Intramolecular cyclopropanation of glycals: studies toward the synthesis of canadensolide, sporothriolide, and xylobovide.

Article abstract of DOI:10.1021/ol016239h

[reaction: see text] The first examples of copper-catalyzed intramolecular cyclopropanations of glycal-derived diazoacetates are reported. The new cyclopropanes are converted into advanced intermediates for the synthesis of bislactone natural products. Sy

Full text of DOI:10.1021/ol016239h

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2563-2566
Intramolecular Cyclopropanation of
Glycals: Studies toward the Synthesis
of Canadensolide, Sporothriolide, and
Xylobovide
Ming Yu, Vincent Lynch,† and Brian L. Pagenkopf*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
pagenkopf@mail.utexas.edu
Received June 6, 2001
ABSTRACT
The first examples of copper-catalyzed intramolecular cyclopropanations of glycal-derived diazoacetates are reported. The new cyclopropanes
are converted into advanced intermediates for the synthesis of bislactone natural products. Synthetic highlights include the selective
monodeprotection of a di-tert-butylsilylene ether and a zinc-mediated ring opening cascade reaction.
Carbohydrates are an indispensable source of materials for
asymmetric synthesis, supported by a history of well-
documented functional group transformations.1 One challenge
in carbohydrate chemistry includes developing economical
and stereoselective methods for the introduction of new
carbon-carbon bonds bearing suitable functional handles.2
Carbon-branched sugars3 are found in numerous natural
products and have been used as starting materials for indole
alkaloid syntheses.4 They commonly occur in the glycon
portion of many antibiotics5 and have been studied during
the elucidation of biochemical pathways.6 Additionally,
naturally occurring macrolides often contain branched polyol
sequences, a structural motif that portends an origin from a
C-branched sugar.7
Glycals continue to attract attention as important substrates
for the development of new synthetic methodologies.8 Their
cyclopropanation is a particularly attractive means for the
efficient introduction of new carbon bonds onto the sugar
backbone. Although the synthesis of cyclopropanated sugars
was first described decades ago,9 their importance continues
(7) Celmer, W. D. Pure. Appl. Chem. 1971, 28, 413-453.
(8) For recent representative examples, see: (a) Kan, C.; Long, C. M.;
Paul, M.; Ring, M. C.; Tully, S. E.; Rojas, C. M. Org. Lett. 2001, 3, 381-
384. (b) Kim, J. Y.; Di Bussolo, V.; Gin, D. Y. Org. Lett. 2001, 3, 303-
306. (c) Tan, D. S.; Schreiber, S. L. Tetrahedron Lett. 2000, 41, 9509-
9513. (d) Evans, D. A.; Trotter, B. W.; Coˆte´, B. Tetrahedron Lett. 1998,
39, 1709-1712. (e) Hosokawa, S.; Kirschbaum, B.; Isobe, M. Tetrahedron
Lett. 1998, 1917-1920. (f) Rainier, J. D.; Allwein, S. P. Tetrahedron Lett.
1998, 9601-9604. (g) DuBois, J.; Tomooka, C. S.; Hong, J.; Carreira, E.
M. J. Am. Chem. Soc. 1997, 119, 3179-3180. (h) Linker, T.; Sommermann,
T.; Kahlenberg, G. J. Am. Chem. Soc. 1997, 119, 9377-9384. (i)
Danishefsky, S. J. Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1380-1419. (j) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 6661-6666.
† Author to whom inquiries concerning the X-ray data should be directed.
(1) Bols, M. Carbohydrate Building Blocks; John Wiley & Sons:
Toronto, 1996.
(2) Lopez, J. C.; Fraser-Reid, B. Chem. Commun. 1997, 2251-2257.
(3) Chapleur, T.; Chetein, F. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S.; Ed.; Marcel Dekker: New York, 1997; pp 207-264.
(4) (a) Pancrazi, A.; Kervagoret, J.; Khuong-Huu, Q. Tetrahedron Lett.
1991, 32, 4303-4306. (b) Khuong-Huu, Q.; Nemlin, J.; Kervagoret, J.;
Pancrazi, A. Tetrahedron 1992, 48, 6689-6700.
(5) (a) Lindberg, B. AdV. Carbohydr. Chem. Biochem. 1990, 48, 279-
318. (b) Grisebach, H. AdV. Carbohydr. Chem. Biochem. 1978, 35, 81-
126.
(6) He, X.; Agnihotri, G.; Liu, H.-w. Chem. ReV. 2000, 100, 4615-
4662.
(9) Brimacombe, J. S.; Evans, M. E.; Forbes, E. J.; Foster, A. B.; Webber,
J. M. Carbohydr. Res. 1967, 4, 239-243.
10.1021/ol016239h CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/19/2001

to prompt investigations that offer improved or alternative
methods for their preparation.10 The reactions of vinyl ethers
with the Simmons-Smith11,12 reagent or dihalocarbene13
provide robust adducts that undergo ring opening reactions
with Lewis acids,12,13 by R alkoxide fragmentation14 or
platinum catalyzed hydration/isomerization.15,16 The facial
selectivity of the intermolecular cyclopropanation of glycal
1 with ethyl diazoacetate showed a pronounced dependency
on the nature of the catalyst (Scheme 1).17 These cyclopro-
tandem ring opening reaction sequence into an advanced
intermediate for the synthesis of the tetrahydro-furo[3,4-b]-
furan-2,4-dione core found in several bislactone natural
products.
The glycals 6a,21 6b,22 and 6c23 and olefin 924 were
synthesized from D-glucose. The diazoesters shown in
Scheme 2 were prepared by a modification of the method
Scheme 2a
Scheme 1a
a Ratio of 2:3:4:5: with cat. Cu0 (ref 17a), 0:0:1:0; with cat.
Rh2(OAc)4 (ref 17c), 31:0:1:0.
a Conditions: (a) (i) p-TolSO2NHNCHCOCl (12), Me2NPh,
DCM/DMF; (ii) Et3N; (b) 5 mol % 13, PhMe, reflux.
panes possess vicinal functional groups that can in principle
work synergistically in a “push-pull” relationship, an
arrangement that engenders useful reactivity for further
transformations when geminal electron-withdrawing groups
are present.18,19
reported in the pioneering contribution by Corey and Myers
on the intramolecular cyclopropanation of diazoacetates.25
Treating a dichloromethane/N,N-dimethylformamide (DMF)
solution of glyoxylic acid chloride p-toluenesulfonylhydra-
zone (12)26 and the alcohol sequentially with N,N-dimethy-
laniline and triethylamine afforded the diazoacetates in
greater than 85% yield. The addition of anhydrous DMF as
cosolvent proved crucial for successful acylation, without
which less than 5% of the desired diazoesters could be
isolated. The cyclopropanations were achieved by the addi-
tion of the diazoester ester to a refluxing solution of 5 mol
% bis(N-tert-butylsalicylaldiminato)copper(II) [Cu(TBS)2]
Herein we describe the first intramolecular cyclopropa-
nation reactions of glucose-derived glycals and the selective
mono-deprotection of a di-tert-butylsilylene ether.20 The new
cyclopropane 8a was transformed by way of a zinc-mediated
(10) For a review, see: Cousins, G. S.; Hoberg, J. O. Chem. Soc. ReV.
2000, 29, 165-174.
(11) Hoberg, J. O.; Claffey, D. J. Tetrahedron Lett. 1996, 37, 2533-
2536.
(12) Hoberg, J. O. J. Org. Chem. 1997, 62, 6615-6618.
(13) Ramana, C. V.; Murali, R.; Nagarajan, M. J. Org. Chem. 1997, 62,
7694-7703.
(14) (a) Mehta, G.; Acharyulu, P. V. R. Indian J. Chem., Sect. B 1998,
37B, 201-204. (b) Mehta, G.; Acharyulu, P. V. R. J. Chem. Soc., Chem.
Commun. 1994, 24, 2759-2760.
(20) For cyclopropanation of carbohydrate-derived silyl enol ethers,
see: (a) Schumacher, R.; Reissig, H.-U. Leibigs Ann. Recueil 1997, 521-
526. (b) Schumacher, R.; Reissig, H.-U. Synlett 1996, 1121-1122.
(21) Hoberg, J. O. Carbohydr. Res. 1997, 4, 365-368.
(22) (a) Fetizon, M.; Khac, D. D.; Tho, N. D. Tetrahedron Lett. 1986,
27, 1777-1780. (b) Kjoelberg, O.; Neumann, K. Acta Chem. Scand. 1993,
47, 843-845.
(15) (a) Beyer, J.; Madsen, R. J. Am. Chem. Soc. 1998, 120, 12137-
12138. (b) Beyer, J.; Skaanderup, P. R.; Madsen, R. J. Am. Chem. Soc.
2000, 122, 9575-9583.
(16) Doyle, M. P.; Leusen, D. V. J. Am. Chem. Soc. 1981, 103, 5917-
5919.
(17) (a) Henry, K. J., Jr.; Fraser-Reid, B. Tetrahedron Lett. 1995, 36,
8901-8904. (b) Timmers, C. M.; Leeuwenburgh, M. A.; Verheijen, J. C.;
van der Marel, G. A.; van Boom, J. H. Tetrahedron Asymmetry 1996, 7,
49-52. (c) Hoberg, J. O.; Claffey, D. J. Tetrahedron Lett. 1996, 37, 2533-
2536.
(18) Wenkert, E. Acc. Chem. Res. 1980, 13, 27-31.
(19) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66-72.
(23) Bartolozzi, A.; Capozzi, G.; Menichetti, S.; Nativi, C. Org. Lett.
2000, 2, 251-253.
(24) Tolstikov, A. G.; Prokopenko, O. F.; Spirikhin, L. F.; Tolstikov,
G. A. Russ. J. Bioorg. Chem. 1993, 19, 139-144.
(25) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559-3562.
(26) Blankley, C. J.; Suture, F. J.; House, H. O. Synthesis 1970, 259-
262.
2564
Org. Lett., Vol. 3, No. 16, 2001

(13)27 in either dichloromethane or toluene. Slow addition
of the diazoester over 8-12 h was necessary to minimize
formation of dimeric fumarates and maleates. The Cu(TBS)2
precatalyst 13 performed admirably in the cyclopropanation
reactions examined for this study, whereas other catalysts,
including Rh2(OAc)4, gave lower yields.28
considerable attention as synthetic targets, with several
reported total syntheses of canadensolide and one of sporo-
thriolide appearing in the literature.32,33 Inspection of xy-
lobovide reveals that, excluding the exocyclic methylene,34
all of the carbons with the correct stereochemistry necessary
for its synthesis are present in cyclopropanes 8a-c.
To demonstrate the potential utility of this methodology
in natural product synthesis, 8a was converted into the
advanced intermediate 19, which, on the basis of literature
precedent,32g,h will provide access to xylobovide 20. The first
synthetic task was the removal of the di-tert-buyl silylene
ether. Complete desilylation with TBAF in THF afforded,
as expected, the corresponding diol in 93% yield. However,
the possibility of achieving a more interesting monodesily-
lation of the di-tert-buylsilylene ether was explored with this
substrate. After some experimentation, it was discovered that
treatment of 8a with BF3‚Et2O in toluene (room temperature
to 85 °C, 30 min) in the presence an HF scavenger such as
allyltrimethylsilane revealed exclusively the primary alcohol
14 in 95% yield.35,36 Conversion of alcohol 14 to iodide 15
(ca. 90%, two steps) set the stage for a zinc-mediated
reductive ring opening cascade.37 Addition of iodide 15 to a
room-temperature suspension of zinc-copper couple38 in dry
THF resulted in rapid reduction and cleavage of the pyran
ether to zinc alkoxide 16, which spontaneously underwent
further ring opening to aldehyde 17. Aldehyde 17 was
converted without purification to the hemiacetal 18 by
desilylation of the di-tert-butylfluorosilyl ether with HF‚
pyridine.39 The di-tert-butylfluorosilyl ether protecting group
utilized in this reaction sequence proved to be quite robust
in the absence of fluoride ion and was labile only upon
exposure for several hours to aqueous solutions at extremes
of pH.
Scheme 2 shows that the intramolecular cyclopropanation
of glycals is compatible with a variety of protecting groups
at the C(4) and C(6) positions, including cyclic silylene or
acetonide groups and acyclic benzyl and TBS groups. Each
of the cyclopropanes shown in Scheme 2 was formed as an
exclusive stereoisomer, as judged by TLC and inspection of
1
the H NMR spectra of the crude reaction mixtures. The
stereochemistry of the cyclopropanation product 8a was
unambiguously established by X-ray crystallographic analysis
of crystals (mp 199.5-201.0 °C), obtained from ethyl acetate/
hexanes, Figure 1. As expected,25 the cyclopropanation is
Figure 1. Chem3D representation of the X-ray structure of
cyclopropane 8a.
Reduction of olefin 18 with hydrogen over palladium on
carbon provided hemiacetal 19 (96%), which maps40 nicely
onto an advanced intermediate in the Fraser-Reid total
not limited to electron-rich olefins, and reaction of 10
proceeded with equal efficiency. In addition to the high
diastereoselectivity inherent to this intramolecular reaction,
the products are formed with equal levels of selectivity
regardless of the protecting groups that are employed at C(4)
and C(6).
The phytotoxic natural product xylobovide 20,29 the
fungicide canadensolide 22,30 and sporothriolide 23,31 an
antibacterial, fungicidal, algicidal, and herbicidal agent, are
closely related natural products that differ simply in the
length of their side chain. These structures have received
(32) (a) Al-Abed, Y.; Naz, N.; Mootoo, D.; Voelter, W. Tetrahedron
Lett. 1996, 37, 8641-8642. (b) Honda, T.; Kobayashi, Y.; Tsubuki, M.
Tetrahedron 1993, 49, 1211-1222. (c) Sharma, G. V. M.; Vepachedu, S.
R. Tetrahedron 1991, 47, 519-524. (d) Honda, T.; Kobayashi, Y.; Tsubuki,
M. Tetrahedron Lett. 1990, 31, 4891-4894. (e) Tochtermann, W.;
Schroeder, G. R.; Snatzke, G.; Peters, E. M.; Peters, K.; Von Schnering,
H. G. Chem. Ber. 1988, 121, 1625-1636. (f) Tsuboi, S.; Muranaka, K.;
Sakai, T.; Takeda, A. J. Org. Chem. 1986, 51, 4944-4946. (g) Anderson,
R. C.; Fraser-Reid, B. J. Org. Chem. 1985, 50, 4786-4790. (h) Anderson,
R. C.; Fraser-Reid, B. Tetrahedron Lett. 1978, 35, 3233-3236. (i) Sakai,
T.; Yoshida, M.; Kohmoto, S.; Utaka, M.; Takeda, A. Tetrahedron Lett.
1982, 23, 5185-5188. (j) Tsuboi, S.; Fujita, H.; Muranaka, K.; Seko, K.;
Takeda, A. Chem. Lett. 1982, 1909-1912. (k) Carlson, R. M.; Oyler, A.
R. J. Org. Chem. 1976, 41, 4065-4069. (l) Kato, M.; Kageyama, M.;
Tanaka, R.; Kuwahara, K.; Yoshikoshi, A. J. Org. Chem. 1975, 40, 1932-
1941.
(33) Sharma, G. V. M.; Krishnudu, K. Tetrahedron Lett. 1995, 36, 2661-
2664.
(34) Grieco, P. A. Synthesis 1975, 67-82.
(35) The generality of this selective monodesilylation protocol will be
described elsewhere.
(36) For the formation of di-tert-butylfluoroethers in synthesis, see: (a)
Sannigrahi, M.; Mayhew, D. L.; Clive, D. L. J. J. Org. Chem. 1999, 64,
2776-2788. (b) Clive, D. L. J.; Cantin, M. J. Chem. Soc., Chem. Commun.
1995, 319-320.
(37) Bernet, B.; Vasella, A. HelV. Chem. Acta 1979, 62, 1990-2016.
(38) LeGoff, E. J. J. Org. Chem. 1964, 29, 2048-2049.
(39) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 455-461.
(40) Hemiacetal 19 differs from the canadensolide intermediate only in
that it bears an ethyl side chain instead of a butyl.
(27) (a) Yokoi, H.; Takeuchi, A.; Yamada, S. Bull. Chem. Soc. Jpn. 1990,
63, 1462-1466. (b) Batley, G. E.; Graddon, D. P. Aust. J. Chem. 1968, 21,
1473-1485.
(28) Under slow addition conditions, other catalysts gave primarily
maleates and fumarates (CuClO4‚(CH3CN)2, toluene, 120 °C; CuBF4‚(CH3-
CN)2, CH2Cl2, 50 °C; CuPF6‚(CH3CN)2, toluene, 120 °C; Cu(OTf)2, CH2-
Cl2, 50 °C) or multiple byproducts (Rh2(OAc)4, CH2Cl2, 50 °C; CuPF6‚(CH3-
CN)2, CH2Cl2, 50 °C) or failed to react (Co(acac)2, CH2Cl2, 50 °C; ZrCl4,
CH2Cl2, 50 °C).
(29) Abate, D.; Abraham, W.-R.; Meyer, H. Phytochemistry 1997, 44,
1443-1448.
(30) McCorkindale, N. J.; Wright, J. L. C.; Brian, P. W.; Clarke, S. M.;
Hutchinson, S. A. Tetrahedron Lett. 1968, 6, 727-730.
(31) Krohn, K.; Ludewig, K.; Aust, H. J.; Draeger, S.; Schulz, B. J.
Antibiot. 1994, 47, 113-118.
Org. Lett., Vol. 3, No. 16, 2001
2565

Scheme 3
synthesis of canadensolide.32g,h Additionally, treatment of
Acknowledgment. We thank The University of Texas
at Austin and the Robert A. Welch Foundation for generous
financial support of our work.
hemiacetal 18 with catalytic H2SO4 in refluxing methanol
afforded acetal 21 in 96% yield. The acetal 21 presents a
convenient divergence point for the synthesis of canaden-
solide 22, sporothriolide 23, and related structures by oxida-
tive olefin cleavage and Wittig homologation (Scheme 3).
Supporting Information Available: X-ray structure data
and CIF file for 8a and detailed experimental procedures
and characterization of all new compounds (7, 8, 10, 11,
14, 15, 21, 24). This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we have prepared advanced intermediates
for the synthesis of bislactone natural products by the
intramolecular cyclopropanation of glycals. Additionally, we
have reported the first monodesilylation of a di-tert-buylsi-
lylene ether.
OL016239H
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Org. Lett., Vol. 3, No. 16, 2001