A Highly Efficient Pinacol Coupling Approach to Trehazolamine Starting from D-Glucose

Article abstract of DOI:10.1021/jo980831b

A short and very efficient synthesis of trehazolamine (3), the aglycon of the potent trehalase inhibitor trehazolin (2), has been achieved starting from D-glucose. The key transformation in this approach is a high-yielding two-step, one-pot sequence consisting of a Swern oxidation of a 1,5-diol followed by a reductive carbocyclization of the resultant 1,5-dicarbonyl compound promoted by samarium diiodide. The overall yield of 3 is 39% over nine steps from 2,3,4,6-tetra-O-benzyl-D-glucose (5). An even shorter synthesis of 30, a diastereoisomeric analogue of 3, is also described starting from 5. The key transformation in this second route is a highly stereoselective ketone oxime ether reductive carbocyclization promoted also by samarium diiodide. The overall yield of 30 is 57% over four steps from 5.

Full text of DOI:10.1021/jo980831b

J . Org. Chem. 1998, 63, 5883-5889
5883
A High ly Efficien t P in a col Cou p lin g Ap p r oa ch to Tr eh a zola m in e
Sta r tin g fr om D-Glu cose
Isabel Storch de Gracia, Hansjo¨rg Dietrich, Sof´ıa Bobo, and J ose Luis Chiara*
Instituto de Quı´mica Orga´nica General, CSIC, J uan de la Cierva, 3, E-28006 Madrid, Spain
Received May 5, 1998
A short and very efficient synthesis of trehazolamine (3), the aglycon of the potent trehalase inhibitor
trehazolin (2), has been achieved starting from D-glucose. The key transformation in this approach
is a high-yielding two-step, one-pot sequence consisting of a Swern oxidation of a 1,5-diol followed
by a reductive carbocyclization of the resultant 1,5-dicarbonyl compound promoted by samarium
diiodide. The overall yield of 3 is 39% over nine steps from 2,3,4,6-tetra-O-benzyl-D-glucose (5).
An even shorter synthesis of 30, a diastereoisomeric analogue of 3, is also described starting from
5. The key transformation in this second route is a highly stereoselective ketone oxime ether
reductive carbocyclization promoted also by samarium diiodide. The overall yield of 30 is 57%
over four steps from 5.
In tr od u ction
Trehalase is an enzyme that specifically hydrolyses
R,R-trehalose (1, Figure 1) to its two glucose units and is
widely distributed in microorganisms, insects, plants, and
animals. Trehalose is ubiquitously found in insects,
being their principal blood sugar and used to support
various energy-requiring functions, such as insect flight.1
Trehalose and trehalase have been reported to participate
also in germination of ascospores in fungi2 and in glucose
transport in mammalian kidney or intestine.3 The
development of specific and potent trehalase inhibitors
is, therefore, of great interest for the control of insects
and certain fungi. One such inhibitor, trehazolin (2), was
isolated in 1991 from the culture broth of Micromono-
spora strain sp. SANK 623904 and from Amycolatopsis
F igu r e 1.
trehalostatica.5 Its peculiar structure, a pseudodisac-
configuration. Trehazolin probably acts as a close mimic
of the substrate R,R-trehalose (1) or, more likely, of the
postulated glycopyranosyl cation intermediate involved
in the hydrolytic step of glycosides or a transition state
leading to it. By systematic chemical modifications of
the sugar10 and the aglycon,6b,d,10d,11 a number of struc-
ture-activity relationships have been established. All
previous total syntheses of 26b,d,7a,c,9 followed a general
retrosynthetic strategy where the molecule is assembled
by linking a protected R-D-glucosyl isothiocyanate (4)9,12
to free or partially protected aminocyclopentitol 3. The
reported syntheses of 3 followed long sequences (g15
steps) starting from myo-inositol,6 D-glucose,7 D-ribono-
lactone,8 or (R)-epichlorohydrin,9 with only modest overall
yields.13 Ketyl radical cyclizations promoted by sa-
marium diiodide are specially well-suited for this en-
deavor since they afford directly a functionalized cycloal-
kanol and proceed under mild conditions, usually in high
yield and with a good level of stereocontrol.14 The use of
chiral polyoxygenated precursors, conveniently prepared
from carbohydrates, could allow the facile preparation
in this way of enantiomerically pure complex cyclitols
such as 3.15 In 1995, we reported a short and stereose-
charide consisting of an R-D-glucopyranose moiety bonded
to a unique aminocyclopentitol (trehazolamine, 3) through
a cyclic isourea group, was confirmed through synthetic
studies6-9 that also allowed establishment of its absolute
*
Corresponding author. Phone: +34-915622900. Fax: +34-
915644853. E-mail: iqolc22@fresno.csic.es.
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Sacktor, B. S.; Wormser-Shavit, E. J . Biol. Chem. 1966, 241, 634.
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Inoue, I.; Shimoda, C. Mol. Gen. Gent. 1981, 183, 32. (c) Thevelein, J .
M.; den-Hollander, J . A.; Shulman, R. G. Proc. Natl. Acad. Sci. 1982,
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Takahashi, S.; Haruyama, H. J . Antibiot. 1991, 44, 1165. (b) Ando,
O.; Nakajima, M.; Hamano, K.; Itoi, K.; Takahashi, S.; Takamatsu,
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46, 1116.
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P. T. M.; Iwashita, T.; Zagorski, M.; Komura, H.; Nomoto, K. J . Chem.
Soc., Chem. Commun. 1991, 919. Initially, the structure of the inhibitor
isolated from this broth was wrongly assigned as 5-epi-trehazolin,
named trehalostatin.
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Commun. 1992, 886. (b) Ogawa, S.; Ushida, C. J . Chem. Soc., Perkin
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M. J . Org. Chem. 1994, 59, 813.
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Soc. 1994, 116, 7461.
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S0022-3263(98)00831-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/30/1998

5884 J . Org. Chem., Vol. 63, No. 17, 1998
Storch de Gracia et al.
Sch em e 1a
lective approach to different diastereoisomeric analogues
of 3 following this approach. The key step was a highly
efficient reductive carbocyclization of carbonyl-tethered
oxime ethers prepared from readily available carbohy-
drate derivatives.16 We now report a new, high-yielding
synthesis of 3 starting from D-glucose via a very efficient
pinacol coupling cyclization promoted by samarium di-
iodide.17 This reducing agent has proven to be specially
convenient at promoting intramolecular pinacol coupling
reactions on polyoxygenated substrates under very mild
conditions, in high yield, and with high diastereoselec-
tivity.18
Resu lts a n d Discu ssion
Our approach to 3 starts from hemiacetal 5 (Scheme
1), readily obtainable from D-glucose in two steps and
commercially available.19 Sodium borohydride reduction
(10) (a) Uchida, C.; Kitahashi, H.; Yamagishi, T.; Iwaisaki, Y.;
Ogawa, S. J . Chem. Soc., Perkin Trans. 1 1994, 2775. (b) Kobayashi,
Y.; Shiozaki, M. J . Antibiot. 1994, 47, 243. (c) Uchida, C.; Kitahashi,
H.; Watanabe, S.; Ogawa, S. J . Chem. Soc., Perkin Trans. 1 1995, 1707.
(d) Uchida, C.; Yamagishi, T.; Kitahashi, H.; Iwaisaki, Y.; Ogawa, S.
Biiorg. Med. Chem. 1995, 3, 1605. (e) Kobayashi, Y.; Shiozaki, M.;
Ando, O. J . Org. Chem. 1995, 60, 2570. (f) Shiozaki, M.; Ubukata, O.;
Haruyama, H.; Yoshiike, R. Tetrahedron Lett. 1998, 39, 1925.
(11) (a) Uchida, C.; Yamagishi, T.; Ogawa, S. Chem. Lett. 1993, 971.
(b) Elliot, R. P.; Hui, A.; Fairbanks, A. J .; Nash, R. J .; Winchester, B.
G.; Way, G.; Smith, C.; Lamont, R. B.; Storer, R.; Fleet, G. W. J .
Tetrahedron Lett. 1993, 34, 7949. (c) Uchida, C.; Kitahashi, H.;
Yamagishi, T.; Iwaisaki, Y.; Ogawa, S. J . Chem. Soc., Perkin Trans. 1
1994, 2775. (d) Uchida, C.; Ogawa, S. Carbohydr. Lett. 1994, 1, 77. (e)
Shiozaki, M.; Kobayashi, Y.; Arai, M.; Haruyama, H. Tetrahedron Lett.
1994, 35, 887. (f) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M.; Haruyama,
H. J . Antibiot. 1994, 47, 932. (g) Shiozaki, M.; Arai, M.; Kobayashi,
Y.; Kasuya, A.; Miyamoto, S.; Furukawa, Y.; Takayama, T.; Haruyama,
H. J . Org. Chem. 1994, 59, 4450. (h) Uchida, C.; Yamagishi, T.;
Kitahashi, H.; Iwaisaki, Y.; Ogawa, S. Bioorg. Med. Chem. 1995, 3,
1605. (i) Uchida, C.; Kitahashi, H.; Watanabe, S.; Ogawa, S. J . Chem.
Soc., Perkin Trans. 1 1995, 1707. (j) Uchida, C.; Ogawa, S. Bioorg. Med.
Chem. 1996, 4, 275. See, also: Ogawa, S. In Carbohydrate Mimics:
Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim 1998,
Chapter 5.
(12) Camarasa, M. J .; Ferna´ndez-Resa, P.; Garc´ıa-Lo´pez, M. T.; G.
de las Heras, F.; Me´ndez-Castrillo´n, P. P.; San Fe´lix, A. Synthesis 1984,
509.
(13) After this paper was submitted for publication, a new synthesis
of 3 and (+)-6-epitrehazolin appeared in the literature: Li, J .; Lang,
F.; Ganem, B. J . Org. Chem. 1998, 63, 3403. For a related formal
synthesis of 3, see: Goering, B. K.; Li, J .; Ganem, B. Tetrahedron Lett.
1995, 36, 8905.
(14) For recent reviews on applications of samarium diiodide in
organic synthesis, see: (a) Molander, G. A.; Harris, G. R. Chem. Rev.
1996, 96, 307. (b) Molander, G. A. Org. React. 1994, 46. (c) Imamoto,
T. Lanthanides in Organic Synthesis; Academic Press: London 1994.
(15) For a recent review on the use of carbohydrate templates for
the preparation of carbocycles, see: Ferrier, R. J .; Middleton, S. Chem.
Rev. 1993, 93, 2779.
(16) (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.
a
Reagents and conditions: (a) NaBH4, EtOH/CH2Cl2 (1:1), rt;
(b) (i) (COCl)2, DMSO, THF, -65 °C, (ii) Et3N, -65 °C to rt; (c)
Sml2, THF/t-BuOH, -50 °C to rt; (d) (MeO)2CMe2, Me2CO, p-TsOH
(cat.), rt; (e) (i) SOCl2, Et3N, CH2Cl2, 0 °C, (ii) RuCl3 (cat.), NalO4,
MeCN/CCl4/H2O (1:1:1.5), rt; (f) 1,1′-thiocarbonyldiimidazole, tolu-
ene, 110 °C.
afforded D-glucitol derivative 6 quantitatively. We have
shown previously16,18c,e that, for those carbocyclizations
involving an aldehyde as pinacol partner, the yield of the
cyclic product can be greatly improved if the oxidation
and the reductive coupling steps are performed in a one-
pot sequence avoiding the isolation of the intermediate
dicarbonyl compound, which is usually rather unstable
and prone to hydration. Thus, Swern oxidation of 6 in
THF followed by dropwise addition of the crude reaction
mixture of keto aldehyde 7 to a freshly prepared solution
of SmI2 in THF20 containing t-BuOH at low temperature
1
afforded a 1:1 mixture (determined by H NMR analysis
of the crude) of cyclic diols 8 and 9 in excellent yield.21,22
Although this mixture could not be separated by column
chromatography, we were able to get diol 8 pure by
recrystallization from EtOAc/hexane. Both cyclic prod-
ucts were shown to have a cis relative stereochemistry
at the two new stereocenters by their ready transforma-
tion into cyclic acetals 10 and 11, cyclic sulfates 12 and
13, or cyclic thionocarbonates 14 and 15 (Scheme 1),
which were in each case readily separable by chroma-
tography. The cis stereoselectivity obtained in this
cyclization is in agreement with previous examples18a-h,j-l
(17) A part of this work was presented at the 2nd Euroconference
on Carbohydrate Mimics; Lago di Garda; 1996. See: Chiara, J . L. In
Carbohydrate Mimics: Concepts and Methods; Chapleur, Y., Ed.;
Wiley-VCH: 1998; chapter 7.
(19) Decoster, E.; Lacombe, J .-M.; Streber, J .-L.; Ferrari, B.; Pavia,
A. A. J . Carbohydr. Chem. 1983, 2, 329.
(18) For examples in the carbohydrate field, see: (a) Chiara, J . L.;
Cabri, W.; Hanessian, S. Tetrahedron Lett. 1991, 32, 1125. (b) Uenishi,
J .; Masuda, S.; Wakabayashi, S. Tetrahedron Lett. 1991, 32, 5097. (c)
Chiara, J . L.; Mart´ın-Lomas, M. Tetrahedron Lett. 1994, 35, 2969. (d)
Guidot, J . P.; Le Gall, T.; Mioskowski, C. Tetrahedron Lett. 1994, 35,
6671. (e) Chiara, J . L.; Valle, N. Tetrahedron: Asymmetry 1995, 6,
1895. (f) Perrin, E.; Mallet, J .-M.; Sinay¨, P. Carbohydr. Lett. 1995, 1,
215. (g) Sawada, T.; Shirai, R.; Iwasaki, S. Tetrahedron Lett. 1996,
37, 885. (h) Kornienko, A.; d’Alarcao, M. Tetrahedron Lett. 1997, 38,
6497. (i) Carpintero, M.; Ferna´ndez-Mayoralas, A.; J aramillo, C. J . Org.
Chem. 1997, 62, 1916. (j) Adinolfi, M.; Barone, G.; Iadonisi, A.;
Mangoni, L.; Manna, R. Tetrahedron 1997, 53, 11767. (k) J enkins, D.
J .; Potter, B. V. L. J . Chem. Soc., Perkin Trans. 1 1998, 41. (l) Adinolfi,
M.; Barone, G.; Iadonisi, A.; Mangoni, L. Tetrahedron Lett. 1998, 39,
2021.
(20) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693.
(21) This key transformation has been reported very recently and
independently by us17 and others (see also the preceding article in this
issue: Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J . Org. Chem. 1998,
63, 5877).18l The slightly different diastereoselectivity obtained in each
case is probably a consequence of the different experimental procedures
followed.
(22) Two very minor cyclopentanediols (A, 0.33%; B, 0.53% yield)
could also be isolated by chromatography and characterized when the
reaction was performed on gram scale (see Experimental Section).
Neither of these compounds formed an isopropylidene acetal, showing
that they are in fact the other two possible diastereoisomeric products,
with trans relative stereochemistry at the new stereocenters (see
Supporting Information for NOESY data).

Pinacol Coupling Approach to Trehazolamine
J . Org. Chem., Vol. 63, No. 17, 1998 5885
Sch em e 2
Sch em e 3
of pinacol coupling reactions promoted by samarium
diiodide, and it has been attributed to the chelated nature
of the transition state involved.18a,23 The complete ster-
9) was being discarded. A route where both diastereoi-
someric diols, 8 and 9, could be carried through to 3 was
evidently highly desirable. With this objective, the
mixture of cyclic thionocarbonates 14 and 15 was con-
verted into the common elimination product 21 in very
good yield by heating with triethyl phosphite28 (Scheme
3). At this point we were prepared to install the requisite
1,2-amino alcohol functionality in a stepwise manner
through stereoselective epoxidation of the double bond
followed by regioselective epoxide opening with a nitrogen
nucleophile. However, epoxidation of 21 with m-CPBA
furnished an inseparable mixture of epoxides (ratio 1.6:
1
eochemistry of 8 and 9 was established by H NMR and
2D NOESY studies (see the Supporting Information). Diol
8 has the correct stereochemistry of trehazolamine (3)
at all except the stereocenter that should support the
amino group. We expected to introduce this function via
a nucleophilic displacement reaction. However, all at-
tempts using cyclic sulfate 12 gave only elimination and
decomposition products. The same result was obtained
with monotriflate 16 (Scheme 2).24 Steric shielding by
the flanking benzyloxy and benzyloxymethyl groups
probably impedes the attack of the nucleophile in the SN2
trajectory. To circumvent these difficulties, we decided
to use a reductive amination strategy. However, the
different conditions tried to selectively oxidize the sec-
ondary alcohol25 produced either keto aldehyde 7 (isolated
as its cyclic monohydrated hemiacetal) or elimination
and decomposition products. Since in other reported
approaches7,11b,e-g to trehazolamine and analogues the
amino group was introduced uneventfully via azide
opening of an epoxide, we tried to transform diol 8 into
the corresponding epoxide 19 of the same sterochemistry
(Scheme 2). However, attempts to convert 8 directly into
halohydrin 20 using Me2C(OAc)COX (X ) Cl or Br)26 gave
monoacetate 18 and decomposition products. A similar
result was obtained when Sharpless’ procedure27 was
tried. Thus, treatment of cyclic ortho ester 17 (1:1
mixture of diastereoisomers) with TMSCl or AcCl pro-
duced again 18 instead of the expected chlorohydrin 20
(X ) Cl).
1
1, determined by H NMR analysis of the crude).29 To
overwhelm the modest diastereofacial preference exhib-
ited by 21, a reagent-control strategy, Sharpless epoxi-
dation,30 was in order. But prior to oxidation, a selective
deprotection of the primary hydroxyl group of 21 was
needed. This could be achieved via an acetolysis-
methanolysis sequence. Treatment of 21 with TMSOTf
in Ac2O31 at low temperature afforded monoacetate 22
in modest yield due to its instability under the reaction
conditions. Other conditions tried did not improve this
result.32 However, the yield of monoacetate was doubled
when the acetolysis was performed on the cyclic thiono-
carbonates 14 and 15 (Scheme 3). The monoacetates 23
and 24 obtained in this way were heated with triethyl
phosphite,28 giving 22 in excellent yield. Methanolysis
of 22 under basic conditions afforded the allylic alcohol
25. Sharpless epoxidation of 25 with diisopropyl L-
tartrate, titanium tetraisopropoxide, and tert-butyl hy-
droperoxide yielded the desired epoxide 26 in very high
yield (Scheme 4).29,33 Using diisopropyl D-tartrate fur-
nished the other epoxide 28 as a single diastereoisomer.29
In all these failed routes to trehazolamine, one-half of
the pinacol coupling product (the “wrong” diastereoisomer
(23) Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989, 111, 8236.
(24) We used different conditions: NaN3 or LiN3 in DMF at room
temperature to 125 °C, n-Bu4NN3 in DMF or toluene at room
temperature to 125 °C.
(25) PCC produced an elimination product, Swern gave decomposi-
tion, Dess-Martin periodinane produced keto aldehyde 8, and n-Bu2-
SnO/Br2 afforded only starting material.
(26) (a) Greenberg, S.; Moffatt, J . G. J . Am. Chem. Soc. 1973, 95,
4016. (b) Robins, M. J .; Hansske, F.; Low, N. H.; Park, J . I. Tetrahedron
Lett. 1984, 25, 367.
(28) Corey, E. J .; Winter, R. A. E. J . Am. Chem. Soc. 1963, 85, 2677.
(29) A similar result was obtained by Shiozaki et al.7c for the
epoxidation of a closely related cyclopentene derivative.
(30) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102, 5974.
For a recent review, see: J ohnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York 1993;
pp 103-158.
(31) (a) Angibeaud, P.; Utille, J .-P. J . Chem. Soc., Perkin Trans. 1
1990, 1490. (b) Angibeaud, P.; Utille, J .-P. Synthesis 1991, 737.
(32) Ynag, G.; Ding, X.; Kong, F. Tetrahedron Lett. 1997, 38, 6725.
(27) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.

5886 J . Org. Chem., Vol. 63, No. 17, 1998
Storch de Gracia et al.
Sch em e 4
Sch em e 5
Swern oxidation and reductive carbocyclization has
proved to be very advantageous when the coupling
involves an aldehyde, giving higher overall yields than
the alternative two-step process.
Exp er im en ta l Section
Gen er a l. NMR sepctra were recorded at 200, 300, or 400
MHz (1H frequency) and at 30 °C. Tetrahydrofuran (THF) was
distilled under argon from sodium-benzophenone, and CH2-
Cl2 was distilled from CaH2. All reactions were performed
under argon with anhydrous freshly distilled solvents. Sa-
marium diiodide was prepared immediately before use by
adding ICH2CH2I in one portion to a suspension of samarium
metal powder (1.2 equiv) in THF (10 mL/mmol of ICH2CH2I)
under argon and stirring vigorously the resultant suspension
for 1-2 h.20 The reductive carbocyclizations were performed
in the presence of the slight excess of samarium metal used
in the preparation of the reagent.
These stereochemical results are in agreement with
Sharpless’ empirical rule.30 Opening of 26 with LiN3/
NH4Cl34 in DMF yielded azide 27 regioselectively and in
high yield. Hydrogenolysis of 27 gave finally trehazola-
mine (3), whose physical and spectroscopic data were
identical to those described for natural5b and synthetic6a,7c
3. An analogous sequence produced trehazolamine di-
astereoisomer 30 from epoxide 28. The described ap-
proach produces trehazolamine (3) in nine steps in an
exceedingly good 39% overall yield from readily available
D-glucose derivative 5. The preparation of trehazolin (1)
from aminocyclitol 3 has been already described in the
literature.6c,d,9
2,3,4,6-Tetr a -O-ben zyl-D-glu citol (6). To a solution of
2,3,4,6-tetra-O-benzyl-D-glucopiranose19 (5.84 g, 10.84 mmol)
in EtOH/CH2Cl2 1:1 (59 mL) at room temperature was added
NaBH4 (1.64 g, 43.21 mmol). After completion of the reaction,
2 M HCl (30 mL) was slowly added, the phases were separated,
and the aqueous phase was extracted with CH2Cl2 (2 × 40 mL).
The combined organic extracts were dried (Na2SO4) and the
solvent was evaporated at reduced pressure. The residue was
purified by flash chromatography (EtOAc/hexane 1:3), afford-
ing 6 (5.74 g, 98%) as a colorless oil. Rf ) 0.37 (EtOAc/hexane
1:2); [R]22 +9.9 (c 1.5, CHCl3);1H NMR (CDCl3) δ 7.41-7.27
D
A shorter, more direct route to 30 was also developed
from D-glucose (Scheme 5). Reductive carbocyclization
of readily available15 keto oxime ether 31 using an excess
of samarium diiodide, under conditions previously de-
scribed by us,16 took place with subsequent N-O reduc-
tive cleavage, affording directly the aminocyclopentitol
32 in an excellent overall yield. Hydrogenolysis of 32
afforded finally 30. This route produced the unnatural
trehazolamine analogue 30 in only four steps from 5 (six
steps from D-glucose) and 57% overall yield.
(m, 20H), 4.79 (d, 1H, J ) 11.3 Hz), 4.79 (d, 1H, J ) 11.6 Hz),
4.71 (d, 1H, J ) 11.3 Hz), 4.68 (d, 1H, J ) 11.6 Hz), 4.67 (d,
1H, J ) 11.3 Hz), 4.62 (d, 1H, J ) 11.9 Hz), 4.60 (d, 1H, J )
11.3 Hz), 4.55 (d, 1H, J ) 11.9 Hz), 4.13-4.06 (m, 1H), 3.96
(dd, 1H, J ) 6.2, 3.6 Hz), 3.91-3.75 (m, 3H), 3.71-3.61 (m,
3H), 3.04 (d, 1H, J ) 5.2 Hz), 2.25 (t, 1H, J ) 6.3 Hz); 13C
NMR (CDCl3) δ 142.2, 142.0, 141.8, 141.6, 132.4-l31.5 (20 C),
83.3, 82.9, 81.4, 81.2, 80.8, 80.2, 78.2, 74.9, 74.5, 65.6.
Cycliza t ion of Com p ou n d
6 t h r ou gh a On e-P ot
Sw er n Oxid a t ion -Sm I2 R ed u ct ive Cou p lin g P r ocess.
Syn t h esis of [1S-(1r,2r,3â,4r,5â)]-3,4,5-t r is(ben zyloxy)-
1-(ben zyloxym eth yl)-1,2-cyclop en ta n ed iol (8) a n d [1R-
(1r,2r,3r,4â,5r)]-3,4,5-tr is(ben zyloxy)-1-(ben zyloxym eth yl)-
1,2-cyclop en ta n ed iol (9). To a solution of (COCl)2 (1.9 mL,
21.84 mmol) in THF (39 mL) at -65 °C was added dropwise a
solution of DMSO (3.4 mL, 43.67 mmol) in THF (39 mL). After
stirring for 15 min at -65 °C, a solution of 6 (3.95 g, 7.28 mmol)
in THF (15 mL + 6 mL rinse) was added dropwise. After
stirring at -65 °C for 45 min, Et3N (10.2 mL, 72.79 mmol)
was added dropwise and the reaction was stirred from -65
°C to room temperature for 1 h. The reaction mixture was
diluted with THF (47 mL) and added dropwise to a freshly
prepared 0.1 M solution of SmI2 in THF (218 mL, 21.84 mmol)
and t-BuOH (1.66 mL, 18.20 mmol) at -50 °C. After stirring
at -50 °C for 3 h, the reaction was allowed to slowly attain
room temperature overnight. Aqueous saturated NaHCO3
Con clu sion
The described synthesis of 3 and 30 demonstrate the
general effectiveness of ketyl radical cyclizations pro-
moted by samarium diiodide for the efficient preparation
of densely functionalized cyclitols under very mild condi-
tions and using readily available carbohydrate deriva-
tives as starting materials. The one-pot sequence of
(33) Traces (e1%) of the other epoxide could be observed in the 1H
NMR of the crude reaction mixture.
(34) VanderWerf, C. A.; Heisler, R. Y.; McEwen, W. E. J . Am. Chem.
Soc. 1954, 76, 1231.

Pinacol Coupling Approach to Trehazolamine
J . Org. Chem., Vol. 63, No. 17, 1998 5887
(200 mL) was added to the reaction mixture and, after stirring
for 30 min, the aqueous phase was extracted with EtOAc (4 ×
150 mL). The combined organic extracts were washed with
10% aqueous Na2S2O3 and dried over Na2SO4. The mixture
was filtered and solvent was removed at reduced pressure. The
crude was purified by flash chromatography (EtOAc/hexane
1:5), affording an inseparable 1:1 mixture of cis diols 8 and 9
(3.54 g, 90%), and the trans diols A (13 mg, 0.33%) and B (21
mg, 0.53%). A pure sample of 8 was obtained by fractional
crystallization from EtOAc/hexane. 8: white solid. Rf ) 0.18
chromatography (EtOAc/hexane 1:10). 12: colorless oil; Rf )
0.46 (EtOAc/hexane 1:3); 1H NMR (CDCl3) δ 7.38-7.25 (m,
20H), 5.09 (d, 1H, J ) 4.7 Hz), 4.75-4.56 (m, 8H), 4.37 (d,
1H, J ) 9.4 Hz), 4.23 (dd, 1H, J ) 8.2, 4.7 Hz), 3.97 (dd, 1H,
J ) 9.4, 8.2 Hz), 3.81 (s, 2H); 13C NMR (CDCl3) δ 137.7, 136.9,
136.8, 136.7, 128.5-127.6 (20 C), 91.4, 85.9, 84.7, 82.6, 82.0,
73.9, 73.8, 73.2, 72.5, 67.6; 13: colorless oil; Rf ) 0.35 (EtOAc/
hexane 1:3); 1H NMR (CDCl3) δ 7.40-7.29 (m, 18H), 7.20-
7.16 (m, 2H), 4.89 (d, 1H, J ) 4.8 Hz), 4.85 (d, 1H, J ) 11.5
Hz), 4.75 (d, 1H, J ) 11.5 Hz), 4.73-4.55 (m, 4H), 4.42 (t, 1H,
J ) 9.0 Hz), 4.42 (d, 1H, J ) 11.7 Hz), 4.33 (d, 1H, J ) 11.7
Hz), 3.94 (d, 1H, J ) 8.8 Hz), 3.79 (dd, 1H, J ) 9.3, 4.8 Hz),
3.67 (d, 1H, J ) 9.4 Hz), 3.49 (d, 1H, J ) 9.4 Hz); 13C NMR
(CDCl3) δ 138.0, 137.4, 136.9, 136.5, 128.6-127.8 (20 C), 88.0,
84.4, 81.2, 78.0, 77.9, 73.9 (2C), 73.5, 72.6, 68.8.
(EtOAc/hexane 1:3); mp 101-103 °C; [R]22 +1.85 (c 1.3,
D
CHCl3); 1H NMR (CDCl3) δ 7.37-7.24 (m, 20H), 4.77 (d, 1H, J
) 11.8 Hz), 4.63 (d, 1H, 11.8 Hz), 4.58-4.56 (m, 6H), 4.02 (t,
1H, J ) 5.3 Hz), 3.97 (td, 1H, J ) 5.8, 0.8 Hz), 3.88 (d, 1H, J
) 4.5 Hz), 3.83 (td, 1H, J ) 4.8, 0.7 Hz), 3.81 (d, 1H, J ) 9.6
Hz), 3.66 (d, 1H, J ) 9.6 Hz), 3.20 (s, 1H), 2.70 (d, 1H, J ) 4.9
Hz); 13C NMR (CDCl3) δ 138.3, 138.1, 137.9, 137.5, 128.4-
127.5 (20 C), 87.0, 85.8, 85.3, 78.5, 77.1, 73.8, 72.4, 72.0, 71.8,
71.7. Anal. Calcd for C34H36O6: C, 75.53; H, 6.71. Found:
C, 75.81; H, 6.80. 9 (as a mixture with 8): Rf ) 0.18 (EtOAc/
hexane 1:3); 1H NMR (CDCl3) δ 7.39-7.24 (m, 20H), 4.73-
4.47 (m, 8H), 4.14 (dd, 1H, J ) 5.7, 4.8 Hz), 4.09 (t, 1H, J )
6.4 Hz), 3.90 (d, 1H, J ) 6.0 Hz), 3.86 (dd, 1H, J ) 6.0, 4.6
Hz), 3.47 (d, 1H, J ) 9.4 Hz), 3.41 (d, 1H, J ) 9.5 Hz), 3.11 (s,
1H), 2.94 (d, 1H, J ) 7.4 Hz); 13C NMR (CDCl3) δ 138.2, 138.0,
137.9, 137.7, 128.5-126.9 (20C), 87.6, 81.6, 81.2, 77.3, 73.5,
73.1, 72.7, 72.2, 71.4, 70.5. A: Rf ) 0.28 (EtOAc/hexane 1:3);
1H NMR (CDCl3) δ 7.37-7.23 (m, 20H), 4.67 (d, 1H, J ) 11.6
Hz), 4.62-4.54 (m, 6H), 4.53 (d, 1H, J ) 11.8 Hz), 4.15 (t, 1H,
J ) 4.9 Hz), 4.07 (dd, 1H, J ) 5.2, 4.1 Hz), 4.01 (td, 1H, J )
5.1, 1.1 Hz), 3.95 (d, 1H, J ) 9.6 Hz), 3.81 (dd, 1H, J ) 4.1,
1.1 Hz), 3.80 (d, 1H, J ) 9.6 Hz), 2.95 (s, 1H), 2.80 (d, 1H, J
) 5.1 Hz); 13C NMR (CDCl3) δ 138.1, 138.0, 137.81, 137.76,
128.5-127.7 (20 C), 88.0, 87.6, 83.2, 80.4, 75.9, 73.8, 72.6, 72.3,
71.9, 70.4. B: Rf ) 0.17 (EtOAc/hexane 1:3); 1H NMR (CDCl3)
δ 7.40-7.24 (m, 20H), 4.81-4.43 (m, 8H), 4.10-4.05 (m, 2H),
3.91 (d, 1H, J ) 7.1 Hz), 3.75 (t, 1H, J ) 6.6 Hz), 3.57 (d, 1H,
J ) 9.8 Hz), 3.49 (d, 1H, J ) 9.8 Hz), 3.04 (d, 1H, J ) 5.6 Hz),
2.99 (s, 1H).
Syn th esis of Cyclic Th ion oca r bon a tes 14 a n d 15.
A
solution of the 1:1 mixture of 8 and 9 (612 mg, 1.13 mmol)
and 1,1′-thiocarbonyldiimidazole (303 mg, 1.70 mmol) in
toluene (7.2 mL) was heated at reflux for 4 h. After removal
of the solvent at reduced pressure, the crude product was
purified by flash column chromatography (EtOAc/hexane 1:6),
to afford 14 (296 mg, 45%) and 15 (342 mg, 52%). 14: colorless
oil. Rf ) 0.45 (EtOAc/hexane 1:4); [R]22 -3.1 (c 1.0, CHCl3);
D
1
IR (film) 2880, 1455, 1320, 1100, 700 cm-1; H NMR (CDCl3)
δ 7.39-7.27 (m, 20H), 5.08 (d, 1H, J ) 4.5 Hz), 4.78-4.56 (m,
8H), 4.20 (d, 1H, J ) 8.4 Hz), 4.09 (dd, 1H, J ) 7.6, 4.5 Hz),
3.95 (t, 1H, J ) 8.4 Hz), 3.86 (d, 1H, J ) 11.7 Hz), 3.76 (d, 1H,
J ) 11.7 Hz); 13C NMR (CDCl3) δ 190.4, 137.6, 136.9, 136.7 (2
C), 128.5-127.6 (20 C), 93.9, 87.5, 85.1, 83.6, 82.8, 73.8 (2 C),
73.0, 72.4, 67.7. Anal. Calcd for C35H34O6S: C, 72.14; H, 5.88.
Found: C, 72.54; H, 6.01. 15: white solid. Rf ) 0.28 (EtOAc/
hexane 1:4); mp 79-81 °C; [R]22D +46.8 (c 1.0, CHCl3); 1H NMR
(CDCl3) δ 7.38-7.26 (m, 18H), 7.22-7.19 (m, 2H), 4.91 (d, 1H,
J ) 5.4 Hz), 4.82 (d, 1H, J ) 11.5 Hz), 4.76 (d, 1H, J ) 11.7
Hz), 4.72 (d, 1H, J ) 12.0 Hz), 4.71 (d, 1H, J ) 11.5 Hz), 4.65
(d, 1H, J ) 12.0 Hz), 4.55 (d, 1H, J ) 11.7 Hz), 4.45 (d, 1H, J
) 11.8 Hz), 4.38 (d, 1H, J ) 11.8 Hz), 4.21 (t, 1H, J ) 8.8 Hz),
3.86 (d, 1H, J ) 8.7 Hz), 3.79 (dd, 1H, J ) 8.8, 8.7 Hz), 3.55
(d, 1H, J ) 10.1 Hz), 3.43 (d, 1H, J ) 10.1 Hz); 13C NMR
(CDCl3) δ 190.6, 137.9, 137.3, 137.0, 136.6, 128.6-127.7 (20
C), 91.2, 84.5, 81.9, 79.1, 78.3, 73.7, 73.6, 73.3, 72.3, 68.4. Anal.
Calcd for C35H34O6S: C, 72.14; H, 5.88. Found: C, 72.20; H,
5.93.
Syn th esis of Aceta ls 10 a n d 11. To a solution of 8 and 9
(10 mg, 0.018 mmol) in acetone (0.5 mL) and 2,2-dimethox-
ypropane (0.5 mL) was added a catalytic amount of PPTS. The
mixture was stirred at room temperature for 3 h. After adding
Et3N (250 µL), the solvent was removed at reduced pressure
and the residue was purified by flash chromatography (EtOAc/
hexane 1:8) to afford 10 (4.5 mg, 43%) and 11 (5.2 mg, 50%).
[3S-(3r,4â,5r)]-3,4,5-Tr is(ben zyloxy)-1-(ben zyloxym e-
th yl)-1-cyclop en ten e (21). A solution of 14 (280 mg, 0.48
mmol) in (EtO)3P (5 mL) was heated at 155 °C for 2 h. The
solvent was removed at reduced pressure and the residue was
purified by flash column chromatography (EtOAc/hexane 1:10)
to afford 21 (226 mg, 93%) as a colorless oil. Following this
procedure, compound 15 afforded 21 in similar yield: Rf ) 0.50
1
10: Rf ) 0.53 (EtOAc/hexane 1:2); H NMR (CDCl3) δ 7.37-
7.25 (m, 20H), 4.81-4.52 (m, 9H), 4.11 (dd, 1H, J ) 9.7, 6.6
Hz), 4.02 (dd, 1H, J ) 9.4, 0.8 Hz), 3.94 (ddd, 1H, J ) 6.6, 2.5,
0.8 Hz), 3.73 (s, 2H), 1.48 (s, 3H), 1.40 (s, 3H); 13C NMR (CDCl3)
δ 138.6, 138.2, 138.1, 138.0, 128.3-127.1 (20 C), 113.1, 88.2,
87.5, 86.6, 85.1, 83.5, 73.7, 72.9, 72.7, 71.7, 69.7, 28.4, 26.8.
(EtOAc/hexane 1:3); [R]22 +37.5 (c 1.7, CHCl3); 1H NMR
D
(CDCl3) δ 7.42-7.31 (m, 20H), 5.98-5.97 (m, 1H), 4.73 (d, 1H,
J ) 11.7 Hz), 4.71 (d, 1H, J ) 9.4 Hz), 4.67 (d, 1H, J ) 9.1
Hz), 4.66 (d, 1H, J ) 11.8 Hz), 4.64 (d, 1H, J ) 9.5 Hz), 4.62
(d, 1H, J ) 11.8 Hz), 4.61 (d, 1H, J ) 11.8 Hz), 4.24 (d, 1H, J
) 11.8 Hz), 4.54-4.53 (m, 1H), 4.30 (t, 1H, J ) 3.8 Hz), 4.19-
4.18 (m, 1H); 13C NMR (CDCl3) δ 143.2, 138.4, 138.3, 138.1,
138.0, 128.3-127.2 (21 C), 91.4, 85.5, 85.2, 72.6, 71.9, 71.6,
70.8, 66.5. Anal. Calcd for C34H34O4: C, 80.60; H, 6.76.
Found: C, 80.74; H, 6.94.
1
11: Rf ) 0.45 (EtOAc/hexane 1:2); H NMR (CDCl3) δ 7.37-
7.17 (m, 20H), 4.84-4.41 (m, 8H), 4.36 (dd, 1H, J ) 4.2 Hz),
4.30 (dd, 1H, J ) 9.0, 7.8 Hz), 3.69 (d, 1H, J ) 7.8 Hz), 3.66
(dd, 1H, J ) 9.0, 4.2 Hz), 3.47 (d, 1H, J ) 9.4 Hz), 3.42 (d, 1H,
J ) 9.4 Hz), 1.38 (s, 3H), 1.26 (s, 3H); 13C NMR (CDCl3) δ 138.7,
138.6, 138.2, 137.7, 128.4-127.4 (20 C), 112.2, 86.4, 84.3, 80.2,
79.7, 78.8, 73.6, 73.1, 72.8, 72.3, 72.0, 26.8, 26.7.
Syn th esis of Cyclic Su lfa tes 12 a n d 13. To a solution of
8 (33 mg, 0.06 mmol) in CH2Cl2 (0.5 mL) at 0 °C were added
Et3N (34 µL, 0.24 mmol) and SOCl2 (7 µL, 0.09 mmol) at 0 °C.
After stirring at 0 °C for 20 min, the reaction was diluted with
Et2O and extracted twice with water. The combined organic
phases were dried over MgSO4 and filtered, and the solvent
was removed at reduced pressure. The residue was dissolved
in CCl4/CH3CN/H2O 1:1:1.5 (0.7 mL) and cooled to 0 °C. NaIO4
(26 mg, 0.12 mmol) and a catalytic amount of RuCl3‚H2O were
added, and the solution was stirred vigorously for 30 min at 0
°C. The reaction was diluted with Et2O, and the organic layer
was washed with brine, concentrated, and filtered through
silica. The solvent was removed at reduced pressure to afford
12 (33 mg, 91%). Following the same procedure for the
mixture of diols 8 and 9, both sulfates 12 and 13 were obtained
in similar yields and could be easily separated by flash
Syn th esis of Th ion oca r bon a te 23 by Acetolysis of 14.
To a solution of 14 (30 mg, 0.05 mmol) in acetic anhydride
(0.5 mL) was added TMSOTf (27 µL, 0.15 mmol). After stirring
for 17 h at room temperature, the mixture was diluted with
CH2Cl2 (2 mL), and aqueous saturated NaHCO3 (2 mL) was
cautiously added. After stirring for 30 min, the aqueous layer
was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic phases were dried over Na2SO4 and concentrated at
reduced pressure. The residue was purified by flash column
chromatography (CH2Cl2/hexane 1:1), affording unreacted 14
(12 mg) and 23 (17 mg, 58%; 88% based on recovered 14). 23
crystallized from ether/hexane as a white solid: Rf ) 0.52
(EtOAc/hexane 1:3); mp 72-73 °C; [R]22D +4.89 (c 0.9, CHCl3);
1H NMR (CDCl3) δ 7.39-7.28 (m, 15H), 4.96 (d, 1H, J ) 4.1
Hz), 4.78-4.60 (m, 6H), 4.59 (d, 1H, J ) 13.2 Hz), 4.36 (d, 1H,

5888 J . Org. Chem., Vol. 63, No. 17, 1998
Storch de Gracia et al.
J ) 13.2 Hz), 4.25 (d, 1H, J ) 7.5 Hz), 4.11 (dd, 1H, J ) 7.0,
4.1 Hz), 3.98 (dd, 1H, J ) 7.5, 7.0 Hz), 2.11 (s, 3H); 13C NMR
(CDCl3) δ 189.6, 169.8, 137.2, 136.5, 136.3, 128.5-127.7 (15
C), 93.0, 87.7, 84.7, 83.4, 82.4, 73.7, 72.9, 72.4, 62.2, 20.4. Anal.
Calcd for C30H30O7S: C, 67.40; H, 5.66. Found: C, 67.65; H,
5.71.
Syn th esis of Th ion oca r bon a te 24 by Acetolysis of 15.
Following the same procedure as for 23, compound 24 was
obtained from 15 in 61% yield (89% based on recovered 15) as
(3 g) in brine (30 mL) was added. After stirring for 15 min,
the aqueous phase was extracted with Et2O (2 × 20 mL), and
the combined organic phases were washed with brine. The
aqueous brine layer was extracted with EtOAc (2 × 20 mL),
and the combined organic phases were dried over MgSO4 and
concentrated at reduced pressure. The residue was purified
by flash column chromatography (EtOAc/hexane 1:3) affording
epoxide 26 (278 mg, 93%). 26 crystallized from Et2O as a white
solid: Rf ) 0.20 (EtOAc/hexane 1:2); mp 73-74 °C; [R]22D +25.9
1
a white solid: Rf ) 0.24 (EtOAc/hexane 1:3); mp 158-160 °C;
(c 1.0, CHCl3); H NMR (CDCl3) δ 7.37-7.27 (m, 15H), 4.57
1
[R]22 +47.0 (c 0.6, CHCl3); H NMR (CDCl3) δ 7.36-7.29 (m,
(d, 1H, J ) 12.0 Hz), 4.55 (s, 2H), 4.46 (d, 1H, J ) 12.0 Hz),
4.44 (d, 1H, J ) 12.3 Hz), 4.37 (d, 1H, J ) 12.3 Hz), 4.08 (dd,
1H, J ) 12.7, 7.0 Hz), 3.99 (t, 1H, J ) 1.2 Hz), 3.96 (d, 1H, J
) 1.1 Hz), 3.95 (m, 1H), 3.87 (dd, 1H, J ) 12.7, 6.2 Hz), 3.63
(s, 1H), 1.85 (t, 1H, J ) 6.7 Hz); 13C NMR (CDCl3) δ 137.6
(3C), 128.4-127.8 (15 C), 89.7, 82.3, 82.0, 72.0 (2 C), 71.6, 68.4,
61.8, 59.5. Anal. Calcd for C27H28O5: C, 74.98; H, 6.52.
Found: C, 74.86; H, 6.44.
D
15H), 4.89 (d, 1H, J ) 5.6 Hz), 4.81 (d, 1H, J ) 11.5 Hz), 4.78
(d, 1H, J ) 11.7 Hz), 4.73 (m, 2H), 4.69 (d, 1H, J ) 11.5 Hz),
4.54 (d, 1H, J ) 11.7 Hz), 4.30 (d, 1H, J ) 12.4 Hz), 4.22 (d,
1H, J ) 8.3 Hz), 4.04 (d, 1H, J ) 12.4 Hz), 3.82 (dd, 1H, J )
8.3, 5.6 Hz), 3.73 (d, 1H, J ) 8.3 Hz), 2.03 (s, 3H); 13C NMR
(CDCl3) δ 190.0, 169.3, 137.4, 136.64, 136.57, 128.3-127.2 (15
C), 90.7, 84.0, 81.0, 78.5, 78.2, 73.0, 72.9, 71.9, 62.5, 19.9. Anal.
Calcd for C30H30O7S: C, 67.40; H, 5.66. Found: C, 67.02; H,
5.66.
[1S-(1r,2â,3r,4â,5r)]-2,3,4-Tr is(ben zyloxy)-1-(h ydr oxym -
eth yl)-6-oxa bicyclo[3.1.0]h exa n e (28). Following the same
procedure as for 26 but using diisopropyl D-tartrate, epoxide
28 was obtained from 25 in 86% yield as a white solid. Rf )
[3S-(3r,4â,5r)]-1-(Acetoxym eth yl)-3,4,5-tr is(ben zyloxy)-
1-cyclop en ten e (22). F r om 23. A solution of 23 (168 mg,
0.32 mmol) in (EtO)3P (3.2 mL) was heated at 155 °C for 3 h.
The solvent was removed at reduced pressure and the residue
was purified by flash column chromatography (EtOAc/hexane
1:10) to afford 22 (140 mg, 97%) as a colorless oil.
F r om 24. A solution of 24 (406 mg, 0.76 mmol) in (EtO)3P
(7.7 mL) was heated at 155 °C for 2 h. The solvent was
removed at reduced pressure and the residue was purified by
flash column chromatography (EtOAc/hexane 1:10) to afford
22 (342 mg, 98%) as a colorless oil.
0.23 (EtOAc/hexane 1:1); mp 141-143 °C; [R]22 +41.3 (c 0.5,
D
1
CHCl3); H NMR (C6D6) δ 7.32-7.24 (m, 5H), 7.21-7.07 (m,
10H), 4.70 (d, 1H, J ) 11.8 Hz), 4.68 (d, 1H, J ) 12.0 Hz),
4.56 (d, 1H, J ) 12.0 Hz), 4.53 (d, 1H, J ) 11.8 Hz), 4.52 (d,
1H, J ) 12.0 Hz), 4.37 (d, 1H, J ) 12.0 Hz), 4.18 (t, 1H, J )
5.8 Hz), 3.89 (d, 1H, J ) 5.8 Hz), 3.62 (dd, 1H, J ) 5.8, 1.3
Hz), 3.58 (m, 2H), 3.23 (d, 1H, J ) 1.3 Hz); 13C NMR (CDCl3)
δ 138.2, 138.0, 137.8, 128.5-127.7 (15 C), 84.0, 81.5, 80.7, 72.5,
72.0, 71.3, 64.3, 59.3, 56.7. Anal. Calcd for C27H28O5: C, 74.98;
H, 6.52. Found: C, 74.58; H, 6.52.
By Acetolysis of 21. To a solution of 21 (20 mg, 0.04 mmol)
in Ac2O (1 mL) at -60 °C was added TMSOTf (8 µL, 0.04
mmol). After stirring at -60 °C for 1 h, the reaction mixture
was diluted with CH2Cl2 (15 mL) and aqueous saturated
NaHCO3 was carefully added. The aqueous layer was ex-
tracted with CH2Cl2 (2 × 30 mL), and the combined organic
extracts were dried over Na2SO4, filtered, and evaporated. The
residue was coevaporated with toluene and purified by flash
chromatography (EtOAc/hexane 1:10) to afford unreacted 21
(3 mg) and 22 (9 mg, 50%; 58% based on recovered 21) as a
[1R-(1r,2â,3r,4â,5â)]-5-Azid o-2,3,4-t r is(b en zyloxy)-1-
(h yd r oxym eth yl)-1-cyclop en ta n ol (27). To a solution of 26
(50 mg, 0.11 mmol) in DMF (2 mL) were added lithium azide
(68 mg, 1.39 mmol) and NH4Cl (74 mg, 1.39 mmol), and this
mixture was stirred at 100 °C for 5 days. After disappearance
of 26 (TLC toluene/acetone 8:1), DMF was evaporated at
reduced pressure. The residue was dissolved in EtOAc (10 mL)
and washed with water (3 mL), and the aqueous phase was
extracted twice with EtOAc. The combined organic phases
were dried over Na2SO4 and filtered, and the solvent was
removed at reduced pressure. The residue was purified by
flash column chromatography (EtOAc/hexane 1:3), affording
azide 27 (48 mg, 89%) as a colorless oil: Rf ) 0.23 (acetone/
colorless oil: 22: Rf ) 0.31 (EtOAc/hexane 1:4); [R]22 +44.0
D
1
(c 1.5, CHCl3); H NMR (CDCl3) δ 7.37-7.29 (m, 15H), 5.90
(m, 1H), 4.75-4.55 (m, 8H), 4.75-4.45 (m, 2H), 4.26 (t, 1H, J
) 3.8 Hz), 2.04 (s, 3H); 13C NMR (CDCl3) δ 170.5, 141.0, 138.2
(2 C), 138.1, 128.4-127.7 (16 C), 91.3, 85.4, 85.3, 72.0, 71.6,
71.0, 60.5, 20.8.
toluene 1:8); [R]22 -12.0 (c 0.6, CHCl3); IR (KBr) 3440, 2100,
D
1080 cm-1; 1H NMR (C6D6) δ 7.30-7.03 (m, 15H), 4.49 (d, 2H,
J ) 11.7 Hz), 4.42 (d, 1H, J ) 11.2 Hz), 4.39 (d, 1H, J ) 11.5
Hz), 4.36 (d, 1H, J ) 11.8 Hz), 4.26 (d, 1H, J ) 11.7 Hz), 4.09
(t, 1H, J ) 5.2 Hz), 3.98 (t, 1H, J ) 5.5 Hz), 3.92 (d, 1H, J )
11.7 Hz), 3.84 (d, 1H, J ) 5.8 Hz), 3.83 (d, 1H, J ) 11.7 Hz),
3.58 (dd, 1H, J ) 5.6, 0.6 Hz), 3.20 (br s, 1H); 13C NMR (CDCl3)
δ 137.7, 137.5, 137.4, 128.7-127.6 (15 C), 88.8, 87.0, 81.0, 80.1,
72.8 (2 C), 72.1, 66.1, 63.2.
[3S-(3r,4â,5r)]-3,4,5-Tr is(ben zyloxy)-1-(h ydr oxym eth yl)-
1-cyclop en ten e (25). A solution of 22 (27 mg, 0.06 mmol) in
CH2Cl2/MeOH 1:1 (2 mL) was treated with a few drops of a
freshly prepared solution of NaOMe in MeOH. After stirring
for 1 h at room temperature, Amberlite IR-120 (H+ type) was
added and the reaction mixture was stirred for 10 min. The
mixture was filtered, the solvent was evaporated at reduced
pressure, and the residue was purified by flash column
chromatography (EtOAc/hexane 1:3) to afford 25 (24 mg, 96%)
[1S-(1r,2r,3â,4r,5â)]-5-Azid o-2,3,4-t r is(b en zyloxy)-1-
(h yd r oxym eth yl)-1-cyclop en ta n ol (29). To a solution of 28
(24 mg, 0.055 mmol) in DMF (1 mL) were added lithium azide
(33 mg, 0.66 mmol) and NH4Cl (36 mg, 0.66 mmol), and this
mixture was stirred at 125 °C overnight. DMF was evaporated
at reduced pressure and the residue was dissolved in EtOAc
(10 mL) and washed with water (3 mL), and the aqueous phase
was extracted twice with EtOAc. The combined organic phases
were dried over Na2SO4 and filtered, and the solvent was
removed at reduced pressure. The residue was purified by
flash column chromatography (EtOAc/hexane 1:3) affording
azide 29 (24 mg, 92%) as a white solid: Rf ) 0.38 (EtOAc/
as a white solid: Rf ) 0.14 (EtOAc/hexane 1:3); mp 78-80 °C;
1
[R]22 +46.5 (c 1.5, CHCl3); H NMR (CDCl3) δ 7.36-7.28 (m,
D
15H), 5.87 (m, 1H), 4.70 (d, 1H, J ) 11.6 Hz), 4.69 (d, 1H, J )
11.8 Hz), 4.63 (d, 1H, J ) 11.7 Hz), 4.63 (d, 1H, J ) 11.7 Hz),
4.59 (d, 1H, J ) 11.7 Hz), 4.56 (d, 1H, J ) 11.7 Hz), 4.50 (m,
2H), 4.28 (dd, 1H, J ) 14.1, 4.6 Hz), 4.25 (t, 1H, J ) 3.8 Hz),
4.19 (dd, 1H, J ) 14.1, 7.1 Hz), 1.92 (dd, 1H, J ) 7.1, 4.6 Hz);
13C NMR (CDCl3) δ 145.1, 138.3, 138.1 (2 C), 128.4-127.8 (15
C), 126.2, 91.6, 86.0, 85.5, 72.0, 71.8, 71.0, 60.3. Anal. Calcd
for C27H28O4: C, 77.86; H, 6.78. Found: C, 78.13; H, 6.85.
[1R-(1r,2r,3â,4r,5r)]-2,3,4-Tr is(ben zyloxy)-1-(h ydr oxym -
eth yl)-6-oxa bicyclo[3.1.0]h exa n e (26). To a solution of
diisopropyl L-tartrate (235 mg, 1.0 mmol) in CH2Cl2 (11 mL)
at -30 °C was added Ti(OiPr)4 (295 µL, 1.0 mmol). After
stirring for 20 min at -30 °C, a solution of 25 (287 mg, 0.69
mmol) in CH2Cl2 (19 mL) was added dropwise. After 20 min,
t-BuOOH (5.5 M in decane, 251 µL, 1.38 mmol) was added and
the stirring continued at -30 °C for 20 h. The reaction
mixture was diluted with Et2O (20 mL) and a solution of NaOH
hexane 1:1); mp 55-57 °C; [R]22 +48.7 (c 0.5, CHCl3); IR
D
(CHCl3) 3540, 2120, 1070, 700 cm-1; 1H NMR (CDCl3) δ 7.40-
7.25 (m, 15H), 4.71 (d, 1H, J ) 11.7 Hz), 4.71 (d, 1H, J ) 11.8
Hz), 4.63 (d, 1H, J ) 11.7 Hz), 4.60 (d, 1H, J ) 11.8 Hz), 4.60
(d, 1H, J ) 11.7 Hz), 4.54 (d, 1H, J ) 11.7 Hz), 3.98 (dd, 1H,
J ) 5.6, 4.2 Hz), 3.94 (d, 1H, J ) 7.4 Hz), 3.86 (d, 1H, J ) 4.2
Hz), 3.74 (dd, 1H, J ) 12.0, 5.4 Hz), 3.73 (ddd, 1H, J ) 7.4,
5.6, 0.7 Hz), 3.50 (ddd, 1H, J ) 12.0, 8.0, 0.7 Hz), 3.27 (s, 1H),
2.06 (dd, 1H, J ) 8.0, 5.4 Hz); 13C NMR (CDCl3) δ 137.7, 137.5,

Pinacol Coupling Approach to Trehazolamine
J . Org. Chem., Vol. 63, No. 17, 1998 5889
137.4, 128.7-127.6 (15 C), 88.8, 87.0, 81.0, 80.1, 72.8 (2 C),
72.1, 66.1, 63.2.
Amino alcohol 32 was recrystallized from i-PrOH as a white
solid: Rf ) 0.55 (CH2Cl2 /MeOH 10:1); mp 105 °C; [R]22 +3.6
D
1
[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 (Tr eh a zola m in e) (3). To a solution of
27 (38 mg, 0.08 mmol) in EtOH/THF 3:1 (4 mL) were added
TFA (31 µL, 0.40 mmol) and 25% Pd(OH)2 on charcoal (135
mg). This mixture was stirred under H2 (2 atm) at room
temperature overnight. The reaction mixture was filtered
through Celite and the filter was washed with MeOH (4 × 50
mL) and water (50 mL). The solvent was removed at reduced
pressure and the residue was purified by column chromatog-
(c 0.6, CHCl3); H NMR (CDCl3) δ 7.36-7.27 (m, 20H), 4.72
(s, 2H), 4.69 (d, 1H, 11.6 Hz), 4.62 (d, 1H, 11.6 Hz), 4.61 (s,
2H), 4.52 (s, 2H), 4.02 (dd, 1H, J ) 6.1, 5.8 Hz), 3.94 (d, 1H, J
) 5.8 Hz), 3.55 (dd, 1H, J ) 7.9, 6.1 Hz), 3.54 (d, 1H, J ) 9.8
Hz), 3.47 (d, 1H, J ) 9.8 Hz), 3.27 (d, 1H, J ) 7.9 Hz), 3.00 (br
s, 1H); 13C NMR (CDCl3) δ 138.4, 138.2, 137.8, 137.7, 128.3-
127.6 (20 C), 86.5 (2C), 81.8, 77.1, 73.6, 73.2, 72.4, 72.3, 71.9,
63.1.
[1S-(1r,2r,3â,4r,5â)]-5-Am in o-1-(h ydr oxym eth yl)-1,2,3,4-
cyclop en ta n etetr ol (30). Following the same procedure as
for 3, its diastereoisomer 30 was obtained from 29 or 32 in
63% and 80% yield, respectively, as a white solid: Rf ) 0.37
+
raphy on Amberlite CG-50 (NH4 type). Elution with 0.5 M
aqueous NH3 afforded 3 (10 mg, 67%) as a white solid after
freeze-drying: Rf ) 0.53 (CH3CN/AcOH/H2O 6:1:3); [R]22D +2.0
1
(CH3CN/AcOH/H2O 6:1:3); mp 121-123 °C; [R]22 +2.3 (c 1.2,
(c 0.6, H2O); H NMR (D2O) δ 4.06 (dd, 1H, J ) 6.8, 5.7 Hz),
D
H2O); 1H NMR (D2O) δ 3.81 (dd, 1H, J ) 8.6, 8.4 Hz), 3.66 (d,
1H, J ) 8.6 Hz), 3.63 (s, 2H), 3.53 (dd, 1H, J ) 8.5, 8.4 Hz),
3.06 (d, 1H, J ) 8.5 Hz); 13C NMR (D2O) δ 79.8, 79.3, 77.3,
75.6, 64.7, 64.4.
3.95 (dd, 1H, J ) 6.6, 5.7 Hz), 3.78 (d, 1H, J ) 6.6 Hz), 3.78
(d, 1H, J ) 11.9 Hz), 3.72 (d, 1H, J ) 11.9 Hz), 3.25 (d, 1H, J
) 6.8 Hz); 13C NMR (D2O) δ 82.2, 81.9, 79.7, 73.7, 61.9, 58.5.
[1S-(1r,2r,3â,4r,5â)]-1-Am in o-3,4,5-t r is(b en xyloxy)-1-
(ben zyloxym eth yl)-1-cyclop en ta n ol (32). To a freshly
prepared 0.1 M solution of SmI2 in THF (31 mL, 3.13 mmol)
and t-BuOH (250 µL, 2.61 mmol) at -30 °C was added
dropwise a solution of 3116 (336 mg, 0.52 mmol) in THF (21
mL). After stirring for 1 h at -30 °C, the cooling bath was
removed, the reaction mixture was allowed to attain room
temperature. Water (282 µL, 15.66 mmol) was added and
stirring continued for 1 h. The reaction mixture was diluted
with EtOAc (50 mL) and aqueous saturated NaHCO3 (100 mL)
was added. The phases were separated, and the aqueous
phase was extracted with EtOAc (3 × 50 mL). The combined
organic extracts were washed with brine and dried over Na2-
SO4. The mixture was filtered and the solvent was removed
at reduced pressure. The crude was purified by flash chro-
matography (CH2Cl2/MeOH 60:1), affording 32 (250 mg, 88%).
Ack n ow led gm en t. This work was supported by
grants PB-93-0127-C02-01 and PB-96-0833 from DGES,
Ministerio de Educacio´n y Cultura of Spain.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 16-18, and
1H NOE data for compounds 12, 13, and trans-diols A and B
(3 pages). This material is contained in libraries on microfiche,
immediately 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.
J O980831B