Asymmetric synthesis of 2,4,6-trideoxy-4-(dimethylamino)-3-C-methyl-l- lyxohexopyranose (Lemonose)

Article abstract of DOI:10.1055/s-0030-1259531

l-Lemonose, the glycosidic part of (-)-lemonomycin, has been synthesized in ten steps with 18% overall yield from d-threonine. The key steps are a double, highly diastereoselective Grignard addition to a Weinreb amide and a chemoselective oxidation of a primary alcohol in the presence of a secondary alcohol, a tertiary alcohol and a tertiary amine, leading directly to the lactol. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259531

576
LETTER
Asymmetric Synthesis of 2,4,6-Trideoxy-4-(dimethylamino)-3-C-methyl-L-
lyxohexopyranose (Lemonose)
A
symmetric Synth
u
esis of
L
emo
i
nose llaume Bernadat,a Nicolas George,a Cédric Couturier,a Géraldine Masson,*a Thierry Schlama,b Jieping Zhu*a,c
a
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: geraldine.masson@icsn.cnrs-gif.fr
b
c
RHODIA, Centre de Recherches et de Technologie de Lyon (CRTL), avenue des Frères Perret, BP 62, 69192 Saint-Fons Cedex, France
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL),
EPFL-SB-ISIC-LSPN, 1015 Lausanne, Switzerland
E-mail: jieping.zhu@epfl.ch
Received 22 December 2010
HO
OH
Abstract: L-Lemonose, the glycosidic part of (–)-lemonomycin,
has been synthesized in ten steps with 18% overall yield from D-
threonine. The key steps are a double, highly diastereoselective
Grignard addition to a Weinreb amide and a chemoselective oxida-
tion of a primary alcohol in the presence of a secondary alcohol, a
tertiary alcohol and a tertiary amine, leading directly to the lactol.
O
O
H
N
H
HO
OH
N
OH
O
O
H
N
MeO
H
N
O
HO
Key words: sugar, aminosugar, lemonomycin, lemonose tetra-
hydroisoquinoline
2
MeO
+
O
OH
OH
NMe2
O
(–)-Lemonomycin (1; Figure 1) was isolated from the fer-
mentation broth of Streptomyces candidus (LL-AP191) in
1964, and its structure was elucidated in 2001 by He and
co-workers.1 The compound contains a complex bridged
tetracyclic core belonging to the tetrahydroisoquinoline
alkaloid family2 and is the only member of this class of al-
kaloids to possess a carbohydrate linkage. This sugar,
2,4,6-trideoxy-4-(dimethylamino)-3-C-methyl-L-lyxohexo-
pyranose (3; lemonose), has been found in a few other nat-
ural products, such as nocathiacin I,3 MJ347-81F4 A,4
glycothiohexide a,5 saccharocarcins,6 and some of the
thiazomycins.7 Lemonomycin exhibits potent antibiotic
activities against methicillin-resistant Staphylococcus au-
reus (MRSA), Bacillus subtilis and vancomycin-resistant
Enterococcus faecium (VREF). It is also cytotoxic against
a human colon tumor cell line (HCT-116). The complex
structure, coupled with its remarkable biological activity,
has made lemonomycin an attractive target for total syn-
thesis. The synthetic efforts have culminated in one total
synthesis by Stoltz8 and five syntheses of tetracyclic
precursors of lemonomycin by Magnus,9 Fukuyama,10
Williams,11 Mulzer,12 and by our group.13
O
1
OH
N
Me
Me
3
Scheme 1 Retrosynthesis of lemonomycin (1)
herein an asymmetric synthesis of 3 using D-threonine as
starting material.
Our first approach is shown in Scheme 2. The D-threonine
starting material was converted into the Weinreb amide of
D-N-Boc-O-TBS threonine (4) following a standard three-
step sequence (Scheme 2). We thought to install the qua-
OH
O
TBSO
O
a–c
d
OMe
OH
N
NH2
BocHN
Me
4
TBSO
O
TBSO
O
OH
e
f
OEt
NHBoc
NHBoc
As part of our program on the synthesis of tetrahydroiso-
quinoline alkaloids,14 we initiated a project directed to-
ward the total synthesis of (–)-lemonomycin (1). Our
retrosynthetic analysis of 1, shown in Scheme 1, involves
late-stage formation of the glycosidic bond between the
lemonomycinone amide fragment 2 and lemonose 3. We
have recently developed a stereocontrolled synthesis of 2:
the aglycon unit of the natural product.13 We describe
5
6
O
O
O
O
g, h
3
OH
OH
NHBoc
NHSO2Ph
7
8
Scheme 2 Reagents and conditions: (a) Boc2O, NaHCO3, H2O,
dioxane, r.t., 15 h; (b) Me(OMe)NH·HCl, EDCI, NMP, CH2Cl2,
–15 °C, 1 h, quant. (2 steps); (c) TBSCl, imidazole, DMF, r.t., 15 h,
99%; (d) MeLi, THF, –40 °C, 45 min, 80%; (e) LDA, EtOAc, THF,
–78 °C, 2 h, 86%; (f) TBAF, THF, 0 °C, 3 h, 61%; (g) TFA, CH2Cl2,
r.t., 1 h; (h) PhSO2Cl, DIPEA, CH2Cl2, r.t., 3 h, 43% (2 steps).
SYNLETT 2011, No. 4, pp 0576–0578
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1259531; Art ID: G35510ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

LETTER
Asymmetric Synthesis of Lemonose
577
Table 1 Addition of the Methyl Group to Allylketone 9; Optimiza-
ternary carbon centre by two consecutive nucleophilic ad-
dition steps. The stereochemical outcome of this sequence
was expected to depend on the order of addition and on the
transition state that governed the nucleophilic addition to
the ketone intermediate. Reaction of 4 with methyllithium
provided methyl ketone 5 in 80% yield, which, upon reac-
tion with the lithium enolate of ethyl acetate, afforded 6 as
a single diastereomer in 86% yield. Treatment of 6 with
tetrabutylammonium fluoride (TBAF) directly afforded
the lactone 7 by a sequence of desilylation and lactoniza-
tion in situ. Compound 7 was subsequently converted into
sulfonamide derivative 8 to determine its stereochemistry.
Comparison of the NMR data of 8 with those of the lem-
onose precursor described in Stoltz’s synthesis allowed us
to conclude that lactone 8, and hence 7, is the C3-epimer
of natural lemonose. The absolute configuration of the ter-
tiary alcohol (C3) in 6 is thus (R), resulting from re-face
addition of the lithium enolate onto the carbonyl group ac-
cording to the Cram-chelating model (Figure 1).15 It is in-
teresting to note that in Stoltz’s synthesis, nucleophilic
addition of the same nucleophile to the methyl ketone,
wherein the vicinal aminoalcohol function was protected
in the form of oxazolidine, afforded the opposite stereoi-
somer according to the Felkin–Ahn model.8,16 Attempts to
reverse the stereochemical course under a variety of con-
ditions failed.17
tion of Reaction Parametersa
Entry
Reagent
Temp (°C) 9/10 (%)b
dr (10)c
4:1
1
2
3
4
MeLi
–78
–78
–78
0
56:28
0:88
MeLi, CeCl3
MeMgBr
MeMgBr
1:1
84:16
43:44
–
>9:1
a All reactions were run for 1 h.
b Isolated yield after purification by column chromatography.
c Ratio estimated by 1H NMR analysis of the crude material.
Although the synthesis shown in Scheme 2 afforded the
C3-epimer of lemonose, the high diastereoselectivity ob-
served in the conversion of methyl ketone 5 into the tertia-
ry alcohol 6 was encouraging. Following the same
strategy, we assumed that it might be possible to obtain
the desired stereoisomer by simply changing the addition
order. This approach is summarized in Scheme 3. Addi-
tion of allylmagnesium bromide to the Weinreb amide 4
afforded the allyl ketone 9 in 78% yield. Conversion of
ketone 9 into the tertiary alcohol 10 was more difficult
than expected. Reaction of 9 with methyllithium gave a
poor yield of tertiary alcohol and a large amount of start-
ing material 9 was recovered, likely due to a competitive
enolization process (Table 1, entry 1). Use of the organo-
cerium reagent, prepared from MeLi and CeCl3 in situ,18
gave 10 in excellent yield, but without any diastereoselec-
tivity (entry 2). The best solution found was to use a
Grignard reagent at 0 °C (entry 4). Under these condi-
X
O
TBSO
BocN
H
OEt
O
re-face attack
M
Figure 1 Cram chelate-type transition state model accounting for tions, the desired product 10 was isolated in 44% yield (dr
the stereoselectivity observed in product 6
> 9:1) together with 43% of recovered starting material
(76% after recycling 9 three times). Ozonolysis of the ter-
minal double bond in 10 with dimethylsulfide as a reduc-
TBSO
O
TBSO
HO
a
b
ing agent yielded the unstable aldehyde. Alternatively,
reduction of the intermediate ozonide by sodium borohy-
dride in ethanol at 50 °C provided alcohol 11 in 81%
yield.19 Subsequent deprotection of the amino group un-
der acidic conditions afforded primary amine 12, which
was submitted to the reductive amination step to furnish
the dimethylamino derivative 13 in 90% yield over two
steps.
4
NHBoc
NHBoc
9
10
TBSO
HO
HO
HO
c
d, e
OH
OH
NHBoc
NH2⋅HCl
11
12
If the primary alcohol of aminotriol 13 could be oxidized
in a selective manner, this material is potentially one step
away from the target aminopyranose 3.20 Initial attempts
to achieve this conversion with hypervalent iodine re-
agents such as O-iodoxybenzoic acid (IBX)21 and Dess–
Martin periodinane (DMP)22 resulted in complex mix-
tures. Swern oxidation also failed to give the desired re-
sults. Although the presence of tertiary amines is tolerated
in hypervalent iodine reagent-mediated oxidation,23 we
suspected that its presence in our case could be problem-
OH
O
HO
HO
g
f
OH
OH
N
Me
Me
N
Me
Me
13
3
Scheme 3 Reagents and conditions: (a) AllylMgBr, THF, –78 °C, 1
h, 78%; (b) MeMgBr, THF, 0 °C, 1 h, 44%; (c) O3, CH2Cl2, –78 °C,
then NaBH4, EtOH, H2O, 50 °C, 30 min, 81%; (d) TBAF, THF, 0 °C,
3 h, 76%; (e) anhydrous HCl, MeOH, r.t., 15 h; (f) Formol,
NaBH3CN, AcOH, MeOH, r.t., 8 h, 90% (2 steps); (g) TFA, DMSO, atic.21b Therefore, we decided to temporarily protect the
r.t., then IBX, 2 h, 95%.
amino function by protonation in situ. Dissolving 13 in
dimethylsulfoxide in the presence of trifluoroacetic acid
(1.1 equiv) followed by addition of IBX (1.2 equiv) af-
Synlett 2011, No. 4, 576–578 © Thieme Stuttgart · New York

578
G. Bernadat et al.
LETTER
(7) Zhang, C.; Herath, K.; Jayasuriya, H.; Ondeyka, J. G.; Zink,
D. L.; Occi, J.; Birdsall, G.; Venugopal, J.; Ushio, M.;
Burgess, B.; Masurekar, P.; Barrett, J. F.; Singh, S. B. J. Nat.
Prod. 2009, 72, 841.
(8) Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am. Chem. Soc.
2003, 125, 15000.
(9) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005, 127,
12476.
(10) Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem.
Commun. 2005, 394.
forded the lactol 3 in 95% yield. The chemoselectivity of
this transformation was truly remarkable, since one sec-
ondary alcohol, one tertiary alcohol, one tertiary amine,
and the resulting lactol function were untouched, provid-
ing us with an efficient way to conclude the synthesis
without extra protection/deprotection steps.
In summary, we have developed an asymmetric synthesis
of lemonose in ten steps with 18% overall yield starting
from readily available D-threonine. Key steps involved
were (a) a sequential double addition of Grignard reagent
to Weinreb amide, creating the quaternary centre with the
desired absolute configuration, and (b) one-step conver-
sion of aminotriol 13 into lactol 3 under oxidative condi-
tions. We believe that such a highly chemoselective
oxidative protocol will find application in the synthesis of
other related systems.
(11) Vincent, G.; Chen, Y.; Lane, J. W.; Williams, R. M.
Heterocycles 2007, 72, 385.
(12) Siengalewicz, P.; Brecker, L.; Mulzer, J. Synlett 2008, 2443.
(13) (a) Wu, Y.-C.; Bernadat, G.; Masson, G.; Couturier, C.;
Schlama, T.; Zhu, J. J. Org. Chem. 2009, 74, 2046.
(b) Couturier, C.; Schlama, T.; Zhu, J. Synlett 2006, 1691.
(14) For syntheses of other natural products belonging to the
same family from our group, see: (a) Wu, Y.-C.; Liron, M.;
Zhu, J. J. Am. Chem. Soc. 2008, 130, 7148. (b) Chen, X.;
Zhu, J. Angew. Chem. Int. Ed. 2007, 46, 3962. (c) Chen, J.;
Chen, X.; Willot, M.; Zhu, J. Angew. Chem. Int. Ed. 2006,
45, 8028. (d) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J.
J. Am. Chem. Soc. 2006, 128, 87. (e) Chen, X. C.; Chen,
J. C.; De Paolis, M.; Zhu, J. J. Org. Chem. 2005, 70, 4397.
(15) (a) Reetz, M. T.; Hüllmann, M.; Seitz, T. Angew. Chem., Int.
Ed. Engl. 1987, 26, 477. (b) Mengel, A.; Reiser, O. Chem.
Rev. 1999, 99, 1191.
(16) (a) Maurer, P. J.; Knudsen, C. G.; Palkowitz, A. D.;
Rapoport, H. J. Org. Chem. 1985, 50, 325. (b) Evans,
D. A.; Hu, E.; Tedrow, J. S. Org. Lett. 2001, 3, 3133.
(17) Selected conditions included: (a) adding HMPT to capture
the counter-ion; (b) adding BF3·OEt2 to pre-complex the
aldehyde, and (c) replacing LDA with KHMDS.
(18) (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura,
Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem.
1984, 49, 3904. (b) Paquette, L. A. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; John
Wiley & Sons: New York, 1995, 1031. (c) Greeves, N.;
Lyford, L. Tetrahedron Lett. 1992, 33, 4759.
(19) Sousa, J. A.; Bluhm, A. L. J. Org. Chem. 1960, 25, 108.
(20) For selective oxidation of primary alcohols in the presence
of secondary alcoholic groups with IBX, see: Corey, E. J.;
Palani, A. Tetrahedron Lett. 1995, 36, 3485.
(21) (a) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano,
G. J. Org. Chem. 1995, 60, 7272. (b) Zhdankin, V. V.;
Stang, P. J. Chem. Rev. 2002, 102, 2523. (c) Richardson,
R. D.; Zayed, J. M.; Altermann, S.; Smith, D.; Wirth, T.
Angew. Chem. Int. Ed. 2007, 46, 6529; and references cited
therein. (d) Moorthy, J. N.; Singhal, N.; Senapati, K. Org.
Biomol. Chem. 2007, 5, 767. (e) Moorthy, J. N.; Singhal, N.;
Senapati, K. Tetrahedron Lett. 2008, 49, 80.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support from CNRS is gratefully acknowledged. G.B.,
N.G and C.C. thank MESR, ICSN and Rhodia, respectively, for
doctoral fellowships.
References and Notes
(1) (a) Whaley, H. A.; Patterson, E. L.; Dann, M.; Shay, A. J.;
Porter, J. N. Antimicrob. Agents Chemother. 1964, 8, 83.
(b) He, H.; Shen, B.; Carter, G. T. Tetrahedron Lett. 2000,
41, 2067.
(2) (a) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669. (b) Siengalewicz, P.; Rinner, U.; Mulzer, J. Chem.
Soc. Rev. 2008, 37, 2676.
(3) (a) Constantine, K. L.; Mueller, L.; Huang, S.; Abid, S.;
Lam, K. S.; Li, W.; Leet, J. E. J. Am. Chem. Soc. 2002, 124,
7284. (b) Leet, J. E.; Li, W.; Ax, H. A.; Matson, J. A.;
Huang, S.; Huang, R.; Cantone, J. L.; Drexler, D.; Dalterio,
R. A.; Lam, K. S. J. Antibiot. 2003, 56, 226. (c) Leet, J. E.;
Li, W.; Ax, H. A.; Matson, J. A.; Huang, S.; Huang, R.;
Cantone, J. L.; Drexler, D.; Dalterio, R. A.; Lam, K. S.
J. Antibiot. 2003, 56, 232.
(4) Sasaki, T.; Otani, T.; Matsumoto, H.; Unemi, N.; Hamada,
M.; Takeuchi, T.; Hori, M. J. Antibiot. 1998, 51, 715.
(5) (a) Steinberg, D. A.; Bernan, V. S.; Montenegro, D. A.;
Abbanat, D. R.; Pearce, C. J.; Korshalla, J. D.; Jacobus,
N. V.; Petersen, P. J.; Mroczenski-Wildey, M. J.; Maiese,
W. M. J. Antibiot. 1994, 47, 887. (b) Northcote, P. T.;
Williams, D.; Manning, J. K.; Borders, D. B.; Maiese,
W. M.; Lee, M. D. J. Antibiot. 1994, 47, 894. (c)Northcote,
P. T.; Siegel, M.; Borders, D. B.; Lee, M. D. J. Antibiot.
1994, 47, 901.
(22) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277. (c) Boeckman, R. K. Jr.; Shao, P.; Mullins, J. J. Org.
Synth. 2000, 77, 141.
(23) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T.
Angew. Chem. Int. Ed. 2003, 42, 4077. (b) Nicolaou, K. C.;
Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004,
126, 5192.
(6) (a) Horan, A. C.; Shearer, M. C.; Hegde, V.; Beyazova,
M. L.; Brodsky, B. C.; King, A.; Berrie, R.; Cardaci, K.;
Nimeck, M. J. Antibiot. 1997, 50, 119. (b) Hegde, V. R.;
Patel, M. G.; Das, P. R.; Pramanik, B.; Puar, M. S.
J. Antibiot. 1997, 50, 126.
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