Synthesis of enantiomerically pure, highly functionalized, medium-sized carbocycles from carbohydrates: Formal total synthesis of (+)-calystegine B2

Article abstract of DOI:10.1021/jo0111107

The free radical cyclization (FR) and the ring-closing metathesis (RCM) reaction have been analyzed in order to develop new and original synthetic protocols for the synthesis of enantiomerically pure, highly functionalized, medium-sized carbocycles from carbohydrates. As a result, we report here for the first time examples of the 7-exo FR cyclization of acyclic radical precursors derived from sugars. This process appears to be extremely sensitive to the conformational mobility of the radical species in the transition state. The use of two isopropylidene groups blocking four of the total present hydroxyl groups and a good radical acceptor (as an α,β-unsaturated ester) are mandatory conditions for a successful ring closure protocol. The RCM reaction by using Grubbs' catalyst on selected carbohydrate-derived precursors has afforded variable yields of the expected unsaturated cycloheptane or cycloctane derivatives. The synthesis of the cycloheptitols has been carried out in good yields, regardless of the absolute configuration at the different stereocenters and the nature of the O-functional groups bound in allylic positions to one of the double bonds implicated in the metathesis reaction. Conversely, in the cyclooctane synthesis, we have observed that the success of the reaction depends not only on the absolute configuration at the different stereocenters close to the double bonds but also on the nature of the O-protecting groups on these stereocenters. Finally, the RCM strategy has been used in an attempt to prepare natural (+)-calystegine B₂ from D-glucose. The synthesis of compound 92 from D-glucose constitutes a formal total synthesis of (+)-calystegine B₂, showing the importance of the steric hindrance in allylic positions for a successful RCM reaction.

Full text of DOI:10.1021/jo0111107

J . Org. Chem. 2002, 67, 3705-3717
3705
Syn th esis of En a n tiom er ica lly P u r e, High ly F u n ction a lized ,
Med iu m -Sized Ca r bocycles fr om Ca r boh yd r a tes: F or m a l Tota l
Syn th esis of (+)-Ca lystegin e B2
J ose´ Marco-Contelles* and Elsa de Opazo
Laboratorio de Radicales Libres (CSIC), C/ J uan de la Cierva 3, 28006-Madrid, Spain
iqoc21@iqog.csic.es
Received November 28, 2001
The free radical cyclization (FR) and the ring-closing metathesis (RCM) reaction have been analyzed
in order to develop new and original synthetic protocols for the synthesis of enantiomerically pure,
highly functionalized, medium-sized carbocycles from carbohydrates. As a result, we report here
for the first time examples of the 7-exo FR cyclization of acyclic radical precursors derived from
sugars. This process appears to be extremely sensitive to the conformational mobility of the radical
species in the transition state. The use of two isopropylidene groups blocking four of the total present
hydroxyl groups and a good radical acceptor (as an R,â-unsaturated ester) are mandatory conditions
for a successful ring closure protocol. The RCM reaction by using Grubbs’ catalyst on selected
carbohydrate-derived precursors has afforded variable yields of the expected unsaturated cyclo-
heptane or cycloctane derivatives. The synthesis of the cycloheptitols has been carried out in good
yields, regardless of the absolute configuration at the different stereocenters and the nature of the
O-functional groups bound in allylic positions to one of the double bonds implicated in the metathesis
reaction. Conversely, in the cyclooctane synthesis, we have observed that the success of the reaction
depends not only on the absolute configuration at the different stereocenters close to the double
bonds but also on the nature of the O-protecting groups on these stereocenters. Finally, the RCM
strategy has been used in an attempt to prepare natural (+)-calystegine B2 from D-glucose. The
synthesis of compound 92 from D-glucose constitutes a formal total synthesis of (+)-calystegine B2,
showing the importance of the steric hindrance in allylic positions for a successful RCM reaction.
In tr od u ction
strates for testing the viability of these strategies for the
preparation of chiral and densely functionalized, medium-
sized carbocycles. An elegant example and precedent for
this strategy was reported by Depezay and co-workers
some years ago.4k
The synthesis of medium-sized rings, notably seven-
and eight-membered ring systems, has usually been
hampered by entropic/enthalpic factors and transannular
interactions between the methylene groups.1 These are
serious limitations, which have usually resulted in low
chemical yields of the desired products.2 Although some
solutions to this formidable challenge have been ad-
vanced using cycloaddition or annulation strategies,3 the
cyclization approach for the synthesis of these structures
still remains a partially unsolved problem.4 In view of
these difficulties, we reasoned that precursors derived
from carbohydrates could probably be excellent sub-
In this paper, we disclose full details of our recent
efforts on the synthesis of polyhydroxylated, medium-
sized ring systems in an enantiomerically pure form.5 We
have particularly directed our attention6to the free radi-
cal mediated (FR) cyclization7 and the ring-closing me-
tathesis (RCM)8 reaction, two well-known strategies for
ring closure protocols. We have applied the FR strategy
to selected carbohydrate precursors 1-6 (Figure 1) and
(1) (a) Molander, G. Acc. Chem. Res. 1998, 31, 603. (b) Iluminati,
G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95. (c) Yet, L. Chem. Rev.
2000, 100, 2963. (d) Yet, L. Tetrahedron 1999, 55, 9349.
(4) For some selected references on the synthesis of seven-membered
ring systems, see: (a) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.;
Pollini, G. P.; Zanirato, V. Tetrahedron 1999, 55, 5923. (b) Lautens,
M.; Rovis, T. J . Am. Chem. Soc. 1997, 119, 11090. (c) Yoshizaki, H.;
Yoshioka, K.; Sato, Y.; Mori, M. Tetrahedron 1997, 53, 5433. (d)
Pearson, A.; Katiyar, S. Tetrahedron 2000, 56, 2297. (e) Pearson, A.;
Srinivassan, K. J . Org. Chem. 1992, 57, 3965. (f) Falk-Heppner, M.;
Hunger, U.; Keller, M.; Kaiser, C.; Krieger, R.; Friz, H.; Prinzbach, H.
Liebigs Ann./ Recl 1997, 1481. (g) Trost, B. M.; Organ, M. G. J . Am.
Chem. Soc. 1994, 116, 10320. (h) J ohnson, C. R.; Bis, S. J . J . Org.
Chem. 1995, 60, 615. (i) J ohnson, C. R.; Golebioski, A.; Steensma, D.
H. J . Am. Chem. Soc. 1992, 114, 9414. (j) Le Merrer, Y.; Gravier-
Pelletier, C.; Maton, W.; Numa, M.; Depezay, J .-C. Synlett 1999, 1322.
(k) Duclos, O.; Dure´ault, A.; Depezay, J . C. Tetrahedron Lett. 1992,
33, 1059. (l) Wender, P. A.; Takahashi, H.; Witulski, B. J . Am. Chem.
Soc. 1995, 117, 4720.
(2) For reviews on the synthesis of eight-membered rings, see: (a)
Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (b) Rousseau,
G. Tetrahedron 1995, 51, 2777. (c) Mehta, G.; Singh, V. Chem. Rev.
1999, 99, 881. For some selected papers, see: (d) Molander, G.; McKie,
J . A. J . Org. Chem. 1994, 59, 3186. (e) Edwards, S. D.; Lewis, T.; Taylor,
R. J . K. Tetrahedron Lett. 1999, 40, 4267. (f) Wang, W.; Zhang, Y.;
Sollogoub, M.; Sinay¨, P. Angew. Chem., Int. Ed. 2000, 39, 2466. (g)
Wang, W.; Zhang, Y.; Zhou, H.; Ble´riot, Y.; Sinay¨, P. Eur. J . Org. Chem.
2001, 1053. (h) Werschkung, B.; Thiem, J . Angew. Chem., Int. Ed. Engl.
1997, 36, 2793. (i) Fu¨rstner, A.; Langemann, K. J . Org. Chem. 1996,
61, 8746. (j) Crimmins, M. T.; Choy, A. L. J . Am. Chem. Soc. 1999,
121, 5653. (k) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J . Am.
Chem. Soc. 2000, 122, 7815. (l) Bourgeois, D.; Mahuteau, J .; Pancrazi,
A.; Nolan, S. P.; Prunet, J . Synthesis 2000, 869. (m) van Hooft, P. A.
V.; Litjens, R. E. J . N.; van der Marel, G. A.; van Boeckel, C. A. A.;
van Boom, J . H. Org. Lett. 2001, 3, 731-735.
(5) Hanessian, H. Total Synthesis of Natural Products: The “Chiron
Approach”; Pergamon Press: Oxford, 1983.
(6) For a previous effort in this area using intramolecular 1,3-dipolar
cycloaddition reaction on 7-alkenyl nitrones derived from D-mannose,
see: Marco-Contelles, J .; de Opazo, E. Tetrahedron Lett. 1999, 40, 4445.
(3) See for example: (a) Rigby, J . H. Acc. Chem. Res. 1993, 26, 579.
(b) Lautens, M. Top. Curr. Chem. 1997, 190, 1.
10.1021/jo0111107 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/07/2002

3706 J . Org. Chem., Vol. 67, No. 11, 2002
Marco-Contelles and de Opazo
F igu r e 1. Radical precursors derived from D-mannose for the
free radical strategy.
F igu r e 3. Radical precursors derived from D-glucose for the
ring-closing metathesis strategy.
Due to the growing number of natural compounds
containing medium-sized rings with attractive biological/
pharmacological activity,9,10 these synthetic efforts will
presumably be useful for a rational design directed
toward the synthesis of some members of this family of
molecules. As a practical example, we describe here our
work directed toward the synthesis of the glucosidase
11
inhibitor (+)-calystegine B2 from D-glucose (Figure 4).
Resu lts a n d Discu ssion
A. F r ee Ra d ica l Cycliza tion Ap p r oa ch . In the last
thirteen years, we have intensively and systematically
analyzed the samarium diiodide and/or tributyltin hy-
dride mediated free radical cyclizations of carbohydrate
F igu r e 2. Radical precursors derived from D-glucose for the
free radical strategy.
(8) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371. (c) Schuster,
M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d)
Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(e) Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833. (f)
Fu¨rstner, A. Top. Catal. 1997, 4, 285. (g) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012. (h) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18. (i) For a recent short review on the synthesis of
medium-sized rings by RCM reaction, see: Maier, M. E. Angew. Chem.,
Int. Ed. 2000, 39, 2073.
to compounds 31-38 (Figure 2), prepared from D-man-
nose and from D-glucose, respectively, to investigate the
scope, synthetic potential, and limitations of this method
for the synthesis of seven- or eight membered-ring
systems. Using the RCM strategy, we have also explored
the reactivity of intermediates (60-66) (Figure 3) ob-
tained form D-glucose for the synthesis of unsaturated
cyclohepta- or cycloctapolyol derivatives.
(9) (a) Banwell, M. G. Aust. J . Chem. 1991, 44, 1. (b) Fraga, B. M.
Nat. Prod. Rep. 1992, 9, 217.
(10) Kupchan, S. M.; Eakin, A.; Thomas, A. M. J . Med. Chem. 1971,
14, 1147.
(11) (a) Goldmann, A.; Milat, M. L.; Ducrot, P. H.; Lallemand, J .-
Y.; Maille, M.; Lepingle, A.; Charpin, I.; Tepfer, D. Phytochemistry
1990, 29, 2125. (b) Goldmann, A.; Message, B.; Tepfer, D.; Molyneux,
R.; Duclos, O.; Boyer, F.-D.; Pan, Y. T.; Elbein, A. D. J . Nat. Prod.
1996, 59, 1137.
(7) (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986. (b) Giese, B.;
Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J .; Trach,
F. Org. React. 1996, 48, 301. (c) Curran, D. P. Synthesis 1988, 417,
489. (d) Motherwell, M. B.; Crich, D. Free Radical Chain Reactions in
Organic Synthesis; Academic Press: London, 1991.

Formal Total Synthesis of (+)-Calystegine B2
J . Org. Chem., Vol. 67, No. 11, 2002 3707
Sch em e 1. Syn th esis of P r ecu r sor 1 for F R
Cycliza tion a
F igu r e 4. Calystegine B2.
precursors for the synthesis of cyclitols.12 Particular effort
has been dedicated to exploring the synthetic scope of
the 6-exo-trig free radical cyclization of acyclic intermedi-
ates12a and branched-chain sugars on furanose tem-
plates.12b Now we have focused our attention into the
7-exo-trig or 7-exo-dig free radical cyclization of open-
chain, conveniently functionalized, radical precursors
derived from sugars. In fact, the 7-exo mode of cyclization
has been scarcely documented in literature,1d,13,14 and to
the best of our knowledge, in the sugar domain, only two
examples have been recently described in furanose15a or
pyranose15b templates.
For the first experiments,16 we have synthesized the
acyclic radical precursors 1-6 (Figure 1) from readily
available and known 2,3:5,6-bis-O-isopropylidene-D-man-
nose (7).17 Following well-known or standard protocols,
we obtained the selected radical precursors according to
the synthetic sequences shown in Schemes 1-5.18a
a
Reagents: (a) see ref 18; (b) NaH, BnBr, Bu4NI, THF, 0 °C
(92%); (c) 4/1 AcOH/H2O, rt (82%); (d) ClTs, py, DMAP, 0 °C (85%);
(e) Ac2O, py, rt (85%); (f) NaI, acetone, reflux (78%).
Sch em e 2. Syn th esis of P r ecu r sor 2 for F R
Cycliza tion a
The addition of ethynylmagnesium bromide to lactol
7 is a known protocol that gives major anti product
(8),19which could be easily manipulated (di-O-benzylation,
acid hydrolysis, and selective tosylation of the primary
hydroxyl group, followed by peracetylation and reaction
with sodium iodide) via intermediates 9-12 for the
synthesis of precursor 1 (Scheme 1). The addition of
lithium phenylacetylide to the same lactol (7) gave major
(12) (a) Marco-Contelles, J .; Mart´ınez-Grau, A. Chem. Soc. Rev.
1998, 27, 155. (b) Marco-Contelles, J .; Alhambra, C.; Mart´ınez-Grau,
A. Synlett 1998, 693 (corrigendum: Synlett 1999, 376).
(13) For some examples of 7-exo cyclizations, see: (a) Stork, G.; Suh,
H. S.; Kim, G. J . Am. Chem. Soc. 1991, 113, 7054. (b) Clark, A. J .;
J ones, K.; McCarthy, C.; Storey, J . M. D. Tetrahedron Lett. 1991, 32,
2829. (c) Boger, D. L.; Mathvink, R. J . J . Org. Chem. 1992, 57, 1429.
(d) Evans, P. A.; Manangan, T. Tetrahedron Lett. 1997, 38, 8165. (e)
Yuasa, Y.; Sato, W.; Shibuya, S. Synth. Commun. 1997, 27, 573. (f)
Miyabe, H.; Torieda, M.; Kiguchi, T.; Naito, T. Synlett 1997, 580. (g)
Kim, S.; Kee, I. S. Tetrahedron Lett. 1993, 34, 4213. (h) Booth, S. E.;
J enkins, P. R.; Swain, C. J . J . Chem. Soc., Chem. Commun. 1991, 1248.
(i) Moody, C. J .; Norton, C. L. Tetrahedron Lett. 1995, 36, 9051. (j)
Boeck, B. D.; Herbert, N.; Pattenden, G. Tetrahedron Lett. 1998, 39,
6971. (k) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew.
Chem., Int. Ed. 2000, 39, 731.
(14) For 7-endo-trig ring closures, see: (a) Redlich, H.; Sudau, W.;
Szardenings, A. K.; Vollerthum, R. Carbohydr. Res. 1992, 226, 57. (b)
Cid, M. M.; Dom´ınguez, D.; Castedo, L.; Va´zquez-Lo´pez, E. Tetrahedron
1999, 55, 5599. (c) Andre´s, C.; Duque-Saldan˜a, J . P.; Iglesias, J . M.;
Pedrosa, R. Synlett 1997, 1391. (d) Brown, C. D. S.; Dishington, A. P.;
Shishkin, O.; Simpkins, N. S. Synlett 1995, 943. (e) Colombo, L.;
Giacono, M. D.; Scolastico, C.; Manzoni, L.; Belvisi, L.; Molteni, V.
Tetrahedron Lett. 1995, 36, 625.
a
Reagents: (a) see ref 20a (lithium phenylacetylide, THF, 0 °C);
(b) NaH, BnBr, Bu4NI, THF, 0 °C (68%); (c) 4/1 AcOH/H2O, rt
(90%); (d) ClTs, py, DMAP, 0 °C (50%); (e) Ac2O, py, rt (85%); (f)
NaI, acetone, reflux (74%).
syn adduct 13 (Scheme 2);20a this is in agreement with
the reported stereoselectivity for the reaction of lithium
reagents with the same substrate.20b The same synthetic
sequence as before for the synthesis of precursor 1 (see
above) finally gave compound 2. The addition of vinyl-
magnesium bromide to intermediate 7 gave major anti
derivative 18 as described.19d This compound was also
transformed into the known diol 19,17 which after selec-
tive tosylation at the primary hydroxyl group, followed
by O-benzoylation and reaction with sodium iodide as
usual, via compounds 20 and 21, afforded precursor 3
(Scheme 3). Using also the alditol 18,19d after perbenzoyl-
ation, partial acid hydrolysis, and bromination, we could
(15) (a) Kim, G.; Kim, H. S. Tetrahedron Lett. 2000, 41, 225. (b)
Leeuwenburgh, M. A.; Litjens, R. E. J . N.; Code´e, J . D. C.; Overkleeft,
H. S.; van der Marel, G. A.; van Boom, J . H. Org. Lett. 2000, 2, 1275.
(16) For a preliminary communication on this subject, see: Marco-
Contelles, J .; de Opazo, E. Tetrahedron Lett. 2000, 41, 5341 (in this
paper, the stereochemistry at carbons C-3 and C-4 in compounds 31
and 32 were drawn incorrectly).
(17) Van Boggelen, M. P.; van Dommelen, B. F. G. A.; J iang, S.;
Singh, G. Tetrahedron 1997, 53, 16897.
(18) (a) See Supporting Information. (b) See Experimental Section.
(19) (a) Buchanan, J . G.; Dunn, A. D.; Edgar, A. R. Carbohydr. Res.
1974, 36, C5-C7. (b) Buchanan, J . G.; Dunn, A. D.; Edgar, A. R.
Carbohydr. Res. 1974, C5, 36. (c) Gaudino, J . J .; Wilcox, C. S. J . Am.
Chem. Soc. 1990, 112, 4374. (d) Shing, T. K. M.; Elsey, D. A.;
Gillhouley, J . G. J . Chem. Soc., Chem. Commun. 1989, 1280.
(20) (a) Marco-Contelles, J .; de Opazo, E.; Arroyo, N. Tetrahedron
2001, 57, 4729. (b) Corey, E. J .; Pan, B. Ch.; Hua, D. H.; Deardorff, D.
R. J . Am. Chem. Soc. 1982, 104, 6816. (c) Marco-Contelles, J .; de Opazo,
E. J . Carbohydr. Chem. 2001, 7-8, 637.

3708 J . Org. Chem., Vol. 67, No. 11, 2002
Marco-Contelles and de Opazo
Sch em e 3. Syn th esis of P r ecu r sor 3 for F R
Cycliza tion a
Sch em e 6. F r ee Ra d ica l Cycliza tion of
P r ecu r sor s 1 a n d 6a
a
Reagents: (a) [(CH3)3Si]3SiH, AIBN, toluene [28, 19% (48%);
29, 0 %]; (b) E3tB (2×), Ph3SnH, -78 °C [28, 80%; 29, 11 %; (E)-
30, 40%; (Z)-30, 17%]; (c) E3tB (2×), Ph3SnH, rt (28, 47%; 29, 16%).
aldehyde 27 was obtained in a very straightforward
process. Subsequent Wittig reaction and standard oxime
ether formation gave precursors 5 and 6, respectively
(Scheme 5). All these precursors showed excellent ana-
lytical and spectroscopic data.18a
From compound 1 and use of TTMS (tristrimethylsi-
lylsilane) (or triphenyltin hydride) plus AIBN, with slow
addition of reagents, an incomplete and complex reaction
resulted, from which we could only isolate the reduced,
uncyclized derivative 28 (Scheme 6). A more clear reac-
tion was observed when AIBN was substituted by tri-
ethylborane. In this case, when the reaction was per-
formed at -78 °C, in addition to product 28 (80%), we
isolated the (Z)-stannylidene derivative 29 in 11% yield.
When the reaction was carried out at room temperature,
we obtained compounds 28 and 29 in 47 and 16% yields,
respectively.18a
a
Reagents: (a) see ref 19d; (b) see ref 17; (c) ClTs, py, 0°C (60%);
(d) BzCl, py, DAMP, 0 °C (70%); (e) NaI, acetone, reflux [50%
(80%)].
Sch em e 4. Syn th esis of P r ecu r sor 4 for F R
Cycliza tion a
a
Reagents: (a) ClBz, py, DMAP, 0 °C (65%); (b) 4/1 AcOH/H2O,
rt (60%); (c) CBr4, Ph3P, rt (60%).
Sch em e 5. Syn th esis of P r ecu r sor s 5 a n d 6 for
F R Cycliza tion a
Radical precursor 2 afforded recovered starting mate-
rial and a complex reaction mixture, which was not
further elaborated. Very surprisingly, the same negative
results were obtained with the isopropylidene-containing
precursors 3 and 4.
In view of these unsuccessful results, we turned our
attention to precursors 5 and 6, where more efficient
radical traps were incorporated. Despite this, for com-
pound 5, a complex reaction occurred from which we
could not reliably identify a reaction product. From oxime
ether 6, only the stannylated derivative 30 (isolated as
a mixture of (E)- and (Z)-isomers) was obtained (Scheme
6).18a After these experiments, it was obvious that more
conformationally restricted precursors were needed for
a successful cyclization.
Then, we designed and prepared derivatives 31-3818a
(Figure 2). These products were obtained from D-glucose
as a starting material via intermediates 3921 and 4422
(Schemes 7 and 8, respectively).
Iodination of compoud 3921 followed by desulfuration
(HgO, HgCl2, acetone, water) afforded aldehyde 4020
(Scheme 7). The preferential anti addition of vinylmag-
nesium bromide, phenylmagnesium bromide, or ethynyl-
magnesium bromide to this aldehyde gave major com-
pounds 31,20a 32,20a and 41,20a respectively. Oxidation of
alcohols 32 and 41 with PCC and Dess-Martin’s23
a
Reagents: (a) t-BuPh2SiCl, py, DMAP, 0 °C (88%); (b) IMe,
NaH, BuNI, THF, 0 °C (60%); (c) Bu4NF, THF, rt (75%); (d) PCC,
CH2Cl2, NaOAc, molecular sieves, rt (65%); (e) Ph3PdCHCO2Me,
CH2Cl2, rt [(E)-5 (77%), (Z)-5 (14%)]; (f) BnONH3Cl, py, rt [9:1 (E)-
6/(Z)-6 (77%)].
prepare precursor 4 (Scheme 4). Finally, and from
intermediate 10 (Scheme 1), after selective silylation at
the primary hydroxyl group, permethylation, desilylation,
and oxidation, via products 24-26, the key and common
(21) Wong, M. Y. H.; Gray, G. R. Carbohydr. Res. 1980, 80, 87.
(22) Ng, C. J .; Stevens, J . D. Methods Carbohydr. Chem. 1968, 7, 7.
(23) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.

Formal Total Synthesis of (+)-Calystegine B2
J . Org. Chem., Vol. 67, No. 11, 2002 3709
Sch em e 7. Syn th esis of th e Ra d ica l P r ecu r sor s
Sch em e 9. F r ee Ra d ica l Cycliza tion of
P r ecu r sor s 36a
31-36a
a
Reagents: (a) see ref 20a; (b) see ref 20a; (c) PCC, NaOAc,
CH2Cl2, molecular sieves, rt [from 32 to 33: 56% (63%)], Dess-
Martin [from 41 to 34: 60% (66%)]; (d) see ref 20c; (e) BnONH3Cl,
py, rt (E, 56%; E + Z (1:1), 33%; total, 89%); (f) Ph3PdCHCO2Me,
CH2Cl2, rt (E, 73%; Z, 8%; total, 81%).
Sch em e 8. Syn th esis of th e Ra d ica l P r ecu r sor s
37 a n d 38a
a
Reagents: (a) AIBN, Bu3SnH, toluene, 80 °C.
Sch em e 10. F r ee Ra d ica l Cycliza tion of
P r ecu r sor s 37 a n d 38a
a
Reagents: (a) AIBN, Bu3SnH, toluene, 80 °C, slow addition,
5 h.
a
Reagents: (a) Ph3PdCHCO2Me, CH2Cl2, rt (4/1 Z/E) (86%);
(b) Dess-Martin [(Z)-45 (56%); (E)-45 + (Z)-45 (6/4, 30%); (c)
aldehyde 46; then, the major (Z)-46 isomer was reacted
with ethynylmagnesium bromide to give an almost
equimolecular mixture of the anti and syn isomers, 37
and 38, respectively. The configuration at the newly
formed stereocenter in these compounds could not be
determined at this point, but it was finally established
in the resulting carbocycles after free radical cyclization
(see below). All these precursors showed excellent ana-
lytical and spectroscopic data.18a
ethynylmagnesium bromide, THF, 0 °C [from (Z)-45].
method gave the ketones 33 and 34, respectively. Don-
doni’s one-carbon homologation24 on aldehyde 4020a af-
forded the expected aldehyde 4320c via intermediate 42.20a
Final oxime ether formation or Wittig reaction on anti
aldehyde 43 gave precursor 35 and the R,â-unsaturated
ester 36 (Scheme 7).
Compound 4422 afforded a mixture of (E)- and (Z)-
isomers of the R,â-unsaturated esters 45, which without
separation, were submitted together to oxidation to give
The results of the cyclization of these substrates are
shown in Schemes 9-11. In the usual free radical
cyclization conditions mediated by tributyltin hydride,
compound 31 afforded compound 47 in a reasonable
(24) Dondoni, A. Synthesis 1998, 1681.

3710 J . Org. Chem., Vol. 67, No. 11, 2002
Marco-Contelles and de Opazo
Sch em e 11. Tr a n sition Sta te for th e F r ee Ra d ica l
Cycliza tion of P r ecu r sor 36
tal conditions followed by chromatography and acetyla-
tion afforded four products (48-51) (Scheme 9). Com-
pound 51 (14%) was the acetylated, unreacted starting
material; product 50 (20%) was the reduced, uncyclized
material oxidized at C-3,29 and finally, compounds 48
(12%) and 49 (14%) were the expected 7-exo-dig resulting
molecules. The structures of these carbocycles were
clearly confirmed by their NMR and analytical data18a
and consequently confirmed the anti stereochemistry at
carbons C-3 and C-4 in precursor 32.
Despite the complex cyclization reaction from precursor
32, these results prove that the 7-exo-dig cyclization of
an acyclic, polyfunctionalized precursor is possible, af-
fording low yields of the desired products. To expand and
improve these results, precursor 33 was submitted to
cyclization, giving compounds 52 and 53, albeit in low
overall yield [26% (30%)] (Scheme 9).18a
Very interestingly, the FR cyclization of precursor 34
(Figure 2) afforded a complex reaction mixture. Unfor-
tunately, we were unable to isolate and reliably identify
a reaction product.
To control the regiochemistry and the efficiency of the
carbocyclization reaction, more friendly radical acceptors
such as the oxime ether (in precursor 35) and the R,â-
unsaturated ester (in precursor 36) were tested next.
Very surprisingly, the cyclization of compound (E)-35
(Figure 2) afforded a complex reaction mixture from
which we could isolate some derivatives in a poor
chemical balance whose structures could not be estab-
lished. This is in sharp contrast to the reported moderate
to good yields in our previously documented reaction of
6-exo-trig free radical of related precursors with oxime
ethers as radical traps.30
Not unexpectedly the free radical cyclization compound
(E)-36 was more satisfactory, and again, only one isomer
(54) (Scheme 10), in 50% chemical yield, was detected
and isolated. The absolute configuration at the newly
formed stereocenter at C-1 was assigned as R on the basis
of the strong NOE effect between H-1 and H-2 and the
full and detailed spectroscopic analysis.18b
chemical yield (50%) (Scheme 9),25 whose NMR and
analytical data clearly confirmed that this material was
the cyclooctane derivative 4718b and, consequently, the
anti stereochemistry at carbons C-3 and C-4 in precursor
31. Briefly, product 47 should be the result of the FR
cyclization of a primary radical into the double bond in
the endo mode. The formation of this 8-endo-trig26
product was not unexpected in view of the theoretical and
experimental results described by Beckwith and Schiess-
er.27 This is indeed a rare example of a FR cyclization
reaction leading to a cyclooctane derivative from carbo-
hydrates26b and confirmed our expectations about the
critical importance of the two isopropylidene groups for
directing and promoting effective ring annulation.28
However, the results were not satisfactory regarding our
decided interest in the preparation of seven-membered
ring systems.
Then, we reasoned that in order to prevent the 8-endo
mode of cyclization, the incorporation of a substituent at
the terminal position, by simple steric interactions, would
prevent this chemical path, favoring the alternate 7-exo
mode of cyclization. To implement this concept, we tested
precursor 32, with a phenyl group located at the terminal
acetylene carbon. FR cyclization in the usual experimen-
The success of the R,â-unsaturated ester as a radical
acceptor moved us to submit radical precursors 37 and
38 to cyclization (Scheme 11). FR cyclization of precursor
37 afforded carbocycle 55 in a reasonable yield (55%). The
same synthetic protocol, from compound 38, afforded
carbocycle 56 in 60% yield. The analytical and spectro-
scopic data showed that, in both cases (55 and 56), only
one stereoisomer at the newly formed stereocenter and
at the exo double bond was present after FR cyclization.
We could also demonstrate that the stereochemistry at
the newly formed stereocenter (C-1) was R in both cases
and the stereochemistry was Z at the exo double bond.18b
In agreement with this, in the 1H NMR spectra of
compound 55, we could detect NOE effects between H-8
and H-9 (securing the Z double-bond geometry), H-1 and
H-9′, H-1 and H-3 (no significant NOE effect could be
detected between protons H-1 and H-2 or H-9) (establish-
ing R as the configuration at C-1), H-5 and H-6, and H-3
and OH (determining the anti stereochemistry in precur-
sor 37). As expected, in the 1H NMR spectra of compound
56, we could detect NOE effects between H-8 and H-9
(25) In this reaction, we also detected traces of a mixture of
compounds (one of them possibly the reduced, uncyclized derivative
of product 31), which we were unable to separate, analyze, and
characterize.
(26) For free radical 8-endo ring closures, see: (a) Manzoni, L.;
Belvisi, L.; Scolastico, C. Synlett 2000, 1287. (b) Chattopadhyay, P.;
Mukherjee, M.; Ghosh, S. Chem. Commun. 1997, 2139. (c) Gibson, S.
E.; Guillo, N.; Tozer, M. J . Chem. Commun. 1997, 637. (d) Hutchinson,
J . H.; Dayhard, T. S.; Gillard, J . W. Tetrahedron Lett. 1991, 32, 573
(in this case, the ratio 7-exo , 8-endo has been justified by the
relatively long Si-O bond and the large O-Si-O bond angle). (e)
Galatsis, O.; Millan, S. D.; Faber, T. J . Org. Chem. 1993, 58, 1215. (f)
Ghosh, K.; Ghosh, A. K.; Ghatak, R. J . Chem. Soc., Chem. Commun.
1994, 629.
(27) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41, 3925.
(28) The importance of preexisting heterocycles in selected positions
and orientations on acyclic precursors for successful carbocyclization
processes has been previously demostrated in our laboratory: (a)
Marco-Contelles, J .; Ruiz, P.; Mart´ınez, L.; Mart´ınez-Grau, A. Tetra-
hedron 1993, 49, 6669. (b) Marco-Contelles, J .; Bernabe´, M.; Ayala,
D.; Sa´nchez, B. J . Org. Chem. 1994, 59, 1234. For an application of
the results reported in ref 28b, see: (c) Go´mez, A. M.; Danelo´n, G. O.;
Valverde, S.; Lo´pez, J . C. J . Org. Chem. 1998, 63, 9626 (corrigendum:
J . Org. Chem. 1999, 64, 7280).
(29) The formation of derivative 50 from compound 32 was unex-
pected and can be possibly attributed to the tin-mediated oxidation of
the propargylic alcohol in the reaction conditions.
(30) Marco-Contelles, J .; Pozuelo, C.; J imeno, M. L.; Mart´ınez, L.;
Mart´ınez-Grau, A. J . Org. Chem. 1992, 57, 2625.

Formal Total Synthesis of (+)-Calystegine B2
J . Org. Chem., Vol. 67, No. 11, 2002 3711
Sch em e 12. Tr a n sition sta te for th e fr ee r a d ica l
cycliza tion of p r ecu r sor 36 P r ecu r sor s 31-33a
F igu r e 5. Grubbs’ catalyst.
Sch em e 13. Tr a n sition Sta te for th e F r ee Ra d ica l
Cycliza tion of p r ecu r sor s 37 a n d 38
(securing the Z double-bond geometry), H-1 and H-9′, and
H-2 and H-4 or H-6, and no NOE effect was detected
between H-1 and H-2 (establishing R as the configuration
at C-1). A very significant vicinal coupling constant (J )
7.9 Hz between protons H-5 and H-6) was analyzed for a
trans arrangement of these protons, in agreement with
the syn stereochemistry at carbons C-7 and C-8 in
precursor 38.
Scheme 12 shows a possible rationale for the formation
of the major isomer during the free radical cyclization of
precursor (E)-36. According to Beckwith’s model,27 in the
transition state leading to carbocycle 55, the 7-exo-trig
free cyclization of the radical species from precursor 36,
conformers 57A and 57B should be operative. In fact, the
chairlike conformer 57A, with most of the substituents
in a preferred pseudoequatorial orientation, with the
O-benzyloxy group at C-3 in an anti orientation regarding
the â-vinyl proton in the double bond, and the radical
trap in a pseudoequatorial orientation, should be more
stable and afford the experimentally observed carbocycle
with the substituent at the newly formed stereocenter
located in the R-orientation. Conversely, conformer 57B
should be more disfavored in the equilibrium of conform-
ers as the radical trap is in a pseudoaxial orientation in
a more sterically demanding situation. For precursors
(Z)-37 and (Z)-38, tributyltin radical attack on the
acetylene moiety gives a vinyl radical species 58A with
the radical acceptor in a pseudoequatorial orientation
(compare with the less favored conformer 58B) (Scheme
13), which should afford, after cyclization, carbocycles 55
and 56 with the same absolute configuration at the newly
formed stereocenters (C-1), regardless of the absolute
configuration at the propargylic carbon in the precursor.
The formation of only one (Z)-stannylidene derivative has
been documented in literature and is consistent with a
reversible attack of the tributyltin radical to give major
cis vinyl radical species A.31
In summary, we have analyzed for the first time the
7-exo free radical cyclization of acyclic radical precursors
derived from sugars for the synthesis of enantiomerically
pure, highly functionalized, medium-sized rings. We
conclude that the FR cyclization strategy is extremely
sensitive to the conformational freedom of the radical
species in the transition state. Apparently, the use of two
isopropylidene groups blocking four of the total present
hydroxyl groups and a good radical acceptor are manda-
tory conditions for a successful ring formation. In these
conditions, we have obtained highly stereoselective reac-
tions, with strong stereochemical control, leading to
almost diastereomerically pure molecules at the newly
formed stereocenters.
B. Rin g-Closin g Meta th esis Ap p r oa ch . We have
also investigated the synthetic possibilities of the in-
tramolecular ring-closing metathesis reaction.8 This is an
increasingly popular method for the preparation of car-
bocycles that has been largely used in sugar templates
for the synthesis of unsaturated cyclopentitols and con-
duritols.32 Particularly attractive in this methodology are
(a) the mild reaction conditions, (b) the cheap and easy
manipulation of the Grubbs’ catalyst (59, Figure 5), and
(c) a simple experimental protocol that usually affords
high chemical yields. Very recently, we reported the first
synthesis of highly functionalized, medium-sized rings
from sugar templates using this strategy.33,b
(31) Nozaki, K.; Oshima, K.; Utimoto, K. J . Am. Chem. Soc. 1987,
109, 2547.

3712 J . Org. Chem., Vol. 67, No. 11, 2002
Marco-Contelles and de Opazo
Sch em e 14. Syn th esis of P r ecu r sor s 60-66a
Sch em e 15. RCM Rea ction of P r ecu r sor s 60-63a
a
Reagents: (a) (i) Ph3PdCH2, THF, -20 °C (84%), (ii) DMSO,
DCC, CF3CO2H, rt, toluene (73%); (b) vinylmagnesium bromide,
THF, 0 °C (60/61, 7/3, 73%); (c) Ac2O, py, rt (from 60 to 62, 90%);
(from 64 to 66, 80%); (d) Dess-Martin (60%); (e) allylmagnesium
bromide, THF, 0 °C (64/65, 9/1, 80%).
In this context, we describe here the synthesis and
RCM of the precursors 60-66 (Figure 3) for the prepara-
tion of unsaturated cyclohepta- and cyclooctapolyols,
respectively. These cycloalkanols are ideal intermediates
for the synthesis of enantiomerically pure polyhydroxyl-
ated heptanes (or octanes), very well-known precursors
for the synthesis of glycosidase inhibitors,34 antitumor-
als,35 or C-glycosides.36
The synthesis of the precursors 60-66 has been
achieved from compound 67 as shown in Scheme 14 from
lactol 4422 (Scheme 8), after Wittig reaction and oxida-
tion.18a Vinylmagnesium bromide addition to aldehyde 67
gave two products (60 and 61) in 73% yield, the major
being the anti isomer 60, which showed a lower vicinal
coupling constant (J 6,7 ) 0 Hz) compared to the value
observed in product 61 (J 6,7 ) 4.0 Hz). This tentative
assignment was confirmed after their transformation into
“cyclic” derivatives (see below). Intermediates 60 and 61
were used to prepare the O-acetyl (62) derivative and the
olefin-tethered, R,â-unsaturated ketone (63). Precursors
(64-66) have also been prepared from the same aldehyde
(67) as shown in Scheme 14.18a In this case, we used the
allylmagnesium bromide reagent for the chain sugar
a
Reagents: (a) Grubbs’ reagent (10%), methylene chloride, rt;
(b) DIBALH, toluene, -78 °C [68 (70%) + 69 (10%)]; (c) Ac2O, py,
rt (96%).
elongation and obtained compounds 64/65 in a better
anti/syn ratio (8:1, respectively) and in good combined
chemical yield (80%). As in the precedent case, the anti/
syn assignment was confirmed after the carbocyclization
step (see below).
(32) For reviews on the metathesis reaction on sugar templates,
see: (a) Roy, R.; Das, S. K. Chem. Commun. 2000, 519. (b) J orgensen,
M.; Hadwiger, P.; Madsen, R.; Stu¨tz, A.; Wrodnigg, T. M. Curr. Org.
Chem. 2000, 4, 565. For selected papers on this subject, see: (c) Ovaa,
H.; Code´e, J . D. C.; Lastdrager, B.; Overkleeft, H. S.; van der Marel,
G. A.; van Boom, J . H. Tetrahedron Lett. 1998, 39, 7987. (d) Ziegler,
F. E.; Wang, Y. J . Org. Chem. 1998, 63, 7920. (e) Kornienko, A.;
d’Alarca, M. Tetrahedron: Asymmetry 1999, 10, 827. (f) Sellier, O.;
Van de Weghe, P.; Le Nouen, D.; Strehler, C.; Eustache, J . Tetrahedron
Lett. 1999, 40, 853. (g) Kapferer, P.; Sarabia, F.; Vasella, A. Helv. Chim.
Acta 1999, 82, 645. (h) Delgado, M.; Mart´ın, J . D. J . Org. Chem. 1999,
64, 4798. (i) Hyldtoft, L.; Poulsen, C. S.; Madsen, R. J . Am. Chem. Soc.
2000, 122, 8444. (j) Dirat, O.; Vidal, T.; Langlois, Y. Tetrahedron Lett.
1999, 40, 4801. (k) Seepersaud, M.; Al-Abed, Y. Org. Lett. 1999, 1, 1463.
(l) Lee, W.-W.; Chang, S. Tetrahedron: Asymmetry 1999, 10, 4473. (m)
Gallos, J . K.; Koftis, T. V.; Sarli, V. C.; Litinas, K. E. J . Chem. Soc.,
Perkin Trans. 1 1999, 3075. (n) Callam, C. S.; Lowary, T. L. Org. Lett.
2000, 2, 167. (o) Ackermann, L.; El Tom, D.; Fu¨rstner, A. Tetrahedron
2000, 56, 2195. (p) Holt, D. J .; Barker, W. D.; J enkins, P. R.; Davies,
D. L.; Garrat, S.; Fawcett, J .; Russell, D. R. Ghosh, S. Angew. Chem.,
Int. Ed. 1998, 37, 3298.
(33) (a) Marco-Contelles, J .; de Opazo, E. J . Org. Chem. 2000, 65,
5416. (b) Marco-Contelles, J .; de Opazo, E. Tetrahedron Lett. 2000,
41, 2439. For other recent papers on the synthesis of cyclohept- and
cyclooctenols via ring-closing metathesis reactions on sugar precursors,
see: (c) Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651. (d) Boyer, F.-D.;
Hanna, I.; Nolan, S. P. J . Org. Chem. 2001, 66, 4094. (e) McNulty, J .;
Grunner, V.; Mao, J . Tetrahedron Lett. 2001, 42, 5609.
(34) Aoyagi, S.; Fujimaki, S.; Kibayashi, C. J . Chem. Soc., Chem.
Commun. 1990, 1457.
(35) Miller, S. A.; Chamberlain, A. R. J . Am. Chem. Soc. 1990, 112,
8100.
With these products in hand, we tested the RCM
reaction in the typical experimental conditions (rt, me-
thylene chloride as the solvent, 0.02 M) using Grubbs’
catalyst (10%). The RCM of the diastereomerically pure
anti precursor 60 gave the expected cycloheptitol (68) in
88% yield (Scheme 15). The RCM of an inseparable
mixture of the anti/syn precursors 60/61 afforded the
mixture of cycloheptitols 68 and 69 in 83% total yield,
which were easily separated by chromatography, allowing
us to obtain pure carbocycle 69. The new compounds
showed good analytical and spectroscopic data.18b Par-
ticularly significant in compound 68 were the trans 1,2-
diaxial (8.7 Hz) vicinal coupling constant for protons H-5/
H-6 and H-5/H-4, which suggests a compound in a
preferred chairlike conformation,4d and the vicinal cou-
pling constant for H-1/H-7 (2.6 Hz), a value that places
these protons in a cis arrangement, coherent with the
assigned anti stereochemistry at carbons C-7/C-6 in
precursor 60. Regarding compound 69, the epimer at C1,
the observed, typical trans 1,2-diaxial vicinal coupling
constants (J 4,5 ) 9.6 Hz, J 5,6 ) 8.3 Hz) indicate that
hydroxyl groups at C1 and C5 are located in a pseu-
doequatorial orientation, suggesting a preferred boatlike
conformation. In agreement with data obtained in com-
(36) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: London,
1995.

Formal Total Synthesis of (+)-Calystegine B2
J . Org. Chem., Vol. 67, No. 11, 2002 3713
Sch em e 16. RCM Rea ction of P r ecu r sor s 64-66a
pound 68 for the vicinal coupling constant for protons
H-1/H-7, here this value is higher (J 1,7 ) 7.9 Hz),
confirming the syn stereochemistry at carbons C-7 and
C-6 in precursor 61. Note also that both precursors 60
and 61 were transformed very efficiently and in a very
quick reaction, regardless of the absolute configuration
at C-7. As shown also by the reactivity of the acetyl
derivative 62 (Scheme 15), the effect of the protecting
group was also negligible, as a good chemical yield of
product 70 (86%) was obtained.
The RCM of the R,â-unsaturated ketone 63 is note-
worthy as the reaction proceeded without any additive
(Lewis acid or titanium complex) to give cycloheptenone
71 in 80% yield. The spectroscopic analysis of this sample
showed the typical pattern for a cyclohept-2-en-1-one.18b
Although it is well-known that electron-deficient alkenes
are poor precursors for RCM reactions,37 some examples
involving mainly acrylates have been described, these
reactions requiring the presence of Lewis acids or tita-
nium complexes.38In fact, olefin-tethered R,â-unsaturated
ketones have been rarely tested in the RCM.39 In a recent
example described by Paquette,39a the use of Grubbs’
catalyst in large amounts and for an extended period of
time gave only a modest yield of the annulated product;
to improve the chemical yield, the new N,N′-bis(mesityl)-
imidazol-2-ylidene Ru-carbene complex had to be used.40
The reduction of ketone 71 with DIBALH, at low tem-
peratures, afforded a mixture of the 1,2-reduced deriva-
tives 68 (major) and 69 (minor), identical in their
spectroscopic and physical data to similar samples ob-
tained in RCM processes (see above), in good yield with
moderate diastereoselectivity (7:1). This result is coherent
with similar observations reported previously.4j,m
a
Reagents: (a) Grubbs’ reagent (10%), methylene chloride (0.02
M), 30 H, rt; (b) Ac2O, py, rt.
medium-sized ring.2 However, and very interestingly, in
the usual conditions, the major anti acetylated precursor
66 afforded the cycloctane 77 in an almost quantitative
yield.
These examples show the importance of the absolute
configuration at the stereocenters at homoallylic positions
and the type of functional or O-protecting groups at these
positions for a successful RCM reaction. This is a very
well-known fact described previously by us33a,b and
others.33c,d,41 In summary, the ring-closing metathesis
reaction, using commercially available Grubbs’ catalyst,
on selected sugar-like precursors has afforded variable
yields of the expected unsaturated cycloheptane or cy-
cloctane derivatives. Cycloheptitols have been obtained
in good yields, regardless of the absolute configuration
at the different stereocenters and the nature of the
functional groups at allylic positions. Conversely, in the
RCM for the cyclooctane synthesis, we have observed that
these factors critically determine the chemical yield and
the efficiency of the ring-closing reaction.
To summarize, the RCM metathesis of the chiral, fully
polyhydroxylated nonadienes (69-72) proceeds efficiently
to give the desired and expected unsaturated cyclohep-
titols in a synthetic protocol that compares very well with
other described approaches.4
As regards the RCM reaction of the analogous chiral,
fully polyhydroxylated 1,9-decadienes for the synthesis
of the unsaturated cyclooctanols, the first experiments
were not very encouraging. Following the general method
for the RCM reaction, precursor 64 afforded a dimer 72
(characterized as its peracetate 73), as the only isolated
compound, in very poor yield (5%) (Scheme 16).18a With
the epimer at C7, precursor 65, the reaction was not very
successful again, as the desired cycloctane 74 was
obtained in 17% yield (27% taking into account the
recovered starting material) along with dimer 75 [1%
yield (2% taking into account the recovered starting
material)], characterized as its peracetate 76.18a As
C. F or m a l Tota l Syn th esis of (+)-Ca lystegin e B2.
To investigate a practical synthetic application of the
RCM reaction in the synthesis of natural products
containing medium-sized rings, we considered the syn-
1
expected, in the H NMR spectrum, we could analyze a
11
vicinal coupling constant, J 1,8 ) 9.5 Hz, a value that
confirmed the syn stereochemistry at carbons C-7 and
C-6 in precursor 74. These results are coherent with
known difficulties reported for the synthesis of this
thesis of (+)-calystegine B2 (Figure 4), a very well-
known glycosidase inhibitor42 that selectively inhibits the
rat liver â-glucosidase and the human lysosomal R-ga-
lactosidase A (R-Gal A) with an IC50 value of 30 µM.
Several syntheses of this molecule have been reported.43
(37) Carda, M.; Castillo, E.; Rodr´ıguez, S.; Uriel, S.; Marco, J . A.
Synthesis 1999, 1639.
(41) (a) Hammer, K.; Undheim, K. Tetrahedron 1997, 53, 5925. (b)
Efskind, J .; Romming, C.; Undheim, K. J . Chem. Soc., Perkin Trans.
1 1999, 1677. (c) Hammer, K.; Romming, C.; Undheim, K. Tetrahedron
1998, 54, 10837. (d) Holt, D. J .; Barker, W. D.; J enkins, P. R.; Davies,
D. L.; Garratt, S.; Fawcett, J .; Russell, D. R.; Ghosh, S. Angew. Chem.,
Int. Ed. 1998, 37, 3298.
(42) For a recent, excellent review on the glycosidase inhibitors,
see: Asano, N.; Nash, R. J .; Molyneux, R. J .; Fleet, G. W. J .
Tetrahedron: Asymmetry 2000, 11, 1645.
(38) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J .; Nolan
S. P. J . Org. Chem. 2000, 65, 2204 and refs 16-18 cited therein.
(39) (a) Efremov, I.; Paquette, L. A. J . Am. Chem. Soc. 2000, 122,
9324. (b) Krikstolaiyte, S.; Hammer, K.; Undheim, K. Tetrahedron Lett.
1998, 39, 7595. (c) Hammer, K.; Undheim, K. Tetrahedron 1997, 53,
2309, 5925.
(40) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.

3714 J . Org. Chem., Vol. 67, No. 11, 2002
Marco-Contelles and de Opazo
Sch em e 17. Rin g-Closin g Meta th esis Ap p r oa ch
for Ca lystegin e B2
Sch em e 18. Syn th esis of th e RCM P r ecu r sor s 79
a n d 83-86a
a
Reagents: (a) see ref 2g,h; (b) BnNH2, CH2Cl2, 5 days, rt (70%),
Our retrosynthetic analysis is shown in Scheme 17. The
key compound 78, with the correct absolute configuration
at the different stereocenters, is conveniently function-
alized for the synthesis of the target molecule after
oxidation and hydrogenation. In turn, it is expected that
this product should result after metathesis reaction of
intermediate 79. The choice of methyl-R-D-glucopyrano-
side 80 as a starting material was the obvious issue.
Then, the synthetic strategy was relayed on by the two-
carbon-chain elongation in a D-glucose derivative at C-1
(possibly via vinylmagnesium addition on a suitable
glucosylamine intermediate) and the one-carbon homolo-
gation at C-6 (possibly via Wittig reaction), the key point
being the control of the desired configuration at the
carbon incorporating the nitrogen substituent.
(c) CH2dCHMgBr, Et2O, rt (65%); (d) Ac2O, py (from 83 to 84,
73%; from 79 to 85, 93%); (e) ClCbz, NaHCO3 (88%); (f) Dess-
Martin (80%).
Sch em e 19. RCM of P r ecu r sor s 85 a n d 86a
To investigate the viability of this strategy, we pre-
pared compound 81 (Scheme 18) as described.2g,h Reaction
of this lactol with benzylamine in methylene chloride
gave an inseparable mixture of anomers 82 in 70% yield.
Vinylmagnesium addition to this mixture afforded the
expected compound 83 as an inseparable mixture of
isomers (1.5:1), the major isomer presumably being the
syn adduct, according to the reported stereoselective syn
addition of allylmagnesium bromide to related substrates
described by Nicotra et al.44 With this satisfactory result,
which enabled us to attack the synthesis of natural (+)-
calystegine B2, we investigated the RCM on precursor
83 or on the differently functionalized compounds (79,
84-86) prepared using standard methodology (Scheme
18).18a
In our standard conditions (see above), using Grubbs’
catalyst, unfortunately in no case was a clear and
efficient carbocyclization observed. Only in the case of
the 3-O-acetyl N-(benzyl)carbamate 85 and the olefin-
tethered R,â-unsaturated ketone 86 did we detect me-
tathesis products 87 and 88, respectively, in low yields
(Scheme 19). These molecules showed good analytical and
spectroscopic data.18a Very interestingly, clear NOE ef-
a
Reagents: (a) Grubbs’ (10%), CH2Cl2, rt, 3 days [8% (40%)];
(b) Grubbs (10%), CH2Cl2, rt, Ti(OPr)4, [4% (6%)].
fects between the corresponding protons, allowed us to
assign the anti stereochemical arrangement at carbons
C-6 and C-7 in product 87 and at carbons C-4 and C-5 in
compound 88.
At this point of the project, we reasoned that the steric
hindrance at the allylic carbon containing the protected
nitrogen atom in our precursors would probably prevent
the carbocyclization reaction. To test this hypothesis we
designed the new precursor 92 (Scheme 20) in which one
of the terminal double bonds has a methylene group in
the allylic position, free of steric constraints. It was
expected that this 1,8-nonadiene should give a convenient
carbocyclic derivative (93) for further transformation into
the desired target molecule. The synthesis of compound
92 has been achieved as shown in Scheme 20, starting
from compound 80 via the known intermediate 89.45 The
reaction of this lactol with benzylamine followed by
treatment with allylmagnesium bromide gave compound
91 in good yield as an inseparable mixture of syn/anti
isomers in a 3:1 ratio, the syn derivative being tentatively
assigned as the major isomer.44 Several synthetic alter-
natives were possible in order to transform this 1,2-diol
into the desired olefin; we chose the most simple protocol
described by Garegg for this transformation.46 Not un-
(43) For the synthesis of calystegine B2 using the RCM reaction,
see: (a) Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2001, 42, 1275. (b)
Skaanderup, P. R.; Madsen, R. Chem. Commun. 2001, 1106. For other
synthetic approaches, see ref 4k and: (c) Faitg, T.; Soulie´, J .; Lalle-
mand, J .-Y.; Ricard, L. Tetrahedron: Asymmetry 1999, 10, 2165. (d)
Soulie´, J .; Faitg, T.; Betzer, J .-F.; Lallemand, J .-Y. Tetrahedron 1996,
52, 15137. (e) Boyer, D.; Lallemand, J .-Y. Tetrahedron 1994, 50, 10443.
(f) Duclos, O.; Mondange, M.; Dure´ault, A.; Depezay, J .-C. Tetrahedron
Lett. 1992, 33, 8061.
(44) Cipolla, L.; La Ferla, B.; Peri, F.; Nicotra, F. Chem. Commun.
2000, 1289.
(45) Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.; Nakata,
M. J . Antibiot. 1991, 44, 456.

Formal Total Synthesis of (+)-Calystegine B2
J . Org. Chem., Vol. 67, No. 11, 2002 3715
°C (bath temperature). After complete reaction, the solvent was
removed and the residue dissolved in a 1:1 mixture of ethyl
ether/15% aqueous solution of KF and vigorously stirred
overnight. Then, the organic layer was separated, dried,
filtered, and evaporated, and the residue was submitted to
chromatography (eluting with hexane/ethyl acetate mixtures)
to give the product.
Sch em e 20. Syn th esis of P r od u ct 92 (F or m a l
Tota l Syn th esis of Ca lystegin e B2)a
Gen er a l Meth od for th e Rin g-Closin g Meta th esis Re-
a ction . To a solution of the precursor in dry methylene
chloride (0.02 M) was added the Grubbs’ catalyst (10% mol).
The mixture was stirred at room temperature for the indicated
time in each case. When the reaction was complete, the solvent
was removed and the residue was submitted to chromatogra-
phy (eluting with hexane/ethyl acetate mixtures) to give the
carbocyclic compound.
F r ee Ra d ica l Cycliza tion of Com p ou n d 31. Precursor
31 (85.3 mg, 0.21 mmol) was treated according to the General
Method for FR Cyclization to give compound25 47 (30 mg, 50%)
after chromatography (93/7 hexane/ethyl acetate). 47: mp 65-
25
67 °C; [R]D +5 (c 0.13, CHCl3); IR (film) ν 3600-3200 (OH),
3000, 2960, 1570, 1350, 1250, 1100 cm-1; 1H NMR (300 MHz,
CDCl3) δ 4.30 (t, J 2,3 ) J 3,4 ) 8.4 Hz, 1 H, H-3), 4.19-4.12 (m,
3 H, H-1, H-4, H-5), 3.71 (dd, J 2,3 ) 8.4 Hz, J 1,2 ) 2.3 Hz, 1 H,
H-2), 2.32 (br t, J ) 7.4 Hz, 1 H, OH), 2.03-1.82 (m, 4 H, 2
H-6, 2 H-8), 1.68-1.50 (m, 2 H, 2 H-7), 1.47, 1.46, 1.44, 1.36
[4 s, 2 × OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) δ 108.4, 108.3
[2 × OC(CH3)2O], 81.4 (C-2), 79.8 (C-4)*, 76.1 (C-5)*, 73.9 (C-
3), 70.0 (C-1), 28.9 (C-6)*, 28.5 (C-8)*, 28.0, 27.2, 26.9, 25.4 [4
C, 2 × OC(CH3)2], 17.7 (C-7); MS (70 eV) m/z 257 (M+ - 15,
40), 157 (16), 139 (26), 115 (20), 93 (20), 43 (100). Anal. Calcd
for C14H24O5: C, 61.74; H, 8.88. Found: C, 62.01; H, 8.71.
F r ee Ra d ica l Cycliza tion of Com p ou n d 36. Precursor
36 (101 mg, 0.18 mmol) was treated according to the General
Method for FR Cyclization (“one-pot” addition) to give com-
pounds 54 [37.8 mg, 50%) after chromatography (87/13 hexane/
a
Reagents: (a) see ref 45; (b) BnNH2, toluene, 80 °C, 2 h (85%);
(c) CH2dCHCH2MgBr, Et2O, rt, (88%); (d) I2, Ph3P, imidazole
(15%); (e) see ref 43a,b.
expectedly, compound 92 was isolated in 15% yield. This
compound showed excellent analytical and spectroscopic
data.18a When we were trying other alternatives in order
to improve this yield, we were aware of the synthesis of
(+)-calystegine B2 via intermediate 92, which after
carbamate protection and RCM efficiently gave product
93 (Scheme 20) using Grubbs’ catalyst.43a This fact
confirmed our hypothesis about the critical (and negative)
influence of the steric effects on precursors 79 and 83-
86.
From a practical point of view, and according to the
literature,43a the synthesis of compound 92 constitutes a
formal total synthesis of (+)-calystegine B2. We are now
investigating other alternatives for the synthesis of this
and other members of this family of compounds. These
results will be reported in due course.
25
ethyl acetate). 54: oil; [R]D -4 (c 0.68, CHCl3); IR (film) ν
2987, 1737, 1455, 1371, 1167, 1047 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.37-7.25 (m, 5 H, OCH2C6H5), 4.74/4.66 (AB
system: d, J ) 11.6 Hz, 2 H, OCH2C6H5), 4.44 (t, J 4,5 ) J 3,4
)
8.9 Hz 1 H, H-4), 4.26 (ddd, J 5,6 ) 7.6 Hz, J 6,7 ) 11.5 Hz, J 6,7′
) 3.1 Hz, 1 H, H-6), 4.17 (t, J 5,6 ) J 4,5 ) 7.6 Hz, 1 H, H-5),
3.78 (br s, 1 H, H-2), 3.68 (dd, J 2,3 ) 2.0 Hz, J 3,4 ) 9.6 Hz, 1 H,
H-3), 3.66 (s, 3 H, CH2CO2CH3), 2.62-2.60 (m, 1 H, H-1), 2.37
(dd, J ) 15.7 Hz, J ) 7.2 Hz, 1 H, CH2CO2CH3), 2.30 (dd, J )
15.7 Hz, J ) 8.5 Hz, 1 H, CH2CO2CH3), 2.08 (ddd, J 6,7 ) 11.5
Hz, J 7,7′ ) 14.7 Hz, J 1,7 ) 2.2 Hz, 1 H, H-7), 1.70 (dd, J 1,7′
)
2.7 Hz, J 7,7′ ) 14.7 Hz, J 6,7′ ) 3.1 Hz, 1 H, H-7′), 1.48, 1.45,
1.44, 1.34 [4 s, 2 × OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) δ
168.5 (CH2CO2CH3), 138.5-127.5 (OCH2C6H5), 110.0/109.2 [2
× OC(CH3)2], 78.8 (C-5), 78.3 (C-3)*, 76.9 (C-2)*, 74.8 (C-4),
73.3 (OCH2C6H5), 72.8 (C-6), 51.9 (CH2CO2CH3), 35.4 (CH2-
CO2CH3), 33.9 (C-1), 28.8 (C-7), 29.7, 27.3 (2 C), 26.6, 24.4 [4
Exp er im en ta l Section
C, 2 × OC(CH3)2O]; MS (70 eV) m/z 420 (M+, 1), 405 (M+
-
15, 16), 304 (14), 231 (7), 198 (4), 91 (100). Anal. Calcd for
Gen er a l Meth od s. Reactions were monitored by TLC using
precoated silica gel aluminum plates containing a fluorescent
indicator. Detection was performed by UV (254 nm) followed
by charring with sulfuric-acetic acid spray, 1% aqueous
potassium permanganate solution, or 0.5% phosphomolybdic
acid in 95% EtOH. Anhydrous Na2SO4 was used to dry organic
solutions during workups, and the removal of solvents was
carried out under vacuum with a rotary evaporator. Flash
column chromatography was performed using silica gel 60
(230-400 mesh) and hexane/ethyl acetate mixtures as the
eluent unless otherwise stated. 1H NMR spectra were recorded
using tetramethylsilane as the internal standard. Values with
an asterisk can be interchanged.
C
23H32O7: C, 65.70; H, 7.67. Found: C, 65.57; H, 7.14.
F r ee Ra d ica l Cycliza tion of Com p ou n d 37. Precursor
37 (37 mg, 0.10 mmol) was treated according to the General
Method for FR Cyclization (slow addition: 5 h) to give
compounds 55 (37 mg, 55%) after chromatography (95/5
25
hexane/ethyl acetate). 55: oil; [R]D -19 (c 0.68, CHCl3); IR
(film) ν 3486, 2928, 1740, 1456, 1372, 1166, 1044 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 5.90 (s, 1 H, H-8), 4.55 (t, J 2,3 ) J 3,4
) 8.9 Hz, 1 H, H-3), 4.43 (d, J 5,6 ) 2.9 Hz, 1 H, H-6), 4.20 (t,
J 4,5 ) J 3,4 ) 8.5 Hz 1 H, H-4), 4.03 (dd, J 5,6 ) 2.9 Hz, J 4,5 ) 8.2
Hz, 1 H, H-5), 3.63 (s, 3 H, CH2CO2CH3), 3.49 (dt, J 1,2 ) J 1,9
)
10.5 Hz, J 1,9′ ) 6.2 Hz, 1 H, H-1), 3.17 (dd, J 1,2 ) 10.5 Hz, J 2,3
) 9.1 Hz, 1 H, H-2), 2.85 (dd, J 9,9′ ) 15.7 Hz, J 1,9′ ) 6.2 Hz, 1
H, H-9′), 2.58 (dd, J 9,9′ ) 15.7 Hz, J 1,9 ) 10.5 Hz, 1 H, H-9),
2.57 (s, 1 H, OH), 1.57, 1.41, 1.38, 1.36 [4 s, 2 × OC(CH3)2O],
1.52-1.24 [m, 18 H, (CH3CH2CH2CH2)3Sn], 0.96-0.85 [m, 9
H, (CH3CH2CH2CH2)3Sn]; 13C NMR (75 MHz, CDCl3) δ 172.8
(CO2CH3), 152.1 (C-7), 128.4 (C-8), 109.4/109.2 [2 × OC(CH3)2],
80.2 (C-2), 80.1 (C-5), 80.0 (C-3), 77.4 (C-4), 77.3 (C-6), 51.5
(CO2CH3), 40.2 (C-9), 29.0, 27.3, 13.6 [(CH3CH2CH2CH2)3Sn],
27.2, 27.0, 26.4, 23.2 [4 C, 2 × OC(CH3)2O], 10.3 [(CH3CH2-
Gen er a l Meth od for F r ee Ra d ica l Cycliza tion . To a
solution of the precursor in toluene (0.02 M) previously
deoxygenated by bubbling argon into the solution was slowly
added a solution of AIBN (0.5 equiv) and Bu3SnH (2 equiv)
via syringe pump in the indicated time under argon and at 80
(46) Garegg, P. J .; Samuelson, B. J . Chem. Soc., Perkin Trans. 1
1980, 2866.

3716 J . Org. Chem., Vol. 67, No. 11, 2002
Marco-Contelles and de Opazo
CH2CH2)3Sn]; MS (70 eV) m/z 617 (M+ - 15, 2), 575 (63), 517
(22), 459 (100), 375 (36), 291 (24), 251 (39), 177 (51), 59 (34).
Anal. Calcd for C29H52O7Sn: C, 55.16; H, 8.29. Found: C,
55.08; H, 8.15.
) 7.5 Hz, J 2,7 ) 2.4 Hz, 1 H, H-2), 5.36 (dd, J 1,2 ) 7.5 Hz, J 1,7
) 2.8 Hz, 1 H, H-1), 4.38 (t, J 5,6 ) J 6,7 ) 7.5 Hz, 1 H, H-6),
4.29 (t, J 4,5 ) J 6,5 ) 8.0 Hz, 1 H, H-5), 4.26-4.22 (m, 2 H, H-7,
H-4), 2.07 (s, 3 H, OCOCH3), 1.45, 1.44, 1.42, 1.36 [4 s, 12 H,
2 × OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) δ 153.8 (OCOCH3),
132.9 (C-3), 124.0 (C-2), 111.5, 110.4 [2 C, OC(CH3)2O], 77.4,
77.3, 76.1, 75.0 (C-7, C-6, C-5, C-4), 69.8 (C-1), 27.1, 27.0, 26.7,
F r ee Ra d ica l Cycliza tion of Com p ou n d 38. Precursor
38 (36 mg, 0.10 mmol) was treated according to the General
Method for FR Cyclization (slow addition: 5 h) to give
compounds 56 (41 mg, 60%) after chromatography (95/5
hexane/ethyl acetate). 56: oil; [R]D25-20 (c 0.31, CHCl3); IR
25.3 [2 × OC(CH3)2O]; MS (70 eV) m/z 298 (M+, 1), 283 (M+
-
15, 27), 225 (4), 123 (30), 113 (11), 59 (16), 43 (100). Anal. Calcd
for C15H22O6: C, 60.39; H, 7.43. Found: C, 60.58; H, 7.65.
(4S,5R,6S,7S)-4,5:6,7-Bis(isop r op ylid en ed ioxy)-2-cyclo-
h ep ten -1-on e (71). Following the General Method for the
Ring-Closing Metathesis Reaction, diastereomerically pure
precursor 63 (59 mg, 0.20 mmol) gave carbocycle 71 (35.7 mg,
70%) after chromatography (4/1 hexane/ethyl acetate). 71: oil;
(film) ν 3467, 2923, 1743, 1456, 1372, 1167, 1047 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 6.01 (s, 1 H, H-8), 4.21 (d, J 5,6 ) 7.9
Hz, 1 H, H-6), 4.20 (t, J 4,5 ) J 3,4 ) 9.6 Hz 1 H, H-4), 4.00 (t,
J 2,3 ) J 3,4 ) 9.4 Hz, 1 H, H-3), 3.90 (dd, J 5,6 ) 7.9 Hz, J 4,5
)
9.2 Hz, 1 H, H-5), 3.62 (s, 3 H, CH2CO2CH3), 3.23 (t, J 1,2 ) J 2,3
) 10.3 Hz, 1 H, H-2), 2.94-2.82 (m, 1 H, H-1), 2.83 (dd, J 9,9′
)
25
15.6 Hz, J 1,9′ ) 4.5 Hz, 1 H, H-9′), 2.71 (s, 1 H, OH), 2.64 (dd,
J 9,9′ ) 15.6 Hz, J 1,9 ) 9.2 Hz, 1 H, H-9), 1.52, 1.39, 1.37, 1.35
[4 s, 2 × OC(CH3)2O], 1.50-1.21 [m, 18 H, (CH3CH2CH2CH2)3-
Sn], 0.94-0.75 [m, 9 H, (CH3CH2CH2CH2) 3Sn]; 13C NMR (75
MHz, CDCl3) δ 172.8 (CO2CH3), 150.9 (C-7), 129.3 (C-8), 110.0/
109.8 [2 × OC(CH3)2], 82.1 (C-5), 80.5 (C-3), 79.8 (C-2), 76.7
(C-4), 74.1 (C-6), 51.7 (CO2CH3), 46.7 (C-1), 35.1 (C-9), 29.2,
27.6, 13.8 [(CH3CH2CH2CH2)3Sn], 27.2, 27.1 (2 C), 24.2 [4 C,
2 × OC(CH3)2O], 12.4 [(CH3CH2CH2CH2)3Sn]; MS (70 eV) m/z
575 (100), 459 (27), 291 (18), 251 (36), 177 (39), 59 (64). Anal.
Calcd for C29H52O7Sn: C, 55.16; H, 8.29. Found: C, 55.23; H,
8.42.
(1R,4S,5R,6R,7R)-4,5:6,7-Bis(isop r op ylid en ed ioxy)-2-
cycloh ep ten -1-ol (68). Following the General Method for the
Ring-Closing Metathesis Reaction, diastereomerically pure
precursor 60 (15 mg, 0.053 mmol) gave carbocycle 68 (12 mg,
88%) after chromatography (85/15 hexane/ethyl acetate). 68:
oil; [R]D25 -3 (c 0.52, CHCl3); IR (film) ν 3479 (OH), 2986, 1656,
1373, 1216, 1061 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.07 (dd,
J 2,3 ) 11.7 Hz, J 3,4 ) 1.7 Hz, 1 H, H-3), 5.82 (ddd, J 2,3 ) 11.7
[R]D +10 (c 0.8, CHCl3); IR (film) ν 2991, 1693, 1374, 1227,
1
1078 cm-1; H NMR (300 MHz, CDCl3) δ 6.75 (dd, J 2,3 ) 12.2
Hz, J 3,4 ) 1.7 Hz, 1 H, H-3), 6.08 (dd, J 2,3 ) 12.2 Hz, J 2,4 ) 3.0
Hz, 1 H, H-2), 4.68 (d, J 6,7 ) 7.4 Hz, 1 H, H-7), 4.57 (t, J 6,7
)
J 5,6 ) 8.1 Hz, 1 H, H-6), 4.53 (ddd, J 2,4 ) 3.0 Hz, J 4,5 ) 8.4 Hz,
J 3,4 ) 1.7 Hz, 1 H, H-4), 3.81 (t, J 5,6 ) J 4,5 ) 8.5 Hz, 1 H, H-5),
1.60, 1.48, 1.45, 1.44 [4 s, 12 H, 2 × OC(CH3)2O]; 13C NMR
(75 MHz, CDCl3) δ 195.9 (CdO), 140.9 (C-3), 128.9 (C-2), 113.6,
111.6 [2 C, OC(CH3)2O], 82.5 (C-7), 80.9 (C-5), 77.3 (C-6), 76.9
(C-4), 27.1, 26.9, 26.8, 26.0 [2 × OC(CH3)2O]; MS (70 eV) m/z
255 (M + 1+, 1), 239 (M+ - 15, 88), 139 (58), 121 (20), 113
(77), 97 (39), 59 (64), 43 (100). Anal. Calcd for C13H18O5: C,
61.41; H, 7.14. Found: C, 61.23; H, 7.34.
Red u ction of (4S,5R,6S,7S)-4,5:6,7-Bis(isop r op ylid en e-
d ioxy)-2-cycloh ep ten -1-on e (71). Ketone 71 (31.2 mg, 0.12
mmol) was dissolved in dry toluene (1.5 mL), cooled at -78
°C, and DIBALH (0.02 mL, 0.13 mmol, 1.1 equiv, 1.0 M in
toluene) was added under argon and stirring. This operation
was repeated twice after 2 h each. After 6 h total, the mixture
was treated with MeOH at this temperature and the reaction
was warmed to room temperature. The salts were filtered over
Celite; the solvent was removed under vacuum, and the
residue was submitted to chromatography (4/1 hexane/ethyl
acetate) to give alcohols 68 (21.6 mg, 70%) and 69 (3.1 mg,
10%).
Hz, J 1,2 ) 7.4 Hz, J 2,4 ) 2.6 Hz, 1 H, H-2), 4.44 (t, J 4,5 ) J 5,6
)
8.7 Hz, 1 H, H-5), 4.35 (dd, J 5,6 ) 8.6 Hz, J 6,7 ) 7.3 Hz, 1 H,
H-6), 4.32 (dd, J 1,2 ) 7.4 Hz, J 1,7 ) 2.6 Hz, 1 H, H-1), 4.23 (dt,
J 4,2 ) J 4,3 ) 2.0 Hz, J 4,5 ) 8.7 Hz, 1 H, H-4), 4.18 (dd, J 6,7
)
7.3 Hz, J 1,7 ) 2.6 Hz, 1 H, H-7), 2.48 (br s, 1 H, OH), 1.57,
1.43 (2 s), 1.42 [4 s, 12 H, 2 × OC(CH3)2O]; 13C NMR (75 MHz,
CDCl3) δ 131.8 (C-3)*, 125.8 (C-2)*, 110.7, 110.1 [2 C,
OC(CH3)2O], 77.5 (C-7), 77.3 (C-5), 77.1 (C-7), 75.4 (C-4), 68.3
(C-1), 29.0, 27.0, 26.7, 24.3 [2 × OC(CH3)2O]; MS (70 eV) m/z
256 (M+, 1), 241 (M+ - 15, 48), 140 (50), 113 (51), 59 (68), 43
(100). Anal. Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C,
61.14; H, 7.64.
Rin g-Closin g Meta th esis Rea ction of Com p ou n d 66.
Following the General Method for the Ring-Closing Metathesis
Reaction, product 66 (131.4 mg, 0.09 mmol) afforded compound
77 (28.6 mg, 99%) after flash chromatography (eluting with
4/1 hexane/ethyl acetate). (1S,5S,6R,SR,8R)-1-O-Acetyl-5,6:
7,8-bis(isop r op ylid en ed ioxy)-3-cyclocten -1-ol (77): oil;
25
[R]D -35 (c 0.48, CHCl3); IR (KBr) ν 2987, 1740, 1373, 1242,
1
1055 cm-1; H NMR (300 MHz, CDCl3) δ 5.89 (dd, J 3,4 ) 11.4
(1S,4S,5R,6R,7R)-4,5:6,7-Bis(isop r op ylid en ed ioxy)-2-
cycloh ep ten -1-ol (69). Following the General Method for the
Ring-Closing Metathesis Reaction, a mixture of precursors 60/
61 (64:36) (49.4 mg, 0.17 mmol) gave carbocycle 68 (25.4 mg,
57%) and 69 (11.5 mg, 26%) after chromatography (9/1 hexane/
Hz, J 4,5 ) 3.9 Hz, 1 H, H-4), 5.53 (ddt, J 3,4 ) 11.4 Hz, J 3,5
)
2.1 Hz, J 2,3 ) J 2′,3 ) 7.2 Hz, 1 H, H-3), 5.05 (d, J 1,2 ) 9.5 Hz,
1 H, H-1), 4.54 (ddd, J 4,5 ) 3.8 Hz, J 5,6 ) 7.5 Hz, J 5,3 ) 2.0 Hz,
1 H, H-5), 4.36 (t, J 7,8 ) J 6,7 ) 7.7 Hz, 1 H, H-7), 4.31 (dd, J 1,8
) 2.0 Hz, J 7,8 ) 7.7 Hz, 1 H, H-8), 4.26 (t, J 6,7 ) J 5,6 ) 7.9 Hz,
1 H, H-6), 2.96 (dddm, J 2,2′ ) 16.4 Hz, J 2,3 ) 7.3 Hz, J 1,2 ) 9.5
Hz, 1 H, H-2), 2.07 (dd, J 2,2′ ) 16.4 Hz, J 2′,3 ) 7.2 H z, 1 H,
H-2′), 2.06 (s, 3 H, OCOCH3), 1.49, 1.45, 1.41, 1.38 [4 s, 12 H,
2 × OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) δ 170.1 (OCOCH3),
135.2 (C-3), 124.2 (C-4), 109.6, 109.2 [2 C, OC(CH3)2O], 81.4
(C-6), 80.8 (C-8), 79.6 (C-7), 74.8 (C-5), 72.9 (C-1), 27.2 (C-2),
27.3, 26.6, 25.9, 24.9 [2 × OC(CH3)2O], 21.0 (OCOCH3); MS
(70 eV) m/z 313 (M+, 1), 297 (M+ - 15, 16), 239 (5), 195 (12),
137 (25), 119 (11), 59 (15), 43 (100). Anal. Calcd for C16H24O6:
C, 61.52; H, 7.74. Found: C, 61.33; H, 7.65.
25
ethyl acetate). 69: oil; [R]D +84 (c 0.77, CHCl3); IR (film) ν
1
3447 (OH), 2989, 1622, 1374, 1222, 1062 cm-1; H NMR (300
MHz, CDCl3) δ 5.84 (ddd, J 2,3 ) 12.1 Hz, J 3,4 ) 2.6 Hz, J 1,3
)
1.6 Hz, 1 H, H-3)*, 5.66 (ddd, J 2,3 ) 12.1 Hz, J 1,2 ) 2.2 Hz, J 2,4
) 1.6 Hz, 1 H, H-2)*, 4.37-4.33 (4.35: dd, J 1,7 ) 8.0 Hz, J 6,7
) 6.5 Hz, 1 H, H-7; overlapping: m, 1 H, H-1), 4.28 (dm, J 4,5
) 8.3 Hz, 1 H, H-4), 3.98 (dd, J 5,6 ) 9.6 Hz, J 6,7 ) 6.5 Hz, 1 H,
H-6), 3.93 (dd, J 5,6 ) 9.6 Hz, J 4,5 ) 8.3 Hz, 1 H, H-5), 2.61 (br
s, 1 H, OH), 1.52, 1.43 (2 s), 1.42 [4 s, 12 H, 2 × OC(CH3)2O];
13C NMR (75 MHz, CDCl3) δ 131.9 (C-2)*, 125.9 (C-3)*, 110.8,
110.1 [2 C, OC(CH3)2O], 77.6 (C-6), 77.5 (C-5), 77.2 (C-7), 75.4
(C-4), 68.4 (C-1), 27.1 (2 C), 26.8, 24.4 [2 × OC(CH3)2O]; MS
(70 eV) m/z 256 (M+, 4), 241 (M+ - 15, 15), 140 (36), 113 (87),
59 (69), 43 (100). Anal. Calcd for C13H20O5: C, 60.92; H, 7.87.
Found: C, 60.88; H, 7.75.
Ack n ow led gm en t. This work was supported by
CICYT, CAM, and COST Action No. D12 (European
Union). Elsa de Opazo is a fellow of the Consejer´ıa de
Educacio´n y Cultura (CAM). J .M.C. thanks Prof. Hanna
and Dr. Boyer for kindly sending us copies of the spectra
of compound 92 and for personal communications, Prof.
F. Nicotra for giving us useful information about the
organometallic addition to N-benzylglucosamines, and
Prof. Madsen for a genereous gift of a Ru-carbene com-
plex.
(1S,4S,5R,6R,7R)-1-O-Acetyl-4,5:6,7-bis(isop r op ylid en e-
dioxy)-2-cycloh epten -1-ol (70). Following the General Method
for the Ring-Closing Metathesis Reaction, precursor 62 (16.2
mg, 0.049 mmol) gave carbocycle 70 (12.6 mg, 86%) after
chromatography (4/1 hexane/ethyl acetate). 70: mp 137-140
25
°C; [R]D -16 (c 0.85, CHCl3); IR (KBr) ν 2926, 1730, 1374,
1243, 1059 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.07 (dd, J 2,3
)
11.5 Hz, J 3,4 ) 1.4 Hz, 1 H, H-3), 5.81 (ddd, J 2,3 ) 11.5 Hz, J 1,2

Formal Total Synthesis of (+)-Calystegine B2
J . Org. Chem., Vol. 67, No. 11, 2002 3717
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis and analytical and spectroscopic data
of compounds 1-6, 9-12, 14-17, 20-30, 33-38, 45, 46, 48-
53, 60-67, 72-77, 79, 82-88, and 90-92 and experimental
procedures for the free radical cyclization of precursors 1, 6,
and 32-33 and the ring-closing metathesis of compounds 64,
65, 85, and 86. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0111107