First example of a new class of conduritols: The 2,3-diamino derivatives. Simple and efficient synthesis of the (1R,2R,3R,4R)-(-)-2,3-diamino-1,4-dimethoxycyclohex-5-ene. 2

Article abstract of DOI:10.1055/s-1998-1906

A smooth synthetic procedure mediated by sulfur was used to produce the (1R,2R,3R,4R)-(-)-2,3-diamino-1,4-dimethoxycyclohex-5-ene starting from D-mannitol.

Full text of DOI:10.1055/s-1998-1906

November 1998
SYNLETT
1197
First Example of a New Class of Conduritols: the 2,3-Diamino Derivatives. Simple and Efficient Synthesis of the
(1R,2R,3R,4R)-(–)-2,3-Diamino-1,4-dimethoxycyclohex-5-ene. 21
Vanda Cerè,* Francesca Peri, Salvatore Pollicino and Alfredo Ricci
Department of Organic Chemistry, “A. Mangini” - University of Bologna, Viale Risorgimento, 4, I-40136 Bologna, Italy
Fax +39 51 6443654; e-mail: cere@ms.fci.unibo.it
Dedicated to the memory of Prof. Antonino Fava (deceased December 19, 1997) Professore Emerito of the University of Bologna.
Received 30 July 1998
Abstract. A smooth synthetic procedure mediated by sulfur was used to
produce the (1R,2R,3R,4R)-(–)-2,3-diamino-1,4-dimethoxycyclohex-5-
ene starting from D-mannitol.
Bäcklund reaction to give the corresponding diazido compound 4.12 The
diamino derivative 5,13 an isostere of conduritol B, was obtained by
selective reduction of 4 with LiAlH4. Intermediate purifications were
not necessary and all the steps were carried out using the crude products
even if analytical samples were obtained for the characterization of each
product. The overall yield of 5 from 1 was 65%.
Conduritols and aminoconduritols are prominent classes of compounds
biologically active as inhibitors of some glycosidases. They are also
very useful intermediates in the synthesis of inositol derivatives2 and
aminocyclitols.3 These products show glycosidase-inhibitory activity
and are also of great interest for the synthesis of aminoglycosidic
antibiotics.4 Several 1,4-inosodiamine and deoxy derivatives have been
found in the fortimicin family which exhibits a broad spectrum of
clinically important antibiotic activities.5 The extensive studies used in
order to understand the structure-activity relationships which rely on
modifications of the diaminocyclitol moieties of these antibiotics,6 have
been hampered by the fact that natural sources of chiral cyclohexanes
substituted with oxygen or nitrogen functional groups are not readily
available. Therefore, the synthesis of polyfunctional configurationally
homogeneous cyclohexane derivatives is interesting.
Since the synthesis of 2,3-diaminoconduritols has never been reported
before, the preparation of this class of compounds would be an attractive
aim considering also their further utilization in the synthesis of 1,2-
diaminoinositols. Many interesting applications have been studied for
these latter compounds, such as the muthasynthesis of new antibiotics7
or their use as ligands in cytostatic platinum complexes.8
Scheme 1
We have recently described1 a simple and efficient synthetic route,
mediated by sulfur, which produces the (–)-1,4-dimethoxy conduritol E
in high yield, starting from D-mannitol and preserving its configuration
at all chiral carbon atoms.
The present results demonstrate an easy and straightforward entry to the
previously unreported 2,3-diaminoconduritols which are of high interest
for their potential as biologically active substances and as precursors of
1,2-diaminocyclitols. A thorough study of the biological activity of 5 is
now in progress.
Since the hydroxy groups at C1 and C4 of this compound are firmly
protected as methyl ethers, we were interested in the possibility of
introducing amino groups at C2 and C3 through direct nucleophilic
substitution, using the usual methods employed for the substitution of
hydroxy groups. A first attempt was made treating the (–)-1,4-
dimethoxy conduritol E with PPh3, DEAD and (PhO)2PON3 for 12 h at
50 °C9 and a second attempt was made using the Mitsunobu reaction
with PPh3, DEAD and phthalimide. In both cases only unreacted
starting material was recovered. A last attempt was made treating the
2,3-dimesyl derivative with NaN3 in DMF for 20 h at 120 °C but even
these conditions were unsatisfactory because only a small amount of
1,4-dimethoxybenzene, together with unreacted reagent, was obtained.
To test the general character of this procedure, its application to other
members of the extensive array of easily available alcohol sugars is
currently underway in our laboratory.
Acknowledgement. We thank Dr. A. Citti for bibliographic research.
This investigation is supported by University of Bologna (funds for
selected research topics A.A. 1995-97), by MURST, Rome, and by the
University of Bologna in the frame of the National Project
“Stereoselezione in Sintesi organica. Metodologie ed Applicazioni”.
References and Notes
In light of these results a direct nucleophilic substitution seemed to be
impossible. Consequently, we started a program of the synthesis of
enantiopure 2,3-diamino-1,4-dimethoxy conduritols by modifying the
strategy described in our previous paper,1 starting as shown in Scheme 1
from the (–)-(3S,4R,5R,6S)-4,5-dimesyl-3,6-dimethoxythiepane 1,10
which is easily synthesized on a multigram scale and in high yield by
means of a simple synthetic route.
(1) Paper 1 in this series: Cerè, V.; Peri, F.; Pollicino, S. Tetrahedron.
Lett. 1997, 38, 7797.
(2) (a) Ley, S. V.; Sternfeld, F.; Taylor, S. Tetrahedron Lett. 1987,
28, 225. (b) Ley, S. V.; Sternfeld, F. Tetrahedron Lett. 1988, 29,
5305. (c) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am.
Chem. Soc. 1990, 112, 9439. (d) Hudlicky, T.; Mandel, M.;
Rouden, J.; Lee, R. S.; Bachmann, B.; Dudding, T.; Yost, K. J.;
Merola, J. S. J. Chem. Soc. Perkin Trans 1, 1994, 553.
Thiepane derivative 1 was subjected to nucleophilic substitution, by
treatment with NaN3, to obtain the diazido derivative 211 with complete
configuration inversion at C4 and C5. Sulfide 2 was oxidized with
MCPBA to give the sulfone 3, which was then subjected to a Ramberg-
(3) (a) Umezawa, W. Adv. Carbohydr. Chem. Biochem. 1974, 30, 11.
(b) Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319.

1198
LETTERS
SYNLETT
(4) (a) Chida, N.; Ohtsuka, M.; Nakazawa, K.; Ogawa, S. J. Org.
Chem. 1991, 56, 2976. (b) Chida, N.; Ohtsuka, M.; Ogawa, S.
Tetrahedron Lett. 1991, 32, 4525. (c) Knapp, S.; Naughton, A. B.
J.; Dhar, T. G. M. Tetrahedron Lett. 1992, 33, 1025. (d) Hudlicky,
T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc. 1994, 116,
5099. (e) Hudlicky, T.; Olivo, H. F.; McKibben, B. J. Am. Chem.
Soc. 1994, 116, 5108.
washed with H2O then with brine. 0.24 g (94 %) of the title
compound were obtained as an oil and used, without any further
purification, for the next reaction. An analytical sample was
purified by flash chromatography (SiO2; petroleum ether/Et2O -
4/1). 1H NMR, (300 MHz, CDCl3) δ: 3.87 (m, 4H, 4CH), 3.40 (s,
6H, 2OCH3), 2.80 (d, 4H, 2CH2, J = 5.82 Hz). 13C NMR (75
MHz, CDCl3), δ: 80.6 (2CHO), 63.3 (2CHN3), 57.6 (2CH3), 29.8
(2CH2). MS (m/z): 230, 227, 202, 187, 171, 144, 117, 90, 58. IR
(5) (a) Nara, T.; Yamamoto, M.; Iwamoto, I.; Takayama, K.; Okachi,
R.; Takasawa, S.; Sato, T.; Sato, S. J. Antibiot., 1977, 30, 533. (b)
Okachi, R.; Takasawa, S.; Sato, T.; Sato, S.; Yamamoto, M.;
Kawamoto, I.; Nara, T. ibid, 1977, 30, 541. (c) Suami, T.; Tadano,
K.; Matsuzawa, K., ibid., 1980, 33, 1289. (d) Kanai, K.;
Nishigaki, J.; Taki, T.; Ogawa, S.; Suami, T., Carbohydr. Res.
1987, 170, 47.
25
(neat) νmax/cm-1: 2940, 2120, 1455, 1355, 1090. [α]D = - 46.6
(c = 1.10, CHCl3).
(12) (–)-(1R,2R,3R,4R)-2,3-Diazido-1,4-dimethoxyconduritol (4).
To 0.29 g (1 mmol) of the derivative 3 were added 2 mL of t-
BuOH, 3 mL of CCl4 and 2.0 g of finely divided KOH under
nitrogen. After strongly stirring for 3 h the reaction mixture was
diluted with water and extracted with CH2Cl2. The organic layers,
washed with brine, were dried and evaporated to give 0.16 g
(78%) of the title compound. An analytical sample was obtained
after chromatography (SiO2; petroleum ether/Et2O - 8/1).1H NMR
(300 MHz, CDCl3) δ: 5.90 (d, 2H, 2CH=, J = 1.71 Hz), 4.01 (m,
2H, 2CHO), 3.95 (m, 2H, 2CHN3), 3.46 (s, 6H, 2CH3). 13C NMR
(75 MHz, CDCl3) δ: 127.5 (2CH=), 75.5 (2CHO), 59.4 (2CHN3),
58.0 (2CH3). MS (m/z): 167, 154, 114, 99, 71. IR (neat) νmax/cm-
(6) Paulsen, H.; Von Deyn, W. Liebigs Ann. Chem., 1987, 141.
(7) Okuda, T.; Ito, Y. Aminoglycosidase Antibiotics, ed. Umezawa,
H.; Hooper, I. R. Springer, Berlin, 1982 p.185 and refs. therein.
(8) (a) Tetsuo, S.; Takeshi, S. Ajinomoto Co. Jap. Pat 61.286.396.
Appl 85/127.551,12th June 1985, 5pp (Chem. Abstr., 1987, 107,
191010p).(b) Hanessian, S.; Theophanides, T. Can. CA 1,282,058
(Cl. CO7F15/00), 26 Mar 1991, Appl. 516,071, 15 Aug 1986; 42
pp (Chem. Abstr., 1992, 116, 119763e).
25
1: 2950, 2120, 1330, 1280, 1100. [α]D = -278.48 (c = 1.05,
(9) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977.
CHCl3).
(13) Representative spectroscopic data for (5): 1H NMR (300 MHz,
CDCl3) δ: 5.96 (m, 2H, 2CH=), 3.72 (m, 2H, 2CHO), 3.37 (s, 6H,
2CH3), 3.00 (m, 2H, 2CHN), 2.00 (sbr, 4H, 2NH2). 13C NMR (75
MHz, CDCl3) δ: 128.7 (2CH=), 76.2 (2CHO), 57.4 (2CH3), 52.2
(10) Kuszmann, J. and Sohàr, P. Carbohydr. Res. 1977, 56, 105.
(11) (–)-(3S,4R,5R,6S)-4,5-Diazido-3,6-dimethoxythiepane (2). To
0.36 g (1 mmol) of the thiepane derivative 1,10 dissolved in 5 mL
of DMSO, 0.20 g (3 mmol) of NaN3 were added. After 20 h at
120 °C the reaction mixture was diluted with 150 mL of AcOEt,
25
(2CHN). MS (m/z): 173, 142, 114, 80, 58. [α]D = -293.0 (c =
1.06, CHCl3).