Cis-stereoselective SmI2-promoted reductive coupling of keto-nitrones: First synthesis of 1-epitrehazolamine

Article abstract of DOI:10.1039/b503981a

An expeditious synthesis of 1-epitrehazolamine is presented from readily available 2,3,4,6-tetra-O-benzyl-D-glucose. The key step involves a samarium diiodide-promoted reductive cyclization of a masked keto-nitrone to form a fivemembered ring aminocyclito

Full text of DOI:10.1039/b503981a

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C O M M U N I C A T I O N
cis-Stereoselective SmI2-promoted reductive coupling of
keto-nitrones: first synthesis of 1-epitrehazolamine
Ge´raldine Masson, Christian Philouze and Sandrine Py*
LEDSS, UMR 5616 CNRS-Universite´ Joseph Fourier, BP 53, 38041, Grenoble, France.
E-mail: sandrine.py@ujf-grenoble.fr; Fax: +(33) 476 635 983; Tel: +(33) 476 514 803
Received 18th March 2005, Accepted 14th April 2005
First published as an Advance Article on the web 28th April 2005
An expeditious synthesis of 1-epitrehazolamine is presented
from readily available 2,3,4,6-tetra-O-benzyl-D-glucose.
The key step involves a samarium diiodide-promoted re-
ductive cyclization of a masked keto-nitrone to form a five-
membered ring aminocyclitol. The excellent cis selectivity
observed in this nitrone–ketone reductive coupling con-
trasts surprisingly with the trans selectivity of ketone–oxime
reductive couplings.
Important efforts in the search for novel aminocyclopentitols1
have been stimulated since this class of compounds has been
recognized as modulators of the activity of glycoprocessing
enzymes.1,2 In addition to their implication in specific cell-surface
recognition and invasion processes, glycoprocessing enzymes
have also been considered carefully as targets for agrochemicals
since the discovery in 1991 of trehazoline, isolated from a
culture broth of Micromonospora sp. SANK 623903 and from
Amycolatopsis trehalostatica.4
Trehazoline (1) is a pseudodisaccharide in which a-D-glucose
is linked to an aminocylopentitol, the trehazolamine (2), by an
isourea functionality (Scheme 1). Until now, trehazoline has
been the best inhibitor (active at nanomolar concentrations) of
trehalase, an enzyme (EC 3.2.1.28) that is essential for survival
of insects, fungus and nematodes.5
Scheme 2 Stereochemical outcome of the SmI2-promoted intramolec-
ular reductive coupling of ketone aldoxime ethers.
pounds.11,12 Evidence was found for the prior reduction of
nitrones by SmI2 followed by coupling of the resulting species to
the carbonyl compounds, the process involving an umpolung of
13
=
the C N bond of nitrones.
Surprisingly, in our first examples of intramolecular nitrone–
carbonyl couplings,11,14 products exhibiting a cis relationship at
the new stereocenters were the only detected. This remarkable
selectivity intrigued us and motivated our study of this reaction
in the case of highly functionalized, carbohydrate-derived sub-
strates. Herein, we report our preliminary results in this field,
that allowed the stereoselective synthesis of 1-epitrehazolamine
(11) from a new D-glucose-derived keto-nitrone (Scheme 3).
The commercially available 2,3,4,6-tetra-O-benzyl-D-glucose
(4) was readily reduced by NaBH4 to the corresponding
glucitol 5.15 Swern oxidation then afforded the keto-aldehyde
6,6g that was not isolated (this compound being prone to
hydration) but instead was treated directly with one eq. of N-
benzylhydroxylamine.16 The formation of the nitrone proved
completely regioselective (on the aldehyde versus ketone) and
the presumed keto-nitrone 7 was isolated in good yield (81% for
two steps) as a stable, white powder. However, careful analysis
of this product revealed that its actual structure was not 7 but
its hydrated counterpart 8,17 isolated as a single isomer. The
Scheme 1
Although several syntheses of trehazoline (1),6 trehazolamine
(2)7 and structural analogues8 have been reported, 1-epi-
trehazolamine has not been prepared to date.9
One of the most extensively investigated approaches for the
synthesis of aminocyclopentitols is the SmI2-promoted reductive
coupling of a ketyl radical anion with an oxime functionality,
that affords generally trans-aminocyclitols as the sole or major
products (Scheme 2, eqn. (a) and (b)).6h,10 In one case however
(Scheme 2, eqn. (c)), a cis-aminocyclitol was obtained, resulting
apparently from conformational restriction in the starting 5,6-
benzylidene ketal-protected keto-oxime.6g
Recently, we have disclosed our results on the first SmI2-
promoted cross-coupling of nitrones with carbonyl com-
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 0 6 7 – 2 0 6 9
2 0 6 7
©

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Fig. 1 X-Ray analysis of compound 10.21
feature supports the involvement of a chelated transition state
for the reaction (Fig. 2).
Fig. 2 Proposed chelated transition state for SmI2-mediated in-
tramolecular nitrone–ketone pinacolic coupling.
While the reductive cyclization of keto-oxime ethers is thought
to involve the initial formation of a ketyl radical anion that
adds to the C–N double bond of the oxime functionality, we
propose that in the present case the initial SET from SmI2 occurs
on the nitrone functionality, in which the basic oxygen atom
can strongly coordinate samarium. Such coordination probably
facilitates an inner sphere electron transfer to the C–N bond, to
produce a radical anion species. Formation of a six-membered
chelate in such an intermediate is likely, which would explain
the exceptional stereoselectivity of the addition to the carbonyl
group, leading to the production of vicinal cis-amino alcohols.
Complete debenzylation of 10 by hydrogenation over Pearl-
man catalyst in the presence of trifluoroacetic acid then pro-
duced 1-epitrehazolamine (11) in 61% yield.22
In conclusion, a stereoselective synthesis of 1-epitrehazol-
amine has been accomplished in only four steps from 2,3,4,6-
tetra-O-benzyl-D-glucose (4) and in a 42% overall yield. The
transformation of 1-epitrehazolamine to the corresponding
analogue of trehazoline for biological evaluation is currently
underway. This work illustrates once again the versatility of SmI2
as a selective reducing agent. Fine tuning of reactivity can be
achieved with this reagent by using two types of molecules,
nitrones and oximes, which are often considered as interchange-
able imine equivalents.
Scheme 3
configuration of 8 was assigned by comparison to related
compounds described in the literature.18
In previous work, we demonstrated that the presence of water
in reaction mixtures was not detrimental to the SmI2-induced se-
lective reduction of nitrones and subsequent reductive couplings,
and even proved beneficial in several cases.13 Therefore, com-
pound 8 was treated with SmI219 (3 eq.) to induce intramolecular
reductive coupling of the masked keto-nitrone 7. However, at
−78 ◦C the reaction did not lead to complete disappearance of
the starting material after 6 h, while several products appeared
on TLC of the reaction mixture. Further analysis showed that
over-reduction of the expected N-hydroxylamine to the corre-
sponding amine was competing with the reductive cyclization
of the starting material. Next, the reaction was performed with
an excess of SmI2 (6 eq.) and the temperature was allowed to
raise to room temperature to complete the transformation of
hydroxylamine 9 to the amine 10.† Under these conditions,
the aminocyclitol 10 was isolated in 75% yield.20 Crystals of
this product could be obtained (by slow evaporation of a 95
: 5 cyclohexane–CH2Cl2 solution) from which X-ray analysis
allowed unequivocal assignement of its structure (Fig. 1).21
Thus, it was verified that SmI2-mediated cyclization of the
masked keto-nitrone 8 yielded exclusively the corresponding
aminocyclitol exhibiting a cis relationship (1S,5S) at the new
stereocenters. While four stereoisomers could have arisen from
this coupling only one was obtained, in which the amino and the
hydroxy groups are cis relative to each other and trans relative to
their vicinal alkoxy neighbouring groups. This stereochemical
Acknowledgements
The authors thank Prof. Yannick Valle´e for his interest in this
work. Financial support by the Centre National de la Recherche
Scientifique (CNRS) and the Universite´ Joseph Fourier is
acknowledged. G. M. is grateful to the French Ministry of
Education, Research, and Technology (MENRT) for a doctoral
fellowship.
Notes and references
† Typical procedure for the preparation of aminocylopentitol 10: a stirred
and carefully deoxygenated solution of the hydrated, masked keto-
nitrone 8 (0.30 g, 0.455 mmol) in dry THF (59 mL) was cooled to
−78 ◦C under argon. A solution of SmI2 (0.08 M) in THF (61 mL,
4.08 mmol) was added dropwise, at −78 ◦C. After stirring the reaction
mixture for 2 h at −78 ◦C, the temperature was slowly raised to room
temperature. After 15 h, the reaction was complete. Aqueous saturated
Na2S2O3 (40 mL) was added and, after stirring for 15 min, the aqueous
phase was extracted with EtOAc (3 × 40 mL). The combined organic
extracts were washed with aqueous NaCl (40 mL), dried over MgSO4,
2 0 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 0 6 7 – 2 0 6 9

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filtered and concentrated in vacuo. The crude residue was purified by
chromatography on silica gel (AcOEt–pentane 1 : 4), to afford the
aminocyclitol 10 (0.287 g, 75%) as a white solid.20
13 G. Masson, P. Cividino, S. Py and Y. Vallee, Angew. Chem., Int. Ed.,
2003, 42, 2265.
14 A full account on stereochemical and mechanistic studies of the
reductive cyclization of keto-nitrones will be reported in due course.
15 E. Decoster, J. M. Lacombe, J. L. Streber, B. Ferrari and A. A. Pavia,
J. Carbohydr. Chem., 1983, 3, 329.
1 (a) A. Berecibar, C. Granjean and A. Siriwardena, Chem. Rev., 1999,
99, 779; (b) Y. Kobayashi, Carbohydr. Res., 1999, 315, 3.
2 (a) A. E. Stu¨tz, Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond, Wiley-VCH, Weinheim, 1999; (b) B. Winchester and G. W.
Fleet, Glycobiology, 1992, 2, 199.
16 A. Dondoni, S. Franco, F. Junquera, F. Merchan, P. Merino and T.
Tejero, Synth. Commun., 1994, 24, 2537.
◦
17 Spectral data for compound 8: white solid, mp 89–90 C; [a]D25
3 (a) O. Ando, H. Satake, K. Itoi, A. Sato, M. Nakajima, S. Takahashi
and H. Haruyama, J. Antibiot., 1991, 44, 1165; (b) O. Ando, M.
Nakajima, K. Hamano, K. Itoi, S. Takahashi, Y. Takamatsu, A.
Sato, R. Enokita and H. Haruyama, J. Antibiot., 1993, 46, 1116.
4 Initially the extracted active product was named trehalostatine
and its aglycone structure was described by mistake as the 4-
epitrehazolamine: (a) T. Nakayama, T. Amachi, S. Murao, T. Sakai,
T. Shin, P. T. M. Kenny, T. Iwashita, M. Zagorski, H. Komura and K.
Nomoto, J. Chem. Soc., Chem. Commun., 1991, 919; the structure of
the natural product, renamed trehazoline, was next corrected: (b) S.
Ogawa, C. Uchida and Y. Yuming, J. Chem. Soc., Chem. Commun.,
1992, 886; (c) S. Ogawa and C. Uchida, J. Chem. Soc., Perkin Trans.
1, 1992, 1939.
−24 (c 1.73, CHCl3). IR (CH2Cl2): 3061, 3037, 2922, 2873, 1608,
1502, 1461, 1355, 1273, 1102, 1077 cm−1 1H NMR (300 MHz,
.
CDCl3) d 3.55 (d, 1H, J = 10.6 Hz, CH2OBn), 3.57 (dd, 1H, J =
3.3 Hz and J = 8.3 Hz, CH(OBn)CHN), 3.68 (d, 1H, J = 7.8 Hz,
CH(OBn)C(OH)OCHN), 3.81 (d, 1H, J = 12.2 Hz, NCH2Ph), 3.98
(d, 1H, J = 10.6 Hz, CH2OBn), 4.10 (dd, 1H, J = 7.8 Hz and
J = 8.3 Hz, CH(OBn)CH(OBn)CHN), 4.16 (d,1H, J = 12.2 Hz,
NCH2Ph), 4.26 (d, 1H, J = 11.8 Hz, OCH2Ph), 4.44 (d, 1H, J =
11.8 Hz, OCH2Ph), 4.54 (d, 1H, J = 11.8 Hz, OCH2Ph), 4.64 (d,
1H, J = 11.8 Hz, OCH2Ph), 4.66 (d, 1H, J = 11.3 Hz, OCH2Ph),
4.77 (d, 1H, J = 11.1 Hz, OCH2Ph), 4.79 (d, 1H, J = 11.3 Hz,
OCH2Ph), 4.81 (d, 1H, J = 3.3 Hz, CHN(OH)Bn), 4.91 (d, 1H,
J = 11.1 Hz, OCH2Ph), 7.02–7.05 (m, 2H, CHarom.), 7.19–7.33 (m,
21H, CHarom.), 7.34–7.41 (m, 2H, CHarom.). 13C NMR (75 MHz,
CDCl3) d 62.2 (NCH2Ph), 68.6 (CH2OBn), 72.6 (OCH2Ph), 73.8
(OCH2Ph), 74.6 (OCH2Ph), 75.5 (OCH2Ph), 79.7 (CH(OBn)CHN),
80.6 (CH(OBn)CH(OH)OCHN), 83.1 (CH(OBn)CH(OBn)CHN),
89.9 (CHN(OH)Bn), 107.7 (C(OH)CH2(OBn)), 127.5, 127.7, 127.8,
127.9, 128.2, 128.3, 128.4, 128.4, 128.5 and 128.6 (25 × CHarom.),
135.9, 137.5, 137.7, 138.3 and 138.7 (5 × Carom.). LRMS (DCI) m/z:
644.3 (M + H)+; 362.1 (M + H–BnOH)+. Anal. calcd for C41H43NO7:
C, 76.49; H, 6.42; N, 2.18. Found: C, 76.25; H, 6.33; O, 2.17%.
18 (a) E. W. Baxter and A. B. Reitz, J. Org. Chem., 1994, 59, 3175 and
references cited therein.
5 For recent reports on trehalase inhibition see: (a) C. Uchida and
S. Ogawa, Rec. Res. Dev. Pure Appl. Chem., 1999, 3, 161; (b) J. L.
Chiara, I. Storch de Gracia, A. Garcia, A. Bastida, S. Bobo and M.
Martin-Ortega, ChemBioChem, 2005, 6, 186.
6 For total syntheses of trehazoline see: (a) Y. Kobayashi, H. Miyazaki
and M. Shiozaki, J. Am. Chem. Soc., 1992, 114, 10065; (b) S. Ogawa
and C. Uchida, Chem. Lett., 1993, 173; (c) Y. Kobayashi, H. Miyazaki
and M. Shiozaki, J. Org. Chem., 1994, 59, 813; (d) C. Uchida, T.
Yamagishi and S. Ogawa, J. Chem. Soc., Perkin Trans. 1, 1994, 589;
(e) C. Uchida, H. Kitahashi, T. Yamagishi, Y. Iwaisaki and S. Ogawa,
J. Chem. Soc., Perkin Trans. 1, 1994, 2775; (f) B. E. Ledford and E. M.
Carreira, J. Am. Chem. Soc., 1995, 117, 11811; (g) A. Boiron, P. Zillig,
D. Faber and B. Giese, J. Org. Chem., 1998, 63, 5877; (h) I. Storch
de Gracia, S. Bobo, M. Martin-Ortega and J. L. Chiara, Org. Lett.,
1999, 1, 1705.
7 For selected syntheses of trehazolamine see: (a) references 8b and 8c;
(b) Y. Kobayashi, H. Miyazaki and M. Shiozaki, Tetrahedron Lett.,
1993, 34, 1505; (c) S. Knapp, A. Purandare, K. Rupitz and S. G.
Withers, J. Am. Chem. Soc., 1994, 116, 7461; (d) I. Storch de Gracia,
H. Dietrich, S. Bobo and J. L. Chiara, J. Org. Chem., 1998, 63, 5883;
(e) M. Seepersaud and Y. Al-Abed, Tetrahedron Lett., 2001, 42, 1471;
(f) M. T. Crimmins and E. A. Tabet, J. Org. Chem., 2001, 66, 4012.
8 For the synthesis of structural analogues see: (a) C. Uchida and S.
Ogawa, Carbohydr. Lett., 1994, 1, 77; (b) C. Uchida, H. Kitahashi,
T. Yamagishi, Y. Iwaisaki and S. Ogawa, J. Chem. Soc., Perkin Trans.
1, 1994, 2775; (c) C. Uchida, H. Kitahashi, S. Watanabe and S.
Ogawa, J. Chem. Soc., Perkin Trans. 1, 1995, 1707; (d) C. Uchida, T.
Yamagishi, H. Kitahashi and S. Ogawa, Bioorg. Med. Chem., 1995, 3,
1605; (e) C. Uchida, H. Kimura and S. Ogawa, Bioorg. Med. Chem.,
1997, 5, 921.
19 (a) P. Girard, J. L. Namy and H. B. Kagan, J. Am. Chem. Soc., 1980,
102, 2693; (b) H. B. Kagan, J. L. Namy and P. Girard, Tetrahedron,
Suppl., 1981, 37, 175; (c) 0.1 M solutions of SmI2 in THF were
prepared according to: E. Hasegawa and D. P. Curran, J. Org. Chem.,
1993, 58, 5008.
20 Spectral data for compound 10: [a]2D5 −15 (c 2.10, CHCl3). IR
(CH2Cl2): 3527, 3412, 3094, 3069, 3029, 2873, 1608, 1502, 1453,
1355, 1273, 1216, 1086, 1029 cm−1 1H NMR (300 MHz, CDCl3)
.
d: 3.19 (d, 1H, J = 7.3 Hz, CHNHBn), 3.58 (d, 1H, J = 9.9 Hz,
CH2OBn), 3.62 (d, 1H, J = 9.9 Hz, CH2OBn), 3.66–3.70 (m, 1H,
CH(OBn)CH(OBn)CHN), 3.80 (s, 2H, NCH2Ph), 3.83–3.91 (m, 2H,
CH(OBn)CH(OBn)C(OH)CH2OBn), 4.51 (d, 1H, J = 11.9 Hz,
OCH2Ph), 4.53 (d, 1H, J = 12.3 Hz, OCH2Ph), 4.55 (d, 1H, J =
12.0 Hz, OCH2Ph), 4.57 (d, 1H, J = 11.9 Hz, OCH2Ph), 4.63 (d, 1H,
J = 12.3 Hz, OCH2Ph), 4.65 (d, 1H, J = 11.9 Hz, OCH2Ph), 4.71
(d, 1H, J = 12.0 Hz, OCH2Ph), 4.75 (d, 1H, J = 11.9 Hz, OCH2Ph),
7.20–7.33 (m, 25H, CHarom.). 13C NMR (75 MHz, CDCl3) d: 52.7
(NCH2Ph), 63.2 (CHNHBn), 72.1 (OCH2Ph), 72.4 (OCH2Ph), 72.9
(OCH2Ph and CH2OBn), 73.8 (OCH2Ph), 76.7 (C(OH)CH2(OBn),
85.3, 85.7 and 88.8 (3 × CH(OBn)), 127.0, 127.5, 127.6, 127.7, 127.8,
127.8, 128.2, 128.3, 128.3, 128.4 (25 × CHarom.), 138.2, 138.3, 138.4,
138.4 and 140.1 (5 × Carom.). LRMS (DCI) m/z: 630.4 (M + H)+.
Anal. calcd for C41H43NO6: C, 78.19; H, 6.88; N, 2.22. Found: C,
78.22; H, 6.73; N, 2.21%.
9 An N-alkoxy-derivative of 1-epitrehazolamine was obtained by SmI2-
promoted reductive cyclization of a 5,6-benzylidene ketal protected
keto-oxime: see reference 6g.
10 (a) J. L. Chiara, J. Marco-Contelles, N. Khiar, P. Gallego, C. Destabel
and M. Bernabe, J. Org. Chem., 1995, 60, 6010; (b) J. L. Chiara, C.
Destabel, P. Gallego and J. Marco-Contelles, J. Org. Chem., 1996, 61,
359; (c) J. Marco-Contelles, P. Gallego, M. Rodriguez-Fernandez, N.
Khiar, C. Destabel, M. Bernabe, A. Martinez-Grau and J. L. Chiara,
J. Org. Chem., 1997, 62, 7397; (d) A. Martinez-Grau and J. Marco-
Contelles, Chem. Soc. Rev., 1998, 27, 155; (e) H. Miyabe, S. Kanehira,
K. Kume, H. Kandori and T. Naito, Tetrahedron, 1998, 54, 5883; (f) S.
Bobo, I. Storch de Gracia and J. L. Chiara, Synlett, 1999, 1551.
11 G. Masson, S. Py and Y. Vallee, Angew. Chem., Int. Ed., 2002, 41,
1772.
12 For reviews on the uses of SmI2 in organic synthesis see: (a) G. A.
Molander and C. R. Harris, Chem. Rev., 1996, 96, 307; (b) G. A.
Molander and C. R. Harris, Tetrahedron, 1998, 54, 3321; (c) A. Krief
and A. M. Laval, Chem. Rev., 1999, 99, 745; (d) P. G. Steel, J. Chem.
Soc., Perkin Trans. 1, 2001, 2727; (e) H. B. Kagan, Tetrahedron, 2004,
59, 10351; (f) D. J. Edmonds, D. Johnston and D. J. Procter, Chem.
Rev., 2004, 104, 3371.
21 Crystal data for compound 10: C41NO5H43, M = 629.79, orthorhom-
˚
˚
˚
bic, a (A) = 5.225(2), b (A) = 15.283(9), c (A) = 43.03(1), U = 3436(2)
3
A , D (g.cm−3) = 1.217, T = 293 K, space group P212121, Z = 4, k
˚
(A) = 0.71073, 2h max (deg) = 50, l (cm−1) 0.79, 15 992 reflexions
˚
measured, 6994 unique (Rint = 0.06), 424 parameters, reflections–
parameters ratio: 12.9, R(F)[I >2r(I)] = 4.8%, RW(F) [all data] =
5.1%, G. O. F. = 1.84‡.
22 Spectral data for compound 11: oil, [a]2D5 +3 (c 0.5, H2O). IR (neat):
3527, 3412, 3094, 3069, 3029, 2873, 1608, 1502, 1453, 1355, 1273,
1216, 1086, 1029 cm−1. 1H NMR (300 MHz, D2O) d: 3.50 (d, 1H, J =
9.3 Hz, CHNH2), 3.72–3.82 (m, 3H, CH2OH and CH(OH)CHNH2),
3.96 (d, 1H, J = 7.7 Hz, CH(OH)C(OH)CH2OH), 4.05 (dd, 1H,
J = 7.7 Hz and J = 8.1 Hz, CH(OH) CH(OH)C(OH)CH2OH).
13C NMR (75 MHz, D2O) d: 57.4 (CHNH2), 64.4 (CH2OH), 74.7
(CH(OH)), 75.4 (C(OH)CH2OH), 78.7 (CH(OH)), 81.6 (CH(OH)).
LRMS (DCI) m/z: 179.9 (M + H)+.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 0 6 7 – 2 0 6 9
2 0 6 9