Fischer carbene catalysis of alkynol cycloisomerization: Application to the synthesis of the altromycin B disaccharide

Article abstract of DOI:10.1021/ol070435s

The tungsten-catalyzed cycloisomerization of alkynyl alcohols can be conducted without using photochemistry, using a stable tungsten Fischer carbene as the precatalyst for this transformation. A variety of alkynyl alcohols undergo cycloisomerization under

Full text of DOI:10.1021/ol070435s

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1737-1740
Fischer Carbene Catalysis of Alkynol
Cycloisomerization: Application to the
Synthesis of the Altromycin B
Disaccharide
BonSuk Koo and Frank E. McDonald*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received February 20, 2007
ABSTRACT
The tungsten-catalyzed cycloisomerization of alkynyl alcohols can be conducted without using photochemistry, using a stable tungsten Fischer
carbene as the precatalyst for this transformation. A variety of alkynyl alcohols undergo cycloisomerization under these conditions to provide
endocyclic enol ethers of five-, six-, and seven-membered ring sizes. The utility of this method is further demonstrated in the stereoselective
synthesis of the disaccharide substructure of altromycin B.
The importance of cyclic enol ethers in synthetic organic
chemistry has been demonstrated in several contexts, includ-
ing the efficient synthesis of a variety of biologically
important carbohydrate- and oligosaccharide-containing natu-
ral products, in which carbohydrate-derived cyclic enol ethers
(glycals) are valuable electrophilic partners for a variety of
glycoside synthesis processes.1 Our laboratory has developed
group VI transition-metal-catalyzed processes for the syn-
thesis of structurally diverse carbohydrates arising from non-
carbohydrate-derived alkynyl alcohols, which has greatly
expanded the scope of available substrates for glycal-based
approaches to glycoconjugate synthesis.2 The various meth-
ods reported by our laboratory for catalytic cycloisomeriza-
tion have utilized photochemical activation of molybdenum
or tungsten carbonyl in the presence of a tertiary amine, with
molybdenum catalysis preferred for the formation of five-
membered rings3 and tungsten catalysis proving more ef-
fective for the synthesis of six-4 and seven-membered ring
cyclic enol ethers5 (Figure 1). However, we are aware that
the requirement for photochemical activation has limited the
exploration and application of this methodology to labora-
tories that have specialized photochemical equipment. Thus,
we describe herein a new catalytic system which does not
require photochemical activation, based on (methoxymethyl-
carbene)pentacarbonyl tungsten (3)6 as a stable and easily
(1) (a) Danishefsky, S. J.; Roberge, J. Y. Pure Appl. Chem. 1995, 67,
1647. (b) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. 1996,
35, 1380. (c) Seeberger, P. H.; Bilodeau, M. T.; Danishefsky, S. J.
Aldrichimica Acta 1997, 30, 75. (d) Williams, L. J.; Garbaccio, R. M.;
Danishefsky, S. J. In Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, p 61.
(e) Priebe, W.; Grynkiewicz, G. In Glycoscience: Chemistry and Biology;
Fraser-Reid, B., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin, 2001; Vol.
1, p 749.
(3) McDonald, F. E.; Gleason, M. M. J. Am. Chem. Soc. 1996, 118,
6648.
(4) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304.
(5) Alca´zar, E.; Pletcher, J. M.; McDonald, F. E. Org. Lett. 2004, 6,
3877.
(6) Tungsten oxacarbene 3 is stable for several months in the dark. (a)
Fischer, E. O.; Maasbo¨l, A. Angew. Chem., Int. Ed. 1964, 3, 850. (b) Lam,
C. T.; Malkiewich, C. D.; Senoff, C. V. Inorg. Synth. 1977, 17, 95. (c)
Matsuyama, H.; Nakamura, T.; Iyoda, M. J. Org. Chem. 2000, 65, 4796.
(2) McDonald, F. E. In Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Elsevier: Amsterdam, 2004; Vol. 5, p 391.
10.1021/ol070435s CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/27/2007

Table 1. Representative Examples of Alkynyl Alcohol
Cycloisomerizations Catalyzed by 3
Figure 1. General concepts for generation of (Et3N)W(CO)5 as a
catalyst for alkynyl alcohol cycloisomerization.
prepared precatalyst for the cycloisomerization of various
alkynyl alcohols. Our design of the nonphotochemical system
is predicated on the reactivity of alkyl-substituted Fischer
carbenes to undergo deprotonation and in some cases
demetalation to vinylic ethers, with amine-metal carbonyl
complexes as the byproduct of base-promoted demetalation
reactions.7
Optimization of conditions was initially conducted pri-
marily with the simple aminoalkynol substrate 4,8 for
conversion into the cycloisomeric enol ether 5. Optimal
results were obtained with 25 mol % of tungsten oxacarbene
3 in the presence of 10 equiv of triethylamine and warming
to 40 °C in THF solvent for 12 h (Table 1, entry 1), at which
time substrate 4 was completely consumed and 5 was
produced in 92% isolated yield. The choice of triethylamine
as base was critically important to the success of this
transformation, as the use of 1,4-diazabicyclo[2.2.2]octane
(DABCO)9 resulted in low conversion of substrate under
nonphotochemical conditions. Similar results were obtained
with the diastereomeric substrate 6 as well as with several
other more complex substrates 8, 10, and 12,10 with products
9, 11, and 13 corresponding to protected glycals of D-
acosamine,11 L-vancosamine,12 and D-saccharosamine,13 re-
spectively. Substrate 14, which differs from 8 only in the
protective group pattern of the two oxygen substituents,
underwent cycloisomerization under the same conditions to
provide the five-membered ring enol ether 15. With slight
a With 40 mol % 3. b After treatment with Ac2O, Et3N, and cat. DMAP.
increases in temperature and reaction time as well as catalytic
loading in some cases, high-yield cycloisomerizations of
alkynyldiols 16 and 18 to the seven-membered ring glycals
17 and 19 (corresponding to septanose glycals of D-glucal
and D-galactal, respectively)5,14 were achieved.
(7) (a) Kreiter, C. G. Angew. Chem., Int. Ed. 1968, 7, 390. (b) Fischer,
E. O.; Plabst, D. Chem. Ber. 1974, 107, 3326. (c) Casey, C. P.; Anderson,
R. L. J. Chem. Soc., Chem. Commun. 1975, 895. (d) Bernasconi, C. F.
Chem. Soc. ReV. 1997, 26, 299.
(8) Davidson, M. H.; McDonald, F. E. Org. Lett. 2004, 6, 1601.
(9) In contrast, DABCO often gives better results vs triethylamine in
the photoactivated catalytic system. (a) McDonald, F. E.; Reddy, K. S. J.
Organomet. Chem. 2001, 617-618, 444. (b) McDonald, F. E.; Reddy, K.
S. Angew. Chem., Int. Ed. 2001, 40, 3653.
(10) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4, 749.
(11) (a) Hauser, F. M.; Ellenberger, S. R. Chem. ReV. 1986, 86, 35. (b)
Baer, H. H.; Georges, F. F. Z. Can. J. Chem. 1977, 55, 1100. (c) Ginesta,
X.; Pasto´, M.; Perica`s, M. A.; Riera, A. Org. Lett. 2003, 5, 3001.
(12) (a) Smith, R. M.; Johnson, A. W.; Guthrie, R. D. J. Chem. Soc.,
Chem. Commun. 1972, 361. (b) Trost, B. M.; Jiang, C.; Hammer, K.
Synthesis 2005, 3335. (c) Hsu, D.-S.; Matsumoto, T.; Suzuki, K. Synlett
2006, 469.
Fischer carbene-catalyzed cycloisomerizations of alkynyl
alcohols 20 with C3- and C4-oxygen substituents9b required
additional optimization relative to the photochemical pro-
cedure (Table 2), as substantial amounts of the exocyclic
glycal were produced from substrate 20b. As reported by
others,15 sterically bulky propargylic substituents are required
for high endo-regioselectivity, but we observed that reduced
(14) (a) Snyder, N. L.; Haines, H. M.; Peczuh, M. W. Tetrahedron 2006,
62, 9301. (b) Ng, C. J.; Stevens, J. D. Carbohydr. Res. 1996, 284, 241.
(15) (a) Wipf, P.; Graham, T. H. J. Org. Chem. 2003, 68, 8798. (b)
Moilanen, S. B.; Tan, D. S. Org. Biomol. Chem. 2005, 3, 798.
(13) Kong, F.; Zhao, N.; Siegel, M.; Janota, K.; Ashcroft, J. S.; Koehn,
F. E.; Borders, D. B.; Carter, G. T. J. Am. Chem. Soc. 1998, 120, 13301.
1738
Org. Lett., Vol. 9, No. 9, 2007

Scheme 1. Synthesis of the Altromycin Disaccharide
Table 2. Comparison of Nonphotochemical Procedure
Catalyzed by 3 vs Photochemical Procedures
entry
substrate
conditionsa
% yield 21
% yield 22
1
2
3
4
5
6
7
8
20a
20a
20b
20b
20b
20c
20c
20c
A
B
A
B
C
A
B
C
53b
92
53
65
75
85
88
88
0b
0
35
20
15
9
7
6
a
A: 40 mol % 3, 10 equiv of Et3N, THF, 60 °C, 24 h. B: 25 mol %
of W(CO)6, 10 equiv of Et3N, THF, hν (350 nm), 60 °C, 6 h. C: 25 mol
b
% of W(CO)6, 2 equiv of DABCO, THF, hν (350 nm), 60 °C, 6 h. 30%
of 20a was recovered.
steric bulk in the O4 methoxymethyl (MOM) protective
group required increasing the steric bulk at O3 to the
triisopropylsilyl ether 20c to obtain good endo-regioselec-
tivity. The formation of exocyclic glycal 22b from substrate
20b was rationalized as the action of tungsten pentacarbonyl
as a Lewis acid to promote cyclization to 25 (Figure 2), but
exo-mode cyclization to 25 relative to rearrangement to the
vinylidene intermediate 24, resulting in the formation of
glycal 21c via endocyclic intermediate 26.16
The utility of the nonphotochemical conditions for tungsten-
catalyzed alkynyl alcohol cycloisomerization is highlighted
in the synthesis of the (N,N-dimethyl)vancosamine-R-(3′-O-
methyl)digitoxose disaccharide substructure of altromycin B
(27, Scheme 1), a glycoconjugate natural product exhibiting
in vivo activities against P388 leukemia as well as colon,
Figure 2. Proposal for substituent effects on regioselectivity.
(16) (a) Sheng, Y.; Musaev, D. G.; Reddy, K. S.; McDonald, F. E.;
Morokuma, K. J. Am. Chem. Soc. 2002, 124, 4149. (b) Nowroozi-Isfahani,
T.; Musaev, D. G.; McDonald, F. E.; Morokuma, K. Organometallics 2005,
24, 2921. (c) Sordo, T.; Campomanes, P.; Die´guez, A.; Rodriguez, F.;
Fan˜ana´s, F. J. J. Am. Chem. Soc. 2005, 127, 944.
increasing the steric bulk at O3 in substrate 20c would
increase the steric interaction between η2-alkyne-tungsten
pentacarbonyl and the O3-protective group, thus disfavoring
Org. Lett., Vol. 9, No. 9, 2007
1739

lung, and ovarian tumors.17,18 Our synthetic strategy for the
altromycin disaccharide relies mainly on iterative application
of tungsten-catalyzed alkynol cycloisomerization for each
of the carbohydrate moieties.2,9,19 The synthesis commenced
with NIS-mediated stereoselective trans-diaxial glycosyla-
tion20 of glycal 21c with the hydroxy â-lactam 28,10,21
followed by radical deiodination to produce O-glycoside 29.
The sequence of lactam opening to methyl ketone and
exchange of N-protective groups to the less basic carbamate
of 30, followed by alkyne desilylation and Felkin-Anh-
controlled reduction under Luche conditions,10 resulted in
stereoselective synthesis of alkynyl alcohol substrate 31.
Cycloisomerization of 31 under the standard conditions
developed for the simpler examples in Table 1 provided the
disaccharide glycal 32 in excellent yield, which was further
converted into the N,N-dimethylamino-O-methyl ether 33.
Although each of the transformations described herein also
proceeds by the photochemical method (in some cases with
lower catalytic loading), these new conditions now mean that
photochemical equipment is no longer required for tungsten-
catalyzed cycloisomerization of alkynyl alcohols. In addition,
our alkynol cycloisomerization procedure requires neither
expensive transition metals nor specialized ligands and is
compatible with a broad range of functional groups.
Acknowledgment. This work was supported by the
National Institutes of Health (R01 CA59703). We thank
Mary H. Davidson, Dr. Joseph M. Pletcher, and Matthew
A. Boone (Emory University) for providing samples of some
of the substrates or advanced synthetic precursors used in
this project. We also thank Rui Cao and Dr. Kenneth I.
Hardcastle (Emory University X-ray Crystallography Labo-
ratory) for providing the crystal structure of â-lactam 28.
(17) (a) Jackson, M.; Karwowski, J. P.; Theriault, R. J.; Hardy, D. J.;
Swanson, S. J.; Barlow, G. J.; Tillis, P. M.; McAlpine, J. B. J. Antibiot.
1990, 43, 223. (b) Brill, G. M.; McAlpine, J. B.; Whittern, D. N.; Buko, A.
M. J. Antibiot. 1990, 43, 229.
(18) For recent synthetic efforts towards substructures of altromycin B:
(a) Pasetto, P.; Franck, R. W. J. Org. Chem. 2003, 68, 8042. (b) Fei, Z.;
McDonald, F. E. Org. Lett. 2005, 7, 3617. (c) Koo, B.; McDonald, F. E.
Org. Lett. 2005, 7, 3621.
(19) (a) McDonald, F. E.; Zhu, H. Y. H. J. Am. Chem. Soc. 1998, 120,
4246. (b) McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979. (c) Trost, B.
M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528.
(20) Thiem, J.; Ossowski, P.; Schwentner, J. Chem. Ber. 1980, 113, 955.
(21) Resolution of racemic â-lactam 28 is described in the Supporting
Information. For different applications of tungsten-catalyzed cycloisomer-
ization methodology applied to aminoglycal synthesis, see: (a) Parker,
K. A.; Chang, W. Org. Lett. 2005, 7, 1785. (b) Parker, K. A.; Chang, W.
Org. Lett. 2003, 5, 3891.
Supporting Information Available: Experimental pro-
cedures and characterization and spectral data on new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL070435S
1740
Org. Lett., Vol. 9, No. 9, 2007