Synthesis of trehazolin from D-glucose

Article abstract of DOI:10.1021/jo980485y

Trehazolin (2) is a specific inhibitor of trehalase, an enzyme that cleaves the reserve carbohydrates of many insects. We describe a short and efficient synthesis of trehazolin (2) and trehazolamine (5) that mimics its hypothetical biosynthesis. Starting molecule for the synthesis of trehazolamine (5) is glucose from which three chiral centers are conserved during the reaction sequence. The remaining two chiral centers of trehazolamine (5) are formed stereoselectively in a reductive cyclization of ketooxime ether 16 and the reduction of oxime ether 18. The overall yield of trehazolamine (5) is 22% over 8 steps from 15. The synthesis of trehazolin (2) from trehazolamine (5) follows a known procedure and is achieved in 63% over 3 steps.

Full text of DOI:10.1021/jo980485y

J . Org. Chem. 1998, 63, 5877-5882
5877
Syn th esis of Tr eh a zolin fr om D-Glu cose
Arnaud Boiron, Peter Zillig, Dominik Faber, and Bernd Giese*
Department of Chemistry, University of Basel, St. J ohanns-Ring 19, CH-4056 Basel, Switzerland
Received March 13, 1998
Trehazolin (2) is a specific inhibitor of trehalase, an enzyme that cleaves the reserve carbohydrates
of many insects. We describe a short and efficient synthesis of trehazolin (2) and trehazolamine
(5) that mimics its hypothetical biosynthesis. Starting molecule for the synthesis of trehazolamine
(5) is glucose from which three chiral centers are conserved during the reaction sequence. The
remaining two chiral centers of trehazolamine (5) are formed stereoselectively in a reductive
cyclization of ketooxime ether 16 and the reduction of oxime ether 18. The overall yield of
trehazolamine (5) is 22% over 8 steps from 15. The synthesis of trehazolin (2) from trehazolamine
(5) follows a known procedure and is achieved in 63% over 3 steps.
In tr od u ction
The enzyme trehalase (R,R-trehalose glucosidase) plays
an important role in the metabolism of insects and fungi
because it cleaves trehalose (1), the characteristic blood
sugar and reserve carbohydrate of many insects.1 Thus,
specific inhibitors of trehalase may find applications in
the regulation of the metabolism of trehalose and func-
tion as insecticides. Trehazolin (2), first isolated in 1991
by Ando and co-workers2 from the culture broth of
Micromonospora strain SANK 62390, has been shown to
be a potent and specific inhibitor of trehalase in vitro
(IC50 ) 0.016 µg/mL for silkworm trehalase). Therefore,
it is not surprising that its total synthesis3 and the
elucidation of structure-activity relationships4 have
received much interest over the past 7 years. Trehazolin
(2) closely resembles R,R-trehalose (1) (Figure 1) and
possesses a pseudo-disaccharide structure composed of
R-D-glucopyranosylamine and trehazolamine (5) linked
by a cyclic isourea group. Thus, an obvious retrosynthe-
sis (Scheme 1) of trehazolin (2) leads to two subunits:
an R-D-glucopyranosyl isothiocyanate (3), which can be
easily generated from 1,6-anhydro-â-D-glucose (4),3c,5 and
the aminocyclopentitol 5, whose synthesis turned out to
be a much more difficult task. Several syntheses of this
highly functionalized molecule 5 have already been
published,3c-e,6 but all existing preparations involve mul-
tistep syntheses and modest overall yields. The known
F igu r e 1. Structural similarities between R,R-trehalose (1)
and trehazolin (2).
Sch em e 1
synthetic procedures have scarcely taken advantage of
the given stereochemistry of starting materials.
* Corresponding author. Phone: ++41-61-2671106. Fax: ++41-61-
2671105. E-mail: giese@ubaclu.unibas.ch.
(1) Elbein, A. D. Adv. Carbohydr. Chem. Biochem. 1974, 30, 227.
(2) 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.
(3) (a) Ogawa, S.; Uchida, C. Chem. Lett. 1993, 173. (b) Uchida, C.;
Yamagishi, T.; Ogawa, S. J . Chem. Soc., Perkin Trans. 1 1994, 589.
(c) Ledford, B. E.; Carreira, E. M. J . Am. Chem. Soc. 1995, 117, 11811.
(d) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J . Org. Chem. 1994, 59,
813. (e) Ogawa, S.; Uchida, C. J . Chem. Soc., Perkin Trans. 1 1992,
1939.
(4) (a) Kobayashi, Y.; Shiozaki, M. J . Org. Chem. 1995, 60, 2570.
(b) Uchida, C.; Ogawa, S. Carbohydr. Lett. 1994, 1, 77. (c) Uchida, C.;
Yamagishi, T.; Kitahashi, H.; Iwaisaki, Y.; Ogawa, S. Bioorg. Med.
Chem. 1995, 3, 1605. (d) Uchida, C.; Ogawa, S. Bioorg. Med. Chem.
1996, 4, 275. (e) Uchida, C.; Kitahashi, H.; Yamagishi, T.; Iwaisaki,
Y.; Ogawa, S. J . Chem. Soc., Perkin Trans. 1 1994, 2775. (f) Uchida,
C.; Kitahashi, H.; Watanabe, S.; Ogawa, S. J . Chem. Soc., Perkin Trans.
1 1995, 1707.
To avoid the construction of each chiral center one after
the other, we looked for a straightforward route making
use of the already present chirality in D-glucose. The key
step in such an approach would be a pinacol coupling of
either a protected keto aldehyde 6 or ketooxime ether 7
(Scheme 1). Both compounds already incorporate three
stereocenters of D-glucose and can easily be prepared
from the latter. As a consequence, such a straightfor-
ward and efficient synthesis of trehazolamine (5) is
strictly connected to the selectivity of the coupling reac-
tion. The concept of this retrosynthesis follows a specu-
lative biosynthesis7 of trehazolin (2), which is outlined
(5) Camarasa, M. J .; Ferna´ndez-Resa, P.; Garc´ıa-Lo´pez, M. T.; De
las Heras, F. G.; Me´ndez-Castrillo´n, P. P.; San Felix, A. Synthesis 1984,
509.
(6) (a) Ogawa, S.; Uchida, C.; Yuming, Y. J . Chem. Soc., Chem.
Commun. 1992, 886. (b) Knapp, S.; Purandare, A.; Rupitz, K.; Withers,
S. G. J . Am. Chem. Soc. 1994, 116, 7461.
S0022-3263(98)00485-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/30/1998

5878 J . Org. Chem., Vol. 63, No. 17, 1998
Boiron et al.
Sch em e 2
Sch em e 3
Sch em e 4
in Scheme 2. Two molecules of glucosamine (8) would
react with a CO2 donor to give the carbodiimide 9, which
leads to the oxazolinone derivative 10. Subsequent regio-
selective oxidation and stereoselective pinacol type cou-
pling would then afford trehazolin (2). In this paper, we
report a straightforward synthesis of trehazolamine (5)
which includes stereoselective pinacol type coupling reac-
tions and a stereoselective oxidation-reduction sequence.
Resu lts a n d Discu ssion
Ring formation via radical cyclization is known to be
stereoselective in many cases.8 Recently, several reports
on intramolecular radical pinacol couplings of dicarbonyl
compounds9 and intramolecular radical cyclizations be-
tween carbonyl groups and oxime ethers10 have been
published. These reactions performed by samarium
diiodide (SmI2) or tributyltin hydride (Bu3SnH) offer
straightforward and selective access to cyclitols and
aminocyclitols starting from protected sugars. Marco-
Contelles and Chiara et al.10d reported the intramolecular
radical cyclization of a ketooxime ether 12a derived from
D-glucose (Scheme 3). This reaction using SmI2 gave
aminocyclitol 13a in good yield as the only diastereoiso-
mer,11 but both newly created stereocenters are opposite
to those of trehazolamine (5). The formation of aminocy-
clitol 13 as the major isomer in the SmI2-induced pinacol
type coupling reaction can be rationalized by a preferred
conformation B of ketooxime 12 in which 1,3-diaxial
repulsion is minimized (Scheme 4).12 Electron transfer
from SmI2 to the carbonyl group leads to an intermediate
ketyl radical anion that undergoes a 5-exo-trig cyclization
reaction with a chairlike transition state. This yields
product 13 with the undesired configurations at the
newly formed stereogenic carbon atoms. To invert the
stereochemistry of the coupling reaction, we connected
the oxygen atoms at C-4 and C-6 by forming a six-
membered cyclic acetal. This changes the orientation of
the keto group, as shown in conformation C (Scheme 4),
and the intermediate ketyl radical anion D is axially
attacked by the oxime ether.13 After another one-electron
(7) To our knowledge the biosynthesis of trehazolin (2) is not known.
(8) (a) Giese, B.; Kopping, B.; Goebel, T.; Dickhaut, J .; Thoma, G.;
Kulicke, K.; Trach, F. Org. React. (N.Y.) 1996, 48, 301. (b) Curran, D.
P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions;
VCH: New York 1996; Chapter 2.
(9) (a) Hays, D. S.; Fu, G. C. J . Am. Chem. Soc. 1995, 117, 7283. (b)
Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989, 111, 8236. (c)
Uenishi, J .; Masuda, S.; Wakabayashi, S. Tetrahedron Lett. 1991, 32,
5097. (d) Chiara, J . L.; Valle, N. Tetrahedron: Asymmetry 1995, 6, 1895.
(e) Chiara, J . L.; Mart´ın-Lomas, M. Tetrahedron Lett. 1994, 35, 2969.
(f) Chiara, J . L.; Cabri, W.; Hanessian, S. Tetrahedron Lett. 1991, 32,
1125. (g) Guidot, J . P.; Le Gall, T.; Mioskowski, C. Tetrahedron Lett.
1994, 36, 6671. (h) Carpintero, M.; Ferna´ndez-Mayoralas, A.; J aramillo,
C. J . Org. Chem. 1997, 62, 1916. (i) Wirth, T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 61. (j) Adinolfi, M.; Barone, G.; Iadonisi, A.; Mangoni,
L. Tetrahedron Lett. 1998, 39, 2021. (k) Chiara, J . L. In Carbohydrate
Mimics: Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH: Wein-
heim, 1998; Chapter 7.
(10) (a) Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T.; Hiramatsu,
H. Tetrahedron Lett. 1995, 36, 253. (b) Chiara, J . L.; Marco-Contelles,
J .; Khiar, N.; Gallego, P.; Destabel, C.; Bernabe´, M. J . Org. Chem. 1995,
60, 6010. (c) Naito, T.; Tajiri, K.; Harimoto, T.; Ninomiya, I.; Kiguchi,
T. Tetrahedron Lett. 1994, 35, 2205. (d) Marco-Contelles, J .; Gallego,
P.; Rodr´ıguez-Ferna´ndez, M.; Khiar, N.; Destabel, C.; Bernarbe´, M.;
Mart´ınez-Grau, A.; Chiara, J . L. J . Org. Chem. 1997, 62, 7397, and
references therein. (e) Tormo, J .; Hays, D. S.; Fu, G. J . Org. Chem.
1998, 63, 201. (f) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543.
(11) Upon cyclization with Bu3SnH of the methylated analogue 12b,
Naito and co-workers10a received a mixture of 13b and its epimer at
the quaternary center with almost no selectivity. Reaction of the
methyloxime ether 12b with SmI2 confirmed the results obtained by
Marco-Contelles:10d almost only 13b was obtained. Thus, the nature
of the metal and not that of the oxime ether seems to determine the
selectivity of the coupling.
(12) (a) Sturino, C. F.; Fallis, A. G. J . Am. Chem. Soc. 1994, 116,
7447. (b) Sturino, C. F.; Fallis, A. G. J . Org. Chem. 1994, 59, 6514.

Synthesis of Trehazolin from D-Glucose
J . Org. Chem., Vol. 63, No. 17, 1998 5879
Sch em e 5a
Sch em e 6
oxidizing agent that gave product 18, but with a modest
yield (44%).21 After deprotection of the tertiary hydroxy
group, the resulting O-methyloxime was reduced to 20
by LiAlH4 in the presence of MeONa22 in THF at -20
°C.23 A possible explanation for the complete stereose-
lectivity of this reaction may be the complexation of
LiAlH4 by the adjacent tertiary hydroxy group, which is
activated by MeONa. In addition, access to the sp2
carbon of the oxime ether is easier from the less shielded
upper side24 of the cyclopentane ring than from below
(two versus three shielding groups). Full deprotection
of 19 with sodium in liquid ammonia afforded trehazol-
amine (5).25 Starting from 15, the overall yield is 22%
for eight steps.
Another possibility to obtain 5 would start from keto
aldehyde 6. Well-known pinacol coupling of 6 afforded
cis-diol 20 as major product (Scheme 6).9j,k However, we
succeeded in neither SN2 displacement of the triflate in
21 by a nitrogen nucleophile nor oxidizing the secondary
hydroxy group of 20.26 It is not surprising that the
oxidation of the secondary hydroxy group in compound
20 is much more difficult than the oxidation of the
methoxyamino group in compound 18, because the R-
effect makes hydroxylamines easier to oxidize than
alcohols.20b
Analogous to a known procedure3a we synthesized
trehazolin (2): The isothiocyanate 33c was coupled with
crude trehazolamine (5) in DMF to give the thiourea
derivative 22. Ring closure to an oxazolin with yellow
HgO and subsequent deprotection with sodium in liquid
ammonia afforded trehazolin (2) that was identical with
the natural product ([R]20D, NMR, TLC).27,28 This three-
step conversion from trehazolamine (5) to trehazolin (2)
occurred in 63% yield (Scheme 7).
a
Reagents and conditions: (a) MeONH2‚HCl, py, 40 °C (quant);
(b) Dess-Martin periodinane, CH2Cl2 (quant); (c) SmI2 (5 equiv),
t-BuOH (2.5 equiv), THF, -78 °C to rt (84%); (d) Ac2O, py, DMAP;
(e) Pb(OAc)4, PhH, 40 °C (44%, two steps); (f) K2CO3, MeOH; (g)
LiAlH4, MeONa, THF, -20 °C (67%, two steps); (h) Na, NH3 (liq),
-78 °C (>90%).
transfer, the aminocyclitol 14 with the desired configu-
ration at the quaternary carbon atom should be formed.
Compound 15, in which the O-atoms at C-4 and C-6
are fixed by a ring, can be easily prepared from D-
glucose.14 Carbohydrate derivative 15 was converted
quantitatively to the open chain O-methyloxime ether.
Dess-Martin oxidation15 afforded ketone 16, which was
used without further purification for the subsequent
intramolecular coupling step (Scheme 5). Treatment of
16 with SmI2 in THF at -78 °C gave exclusively dia-
stereoisomer 17 in 84% yield.16 The configuration at the
newly created chiral centers in 17 was established by 1H
NMR analysis and NOE measurements.17 The stereo-
chemistry of aminocyclitols 17 and 5 differs only in the
configuration at C-1,18 which carries the O-methylhy-
droxyamino group. We decided to invert the configura-
tion at this stereocenter in an oxidation-reduction
sequence in order to preserve the stereochemistry of the
quaternary carbon C-5. However, several attempts to
oxidize the methoxyamine 17 to the desired O-methyl-
oxime failed, and protection of the tertiary alcohol of 17
turned out to be necessary.19 The oxidation of the
acetylated O-methoxyamine to the oxime ether 18 was
also not an easy task. Lead tetraacetate20 was the only
Con clu sion
A straightforward “stereoeffective” short synthesis of
trehazolamine (5) including two highly stereoselective
(19) The use of most oxidizing agents resulted in formation of
compound 16.
(20) (a) Norman, R. O. C.; Purchase, R.; Thomas, C. B. J . Chem.
Soc., Perkin Trans. 1 1972, 1701. (b) Weiss, R. H.; Furfine, E.;
Hausleden, E.; Dixon, D. W. J . Org. Chem. 1984, 49, 4969.
(21) Swern oxidation, Dess-Martin periodinane, Br2/Et3N, Br2/
Na2CO3, TEMPO or NaOCl failed.
(22) In the absence of MeONa, the reaction was messy.
(23) Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem. Soc. J pn.
1986, 59, 525.
(13) (a) Wu, Y.; Houk, K. N. J . Am. Chem. Soc. 1992, 114, 1656. (b)
Inanaga, J .; Katsuki, J .; Ujikawa, O.; Yamaguchi, M. Tetrahedron Lett.
1991, 32, 4921.
(14) Qiao, L.; Veredas, J . C. J . Org. Chem. 1993, 58, 3480.
(15) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899, and
references therein.
(24) Reference plane: paper sheet; molecule as depicted in Scheme
5.
(25) 1H and 13C NMR as well as TLC of product 5 were identical to
that already described in the literature.3d,6a The [R]20 measured was
D
not significant because the literature value6a ([R]20 ) +1.7 (c 0.41,
D
MeOH)) is very low.
(16) Almost the same results (yield and diastereoselectivity) were
obtained at 0 °C. When the reaction was performed with Bu3SnH/
AIBN in refluxing benzene a mixture of products 17 and its epimer
at the quaternary center epi-17 were obtained (see Experimental
Section).
(17) See Supporting Information.
(18) Using carbohydrate numbering.
(26) For more details see Supporting Information.
(27) Found for 2: [R]20 ) +122 (c 0.49, H2O); literature: [R]20
)
D
D
+99.5 (c 0.41, H2O),2 [R]20 ) +105 (c 0.36, H2O),3a [R]20D ) +112.7 (c
D
0.59, H2O).3b
(28) With regard to the literature,3c intermediates in the transfor-
mation of 5 to 2 showed different physical data (1H NMR, 13C NMR,
[R]20D, IR, TLC).

5880 J . Org. Chem., Vol. 63, No. 17, 1998
Boiron et al.
Sch em e 7a
(Na2SO4), and concentrated in vacuo to afford 16 (mainly E,
1.14 g, quant.) as a yellowish oil. The crude ketone 16 was
used without further purification for the following step: Rf )
0.44 (E and Z) (pentane/CH2Cl2/Et2O 10:10:1); IR (film) (E-
isomer) ν 1738, 1606, 1100 (br) cm-1 1H NMR (CDCl3) δ
;
E-isomer, 7.68 (d, J ) 7.9 Hz, 1H), 7.59 (d, J ) 8.4 Hz, 2H),
7.28 (d, J ) 6.8 Hz, 2H), 7.23-7.00 (m, 11H), 5.38 (s, 1H),
4.72, 4.57 (2 AB, J AB ) 11.5 Hz, 2H), 4.52, 4.31 (2 AB, J AB
)
11.6 Hz, 2H), 4.62-4.52 (m, 2H), 4.22 (d, J ) 17.6 Hz, 1H),
4.39 (dd, J ) 2.5, 6.9 Hz, 1H), 3.73 (s, 3H), 3.86 (d, J ) 17.6
Hz, 1H); 13C NMR (C6D6) δ E-isomer, 204.2, 148.2, 138.5, 138.2,
137.9, 129.1, 128.5, 128.4, 128.4, 128.1, 127.9, 127.7, 126.6,
99.0, 82.2, 78.9, 76.7, 74.6, 72.5, 71.7, 61.6; Z-isomer, 204.2,
149.6, 138.7, 138.2, 138.0, 129.1, 128.5, 128.4, 128.4, 128.1,
127.9, 127.7, 126.6, 99.1, 82.0, 78.7, 76.7, 74.8, 72.4, 71.7, 61.8;
MS (FAB + KCl) m/z 514 (MK+), 476 (MH+). Anal. Calcd for
a
Reagents and conditions: (a) DMF (69%); (b) HgO, MeCN; (c)
Na, NH3 (liq), -78 °C (91%, two steps).
steps has been achieved. Our synthesis takes advantage
of the chirality of D-glucose and provides a tool for the
inversion of a stereocenter carrying an amino group
adjacent to a hydroxy group.
C
28H29NO6 (475.54): C, 70.72; H, 6.15; N, 2.94. Purification
was not possible.
[1R-(1r,2r,3â,4r,5â)]-5,6-O-Ben zylid en e-3,4-b is(p h en -
ylm eth oxy)-2-(m eth oxyam in o)cyclopen tan ol (17) an d [1S-
(1r,2â,3r,4â,5r)]-5,6-O -B e n zy lid e n e -3,4-b is (p h e n y l-
m eth oxy)-2-(m eth oxya m in o)cyclop en ta n ol (epi-17). Cy-
cliza tion w ith Sm I2. To a stirred and carefully deoxygenated
(evaporation at the vacuum pump, Ar; 3×) solution of dried
crude keto methyloxime 16 (E/Z 5:1; 1.91 g, 4.02 mmol) and
t-BuOH (1.10 mL, 11.7 mmol, 2.9 equiv) in dry THF (220 mL)
was added at -78 °C a ca. 0.1 M solution of SmI2 (commercial,
186 mL, 18.6 mmol, 4.6 equiv) in THF. After 2 h of stirring
at -78 °C, the temperature was slowly raised to room
temperature overnight. Extraction of the yellow solution with
Et2O, NaHCO3, 10% Na2S2O3, and brine, drying (Na2SO4), and
evaporation in vacuo afforded 17 with minor impurities.
Filtration over a bed of silica gel (pentane/CH2Cl2/Et2O 2:1:1)
gave 17 (1.63 g, 84%).
Exp er im en ta l Section
Gen er a l. Unless otherwise stated, reactions were con-
ducted under an atmosphere of Ar. All reagents were com-
mercially available and used without further purification.
Solvents for workup and flash chromatography are distilled
prior to use. Dry CH2Cl2, dry benzene, and dry DMSO were
obtained commercially, and THF was freshly distilled from
sodium/benzophenone. Flash column chromatography was
performed on silica gel 60 (230-400 mesh). Melting points
are uncorrected. NMR spectra were recorded at 300 MHz (1H)
and 75 MHz (13C) at room temperature unless otherwise
mentioned. Chemical shifts are reported in ppm downfield
from TMS or with reference to solvent. Mass spectroscopy was
performed with an FAB ionization method (matrix: nitroben-
zyl alcohol) and addition of potassium chloride.
Syn th esis of 4,6-O-Ben zylid en e-2,3-O-bis(p h en ylm eth -
yl)-1-(O-m eth yloxim e)-D-xylo-h exos-5-u lose (16). A solu-
tion of 1514 (3.32 g, 7.39 mmol) and MeONH2‚HCl (2.46 g, 29.4
mmol, 4 equiv) in dry pyridine (60 mL) was stirred at 40-45
°C for 24 h. Concentration in vacuo and coevaporation with
PhMe afforded a yellow residue which was extracted with
CH2Cl2 and H2O, dried (Na2SO4), and concentrated in vacuo.
The yellowish oil (E/Z 5:1, 3.52 g, quant.) obtained was used
without further purification for the next step: Rf ) 0.43 (E-
isomer); Rf ) 0.29 (Z-isomer) (pentane/CH2Cl2/Et2O 1:1:1); IR
(film) (E/Z 5:1) ν 3473, 1393, 1076, 1049 cm-1; 1H NMR (CDCl3)
δ E-isomer, 7.47-7.26 (m, 15H), 7.42 (d, J ) 7.9 Hz, 1H), 5.37
(s, 1H), 4.81, 4.69 (2 AB, J AB ) 11.8 Hz, 2H), 4.68, 4.52 (2 AB,
J AB ) 11.6 Hz, 2H), 4.45 (dd, J ) 6.3, 7.9 Hz, 1H), 4.21 (dd, J
) 5.2, 10.7 Hz, 1H), 3.90 (m, 1H), 3.88 (dd, J ) 3.4, 6.3 Hz,
1H), 3.87 (s, 3H), 3.68 (dd, J ) 3.4, 9.3 Hz, 1H), 3.48 (dd, J )
10.2, 10.7 Hz, 1H), 2.02 (d, J ) 4.1 Hz, OH); Z-isomer, 7.47-
7.26 (m, 15H), 6.85 (d, J ) 7.1 Hz, 1H), 5.40 (s, 1H), 5.18 (dd,
J ) 5.5, 7.1 Hz, 1H), 4.79, 4.67 (2 AB, J AB ) 11.8 Hz, 2H),
4.63, 4.54 (2 AB, J AB ) 11.6 Hz, 2H), 4.21 (dd, J ) 5.2, 10.7
Hz, 1H), 3.90 (m, 1H), 3.88 (m, 1H), 3.83 (s, 3H), 3.68 (dd, J )
5.3, 10.7 Hz, 1H), 3.49 (dd, J ) 10.2, 10.7 Hz, 1H), 1.93 (d, J
) 4.1 Hz, OH); 13C NMR (CDCl3) δ E-isomer, 147.5, 137.6,
137.4, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 101.1,
80.4, 77.4, 77.0, 74.0, 71.6, 70.7, 61.9, 61.8; Z-isomer, 149.6,
137.7, 137.5, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8,
101.2, 80.5, 77.0, 71.6, 74.1, 72.4, 70.8, 62.2, 62.0; MS (FAB +
KCl) m/z 516 (MK+), 478 (MH+). Anal. Calcd for C28H31NO6
(477.56): C, 70.41; H, 6.55; N, 2.93; Found: C, 70.25; H, 6.53;
N, 2.87.
Cycliza tion w ith Bu 3Sn H. A stirred solution of dried
crude keto methyloxime 16 (567 mg, 1.09 mmol) in dry benzene
(40 mL) was heated to reflux. A solution of Bu3SnH (1.33 mL,
5.00 mmol, 4.6 equiv) and AIBN (82 mg, 0.50 mmol, 0.46 equiv)
in benzene (12 mL) was then added over a period of 4 h. After
another 2 h, the reaction mixture was cooled to room temper-
ature and concentrated in vacuo to a cloudy, colorless oil.
Purification by flash chromatography (pentane/CH2Cl2/Et2O
2:1:1) resulted in a mixture of compounds 17 and epi-17 (17/
epi-17 1.7:1). Further purification by flash chromatography
on alumina (pentane/CH2Cl2/acetone 10:10:1) afforded epi-17
with some tin impurities (80 mg, 15%) and a mixture of 17,
epi-17, and tin impurities (190 mg, 35%). 17: Rf ) 0.41 (SiO2,
pentane/CH2Cl2/Et2O 1:1:1), Rf ) 0.23 (alumina neutral,
pentane/CH2Cl2/acetone 5:5:1); [R]20 ) -8.2 (c 1.16, CHCl3);
D
IR (film) ν 3460 (br), 1610, 1460, 1100 (br) cm-1 1H NMR
;
(CDCl3) δ 7.50-7.20 (m, 15H), 5.88 (d, J ) 2.8 Hz, NH), 5.49
(s, 1H), 4.70, 4.50 (2 AB, J AB ) 11.8 Hz, 2H), 4.63, 4.51 (2 AB,
J AB ) 11.7 Hz, 2H), 4.32 (d, J ) 11.3 Hz, 1H), 4.08 (s, 1H),
4.06 (dd, J ) 4.0, 9.2 Hz, 1H), 3.99 (d, J ) 4.0 Hz, 1H), 3.92
(dd, J ) 2.8, 9.2 Hz, 1H), 3.81 (d, J ) 11.3 Hz, 1H), 3.64 (s, br,
OH), 3.51 (s, 3H); 13C NMR (CDCl3) δ 138.0, 137.6, 137.5,
129.0, 128.4, 128.2, 128.1, 127.9, 127.9, 127.7, 126.3, 100.3,
87.6, 83.7, 83.2, 72.2, 71.9, 70.9, 70.5, 65.1, 62.0; MS (FAB +
KCl) m/z 516 (MK+), 478 (MH+). Anal. Calcd for C28H31NO6
(477.56): C, 70.42; H, 6.54; N, 2.93. Found: C, 70.30; H, 6.73;
N, 2.94. epi-17: Rf ) 0.41 (SiO2, pentane/CH2Cl2/Et2O 1:1:1);
Rf ) 0.35 (alumina neutral, pentane/CH2Cl2/acetone 5:5:1); 1H
NMR (CDCl3) δ 7.55-7.24 (m, 15H), 5.56 (s, 1H), 5.15 (d, J )
4.8 Hz, NH), 4.77, 4.65 (2 AB, J AB ) 11.8 Hz, 2H), 4.63 (s,
2H), 4.38 (dd, J ) 5.1, 9.1 Hz, 1H), 4.16 (d, J ) 11.0 Hz, 1H),
4.09 (d, J ) 9.1 Hz, 1H), 4.03 (d, J AB ) 11.0 Hz, 1H), 3.68 (dd,
J ) 2.5, 5.1 Hz, 1H), 3.47 (dd, J ) 2.5, 4.8 Hz, 1H), 3.46 (s,
3H), 3.27 (s, br, OH); 13C NMR (CDCl3) δ 138.2, 137.9, 137.1,
129.1, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 127.5, 126.0,
101.5, 84.4, 84.0, 83.5, 73.9, 72.4, 71.8, 71.7, 68.3, 61.5; 13C
NMR (C6D6) δ 139.1, 138.8, 138.0, 129.1, 128.3, 128.2, 128.1,
128.0, 127.9, 127.7, 127.5, 126.0, 101.7, 84.8, 84.5, 84.2, 74.2,
72.6, 72.1, 71.7, 68.7, 61.2. Further characterization was not
possible.
To a solution of Dess-Martin periodinane15 (1.31 g, 3.09
mmol) in dry CH2Cl2 (40 mL) was added after 10 min a solution
of crude oxime ether of 15 (1.06 g, 2.21 mmol) in dry CH2Cl2
(12 mL). The mixture was stirred at room temperature until
no starting material could be detected by TLC (2-3 h). After
dilution with Et2O (15 mL) and stirring for 10 min, the foggy
solution was extracted with Et2O, a solution of 10 g of Na2S2O3
in saturated NaHCO3 (80 mL), and saturated NaHCO3, dried

Synthesis of Trehazolin from D-Glucose
J . Org. Chem., Vol. 63, No. 17, 1998 5881
Syn th esis of [2R-(2r,3â,4r,5â)]-2-(Acetyloxy)-1-(O-m eth -
yloxim e)-3,6-O-b en zylid en e-4,5-b is(p h en ylm et h oxy)cy-
clop en ta n on e (18). To a stirred solution of alcohol 17 (1.63
g, 3.41 mmol) in dry pyridine (15 mL) were added at room
temperature Ac2O (8.0 mL, 85 mmol, 25 equiv) and DMAP
(30 mg). After one night of stirring at room temperature,
the reaction mixture was slowly quenched by addition of
MeOH (50 mL) and stirred for another 2 h. After evaporation
to dryness, the residue was extracted with Et2O, saturated
NH4Cl, and brine and dried (MgSO4), and the solvent was
evaporated in vacuo to give the acetate of 17 (1.78 g, quant.)
-19 (c 0.76, CHCl3); IR (film) ν 3420 (br), 1497, 1454, 1097
(br) cm-1; 1H NMR (CDCl3) δ 7.47-7.28 (m, 15H), 6.22 (d, J )
7.8 Hz, NH), 5.65 (s, 1H), 4.64, 4.59 (2 AB, J AB ) 11.8 Hz,
2H), 4.62 (s, 2H), 4.44 (d, J ) 11.5 Hz, 1H), 4.26 (dd, J ) 4.0,
6.1 Hz, 1H), 4.12 (dd, J ) 2.1, 4.0 Hz, 1H), 4.03 (d, J ) 2.1 Hz,
1H), 3.75 (dd, J ) 6.1, 7.8 Hz, 1H), 3.73 (d, J ) 11.5 Hz, 1H),
3.51 (s, 3H), 2.70 (s, OH); 13C NMR (CDCl3) δ 138.4, 137.9,
137.5, 128.9, 128.4, 128.3, 128.2, 127.8, 127.8, 127.7, 126.2,
98.4, 86.3, 85.6, 81.4, 76.7, 72.5, 72.1, 69.2, 67.5, 61.2; MS (FAB
+ KCl) m/z 516 (MK+), 478 (MH+), 325. Anal. Calcd for
C
28H31NO6 (477.56): C, 70.42; H, 6.54; N, 2.93. Found: C,
as yellowish oil: Rf ) 0.30 (pentane/CH2Cl2/Et2O 2:2:1); [R]20
70.47; H, 6.78; N, 3.01.
D
) -18.1 (c 1.1, CHCl3); IR (film) ν 3240 (br), 1644, 1090 (br)
[1R-(1r,2â,3r,4â,5â)]-5-Am in o-1-(h ydr oxym eth yl)-1,2,3,4-
cyclop en ta n etetr ol (5). To a stirred mixture of sodium (240
mg, 10 mmol, 110 equiv) in liquid ammonia (15 mL) at -78
°C was added a solution of compound 19 (43.1 mg, 0.093 mmol)
in dry THF (3 mL). After 30 min at -78 °C, NH4Cl (700 mg,
13 mmol, 145 equiv) was added and ammonia allowed to
evaporate at room temperature. Salts were removed using
cation exchange chromatography (34 cm3 wet Dowex 50 WX4,
elution with 0.5 M NH4OH) to afford 5 (14.3 mg, >90%
according to 1H NMR) with some minor impurities. The
obtained crude product was used without further purification
(yield calculated after following step): Rf ) 0.26 (MeCN/H2O/
cm-1 1H NMR (CDCl3) δ 7.50-7.23 (m, 15H), 6.48 (s, NH),
;
5.51 (s, 1H), 4.87 (dd, J ) 3.9, 10.4 Hz, 1H), 4.72, 4.53 (2 AB,
J AB ) 11.8 Hz, 2H), 4.60, 4.53 (2 AB, J AB ) 12.0 Hz, 2H), 4.53
(d, J ) 10.4 Hz, 1H), 4.09 (d, J ) 12.1 Hz, 1H), 4.07 (s, 1H),
3.92 (d, J ) 3.9 Hz, 1H), 3.84 (d, J ) 12.1 Hz, 1H), 3.72 (s,
3H), 2.18 (s, 3H); 13C NMR (CDCl3) δ 175.5, 138.0, 137.6, 137.4,
129.1, 128.3, 128.3, 128.1, 127.8, 127.7, 126.2, 100.4, 86.6, 82.7,
80.6, 72.3, 71.6, 70.7, 69.8, 68.4, 62.1, 21.0; MS (FAB + KCl)
m/z 558 (MK+), 520 (MH+), 414. Anal. Calcd for C30H33NO7
(519.60): C, 69.35; H, 6.40; N, 2.70. Found: C, 69.16; H, 6.58;
N, 2.79.
1
To a stirred solution of the acetate of 17 (202 mg, 0.389
mmol) in dry benzene (20 mL) was added at room temperature
in three portions (every 12 h) Pb(OAc)4 (300 mg, 0.67 mmol,
1.74 equiv). The mixture was stirred at 40 °C for a total of 40
h and then quenched with saturated NaHCO3, extracted with
Et2O, saturated NaHCO3 and brine. Drying of the combined
organic extracts (MgSO4) and evaporation in vacuo gave a oily
residue. Flash chromatography (pentane/CH2Cl2/Et2O 8:3:1)
afforded product 18 (88 mg, 44%) as a yellowish oil. Rf ) 0.38
AcOH 3:5:2); H NMR (CD3OD) δ 3.94 (dd, J ) 5.0, 6.9 Hz,
1H), 3.85 (dd, J ) 5.0, 6.2 Hz, 1H), 3.78 (d, J ) 11.8 Hz, 1H),
3.68 (d, J ) 11.8 Hz, 1H), 3.68 (d, J ) 6.2 Hz, 1H), 3.15 (d, J
) 6.9 Hz, 1H); 13C NMR (CD3OD) δ 83.9, 83.1, 79.5, 73.8, 63.5,
59.9.
[1R -(1r,2â,3r,4â,5r)]-N -[2,3,4,5-Te t r a h yd r oxy-2-(h y-
dr oxym eth yl)cyclopen tyl]-N′-[2,3,4-tr is-O-(ph en ylm eth yl)-
r-D-glu cop yr a n osyl]th iou r ea (22). To a solution of crude
5 (product from the previous step; 0.105 mmol) in DMF (1 mL)
was added a solution of 33c (62.0 mg, 0.126 mmol, 1.2 equiv)
in DMF (1 mL). After 24 h, the solvent was evaporated and
the residue purified by flash chromatography (CH2Cl2/MeOH
20:1 to 10:1) to afford the thiourea derivative 22 (48.5 mg, 69%,
2 steps) as a colorless oil. Data different from the literature:
3c Rf ) 0.22 (CH2Cl2/MeOH 10:1); [R]20D ) +153 (c 2.42, CHCl3);
IR (KBr) ν 3405 (br), 1541, 1490, 1363, 1070 (br) cm-1; 1H NMR
(CD3CN) δ 7.80 (br, NH), 7.33-7.25 (m, 15H), 7.13 (br, NH),
5.61 (br, 1H), 4.89-4.56 (m, 8H), 4.30-4.06 (m, 4H), 3.89-
3.29 (m, 12H); 13C NMR (CD3CN) δ 185.4, 140.0, 139.5, 138.8,
129.4, 129.3, 129.2, 129.1, 129.0, 128.9, 128.8, 128.6, 128.5,
83.6, 83.5, 82.5, 82.3, 80.1, 78.9, 78.4, 76.0, 75.5, 75.4, 73.5,
73.2, 63.3, 62.9, 62.2; MS (FAB + KCl) m/z 709 (MK+), 671
(MH+).
(pentane/CH2Cl2/Et2O 4:1:1); [R]20 ) -1.5 (c 1.1, CHCl3); IR
D
(film) ν 1732 (br), 1651 cm-1
;
1H NMR (CDCl3) δ 7.47-7.25
(m, 15H), 5.74 (s, 1H), 5.09 (dd, J ) 1.1, 2.4 Hz, 1H), 4.81 (dd,
J ) 1.1, 2.7 Hz, 1H), 4.76, 4.62 (2 AB, J AB ) 11.4 Hz, 2H),
4.52, 4.47 (2 AB, J AB ) 11.8 Hz, 2H), 4.47, 4.39 (2 AB, J AB
)
11.1 Hz, 2H), 4.07 (dd, J ) 2.4, 2.7 Hz, 1H), 4.00 (s, 3H), 1.98
(s, 3H); 13C NMR (CDCl3) δ 170.2, 157.1, 138.2, 137.7, 137.5,
129.1, 128.3, 128.3, 128.2, 128.1, 127.8, 127.7, 127.7, 126.4,
98.5, 85.8, 80.1, 80.0, 80.2, 72.9, 71.9, 65.0, 62.9, 21.8; MS (FAB
+ KCl) m/z 556 (MK+), 518 (MH+), 412. Anal. Calcd for
C
30H31NO7 (517.58): C, 69.62; H, 6.04; N, 2.71. Found: C,
69.34; H, 6.18; N, 2.70.
Syn t h esis of [1R-(1r,2â,3â,4r,5â)]-5,6-O-Ben zylid en e-
3,4-b is(p h e n ylm e t h oxy)-2-(m e t h oxya m in o)cyclop e n -
ta n ol (19). Methyloxime 18 (92.0 mg, 0.178 mmol) and K2CO3
(10 mg) in MeOH (5 mL) were stirred at room temperature
for 30 min. Extraction with Et2O, saturated NaHCO3, and
brine, drying (MgSO4), and evaporation of solvents at reduced
pressure gave the alcohol of 18 (88 mg, quant.) as a yellowish
oil: Rf ) 0.30 (pentane/CH2Cl2/Et2O 3:1:1); [R]20D ) +23 (c 1.0,
CHCl3); IR (film) ν 3510 (br), 1078 (br) cm-1; 1H NMR (CDCl3)
Syn th esis of Tr eh a zolin (2). To a solution of the thiourea
22 (48.4 mg, 0.0722 mmol) in dry MeCN (4 mL) was added in
three portions yellow HgO (155 mg, 0.72 mmol, 10 equiv). After
24 h of vigorous stirring, the mixture was filtered through a
bed of Celite and the latter rinsed with CH2Cl2/MeOH 5:1. A
second filtration over silica gel (CH2Cl2/MeOH 5:1) afforded
protected trehazolin (45.5 mg, quant.) as a colorless oil which
was used without further purification. Data different from
δ 7.45-7.24 (m, 15H); 5.52 (s, 1H); 4.77, 4.64 (2 AB, J AB
11.6 Hz, 2H); 4.73 (d, J ) 1.5 Hz, 1H); 4.51, 4.45 (2 AB, J AB
)
)
the literature:3c Rf ) 0.15 (CH2Cl2/MeOH 10:1); [R]20 ) +69
D
11.8 Hz, 2H), 4.59 (d, J ) 11.1 Hz, 1H), 4.27 (dd, J ) 1.3, 1.5
Hz, 1H), 4.02 (d, J ) 1.3 Hz, 1H), 3.97 (d, J ) 11.1 Hz, 1H),
4.02 (s, 3H); 13C NMR (CDCl3) δ 160.9, 138.3, 137.4, 136.7,
129.1, 128.6, 128.2, 128.1, 127.8, 127.6, 126.6, 100.3, 72.5, 83.9,
83.0, 78.2, 72.9, 72.0, 69.5, 62.6; MS (FAB + KCl) m/z 514
(MK+), 476 (MH+), 370. Anal. Calcd for C28H29NO6 (475.55):
C, 70.72; H, 6.15; N, 2.94. Found: C, 70.66; H, 6.27; N, 2.86.
To a stirred solution of LiAlH4 (202 mg, 5.3 mmol, 35 equiv)
and MeONa (164 mg, 3.04 mmol, 20 equiv) in dry THF (5 mL)
at -78 °C was added after 15 min a solution of the alcohol of
18 (72.3 mg, 0.152 mmol) in dry THF (3 mL). The temperature
was raised to -20 °C and maintained until TLC analysis
showed no more starting material. Careful quenching with
water (10 mL) at -78 °C and extraction at room temperature
with Et2O, saturated NaHCO3, and brine followed by drying
(MgSO4) and evaporation of solvents at reduced pressure gave
(c 0.79, CHCl3); IR (KBr) ν 3408 (br), 1664 (br), 1453, 1384,
1069 (br) cm-1; 1H NMR (CD3CN) δ 7.29-7.21 (m, 15H), 5.50
(d, J ) 4.9 Hz, NH), 4.86-4.68 (m, 6H), 4.59-4.37 (m, 6H),
4.00 (s, br, 1H), 3.89-3.53 (m, 10H), 3.35 (t, J ) 6.8 Hz, 1H);
13C NMR (CD3CN) δ 161.4, 140.1, 139.6, 139.1, 129.4, 129.3,
129.2, 129.1, 128.9, 128.9, 128.8, 128.6, 128.4, 88.8, 84.1, 82.2,
81.9, 81.7, 79.6, 79.2, 78.7, 76.1, 75.9, 75.5, 72.8, 72.5, 63.9,
62.3; MS (FAB + KCl) m/z 675 (MK+), 637 (MH+), 205.
To a stirred mixture of sodium (92 mg, 4.0 mmol, 60 equiv)
in liquid ammonia (10 mL) at -78 °C was added a solution of
the protected trehazolin (42.6 mg, 0.0670 mmol) in dry THF
(4 mL). After 30 min at -78 °C, NH4Cl (270 mg, 5.0 mmol,
75 equiv) was added and ammonia allowed to evaporate at
room temperature. Chromatography (12.5 cm3 wet Dowex 50
WX4, elution with 0.5 M NH4OH) followed by lyophilization
provided trehazolin (2) (22.4 mg, 91%): Rf ) 0.40 (MeCN/H2O/
a
pale yellow residue. Flash chromatography (pentane/
CH2Cl2/Et2O 2:1:1) afforded product 19 (48.2 mg, 67%) as a
yellowish oil: Rf ) 0.15 (pentane/CH2Cl2/Et2O 3:1:1); [R]20
AcOH 6:3:1); [R]20 ) +122 (c 0.49, H2O); 1H NMR (D2O) 5.15
D
(d, J ) 5.2, 1H); 4.76 (dd, J ) 2.4, 8.5, 1H), 4.17 (d, J ) 8.5
Hz, 1H)), 4.02 (dd, J ) 2.3, 4.7 Hz, 1H), 3.77 (d, J ) 4.7 Hz,
)
D

5882 J . Org. Chem., Vol. 63, No. 17, 1998
Boiron et al.
1H), 3.63 (d, J ) 12.1 Hz, 1H), 3.62 (dd, J ) 2.2, 12.1 Hz, 1H),
3.57 (dd, J ) 5.2, 9.8 Hz, 1H), 3.55 (dd, J ) 4.9, 12.1 Hz, 1H),
3.52 (d, J ) 12.1 Hz, 1H), 3.46 (dd, J ) 8.7, 9.8 Hz, 1H), 3.37
(ddd, J ) 2.2, 4.9, 10.2 Hz, 1H), 3.22 (dd, J ) 8.7, 10.2 Hz,
1H); 13C NMR (D2O) δ 161.0, 87.3, 82.8, 80.6, 80.3, 80.1, 73.0,
72.9, 72.0, 69.9, 69.5, 61.9, 60.6.
Su p p or tin g In for m a tion Ava ila ble: HETCOR data of
17, tables of 1H NOE differences of 17 and epi-17, experimental
procedures and physical data of the products 6, 20 and 21,
and attempts of transformation of 20 and 21 to 5 (11 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Ack n ow led gm en t. This work was supported by
Novartis AG. We are grateful to Dr. Anthony O’Sullivan
and Dr. Thomas Fru¨h for helpful discussions.
J O980485Y