccharides. These are commonly
known as azasugars or iminosugars, where in the ring oxygen
of the sugar moiety is replaced by nitrogen atom. They are in
general found to be potent inhibitors of many carbohydrate-
processing enzymes
and could be very useful for the
2
3
treatment of various diseases such as diabetes , cancer and
4
5
viral infections including AIDS . Natural or synthetically
produced six membered iminosugars (polyhydroxylated
piperidines) effectively inhibit the oligosaccharide processing
Figure 1. Some of polyhydroxylated piperidines and pyrrolidines
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com.
_______________
*Corresponding author. Tel./fax: +91 40 27193003.

2
Tetrahedron Letters
Due to their promising therapeutic profiles, many reports have
been disclosed for the synthesis of DNJ 1, its isomers,
enzymes, especially glycosidases and glycosyltransferases
which are involved in a whole range of the essential
biological transformations.6 Some of the polyhydroxylated
piperidines are used as drugs for the treatment of various
diseases.7 Miglustat (Zavesca®, 2) and Miglitol (Glyset®, 3)
17, 18
homoanalogues
and also hyacinthacine A5 199 using
different strategies. Majority of the synthesis are based on the
chiron approach but many of them are lacking stereo
selectivity and general applicability.20 Herein, we wish to
report an efficient and highly stereoselective approach to
are currently used in the market for the treatment of
polyhydroxylated
piperidines
such
as
L-1-
7, 8
Gaucher’s disease and type-II diabetes (fig. 1)
and these
22
deoxyallonijirimycin 518,19,21 L-homo-1-deoxyazaallose 6
and pyrrolidizine 5-epi hyacynthecine A5 10. Over the past
few years, our group has been involved in the synthesis of
some iminosugars or azasugars and phytosphingosines
starting from the readily available materials.23, 24 Recently we
reported a highly stereoselective nucleophilic addition on N-
glycosylamine 12 to give exclusively anti amino hydroxyl
are derivatives of 1-Deoxynojirimycin (DNJ, 1), a natural
compound. Some more derivatives have also been found to
be Glucosylceramide synthase inhibitors, which are useful in
9
the therapy of HIV and Hepatitis C infection.8,
1-
Deoxymannonojirimycin 4 and L-1-deoxyallonojirimycin 5
have good inhibitory activity towards human lysosomal α-
mannosidase 10, which plays a vital role in maintaining
cellular homeostasis.11 Polyhydroxylated pyrrolizidines such
as hyacinthacine family having one carbon side chain at C(3)
and/or C(5) have shown significant activity against viral
infections, cancer and diabetes.12,13 For example australine 7
unit 11 24, and its application in the synthesis of some bicyclic
25
iminosugars.
In this publication we are presenting the
extension of our strategy for the synthesis of polyhdroxylated
piperdines 5, 6 and 5-epi hyacynthecine A5 10. As per the
retrosynthetic analysis (Scheme 1). The glycosylamine 12
and hyacinthacine A2
8
are good
inhibitors of
was synthesized from the commercially available D-ribose in
14
amyloglucosidase
and was found to display antiviral and
25
three step procedure
.
Nucleophilic addition on
anti-HIV activity.15 Compounds hyacinthacine A2 8,
hyacinthacine A5 9 and 5-epi hyacynthecine A5 10 are also
good inhibitors of amyloglucosidase. 16
o
glycosylamine 12 with vinylmagnesium bromide at -78 C in
dry tetrhydrofuran gave the anti adduct 11 exclusively in 72%
yield (Scheme 2). 24, 25The formation of anti product can be
explained via seven membered chelation or felkin anh
model.24
Scheme1. Retrosynthetic analysis

Scheme 2. Preparation of key intermediate erythro amino alcohol 11
For the synthesis of L-1-deoxyallonojirimycin 5 (Scheme 3),
piperidine ring, deprotection of the benzyloxycarbonyl,
benzyl, methoxymethyl and acetonide groups.
compound 11 was treated with benzyloxycarbonyl chloride
and sodium bicarbonate in methanol to give the NCbz
derivative 13 in 98% yield. Ozonolysis of the terminal olefin
in 13 gave the corresponding aldehyde, which was reduced
with sodium borohydride in methanol to afford the desired
diol 14 in 85% yield. Masking of the diol functionality in 14
as methoxy methyl ethers with methoxy methyl chloride and
diisopropylethylamine in dichlromethane furnished the
required compound 15 in 93% yield. Deprotection of silyl-
ether in 15 with tetrabutylammonium flouride in
tetrahydrofuran gave the primary alcohol 16 in 90% yield. For
the construction of the piperidne ring, compound 16 was
subjected to mesylation using mesyl chloride, triethylamine
and N, N-dimethylamino pyridine in dichloromethane at 0 oC,
the crude mesylate derivative on hydrogenolysis in presence
of palladium on carbon and then treatment of the crude with
6M hydrochloric acid afforded the required final product L-
1-deoxyallonijirimycin 5 as hydrochloride salt. The spectral
and analytical data of 5 were in accordance with the reported
values. 21The conversion of 16 to 5 has taken place in three
steps without any isolation and purification of the
intermediates. This transformation involves cyclisation to
For the synthesis of L-homo-1-deoxyazaallose 6 (Scheme 4),
the terminal olefin in 13 was subjected to
hydroboration/oxidation using borane dimethylsulphide in dry
tetrahydrofuran followed by treatment with sodiumhydroxide
and hydrogen peroxide at 0 oC gave the diol 17 in 80% yield.
The diol functionality in 17 was converted to methoxymethyl
ethers to furnish 18 in 90% yield. Treatment of 18 in
tetrahydrofuran with tetrabutylammonium flouride afforded
the primary alcohol 19 in 89% yield. Alcohol 19 on
mesylation using mesyl chloride and triethylamine in
dichloromethane gave the mesylated product, which on
hydrogenolysis in the presence of catalytic palladium on
carbon and cleavage of the protecting groups under acidic
condition, gave the desired final product L-homo-1-
deoxyazaallose 6 as hydrochloride salt in 85% yield (over 2
steps), whose spectral and physical data were in good
agreement with the reported values. 22
Scheme 3. Synthesis of L-1-deoxyallonojirimycin 5

4
Tetrahedron Letters
Scheme 4. Synthesis of L-homo-1-deoxyazaallose 6
Scheme 5: Synthesis of acetyl derivative of 5-epi hyacinthacine A5
Our next task was to synthesise 5-epi-hyacinthacine A5 10
from compound 11 as shown in Scheme 5. The compound 11
underwent SN2 cyclisation by treating with mesyl chloride in
the presence of pyridine and triethylamine (2:1) to give 2, 5
disubstituted pyrrolidine compound 20 in 60% yield. This
differentially disubstituted pyrrolidine compound 20 is a good
template for the synthesis of polyhydroxy pyrrolidine
skeletons. The compound 20 was subjected to cross
metathesis with methyl vinyl ketone using Grubb’s second
generation catalyst to afford the desired α,β-unsaturated
carbonyl compound 21 in 75% yield. Hydrogenation of 21 to
22 using Pd-C: Pd(OH)2 (1:1) in ethanol gave 22 in 80 %
yield. Conversion of 21 to 22 is a tandem process which
involves debenzylation, reduction of double bond via cyclic
enamine formation and then reduction of enamine from the
less hindered side. Then global deprotection of the compound
22 with 4N HCl in methanol followed by treatement with
acetic anhydride and pyridine gave the acetyl derivative of (-)-
5-epi- hyacinthacine A5 23 in 60 % over two steps. The
spectral and physical data of compound 23 were in good
agreement with the literature values.19
In summary, a simple, efficient and divergent synthesis of
imino sugars such as L-1-deoxyallonijirimycin, L-homo-1-
deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine
A5 has been achieved from the commercially available D-
ribose. The key reactions are highly stereoselective
nucleophilc addition, reductive amination and cross
metathesis.
Acknowledgments

C.M.R and M.V.R thanks CSIR and A.R thanks UGC and
New Delhi for financial support as part of XII Five Year plan
programme under title ORIGIN and Denova (CSC-0108).
The authors also thank Director, CSIR-IICT for the constant
support and encouragement.
L.; I. Robina. Curr. Org. Synth. 2011, 8, 102; (d). F.
Ouladi.; S. Front-Deschamps.; E. Gallienne.; E. Lesellier.;
K. Ikeda.; N. Asano.; P. Compain.; O. R. Martin. Chem.
Med. Chem. 2011, 6, 35.
7. G. Horne.; F. X. Wilson.; J. Tinsley.; D. H. Williams.; R.
Storer. drug discovery today 2011, 16, 107.
References
8 (a). R. A. Dwek.; T. D. Butters.; F. M. Platt.; N. Zitzmann.
Nat. Rev. Drug Discovery 2002, 1, 65; (b). B. L. Stocker.;
E. M. Dangerfield.; A. L. Win-Mason.; G. W. Haslett.; M.
S. M. Timmer. Eur. J. Org. Chem. 2010, 1615; (c). R. J.
B. H. N.van den Berg.; T. Wennekes.; A. Ghisaidoobe.;
W. E. Donker-Koopman.; A. Strijland.; R. G. Boot.; G. A.
van der Marel.; J. M. F. G. Aerts.; H. S. Overkleeft. Med.
Chem. Lett. 2011, 2, 519.
1. (a). V. H. Lillelund.; H. H. Jensen.; X. Liang.; M. Bols,
Chem. Rev. 2002, 102, 515; (b). N. Asano.; R. J. Nash.; R.
J. Molyneaux.; G. W. J. Fleet. Tetrahedron: Asymmetry
2000, 11, 1645; (c). P. Greimel.; J. Spreitz.; A. E. Stutz.;
T. M. Wrodnigg. Curr. Top. Med. Chem. 2003, 3, 513.
2. (a). Y. Yoshikuni.; Y. Ezure.; T. Seto.; K. Mori.; M.
Watanabe.; H. Enomoto. Chem. Pharm. Bull. 1989, 37,
106; (b). M. Kimura.; F. J. Chen.; N. Nakashima.; I.
Kimura.; N. Asano.; S. J. Koya. Trad. Med. 1995, 12, 214;
(c). S. Horii.; H. Fukase.; T. Matsuo.; Y. Kameda.; N.
Asano.; K. J. Matsui. Med. Chem. 1986, 29, 1038; (d). K.
M. Robinson.; M. E. Begovic.; B. L. Reinhart.; E. W.
Heineke.; J. -B. Ducep.; P. R. Kastner.; F. N. Marshall.; C.
Danzin. Diabetes 1991, 40, 825.
9. (a). A. B. Hughes.; A. J. Rudge. Nat. Prod. Rep. 1994,
135; (b). B. Winchester.; G. W. J. Fleet. Glycobiology
1992, 2, 199.
10. A. Kato.; N. Kato.; E, Kano.; I. Adachi.; K. Ikeda.; L. Yu.;
T. Okamoto.; Y. Banba.; H. Ouchi.; H. Takahata.; N.
Asano. J. Med. Chem. 2005, 48, 2036.
11. M. Venkatesan.; D. A.Kuntz.; D. R. Rose, Protein Science
2009, 18, 2242.
3. (a). Y. Nishimura. Curr. Top. Med. Chem. 2003, 3, 575;
(b). S. Hakomori. Cancer Res. 1985, 45, 2405; (c). Y.
Nishimura. In Studies in Natural Products Chemistry; Ed.
Atta-ur-Rahman.; Elsevier Science: B. V.: Amsterdam
1995, 16, 75; (d). P. E. Gross.; M. A. Baker.; J. P. Carver.;
J. W. Dennis. Clin. Cancer Res. 1995, 1, 935.
12. (a). D. D. Dhavale.; M. M. Matin. ARKIVOC 2005, 110;
(b). D. D. Dhavale.; M. M. Matin.; T. Sharma.; S. G.
Sabharwal. Biorg. Med. Chem. 2003, 11, 3295; (c). P.
Szolcsányi.; T. Gracza.; M. Koman.; N. Prónayovác.; T.
Liptaj. Chem. Comm. 2000, 471; (d). N. N. Saha.; V. N.
Desai.; D. D. Dhavale. Tetrahedron 2001, 57, 39; (e). D.
D. Dhavale.; V. N. Desai.; N. N. Saha.; J. N. Tilekar.
ARKIVOC 2002, 91; (e). V. N. Desai.; N. N. Saha.; D. D.
Dhavale. Chem. Comm. 1999, 1719; (f). D. D. Dhavale.;
V. N. Desai.; M. D. Sindkhedkar.; R. S. Mali.; C.
Castellari.; C. Trombini. Tetrahedron: Asymmetry 1997, 8,
1475; (g). C. H. Wong.; L. Provencher.; J. A. Porco Jr.; S.
-H. Jung.; Y. -F. Wang.; L. Chen.; R. Wang.; D. H.
Steensma. J. Org. Chem. 1995, 60, 1492; (h). G. Le Bouc.;
C. Thomassigny.; C. Greck. Tetrahedron: Asymmetry
2006, 17, 2006.
4. (a). C. Wohlfarth.; T. Efferth. Acta Pharmacol Sin 2009,
30, 25; (b). G. W. J. Fleet.; A. Karpas.; R. A. Dwek.; L. E.
Fellows.; A. S. Tyms.; S. Petursson.; S. K. Namgoong.; N.
G. Ramsden.; P. W. Smith.; J. C. Son.; F. Wilson.; D. R.
Witty.; G. S. Jacob.; T. W. Rademacher. FEBS Lett. 1988,
237, 128.
5. (a). P. Greimel.; J. Spreitz.; A. E. Stutz.; T. M. Wrodnigg.
Curr. Top. Med. Chem. 2003, 3, 513; (b). D. L. Taylor.; P.
Sunkara.; P. S. Liu.; M. S. Kang.; T. L. Bowlin.; A. S.
Tyms. AIDS 1991, 5, 693.
6. (a). Iminosugars: From Synthesis to Therapeutic
Applications, ed. P. Compain.; O. R. Martin. Wiley-VCH,
Weinheim, Germany, 2007; (b). A. E. Stutz, Iminosugars
as Glycosidase Inhibitors: Nojirimycin and Beyond,
Wiley-VCH: Weinheim, Germany, 1999; (c) E. Moreno-
Clavijo.; A. T. Carmona.; A. J. Moreno-Vargas.; Molina
13. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2000, 11, 1645; (b) Pearson,
M. S. M.; Mathé-Allainmat, M.; Fargeas, V.; Lebreton, J.
Eur. J. Org. Chem. 2005, 2159; (c) Lillelund, V. H.;

6
Tetrahedron
Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102,
G. Davies.; A. L. A. Figuccia.; A. M. Fletcher.; P. M.
Roberts.; J. E. Thomson. Org. Lett. 2013, 15, 2042; (k). I.
Dragutan.; V. Dragutan.; A. Demonceau. RSC. Adv. 2012,
2, 719 and references cited therein.
515.
14. Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.;
Girdhar, A.; Ramsden, N. G.; Peach, J. M.; Hegarty, M.
P.; Scofield, A. M. Phytochemistry 1990, 29, 111.
19. (a) Izquierdo, Isidoro. ;T. Plaza, Marı´a. ; Tamayo, Juan
15. (a) Fellows, L.; Nash, R. PCT Int. Appl. WO GB
Appl.89/7,951; Chem. Abstr. 1991, 114, 143777s; (b)
Taylor, D.L.; Nash, R.; Fellows, L. E.; Kang, M. S.; Tyms,
A. S. Antiviral Chem. Chemother. 1992, 3, 273.
A.;
Sa´nchez-Cantalejo,
Fernando.
Tetrahedron:
Asymmetry 2007, 18, 2211–2217. (b) Kaliappan, Krishna
P. ; Das, Prasanta. Synlett 2008, 6, 841–844.
20. E. N. Tzanetou.; K. M. Kasiotis.; P. Magiatis.; S. A.
Haroutounian. Molecules, 2007, 12, 735.
16. Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.;
Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J.
Nat. Prod. 2002, 65, 1875–1881;
21. A. Guaragna.; S. D’Errico.; D. D. Alonzo.; S. Pedatella.;
G. Palumbo. Org. Lett. 2007, 9, 3473.
17. For the synthesis of L-1-deoxyallonijirimycin see: (a). P.
Gupta.; Y. D. Vankar. Eur. J. Org. Chem. 2009, 1925; (b).
S. Ghosh.; J. Shashidhar.; D. S. Kumar. Tetrahedron Lett.
2006, 47, 6041; (c). H. -J. Altenbach.; K. Himmedldirk.
Tetrahedron 1995, 52, 1077; (d). X. -D. Wu.; S. -K.
Khim.; X. Zhang.; E. M. Cederstrom.; P. S. Mariano. J.
Org. Chem. 1998, 63, 841; (e). H. Takahata.; Y. Banba.;
M. Sasatani.; H. Nemoto.; A. Kato.; I. Adachi.
Tetrahedron 2004, 60, 8199;
22. C. Herdeis.; T. Shiffer. Tetrahedron 1996, 52, 14745.
23. (a). J. S. Reddy.; B. V. Rao. J. Org. Chem. 2007, 72,
2224; (b). B. Chandrasekhar.; A. Madhan.; B. V. Rao.
Tetrahedron 2007, 63, 8746; (c). G. Bhaskar.; B. V. Rao.
Tetrahedron Lett. 2003, 44, 915;(d) Y. Jagadeesh.; J. S.
Reddy.; B. V. Rao.; J. L. Swarnalatha. Tetrahedron 2010,
66, 1202; (e). B. Chandrasekhar.; J. P. Rao.; B. V. Rao.; P.
Naresh. Tetrahedron Lett. 2011, 52, 5921; (f). A.
Rajender.; J. P. Rao.; B. V. Rao. Tetrahedron: Asymmetry
2011, 22, 1306; (g). J. P. Rao.; B. V. Rao.; J. L.
Swarnalatha. Tetrahedron Lett. 2010, 51, 3083; (g). A.
Rajender.; B. V. Rao. Tetrahedron Lett. 2013, 54, 2329.
24. (a). G. S. Rao.; B. V. Rao. Tetrahedron Lett. 2011, 52,
4861; (b). M. V. Rao, B. V. Rao, B. Ramesh. Tetrahedron
Lett. 2014, 55, 5921.
18. (a). D. Alessandro.; R. Barbara.; M. Alberto.; Daniela,
Synlett 2004, 1711; (b). B. -C. Hong.; Z. -Y. Chen.; A.
Nagarajan.; R. Kottani.; V. Chavan.; W. -H. Chen.; Y. -F.
Jiang.; S. -C. Zhang.; J. -H. Liao.; S. Sarshar. Carbohydr.
Res. 2005, 340, 2457; for the recent articles and reviews of
some polyhydroxylated pipiperidines: (c). B. L. Stocker.;
E. M. Dangerfield.; A. L. Win-Mason.; G. W. Haslett.; M.
S. M. Timmer. Eur. J. Org. Chem. 2010, 1615; (d). M. A.
Wijdeven.; J. Willemsen.; F. P. J. T. Rutjes. Eur. J. Org.
Chem. 2010, 2831; (e). R. Sridhar.; B. Srinivas.; K. R.
Rao. Tetrahedron 2009, 65, 10701; (f). R. Rengasamy.;
M. J. Curtis-Long.; W. D. Seo.; S. H. Jeong.; I. -Y. Jeong.;
K. H. Park. J. Org. Chem. 2008, 73, 2898; (g). G.
Danoun.; J. Ceccon.; A. E. Greene.; J. -F. Poisson. Eur. J.
Org. Chem. 2009, 4221; (h). A. M. C. H.van den
Nieuwendijk.; M. Ruben.; S. E. Engelsma.; M. D. P.
Risseeuw.; R. J. B. H. N. Van den Berg.; R. G. Boot.; J.
M. Aerts.; J. Brussee.; G. A. Van der Marel.; H. S.
Overkleeft. Org. Lett. 2010, 12, 3957; (i) I. Dragutan.; V.
Dragutan.; C. Mitan.; H. C. M. Vosloo.; L. Delaude.; A.
Demonceau. Beilstein J. Org. Chem. 2011, 7, 699; (j). S.
25. A. Rajender.; J. P. Rao.; B. V. Rao. Eur. J. Org. Chem.
2013, 1749.
Supplementary material

Click here to remove instruction text...

8
Tetrahedron
Graphical Abstract
To create your abstract, type over the instructions in the
A common approach to the total synthesis of L-1-deoxy
allonijirimycin, L-homo-1-deoxyazaallose and triacetyl
derivative of 5-epi-hyacinthacineA5
Leave this area blank for abstract info.
Chinthala Muniraju, Maddimsetti Venkateswara Rao, Anugula Rajender and Batchu Venkateswara Rao*
template box below.
Fonts or abstract dimensions should not be changed or altered.

Highlights:
1. Explanation has been given for key steps in
the manuscript.
2. All the abbreviations have been defined in
schemes 3-5.
3. We have indicated the overall yield in
Graphical abstract.
4. The hydrochloride salts of the compound 5
+
and 6 indicated as H2 Cl- in the manuscript.