Synthesis of pentahydroxylated pyrrolizidines and indolizidines

Article abstract of DOI:10.1021/jo900801c

(Equation Presented) 1,3-Dipolar cycloaddition reaction of nitrone 7 and chemo-enzymatically obtained alkenediols 12 and 13 has been used in the synthesis of pentahydroxylated pyrrolizidines (8 and 10) and indolizidines (9 and 11). The pyrrolizidinic and

Full text of DOI:10.1021/jo900801c

pubs.acs.org/joc
structure: pyrrolidines, piperidines, pyrrolizidines, indolizi-
Synthesis of Pentahydroxylated Pyrrolizidines and
Indolizidines†
dines, and nor-tropanes, all of them presenting several poly-
hydroxylation patterns within each group. Because of the
resemblance to carbohydrates, they have been employed as
tools in glycobiology to study recognition processes, particu-
larly those concerning the reactions catalyzed by glycosidases
and glycosyltranferases.3 The ubiquity of these enzymes in
living organisms, the tasks they play in vital processes like cell
function and recognition,4 and their role in the etiology of
diseases like cancer, HIV, and diabetes5 have raised the need
for new and active compounds against them.
Juan A. Tamayo,* Francisco Franco, Daniele Lo Re, and
ꢀ
Fernando Sanchez-Cantalejo
Department of Medicinal and Organic Chemistry, Faculty of
Pharmacy, University of Granada, Campus de Cartuja,
s/n 18071 Granada, Spain
jtamayo@ugr.es
Iminosugars are recognized by glycoside-processing en-
zymes because of their similarity to saccharides. In their
catalytic site, these carbohydrate mimics can be protonated
by a carboxylic moiety thus rendering the enzyme inhibi-
tion.6 In this respect, polyhydroxylated alkaloids contain in
their structure several stereogenic centers susceptible of
being modified, and hence making possible the synthesis of
a variety of stereoisomers with potential value as therapeutic
agents.5 (þ)-Casuarine (1) and (þ)-castanospermine (2) are
two examples of natural polyhydroxylated pirrolizidine and
indolizidine, respectively, both among the most active dis-
covered so far.7 In addition, and like Hyacinthacines C1 (3),
C2 (4), C3 (5), and C5 (6) (Figure 1), compounds 1 and 2
represent some of the most highly oxygenated natural ami-
no-sugars analogues identified.8 Several syntheses of these
Received April 17, 2009
(3) (a) Sinnot, M. L. Chem. Rev. 1990, 90, 1171. (b) Legler, G. Adv.
Carbohydr. Chem. Biochem. 1990, 48, 319. (c) Fleet, G. W. J.; Winchester, B.
Glycobiology 1992, 2, 199. (d) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet,
G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645.
(4) (a) Asano, N. Glycobiology 2003, 13, 93R. (b) Davies, G. J.; Gloster,
T. M.; Henrissat, B. Curr. Opin. Struct. Biol. 2005, 15, 637. (c) Rempel, B. P.;
Withers, S. G. Glycobiology 2008, 18, 570. (d) Nash, R. J. Bioactive Natural
Products; Colegate, S. M., Molyneux, R. J., Ed.; Summit Wales Limited:
Aberystwyth, UK, 2008; p 407. (e) Asano, N. Modern Alkaloids 2008, 111.
(5) (a) Iminosugars as Glycosidases Inhibitors: Norjirmycin and Beyond;
1,3-Dipolar cycloaddition reaction of nitrone 7 and che-
mo-enzymatically obtained alkenediols 12 and 13 has
been used in the synthesis of pentahydroxylated pyrroli-
zidines (8 and 10) and indolizidines (9 and 11). The
pyrrolizidinic and indolizidinic skeletons were built after
internal n-alkylation of the suitably functionalized pyr-
roloisoxazolidine intermediates obtained by the neces-
sary protecting group manipulations. This method
expands the scope of cycloaddition reactions in the
synthesis of new and highly polyhydroxylated sugar-like
alkaloids.
€
Stutz, A., Ed.; Wiley-VCH: Weinheim, Germany, 1999. (b) Asano, N.; Nash,
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645. (c)
Asano, N. Curr. Top. Med. Chem. 2003, 3, 471. (d) Cipolla, L.; La Ferla, B.;
Nicotra, F. Curr. Top. Med. Chem. 2003, 3, 485. (e) Butters, T. D.; Dwek, R. A.;
Platt, F. M. Curr. Top. Med. Chem. 2003, 3, 561. (f) Martin, O. R.; Compain, P.
Curr. Top. Med. Chem. 2003, 3, 541. (g) de Melo, E. B.; Gomes, A. D.; Carvalho,
I. Tetrahedron 2006, 62, 10277.
(6) (a) Asano, N.; Kato, A.; Oseki, K.; Kizu, H.; Matsui, K. Eur. J.
Biochem. 1995, 229, 369. (b) Legler, G. Glycosidase Inhibition by Basic
Sugar Analogs and the Transition State of Enzymatic Glycoside Hydrolysis.
€
In Iminosugars as Glycosidase Inhibitors; Stutz, A., Ed.; Wiley-VCH:
Weinheim, Germany, 1999, p 31. (c) Rye, C. S.; Withers, S. G. Curr. Opin.
Chem. Biol. 2000, 4, 573. (d) Jensen, H. H.; Lyngbye, L.; Bols, M. Angew. Chem.,
Int. Ed. 2001, 40, 3447. (e) Varrot, D.; Tarling, C. A.; Macdonald, J. M.; Stick, R.
V.; Zechel, D. L.; Withers, S. G.; Davies, G. J. J. Am. Chem. Soc. 2003, 125, 7496.
(7) For Castanospermine see: (a) Humphries, M. J.; Matsumoto, K.;
White, S. L.; Olden, K. Cancer Res. 1986, 46, 5215. (b) Walker, B. D.;
Kowalski, M.; Goh, W. C.; Kozarsky, K.; Krieger, M.; Rosen, C.; Rohrsch-
neider, L.; Haseltine, W. A.; Sodroski, J. Proc. Natl. Acad. Sci. U.S.A. 1987,
84, 8120. (c) Sunkara, P. S.; Taylor, D. L.; Kang, M. S.; Bowling, T. L.; Liu,
P. S.; Tyms, A. S. Lancet 1989, 1206. For Casuarine see: (d) Bell, A. A.;
Pickering, L.; Watson, A. A.; Nash, R. J.; Pan, Y. T.; Elbein, A. D.; Fleet, G.
W. J. Tetrahedron Lett. 1997, 38, 5869. (e) Cardona, F.; Parmeggiani, C.;
Faggi, E.; Bonaccini, C.; Gratteri, P.; Sim, L.; Gloster, T. M.; Roberts, S.;
Davies, G. J.; Rose, D. R.; Goti, A. Chem.;Eur. J. 2009, 15, 1627.
(8) (a) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.; Kizu,
H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Wormald, M. R.; Fleet, G. W.
J.; Asano, N. Carbohydr. Res. 1999, 316, 95. (b) Asano, N.; Kuroi, H.; Ikeda,
K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1. (c) Kato, A.; Kato, N.;
Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano,
N.; Nash, R. J. J. Nat. Prod. 2007, 70, 993.
Polyhydroxylated alkaloids are a well-known group of
natural compounds. They are normally isolated from water-
soluble fractions of medicinal plants,1 and microbial cultures.2
Also known as iminosugars or azasugars this family of com-
pounds is classified into five different classes according to their
†
a
ꢀ
Dedicated to Professor M Teresa Plaza Lopez-Espinosa on the occasion of
her retirement.
*To whom correspondence should be addressed. Fax: 0034-958-243845.
(1) (a) Yagi, M.; Kouno, T.; Aoyagi, Y.; Murai, H. Nippon Nogeikagaku
Kaishi 1976, 50, 571. (b) Murao, S.; Miyata, S. Agric. Biol. Chem. 1980, 44,
219. (c) Watanabe, S.; Kato, H.; Nagayama, K.; Abe, H. Biosci. Biotechnol.
Biochem. 1995, 59, 936.
(2) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R.
J. Phytochemistry 2001, 256.
DOI: 10.1021/jo900801c
r
Published on Web 07/02/2009
J. Org. Chem. 2009, 74, 5679–5682 5679
2009 American Chemical Society

Tamayo et al.
JOCNote
FIGURE 2. Novel non-natural pentahydroxylated pyrrolizidines
(8, 10), indolizidines alkaloids (9, 11), and dipolarophiles 12 and 13.
SCHEME 1. Retrosynthetic Analysis for Pentahydroxylated
Pyrrolizidines and Indolizidines
FIGURE 1. Examples of natural polyhydroxylated azasugar alka-
loids.
and related compounds can be found in the literature.9 One
popular and successful approach, because of its simplicity and
high overall yield, are 1,3-dipolar cycloaddition reactions on
cyclic nitrones.10 This method allows the introduction of the
nitrogen functionalityintothe cyclic system andthe formation
of two crucial bonds, C-C and C-O, in a single step, with the
advantage of a high diastereoselectivity.10f
A retrosynthetic analysis for indolizidine and pyrrolizi-
dine structures (Scheme 1) shows that their bicyclic rings
can both be achieved in several steps by means of inter-
mediate A. This substrate may result from a 1,3-dipolar
cycloaddition reaction of protected nitrone 7 and alkene-
diol derivative B. Subsequent protecting group modifica-
tions with the introduction of the necessary leaving group
would afford pyrroloisoxazolidine intermediates (C and D).
Final N-O cleavage of these intermediates would yield,
after intramolecular N-alkylation, both the indolizidine
and pyrrolizidine skeletons.
We report in this note on the synthesis of new pentahy-
droxy pyrrolizidines and indolizidines (8, 10 and 9, 11,
respectively, Figure 2) by means of a 1,3-dipolar cycloaddi-
tion of suitably protected cyclic nitrone 7, derived from
D-arabinose, with chemoenzymatically prepared 3-buten-
1,2-diol derivatives 12 and 13. The use of Chirazyme L-2,
c.-f., C2, lyo from Candida antarctica lipase-B in the regio-
selective transesterification of racemic mixtures of diols has
been described.11 Thus, when (R,S)-3-buten-1,2-diol was re-
acted with vinyl acetate in the presence of Chirazyme L-2, c.-f.
at room temperature, the chemoenzymatic reaction caused
selective acetylation of the mixture yielding first (R)-di-O-
acetyl-3-buten-1,2-diol (12, 44%, 64% ee) and second (S)-1-
O-acetyl-3-buten-1,2-diol (13, 46%, 61% ee)12 (Scheme 2),
which were easily separated by flash chromatography. With
chirons 12 and 13 in our hands we attempted the cycloaddition
reaction (Scheme 2). In this regard, nitrone 710d,10e,13 was
initially reacted with derivative 13. Pyrroloisoxazolidine 14
(70%) was isolated as the major adduct and its absolute
configuration was confirmed by NOE experiments. As pre-
dicted, the cycloaddition reaction proceeded through an exo-
mode to achieve predominantly the exo-anti cycloadduct 14,
anti referring to the relative position of the nitrone C-2 sub-
stituent and the direction of the incoming alkene.10b,10e,10f,10h-10j
Cycloadduct 14 was next transformed into mesylate 15. To
our delight, N-O cleavage of 15 using Zn/AcOH afforded
(9) For selected syntheses of Castanospermine and analogues see: (a)
Zhao, H.; Mootoo, D. R. J. Org. Chem. 1996, 61, 6762. (b) Michael, J. P. Nat.
Prod. Rep. 2004, 21, 625. (c) Karanjule, N. S.; Markad, S. D.; Shinde, V. S.;
Dhavale, D. D. J. Org. Chem. 2006, 71, 4667. (d) Izquierdo, I.; Tamayo, J. A.;
Rodriguez, M.; Franco, F.; Lo Re, D. Tetrahedron 2008, 64, 7910. (e)
Machan, T.; Davis, A. S.; Liawruangrath, B.; Pyne, S. G. Tetrahedron
2008, 64, 2725. For selected syntheses of Casuarine and analogues see: (f)
Bell, A. A.; Pickering, L.; Watson, A. A.; Nash, R. J.; Pan, Y. T.; Elbein, A.
D.; Fleet, G. W. J. Tetrahedron Lett. 1997, 38, 5869. (g) Denmark, S. E.;
Hurd, A. R. J. Org. Chem. 2000, 65, 2875. (h) Izquierdo, I.; Plaza, M. T.;
Tamayo, J. A. Tetrahedron 2005, 61, 6527. (i) Izquierdo, I.; Plaza, M. T.;
Tamayo, J. A. J. Carbohydr. Chem. 2006, 25, 281. (j) Van Ameijde, J.; Horne,
G.; Wormald, M. R.; Dwek, R. A.; Nash, R. J.; Jones, P. W.; Evinson, E. L.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2006, 17, 2702.
(10) For selected synthesis see : (a) McCaig, A. E.; Wightman, R. H.
Tetrahedron Lett. 1993, 34, 3939. (b) Goti, A.; Cicchi, S.; Cacciarini, M.;
Cardona, F.; Fedi, V.; Brandi, A. Eur. J. Org. Chem. 2000, 3633. (c) Goti, A.;
Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A. Org. Lett. 2001,
3, 1367. (d) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A.
Tetrahedron Lett. 2003, 44, 2315. (e) Carmona, A. T.; Wightman, R. H.;
Robina, I.; Vogel, P. Helv. Chim. Acta 2003, 86, 3066. (f) Cordero, F. M.;
Pisaneschi, F.; Batista, K. M.; Valenza, S.; Machetti, F.; Brandi, A. J. Org.
Chem. 2005, 70, 856. (g) Akai, S.; Tanimoto, K.; Kanao, Y.; Omura, S.; Kita,
Y. Chem. Commun. 2005, 18, 2369. (h) Argyropoulos, N. G.; Panagiotidis,
T.; Coutouli-Argyropoulou, E.; Raptopoulou, C. Tetrahedron 2007, 63, 321.
(i) Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Syntheis 2007, 4, 485–504.
(j) Stecko, S.; Jurczak, M.; Urbanczyk-Lipkowska, Z.; Solecka, J.; Chmielewski,
M. Carbohydr. Res. 2008, 343, 2215.
(11) (a) Izquierdo, I.; Plaza, M. T.; Rodriguez, M.; Tamayo, J. A.
Tetrahedron: Asymmetry 2000, 11, 1749. (b) Naoshima, Y.; Kamezawa,
M.; Kimura, T.; Okimoto, F.; Watanabe, M.; Tachibana, H.; Ohtani, T.
Recent Res. Dev. Org. Bioorg. Chem. 2001, 4, 1. (c) Izquierdo, I.; Plaza, M. T.;
Rodriguez, M.; Tamayo, J. A. Eur. J. Org. Chem. 2002, 2, 309. (d) Izquierdo,
I.; Plaza, M. T.; Rodriguez, M.; Tamayo, J. A. Synthesis 2003, 9, 1357.
(e) Adachi, S. Handbook of Industrial Biocatalysis; Taylor & Francis/CRC:
Boca Raton, FL, 2005; pp 10/1-10/15.(f) Izquierdo, I.; Plaza, M. T.;
Tamayo, J. A.; Franco, F.; Sanchez-Cantalejo, F. Tetrahedron 2008, 64,
4993.
(12) The ee of (R)-di-O-acetyl-3-buten-1,2-diol (64% ee) and (S)-1-O-
acetyl-3-buten-1,2-diol (61% ee) were determined by chiral GLC (see Sup-
porting Information).
ꢀ
(13) (a) Desvergnes, S.; Py, S.; Vallee, Y. J. Org. Chem. 2005, 70, 1459. (b)
Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A. J. Org. Chem. 2006, 71, 1614.
5680 J. Org. Chem. Vol. 74, No. 15, 2009

Tamayo et al.
JOCNote
SCHEME 2. Synthesis of Pyrrolizidine 8
SCHEME 4. Synthesis of Pyrrolizidine 10
SCHEME 5. Synthesis of Indolizidine 11
SCHEME 3. Synthesis of Indolizidine 9
then chemically modified in two steps to afford silyl derivative
27. As described before, leaving group introduction in 27
followed by N-O cleavage and intramolecular N-alkylation
afforded pyrrolizidine 29 through intermediate 28. Protecting
group removal yielded 10 (31% overall yield, from 25).
Likewise, cycloadduct 25 was employed in the synthesis of
indolizidine 11. Alcohol 27, previously obtained from 25,
was conveniently transformed into methanesulfonate 33. As
described in Scheme 5, 33 was transformed into indolizidine
34 by means of intermediate E (not isolated). Final benzyl
groups removal in 34 yielded indolizidine 11 (28% overall
yield from 27).
In conclusion, a convenient and efficient method to
synthesize chemical libraries of pyrrolizidines and indolizi-
dines alkaloids is described. By way of 1,3-dipolar cycload-
dition reaction and intramolecular N-alkylation as key
reactions, four new highly polyhydroxylated azasugar alka-
loids (8, 9, 10, and 11) have been characterized. This is an
example of diversity-oriented organic synthesis14 based on
the versatility of two chemoenzymatically prepared alkene-
diols 12 and 13. To the best of our knowledge these are the
first examples of pyrrolizidine and indolizidine alkaloids
presenting such hydroxylation patterns. Further investiga-
tions on the biological activity of these compounds will be
published in due course.
pyrrolizidine 16 (60%) in a single step through intramole-
cular N-alkylation that took place spontaneously after basic
workup (TLC evidence). The stereochemistry of 16 was
confirmed by analytical and spectroscopic analysis and
matched with the one predicted. Deacetylation of 16 with
Ambersep 900 (OH- form) resin to diol 17 (83%) and
subsequent catalytic hydrogenation in acidic media afforded
pyrrolizidine 8 (22% overall yield).
On a similar approach, introduction of a leaving group at
the primary OH group at C-20 in pyrroloisoxazolidine 14
could give rise to the indolizidine skeleton (see intermediate
D, Scheme 1). Hence, attempts to orthogonally protect the
OH group at C-10 in 14 with MEMCl, TBDMSCl, or TESCl
proved unsuccessful, probably because of the steric hin-
drance posed by the benzyl groups at the C-4 and C-6
positions. Only acetylation was effective at the cost of an
increased number of steps. Thus (see Scheme 3), intermediate
21, obtained from alcohol 14 in four steps (36% yield), was
transformed into methanesulfonyl derivative 22 and, as
described for derivative 15, converted into indolizidine 23
(68%). Its absolute configuration was confirmed by NOE
experiments. Protecting groups removal of 23 afforded
indolizidine 9 in 6% overall yield.
Experimental Section
Once we probed the convenience of this methodology in the
synthesis of pyrrolizidine 8 and indolizidine 9 alkaloids, chiron
12 was used in the synthesis of compounds 10 and 11, epimers
at C-5 and C-6 of 8 and 9, respectively. Hence, compound 25
was obtained as the major product (74% yield) in the cycload-
dition reaction of nitrone 7 with alkene 12 (Scheme 4). 25 was
Enzymatic Acetylationof Racemic 3-Buten-1,2-diol. Toa gently
stirred solution of (R,S)-3-buten-1,2-diol (8.8 g, 100 mmol) and
(14) For selected reviews see: (a) Schreiber, S. L. Science 2000, 287, 1964.
(b) Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867. (c) Spandl, R. J.; Bender,
A.; Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149.
J. Org. Chem. Vol. 74, No. 15, 2009 5681

Tamayo et al.
JOCNote
vinyl acetate (18.5 mL, 200 mmol) in TBME-ether (1:1, 150 mL)
was added Chirazyme L-2, c.-f. C2 (200 mg), and the mixture was
maintained at rt with stirring. The reaction was monitored by
GLC analysis (see the Supporting Information) and after 7 h
revealed the absence of starting material and the presence of two
higher retention time compounds. The enzyme was removed
by filtration and thoroughly washed with ether. The filtrate
and washings were concentrated to a residue that was subjected
to column chromatography (Et2O-hexane, 1:1) to afford first
(R)-di-O-acetyl-3-buten-1,2-diol (12, 7.7 g, 44%),15 tR=4.25 min
(conditions A: see the Supporting Information); tR=10.73 min
(conditions B); ee 64%, [R]25D -3.4, [R]24577 -4.2, [R]25546 -5.8,
2.08 (2s, 6H, 2 Ac); 13C NMR (75 MHz, CDCl3) δ 170.9 and
170.3 (2 Ac), 138.5, 138.2, 138.0, 128.8, 128.7, 128.6, 128.13,
128.09, 128.06, 128.04, 128.00, 127.8 (Ph), 87.4 (C-4), 84.2 (C-5),
75.4 (C-2), 73.6, 72.5, 72.1 (3 CH2Ph), 71.5 (C-8), 70.3 (C-6),
70.1 (C-7), 68.4 (C-3a), 63.1 (C-9), 36.4 (C-3), 21.3 and 21.0
(2 CH3CO); HRMS (NALDI-TOF) cacld for C34H40NO8
[MþH]þ 612.2573, found 612.2524.
(1R,2R,3R,5R,6R,7aR)-1,2-Benzyloxy-3-benzyloxymethyl-5-
tert-butyldiphenylsilyloxymethyl-6-hydroxypyrrolizidine (29). A
mixture of 28 (133 mg, 0.16 mmol) and Zn dust (80 mg) in
AcOH/H2O 9:1 (2 mL) was heated to 60 °C for 6 h. TLC
(AcOEt-hexane, 3:1) showed the absence of 28 and the presence
of a compound with a lower Rf. The reaction mixture was
filtered through cotton and washed with AcOEt. The solvent
was washed with a saturated solution of Na2CO3 and evapo-
rated to a residue that was purified by FC (AcOEt-hexane,
3:1) to afford 29 (90 mg, 76%) as a colorless syrup. [R]25D -2.3,
[R]25
-8.5 (c 1 in CHCl3) [lit.15 [R]25 þ4.9, [R]24
þ6.9,
405
D
577
[R]25 þ9.8 (c 2.1 in CHCl3) for (S)-12]. Second was obtained
546
(S)-1-O-acetyl-3-buten-1,2-diol (13, 6.12 g, 46.4%), [R]24 -3.7
D
(c 2 in CHCl3), tR = 3.03 min (conditions A). Conventional
acetylation of (S)-13 (260 mg, 1.97 mmol) in anhydrous pyridine
(1 mL) and Ac2O (0.5 mL) gave, after column chromatography
(Et2O-hexane, 1:1), (S)-(þ)-12 (289 mg, 84%), tR = 4.25 min
(conditions A), tR=10.24 min (conditionsB), ee61%, [R]27D þ3.8
(c 2.6 in CHCl3). The spectroscopic data of 13 were identical with
those previously reported.16
[R]25
-38 (c 0.5 in CHCl3); IR νmax/cm-1 3417 (OH);
405
1H NMR (500 MHz, CDCl3) δ 7.74-7.21 (m, 25H, 5 Ph),
4.51-4.35 (m, 6H, CH2Ph), 4.27 (br d, 1H, H-6), 4.11 (m, 2H,
0
H-2,9), 4.05 (dd, 1H, J9,9 =10.6 Hz, J5,9 =6.0 Hz, H-9 ), 4.00
0
0
(br s, 1H, H-1), 3.72 (br t, 1H, H-3), 3.63 (m, 1H, H-7a), 3.42 (m,
2H, H-8,80), 3.31 (br dd, 1H, H-5), 2.29 (ddd, 1 H, J7,7 =14.0 Hz,
(10S,2R,3aR,4R,5R,6R)-4,5-Dibenzyloxy-6-benzyloxymethyl-
2-(1,2-diacetyloxyethyl)hexahydropyrrolo[1,2-b]isoxazole (25).
A solution of 7 (54 mg, 0.13 mmol) and 12 (60 mg, 0.46 mmol)
in anhydrous DCM (0.2 mL) was heated at 70 °C under
microwave irradiation in a sealed tube with an Ar atmosphere.
After 4 h, TLC (AcOEt-hexane, 3:1) revealed the presence of a
new compound of higher Rf. The solvent was removed and the
residue was purified by FC (AcOEt-hexane, 1:3) yielding 25
(56 mg, 74%) as a colorless syrup: [R]30D -51 (c 1 in CHCl3); IR
0
J=6.0 Hz, J=9.5 Hz, H-7), 1.84 (ddd, 1H, J=5.2 Hz, J=
7.9 Hz), 1.07 (s, 9H, CMe3); 13C NMR (125 MHz, CDCl3)
δ 138.5, 138.1, 137.3, 135.7, 133.3, 133.2, 129.7, 128.4, 128.2,
128.0, 127.9, 127.8, 127.73, 127.70, 127.61, 127.57, 127.4, (Ph),
88.6 (C-1), 86.2 (C-2), 74.2 (C-6), 73.0 (Bn), 72.6 (C-8), 71.8 (Bn),
71.5 (Bn), 68.2 (C-7a), 67.5 (C-5), 62.9 (C-3), 61.3 (C-9), 39.4
(C-7), 26.9 (CMe3), 19.2 (CMe3); HRMS (NALDI-TOF) cacld
for C46H54NO5Si [MþH]þ 728.3777, found 728.3771.
ν
max/cm-1 1748 (CO); 1H NMR (500 MHz, CDCl3) δ 7.44-7.22
0
(m, 15H, 3Ph), 5.16 (dt, 1H, J8,9 =6.2, J2,8=5.8, J8,9=3.2 Hz,
Acknowledgment. Major support was provided by Ministerio
0
H-8), 4.64-4.48 (m, 6H, 3 CH2Ph), 4.39 (dd, 1H, J9,9 =12.2 Hz,
ꢀ
de Educacion y Ciencia of Spain (Project ref. CTQ2006-14043).
Additional support was provided by Junta de Andalucıa (Group
BIO-250). We also acknowledge the University of Granada
H-9), 4.31 (br q, 1H, H-2), 4.11 (dd, 1H, H-90), 4.07 (dd, 1H,
´
J
5,6=5.6, J4,5=4.1 Hz, H-5), 3.98 (t, 1H, J3a,4=3.7 Hz, H-4),
0
3.83-3.74 (m, 1H, H-3a), 3.71 (dd, 1H, J7,7 = 9.9 Hz, J6,7 =
4.6 Hz, H-7), 3.61 (dd, 1H, J6,7 =6.4 Hz, H-7 ), 3.34 (br q, 1H,
0
ꢀ
(Spain) for a grant (D.L.R.) and Fundacion Ramon Areces for
ꢀ
0
a grant (F.S.-C.).
0
H-6), 2.33 (ddd, 1H, J3,3 =12.6 Hz, J3,3a=8.8 Hz, J2,3=7.0 Hz,
0
0
H-3), 2.24 (dt, 1H, J3 ,3a=7.23 Hz, J2,3 =8.8 Hz, H-3 ), 2.1 and
0
Supporting Information Available: Characterization data,
full experimental procedures and copies of NMR spectra and
chromatograms. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) (a) Kowalczyk, A.; Harris, C. M.; Harris, T. M. Chem. Res. Toxicol.
2001, 14, 746. (b) Ono, H.; Retboll, M. Japanese Patent 2002-105028, April
10, 2002.
(16) Kirsch, S. F.; Overman, L. E. J. Am. Chem. Soc. 2005, 127, 2866.
5682 J. Org. Chem. Vol. 74, No. 15, 2009