Cyclopentanes from N-amino-glyconolactams. A synthesis of mannostatin A

Article abstract of DOI:10.1039/b301213a

Oxidation of a N-amino-ribonolactam with lead tetraacetate yields two cyclopentanes; the major one was transformed into the α-mannosidase inhibitor mannostatin A.

Full text of DOI:10.1039/b301213a

Cyclopentanes from N-amino-glyconolactams. A synthesis of
mannostatin A
Guixian Hu, Martin Zimmermann, Chepuri Venkata Ramana and Andrea Vasella*
Laboratorium für Organische Chemie, ETH-Hönggerberg, CH-8093 Zürich, Switzerland.
E-mail: vasella@org.chem.ethz.ch
Received (in Cambridge, UK) 30th January 2003, Accepted 3rd March 2003
First published as an Advance Article on the web 18th March 2003
Oxidation of a N-amino-ribonolactam with lead tetraacetate
yields two cyclopentanes; the major one was transformed
into the a-mannosidase inhibitor mannostatin A.
9.7 Hz. It should enhance the nucleophilicity of C(1)OH and
allow a regioselective acylation. Indeed, benzoylation of 7 by
8
treatment with TMEDA and BzCl at 240 °C gave a mixture of
a monobenzoate 8 (71%), a dibenzoate 9 (7%), and recovered 7
(13%). Crystal structure analysis of the dibenzoate 9‡ estab-
lished the configuration of 7, and further evidenced the structure
of 6.† Similarly to this benzoylation, triflation at 260 °C of 7
proceeded selectively to provide the monotriflate 10 (91%)
which was mesylated to yield 99% of 11 (Scheme 2). Treating
11 with excess NaSMe in THF gave the mesyloxy thioether 12
(95%). Substitution of the mesyloxy group by azide did not
proceed at r.t., and increasing the temperature led to elimination
only. Desilylation of 12 at r.t. provided the alcohol 13, besides
the corresponding epoxide; desilylation at 230 °C yielded 99%
of 13. The trichloroacetimidate 14 was formed in high yield by
treating 13 with trichloroacetonitrile in the presence of DBU.
Cyclisation of isolated 14 in the presence of diisopropylethyla-
mine provided 15 in a rather low yield, while treating the
alcohol 13 and trichloroacetonitrile sequentially with DBU and
diisopropylethylamine yielded 80% of the desired oxazoline
15§ besides 13% of the trichloroacetamide 14. Hydrolysis of 15
Several highly functionalized cyclopentanes are strong glycosi-
dase inhibitors; pertinent examples are mannostatin A (1) and
1
2
B, trehazolin, and allosamidine. Carbohydrates are attractive
starting materials for the synthesis of such highly functionalized
cyclopentanes, and the methods for the transformation of
monosaccharides and inositols into cyclopentanes have been
reviewed.2 In the context of our work on the inhibition of
,3
4
mannosidases we required mannostatin A (1). This glycosidase
1
a,b
inhibitor was isolated by Aoyagi and collaborators
in 1989,
2,5
and several syntheses of 1 have been reported. Two use
ribose5 as starting material and proceed via an aldolisation,
and one starts from myo-inositol.5
b,f
a,h,i
6
We considered the unexplored N-aminoglyconolactams
attractive starting materials for the synthesis of highly function-
alized carbocyclic compounds. Oxidation of N-aminoglycono-
lactams should lead to N-acyl-1,1-diazenes that may lose
nitrogen and cyclize. Indeed, sulfoximine precursors of N-
aminopyrrolidinone-derived diazenes were thermally or photo-
chemically transformed into cyclobutanones,6d while oxidation
of an N-aminobutyrolactam with tBuOCl led to a cyclic N-acyl-
1
13
with HCl in MeOH afforded 1·HCl.¶ Its H and C NMR
spectra and its specific rotation are in agreement with published
data.1 Acetylation of 1·HCl provided the known tetraacetate
b,5
6e
1
13
1,1-diazene and hence to a pyridazinone.
16.¶ Its melting point and its H and C NMR data are in
5
The N-aminoribonolactam 4† was chosen as starting material
for the synthesis of mannostatin A (1). This N-aminolactam was
prepared in two high-yielding steps from the known mesylate 2
agreement with literature, and its specific rotation corresponds
to the highest published value.5h The free base 1¶ was obtained
+
by chromatography of 1·HCl on Amberlite IR-120 (H ) resin
that is available in a yield of 90% from
D
-ribonolactone
using 0.5 M aqueous ammonia as eluent. It inhibited jack bean
7
1c
(Scheme 1). Oxidation of 4 with Pb(OAc)
4
in toluene gave a
a-mannosidase with IC50 = 48 nM (lit. IC50 = 70 nM).
mixture of the acetoxyepoxide 6† and the diazoketone 5† that
were isolated in 48 and 27% yield, respectively.
4
Reduction of 6 with LiAlH gave the trans-diol 7.† A H-bond
between HO–C(1) and O–C(2) was evidenced by J(HCOH) of
Scheme 2 Reagents and conditions: i, Ms
15-crown-5, THF, r.t., 95%; iii, TBAF, 230 °C, 99%; iv, Cl
xylene, r.t., 3 h, then (i-Pr) NEt, 110 °C, 14 h, 15 (80%) and 14 (13%); v,
2
O, py, 0 °C, 99%; ii, NaSMe,
Scheme 1 Reagents and conditions: i, NH
TBSOTf, Py, 0–23 °C, 85%; iii, Pb(OAc) , toluene, 5 (27%), 6 (48%); iv,
LiAlH , THF, 0 °C, 81%; v, BzCl, TMEDA, CH Cl , 240 °C, 8 (71%), 9
7%); vi, Tf O, py, 260 °C, 91%.
2
NH
2
·H
2
O, r.t., quant.; ii,
3
CCN, DBU, o-
4
2
4
2
2
2
7 M HCl/MeOH (1+1), r.t., 94–98%; vi, Ac O, py, 93%; vii, Amberlite IR-
+
(
2
120 (H ), 80%.
9
52
CHEM. COMMUN., 2003, 952–953
This journal is © The Royal Society of Chemistry 2003

To rationalise the conspicuous endo-orientation of the
acetoxy group of 6, we assume that 6 results from electro-
cyclisation of an acetoxy carbonyl ylide. This carbonyl ylide
may be formed by nitrogen extrusion from an acetoxy
suppdata/cc/b3/b301213a/ for crystallographic data in .cif or other elec-
tronic format.
1
§
0
4
2
Selected data of 15: H NMR (300 Hz, CDCl
3
): 5.25 (ddd, J = 8.0, 5.9,
.6, irrad. at 3.55?dd, J = 8.4, 5.9, H–C(4)); 4.82 (t, J = 5.6, H–C(3));
.61 (dd, J = 8.1, 2.2, irrad. at 3.55?d, J = 8.3, H–C(5)); 4.58 (dd, J = 5.6,
1
,3,4-oxadiazoline. The formation of this oxadiazoline from 4
.2, irrad. at 3.55?d, J = 5.6, H–C(2)); 3.58–3.51 (m, H–C(1)); 2.25 (s,
9
may begin with a well-precedented N-acetoxylation that is
followed by ring expansion to an N-acyldiazene, isomerisation,
acetoxylation, and ring closure.10 This reaction mechanism and
the chemistry of the diazoketone 5 are under investigation.
We thank the Swiss National Science foundation, F.
Hoffmann-La Roche AG, Basel, and Oxford GlycoSystems,
Abingdon, for generous support.
13
MeS); 1.49, 1.33 (2s, Me
12.9 (s, Me
(d, C(1)); 26.5, 24.4 (2q of Me C); 15.6 (q, MeS). ESI-MS: 346, 348, 350,
2 3
C). C NMR (75 Hz, CDCl ): 162.1 (s, CNN);
1
2
C), 86.4, 85.2, 80.3, 79.6 (4d, C(2), C(3), C(4), and C(5)); 53.1
2
+
352 ([M + H] ). Anal. calc. for C11
3 3
H14NO SCl (346.66): C 38.11, H 4.07,
N 4.04, S 9.25, Cl 30.68; found: C 38.32, H 4.30, N 4.04, S 9.20,
3
¶
0.61%.
Selected data of 1·HCl: [a]
2
5
D
D
= +7.5 (c = 0.95, MeOH); [a] = +5.9
5
d
(c = 1.08, MeOH); selected data of 16: m.p. 121.5–122.5 °C; m.p. 121
1b
5b
5h
5i
25
°
C; m.p. 119–120 °C; m.p. 122–123 °C; m.p. 119–121 °C. [a]
D
=
5
b
28
+
18.3 (c = 1.02, CHCl
3
); [a]
D
= +8.5 (c = 0.9, CHCl
3
); [a]
D
= +7.4
). Synthetic (+)-1
-mannosidase with IC50 = 48 nM; (p-nitrophenyl a-
-mannopyranoside, acetate buffer, pH 4.5).
5i
27
5h
(c = 0.45, CHCl
3
); [a]
D
= +16 (c = 0.88, CHCl
3
Notes and references
inhibited jack bean a-
D
D
†
All new compounds showed satisfactory spectroscopic and mass
1
spectrometry data. Selected data of 4: H NMR (300 MHz, CDCl
J = 5.9, H–C(2)); 4.46 (s, exchanged with D O, NH ); 4.39 (br. dd, J = 5.9,
O and irrad. at 3.41?sharp dd, J = 6.2, 2.5, H–C(3));
.12 (ddd, J = 9.3, 4.7, 2.5, H–C(4)); 3.76 (dd, J = 11.8, 9.3, H–C(5)); 3.41
C); 0.90 (s, Me C);
Si). C NMR (75 MHz, CDCl ): 166.4 (s, CNO);
C); 76.7 (d, C(2)); 73.8 (d, C(3)); 65.7 (d, C(4)); 52.1 (d, C(5));
C); 26.0 (q, Me C); 25.6 (q, Me C); 18.5 (s, Me C); 24.35,
4.45 (q, Me Si). Anal. calc. for C14 Si (316.47): C 53.13, H 8.92,
N 8.85; found: C 53.39, H 8.86, N 8.86%. 5: IR (CHCl ): 3019m, 2954w,
932w, 2860w, 2102s, 1679s, 1472w, 1384w, 1375m, 1349m, 1326m,
3
): 4.47 (d,
2
2
1 (a) T. Aoyagi, T. Yamamoto, K. Kojiri, H. Morishima, M. Nagai, M.
Hamada, T. Takeuchi and H. Umezawa, J. Antibiot., 1989, 42, 883; (b)
H. Morishima, K. Kojiri, T. Yamamoto, T. Aoyagi, H. Nakamura and Y.
Iitaka, J. Antibiot., 1989, 42, 1008; (c) J. E. Tropea, G. P. Kaushal, I.
Pastuszak, M. Aoyagi, R. J. Molyneux and A. D. Elbein, Biochemistry,
1990, 29, 10062.
1.9, addition of D
2
4
(ddd, J = 11.8, 4.7, 1.25, H–C(5A)); 1.43, 1.39 (2s, Me
2
3
13
0.123, 0.112 (2s, 2 Me
111.2 (s, Me
27.2 (q, Me
2
3
2
2
3
2
3
2 Their chemistry has been reviewed, see: A. Berecibar, C. Grandjean and
A. Siriwardena, Chem. Rev., 1999, 99, 779.
2
2
28 2 4
H N O
3
3 (a) A. D. Borthwick and K. Biggadike, Tetrahedron, 1992, 48((4)), 571;
(b) R. J. Ferrier and S. Middleton, Chem. Rev., 1993, 93, 2779; (c) A.
Martínez-Grau and J. Marco-Contelles, Chem. Soc. Rev., 1998, 27, 155;
(d) J. Marco-Contelles, C. Alhambra and A. Martínez-Grau, Synlett,
1998, 693; (e) P. I. Dalko and P. Sinaÿ, Angew. Chem., Int. Ed., 1999,
38, 773.
4 (a) A. Vasella, G. J. Davies and M. Böhm, Curr. Opin. Chem. Biol.,
2002, 6, 619; (b) L. Remen and A. Vasella, Helv. Chim. Acta, 2002, 85,
1118; (c) E. Lorthiois, M. Meyyappan and A. Vasella, Chem. Commun.,
2000, 29, 1829; (d) C. V. Ramana and A. Vasella, Helv. Chim. Acta,
2000, 83, 1599.
5 (a) S. Ogawa and Y. Yuming, J. Chem. Soc., Chem. Commun., 1991,
890; (b) S. Knapp and T. G. M. Dhar, J. Org. Chem., 1991, 56, 4096; (c)
B. M. Trost and D. L. Van Vranken, J. Am. Chem. Soc., 1991, 113, 6317;
(d) S. B. King and B. Ganem, J. Am. Chem. Soc., 1991, 113, 5089; (e)
B. M. Trost and D. L. Van Vranken, J. Am. Chem. Soc., 1993, 115, 444;
(f) C. Li and P. L. Fuchs, Tetrahedron Lett., 1994, 35, 5121; (g) S. B.
King and B. Ganem, J. Am. Chem. Soc., 1994, 116, 562; (h) S. Ogawa,
H. Kimura, C. Uchida and T. Ohashi, J. Chem. Soc., Perkin Trans. 1,
1995, 1695; (i) S. Ogawa and Y. Yuming, Bioorg. Med. Chem., 1995, 3,
939; (j) R. Ling and P. S. Mariano, J. Org. Chem., 1998, 63, 6072.
6 For the formation of an N-aminoriburonolactam, see (a) R. R. Schmidt,
K.-H. Jung and P. Hermentin, Chem. Ber., 1978, 111, 3311; (b) for
leading references to the chemistry of non-carbohydrate derived N-
aminolactams, see P. A. S. Smith, Derivatives of Hydrazine and Other
Hydronitrogens Having N–N Bonds, The Benjing/Cummings Publish-
ing, Massachusetts, 1983; (c) R. Braslau, M. O. Anderson, F. Rivera, A.
Jimenez, T. Haddad and J. R. Axon, Tetrahedron, 2002, 58, 5513; (d) R.
D. Miller, P. Gölitz, J. Janssen and J. Lemmens, J. Am. Chem. Soc.,
1984, 106, 7277; (e) R. D. Miller, P. Gölitz, J. Janssen and J. Lemmens,
J. Am. Chem. Soc., 1984, 106, 1508.
2
1
1
306w, 1255m, 1156m, 1133m, 1102m, 873m, 840m. H NMR (300 MHz,
): 5.33 (d, J = 5.3, H–C(2)); 4.62 (t, J ≈ 5.4, H–C(3)); 4.49 (d, J =
.6, H–C(4)); 1.48, 1.39 (2s, Me C); 0.93 (s, Me C); 0.18, 0.16 (2s, Me Si).
): 190.8 (s, CNO); 113.5 (s, Me C); 81.3 (d,
C(2)); 76.3 (d, C(3)); 68.8 (d, C(4)); 27.4, 26.1 (2q, Me C); 25.8 (q, Me C);
8.5 (s, Me Si). Anal. calc. for C14 Si
312.44): C 53.82, H 7.74, N 8.97; found: C 53.91, H 7.65, N 8.89%. 6: IR
CHCl ): 3031w, 2952m, 2932m, 2858m, 1779s, 1472w, 1464w, 1438w,
373m, 1251m, 1167m, 1136s, 1090s, 1018m, 973w, 866s, 839s. H NMR
300 MHz, CDCl ): 5.01 (dd, J = 5.3, 1.0, H–C(2)); 4.41 (td, J ≈ 5.4, 1.0,
H–C(3)); 3.94 (d, J = 5.6, H–C(4)); 3.74 (t, J = 1.0, H–C(5)); 2.15 (s,
CDCl
3
5
2
3
2
13
C NMR (75 MHz, CDCl
3
2
2
3
1
(
(
1
(
3
C); 24.3, 24.7 (2q, Me
2
24 2 4
H N O
3
1
3
13
OAc); 1.49, 1.36 (2s, Me
MHz, CDCl ): 169.4 (s, CNO); 113.7 (s, Me
C(3)); 78.0 (d, C(2)); 69.6 (d, C(4)); 64.2 (d, C(5)); 26.9, 26.1 (2q of Me
q of Me C); 21.2 (q, OAc); 18.8 (s, Me C); 24.3, 24.9 (2q, Me Si). ESI-
MS: 345 ([M + H] ); 362 ([M + H
Anal. calc. for C16 Si (344.48): C 55.79, H 8.19; found: C 55.82, H
.21%. 7: H NMR (300 Hz, CDCl ): 4.44, 4.41 (2t, J ≈ 5.8, H–C(2), H–
C(3)); 3.88 (td, J = 8.7, 2.2, H–C(5)); 3.60 (dd, J ≈ 9.0, 5.0, H–C(4)); 3.59
td, J = 10.0, 5.6, H–C(1)); 2.63 (d, J = 9.7, exchanged with D O, HO–
C(1)); 2.46 (br.d, J = 2.2, exchanged with D O, HO–C(5)); 1.48, 1.32 (2s,
Me C); 0.92 (s, Me C); 0.14, 0.10 (2s, Me
Si). 1 C NMR (75 Hz, CDCl
11.4 (s, Me C); 79.5 (d, C(5)); 77.6, 75.4 (2d, C(2) and C(3)); 74.4 (d,
C(4)); 73.2 (d, C(1)); 25.9 (3q of Me C, 2q of Me C); 24.3 (2q of Me C);
8.4 (s, Me C); 24.55, 24.50 (2q, Me Si). HI-MALDI-MS: 327.1595 (7.3,
SiNa, [M + Na] , calc. 327.1604). For 5, strong IR-bands at 2102
2
C); 0.92 (s, Me
3
C); 0.12 (s, Me
C); 86.8 (s, C(1)); 81.4 (d,
C,
2
Si). C NMR (75
3
2
2
3
3
3
2
+
+
+
+
2
O] ); 367 ([M + Na] ); 383 ([M + K] ).
28 6
H O
1
8
3
(
2
2
3
2
3
2
3
):
1
2
3
2
2
1
3
2
+
14 28 5
C H O
21
13
and 1679 cm and a C singlet at 190.8 ppm evidence the diazo and the
carbonyl groups. For 6, a strong IR band at 1779 cm , a H singlet at 2.15
21
1
13
ppm, and a C singlet at 169.4 ppm evidence the acetoxy group. A dd at
.01 ppm (J = 5.3, 1.0) and the td at 4.41 ppm (J ≈ 5.4, 1.0) were assigned
to H–C(2) and H–C(3), respectively; a d (J = 5.6) resonating at higher fields
3.94 ppm) was assigned to H–C(4), geminal to the silyloxy group. A t at
.74 ppm (J = 1.0) was assigned to H–C(5). A NOE (6.6%) between the dd
5
7 (a) R. Bisaz, Ph.D, ETH-Zürich, 1975; (b) H. Kold, I. Lundt and C.
Pedersen, Acta Chem. Scand., 1994, 48, 675.
(
3
8 G. Hu and A. Vasella, Helv. Chim. Acta, 2002, 85, 4369.
9 (a) R. S. Atkinson and B. J. Kelly, J. Chem. Soc., Chem. Commun.,
1987, 1362; (b) R. S. Atkinson and B. J. Kelly, J. Chem. Soc., Chem.
Commun., 1989, 836; (c) R. S. Atkinson, M. J. Grimshire and B. J.
Kelly, Tetrahedron, 1989, 45, 1362.
10 (a) D. C. Iffland, L. Salisbury and Wm. R. Schafer, J. Am. Chem. Soc.,
1961, 83, 747; (b) R. W. Hoffmann and H. J. Luthardt, Tetrahedron
Lett., 1966, 411; (c) W. A. F. Gladstone and R. O. C. Norman, J. Chem.
Soc. (C), 1966, 1531; (d) R. W. Hoffmann and H. J. Luthardt, Chem.
Ber., 1968, 101, 3851; (e) R. W. Hoffmann and H. J. Luthardt, Chem.
Ber., 1968, 101, 3861; (f) A. Stojiljkovic, N. Orbovic, S. Sredojevic and
M. Lj. Mihailovic, Tetrahedron, 1970, 26, 1101.
at 5.01 ppm (H–C(2)) and the td at 4.41 ppm (H–C(3)) and a NOE (5.7%)
between the td at 4.41 ppm (H–C(3)) and the d at 3.94 ppm (H–C(4))
evidence that (H–C(2)), (H–C(3)), and (H–C(4)) are cis to each other while
a weak NOE of 2.8% between the d at 3.94 ppm (H–C(4)) and the t at 3.74
ppm (H–C(5)) evidences that (H–C(5)) is trans to (H–C(4)).
‡
Crystal data for 9: C28
36 7
H O Si, M = 512.66, monoclinic, a = 6.3780(10),
3
b = 19.449(5), c = 11.752(3) Å, V = 1420.4(6) Å , T = 293(2) K, space
1 a
, Z = 2, m(Cu-K
) = 1.076 mm2 , 2627 reflections measured,
1
group P2
283 unique (Rint = 0.027). Flack = 20.10(7). R1 = 0.0509. The final
2
2
wR(F ) was 0.1632 (all data). CCDC 202048. See http://www.rsc.org/
CHEM. COMMUN., 2003, 952–953
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