A concise and highly efficient synthesis of trehazolin and trehalamine starting from D-mannose

Article abstract of DOI:10.1021/ol990904t

(formula presented) A concise synthesis of trehazolin, its aglycon, trehalamine, and a known analogue has been developed starting from D-mannose. This new approach features a very stereoselective and high-yielding ketone-oxime ether reductive carbocyclization promoted by samarium diiodide as a key step for the preparation of the aminocyclitol component and a mild and very efficient intramolecular triflate displacement reaction for the construction of the oxazoline ring.

Full text of DOI:10.1021/ol990904t

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1705-1708
A Concise and Highly Efficient
Synthesis of Trehazolin and
Trehalamine Starting from D-Mannose
Isabel Storch de Gracia, Sof´ıa Bobo, Mar´ıa D. Mart´ın-Ortega, and
Jose Luis Chiara*
Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la CierVa, 3,
E-28006 Madrid, Spain
jl.chiara@iqog.csic.es
Received August 3, 1999
ABSTRACT
A concise synthesis of trehazolin, its aglycon, trehalamine, and a known analogue has been developed starting from D-mannose. This new
approach features a very stereoselective and high-yielding ketone−oxime ether reductive carbocyclization promoted by samarium diiodide as
a key step for the preparation of the aminocyclitol component and a mild and very efficient intramolecular triflate displacement reaction for
the construction of the oxazoline ring.
Trehalose (1, Figure 1) is ubiquitously found in insects, being
their principal blood sugar and used to support various
energy-requiring functions, such as insect flight. Trehalose
and trehalase have been reported to participate also in
germination of ascospores in fungi. The development of
specific and potent trehalase inhibitors is, consequently, of
great interest for the plant protection industry. One such
inhibitor, trehazolin (2), was isolated in 1991 from the culture
broth of Micromonospora strain sp. SANK 62390 and from
Amycolatopsis trehalostatica.1 Previous syntheses of 2
involved rather long sequences (15-23 steps) with low
overall yields (<5%).2 The strategies adopted to this end
comprised aldol-like reactions, 1,3-dipolar cycloaddition
(1) For a recent review on natural aminocyclopentitol glycosidase
inhibitors, see: Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. ReV.
1999, 99, 779-844. See also: Kobayashi, Y. Carbohydr. Res. 1999, 315,
3.
Figure 1.
(2) (a) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J. Org. Chem. 1994,
59, 813 and references therein. (b) Uchida, C.; Yamagishi, T.; Ogawa, S.
J. Chem. Soc., Perkin Trans. 1 1994, 589 and references therein. (c) Ledford,
B. E.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 11811. (d) Li, J.; Lang,
F.; Ganem, B. J. Org. Chem. 1998, 63, 3403 and references therein. (e)
reactions and radical carbocyclizations of carbohydrate
derivatives, desymmetrization of substituted cyclopentene-
Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J. Org. Chem. 1998, 63, 5877.
4-meso-diols, and heterocycloadditions of cyclopentadienes.
10.1021/ol990904t CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/22/1999

Ketyl radical cyclizations promoted by samarium diiodide3
are especially well suited for this endeavor since they afford
directly a functionalized cycloalkanol and proceed under very
mild conditions, usually in high yield and with a good level
of stereocontrol. The use of chiral polyoxygenated precursors,
conveniently prepared from carbohydrates, allows the facile
preparation in this way of a diversity of enantiomerically
pure complex cyclitols such as those present in the amino-
cyclopentitol class of glycosidase inhibitors.1
We have recently reported a short and very efficient
synthesis of trehazolamine (3), the aminocyclitol moiety of
2, using D-glucose as starting material and a high yielding
CdO/CdO reductive carbocyclization as a key step.4 Herein
we disclose a new and more direct route to 2 and its aglycon,
trehalamine (4), starting from D-mannose.5 This new ap-
proach features a very stereoselective and high-yielding
CdO/CdNOR reductive carbocyclization2e,6,7 as key step for
the preparation of the aminocyclitol component and a mild
and very efficient intramolecular triflate displacement reac-
tion for the construction of the oxazoline ring.
chemistry at the quaternary center generated in the cycliza-
tion, and the hydroxyl group vicinal to the oxime ether
is conveniently differentiated to allow further necessary
manipulations at this position in the resultant cyclitol.
Compound 11 was readily prepared from D-mannose as
shown in Scheme 1. Zemple´n deacetylation of known phenyl
1-thio-R-D-mannopyranoside 5,8 followed by monoacetona-
tion under kinetic conditions,9 gave diol 6. Regioselective
benzylation of the equatorial hydroxyl of 6 using tin
activation10 and acetylation of the remaining hydroxyl
produced the fully protected thiomannoside 8. Mild hydroly-
sis of the thiophenyl glycoside under oxidative conditions11
provided hemiacetal 9 that was subsequently condensed with
O-benzylhydroxylamine to give 10 as a mixture of isomeric
oxime ethers (E/Z ) 8:1). Oxidation of 10 using the Dess-
Martin periodinane12 afforded keto-oxime 11.13
When compound 11 (mixture of oximes) was treated with
SmI2 (3 equiv) under our previously optimized conditions,4,7
a smooth cyclization took place to give O-benzylhydroxy-
lamine 12 as a single diastereoisomer in good yield (Scheme
2). Using a larger excess of reducing agent (6 equiv) in the
On the basis of previous observations on the general
diastereoselectivity trends shown by CdO/CdNOR reductive
carbocyclizations promoted by samarium diiodide7 and the
stereodirecting effect exerted by a cyclic ketone,2e,5,7d we
designed compound 11 (Scheme 1) as the key carbocycliza-
Scheme 2
Scheme 1
presence of water effected also the subsequent reduction of
the hydroxylamino group to give the corresponding free
amine.4,7 In situ treatment with excess Ac2O and pyridine
provided acetamide 13 in quantitative overall yield. Alter-
tion precursor. This compound contains a cyclic acetal
flanking the carbonyl group for the control of the stereo-
(5) This work was presented in part at the 19th International Carbohydrate
Symposium, San Diego, 1998; Abstract BP050.
(6) (a) Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 2821. (b)
Hanamoto, T.; Inanaga, J. Tetrahedron Lett. 1991, 32, 3555. (c) Shono, T.;
Kise, N.; Fujimoto, T. Tetrahedron Lett. 1991, 32, 525. (d) Shono, T.; Kise,
N.; Fujimoto, T.; Yamanami, A.; Nomura, R. J. Org. Chem. 1994, 59, 1730.
(e) Naito, T.; Tajiri, K.; Harimoto, T.; Ninomiya, I.; Kiguchi, T. Tetrahedron
Lett. 1994, 35, 2205. (f) Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T.
Tetrahedron Lett. 1995, 36, 253. (g) Tormo, J.; Hays, D. S.; Fu, G. C. J.
Org. Chem. 1998, 63, 201. (h) Naito, T.; Nakagawa, K.; Nakamura, T.;
Kasei, A.; Ninomiya, I.; Kigushi, T. J. Org. Chem. 1999, 64, 2003, and
references cited therein.
(3) For recent reviews on applications of samarium diiodide in organic
synthesis, see: (a) Molander, G. A.; Harris, G. R. Tetrahedron 1998, 54,
3321. (b) Molander, G. A.; Harris, G. R. Chem. ReV. 1996, 96, 307. (c)
Molander, G. A. Org. React. 1994, 46, 211. (d) Imamoto, T. Lanthanides
in Organic Synthesis; Academic Press: London, 1994. (e) Molander, G.
A. Org. React. 1994, 46, 211. (f) Molander, G. A. Chem. ReV. 1992, 92,
29.
(4) Storch de Gracia, I.; Dietrich, H.; Bobo, S.; Chiara, J. L. J. Org.
Chem. 1998, 63, 5883.
1706
Org. Lett., Vol. 1, No. 11, 1999

natively, addition of an aqueous solution of LiOH to the
crude reaction mixture produced the hydrolysis of the ester
to afford aminodiol 14, also in quantitative overall yield.
The stereochemistry of the carbocyclic products was
unambiguously established through 1H NMR and 2D NOE-
SY studies.14 Compounds 12-14 have the correct stereo-
chemistry of trehazolamine (3) at all except the stereocenter
corresponding to C-2 in the starting sugar, as initially
envisioned. This stereochemical outcome can be rationalized
in terms of transition state A,2e,7d where the more stable axial
ketyl radical anion15 attacks the oxime group in its conforma-
tion with the least 1,3-allylic strain.
triflic anhydride in the presence of pyridine at low temper-
ature, a smooth cyclization took place by intramolecular SN2
displacement of the triflate ester in transient intermediate
17 by the carbonyl oxygen to give oxazoline 18 in good yield
(Scheme 3).16 Compound 18 was fully deprotected by
catalytic hydrogenolysis of the O-benzyl group followed by
acidic hydrolysis of the oxazoline and the isopropylidene
groups to yield trehazolamine (3). The physical and spec-
troscopic data of synthetic 3 were identical to those described
for the natural compound.17 This route afforded 3 in 14 steps
and 29% overall yield from D-mannose.
With the final objective of applying this procedure in the
final steps of our synthesis of trehazolin (2), we set out to
test it for the construction of a 2-aminooxazoline ring. Thus,
model N-alkyl and N-aryl ureas 19 and 20 (Scheme 4),
Scheme 4
However, all attempts to selectively invert the stereo-
chemistry of this center in the de-O-acylated derivatives 15
and 16 (Scheme 3) using either Mitsunobu conditions or a
Scheme 3
respectively, were prepared in high yield by treatment of 14
with the corresponding isocyanates. Gratifyingly, the reaction
of 19 and 20 with triflic anhydride in the presence of pyridine
at low temperature produced the 2-aminooxazolines 21 and
22, respectively, in high yield with concomitant inversion
of stereochemistry at the required position. Complete depro-
tection of 21 by hydrogenolysis under acidic conditions
afforded trehalamine (4). The physical and spectroscopic data
of synthetic 4 were identical to those described for the natural
compound.17 This route to 4 involved 13 steps and proceeded
in 37% overall yield from D-mannose. Deprotection of 22
(9) Gelas, J.; Horton, D. Carbohydr. Res. 1978, 67, 371.
(10) Grindley, T. B. AdV. Carbohydr. Chem. Biochem. 1998, 53, 17.
(11) (a) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T.
J.; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.;
Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7593. (b) Motawia, M. S.;
Marcussen, J.; Moeller, B. L. J. Carbohydr. Chem. 1995, 14, 1279.
(12) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(13) PCC or Swern oxidation proceeded with partial epimerization at
C-4 (sugar numbering).
two-step oxidation-reduction sequence failed. After some
experimentation, we found that when 16 was treated with
(7) For previous work from our group on CdO/CdNOR reductive
carbocyclizations promoted by samarium diiodide, see ref 4 and the
following: (a) Chiara, J. L.; Marco-Contelles, J.; Khiar, N.; Gallego, P.;
Destabel, C.; Bernabe, M. J. Org. Chem. 1995, 60, 6010. (b) Marco-
Contelles, J. L.; Gallego, P.; Rodr´ıguez-Ferna´ndez, M.; Khiar, N.; Destabel,
C.; Bernabe´, M.; Mart´ınez-Grau, A.; Chiara, J. L. J. Org. Chem. 1997, 62,
7397. (c) Chiara, J. L. in Carbohydrate Mimics: Concepts and Methods;
Chapleur, Y., Ed.; Wiley-VCH: New York, 1998; Chapter 7. (d) Bobo, S.;
Storch de Gracia, I.; Chiara, J. L. Synlett, in press.
1
(14) See Supporting Information for H NMR and NOESY data.
(15) (a) Wu, Y.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 1656. (b)
Inanaga, J.; Katsuki, J.; Ujikawa, O.; Yamagushi, M. Tetrahedron Lett. 1991,
32, 4921.
(16) For a former report on oxazoline ring formation under similar
conditions, see: Kuo, C. H.; Wendler, N. L. Tetrahedron Lett. 1978, 211.
(17) Ando, O.; Nakajima, M.; Hamano, K.; Itoi, K.; Takahashi, S.;
Takamatsu, Y.; Sato, A.; Enokita, R.; Okazaki, T.; Haruyama, H.; Kinoshita,
T. J. Antibiot. 1993, 46, 1116.
(8) Kametani, T.; Kawamura, K.; Honda, T. J. Am. Chem. Soc. 1987,
109, 3010.
Org. Lett., Vol. 1, No. 11, 1999
1707

under similar conditions gave 23 that was recently prepared
by Ogawa and co-workers18 and shown to be a moderate
R-glucosidase inhibitor.
With this success in hand, we were now ready to complete
our synthesis of 2. As in previously described routes,2 we
condensed our aminocyclitol 14 with R-glucosyl isothiocy-
anate 2419 to give thiourea 25 (Scheme 5). Treatment of 25
26 with triflic anhydride and pyridine under our previously
optimized conditions produced the smooth cyclization to the
2-aminooxazoline 27 in very good yield with concomitant
inversion of stereochemistry, as required. Hydrogenolysis of
the O-benzyl groups and acid cleavage of the isopropylidene
acetal afforded finally trehazolin (2), whose physical and
spectroscopic data were identical to those described for the
natural compound.21 This new route to 2 involved only 14
chemical operations from commercially available D-mannose
and proceeded in 34% overall yield, a considerable improve-
ment over previous strategies.
Scheme 5
In summary, we have developed a concise and efficient
synthesis of trehazolin (2), trehalamine (4), and known18
trehazolin analogue 23 using D-mannose as starting material.
The approach underscores the utility of CdO/CdNOR
reductive carbocyclizations promoted by samarium diiodide
for the efficient preparation of complex aminocyclitols under
very mild conditions. The hydroxyl group at C-2 in the
starting sugar played a key dual role along the route. First,
it served as an element of stereocontrol in the carbocycliza-
tion reaction. Second, it allowed the subsequent construction
of the oxazoline ring under very mild conditions by an
intramolecular SN2 reaction that adjusted the final stereo-
chemistry of the carbocycle. This strategy opens a facile entry
to the stereocontrolled preparation of a diversity of analogues
of 2,1 work that is currently in progress in our laboratory.22
Acknowledgment. This work was supported by Grant
PB-96-0833 from DGES, Ministerio de Educacio´n y Cultura
of Spain. A predoctoral fellowship (to I.S.de G.) from
Ministerio de Educacio´n y Cultura is also gratefully ac-
knowledged.
Supporting Information Available: Complete experi-
mental procedures and characterization data for the new
compounds in Schemes 1-5 and 1H NOE data for compound
12. This material is available free of charge via the Internet
at http://pubs.acs.org.
with aqueous acetonitrile in the presence of yellow HgO gave
urea 26 in quantitative yield.20 In the event, the reaction of
OL990904T
(18) Uchida, C.; Kimura, H.; Ogawa, S. Bioorg. Med. Chem. 1997, 5,
921.
(19) Camarasa, M. J.; Ferna´ndez-Resa, P.; Garc´ıa-Lo´pez, M. T.; Go´mez
de las Heras, F.; Me´ndez-Castrillo´n, P. P.; San Fe´lix, A. Synthesis 1984,
509.
(20) For a recent review on thiocarbonyl to carbonyl group conversion,
see: Corsaro, A.; Pistara`, V. Tetrahedron 1998, 54, 15027.
(21) Ando, O.; Satake, H.; Itoi, K.; Sato, A.; Nakajima, M.; Takahashi,
S.; Haruyama, H.; Ohkuma, Y.; Kinoshita, T.; Enokita, R. J. Antibiot. 1991,
44, 1165.
(22) 2-Aminothiazoline analogues of 2 can be readily obtained by reaction
of 14 with an isothiocyanate followed by treatment of the corresponding
thiourea with triflic anhydride and pyridine at low temperature (I. Storch
de Gracia and J. L. Chiara, unpublished results).
1708
Org. Lett., Vol. 1, No. 11, 1999