Radical cyclization of sugar-derived β-(alkynyloxy)acrylates: Synthesis of novel fused ethers

Article abstract of DOI:10.1021/ol0000408

(equation presented) Tributyltin radical mediated cyclization of carbohydrate-derived β-(alkynyloxy)acrylates leading to highly functionalized cis-and trans-fused bicyclic ethers of various ring sizes is described. The efficacy of the radical cyclization is nicely illustrated in the iterative construction of a frans-fused tricyclic tetrahydropyran.

Full text of DOI:10.1021/ol0000408

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1275-1277
Radical Cyclization of Sugar-Derived
â-(Alkynyloxy)acrylates: Synthesis of
Novel Fused Ethers
Michiel A. Leeuwenburgh, Remy E. J. N. Litjens, Jeroen D. C. Code´e,
Herman S. Overkleeft, Gijsbert A. van der Marel, and Jacques H. van Boom*
Leiden Institute of Chemistry, P.O. Box 9502, 2300 RA Leiden, The Netherlands
j.boom@chem.leidenuniV.nl
Received February 22, 2000
ABSTRACT
Tributyltin radical mediated cyclization of carbohydrate-derived â-(alkynyloxy)acrylates leading to highly functionalized cis- and trans-fused
bicyclic ethers of various ring sizes is described. The efficacy of the radical cyclization is nicely illustrated in the iterative construction of a
trans-fused tricyclic tetrahydropyran.
The development of synthetic procedures toward fused
oxacycles, which are key structural elements in many marine
toxins such as the brevetoxins1 and ciguatoxins,2 has received
considerable attention over the past decade.3 In this respect,
we4 and others5 recently showed the versatility of carbohydrate-
derived dienes (A, Scheme 1) and enynes in the ring closing
adopted for the conversion of appropriate carbohydrate-
derived â-(alkynyloxy)acrylates C (see Scheme 1) into highly
functionalized bicyclic ethers of type D.
We here report the general usefulness of this approach in
the construction of cis- and trans-fused bicyclic ethers of
various ring sizes (i.e., D, n ) 0-3), as well as the feasibility
(1) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.-C.; Golik,
J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773. Shimizu,
Y.; Chou, H. N.; Bando, H.; Van Duyne, G.; Clardy, J.-C. J. Am. Chem.
Soc. 1986, 108, 514-515. Total synthesis: Nicolaou, K. C.; Rutjes, F. P.
J. T.; Theodorakis, E. A.; Tiebes, J.; Sato, M.; Untersteller, E. J. Am. Chem.
Soc. 1995, 117, 1173 and references therein.
Scheme 1
(2) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T.
J. Am. Chem. Soc. 1990, 112, 4380-4386. Satake, M.; Murata, M.;
Yasumoto, T. Tetrahedron Lett. 1993, 34, 1975. Lewis, R. J.; Vernoux,
J.-P.; Brereton, I. M. J. Am. Chem. Soc. 1998, 120, 5914.
(3) For reviews about polycyclic ether synthesis, see: Alvarez, E.; Pe´rez,
R.; Rico, M.; Rodr´ıguez, R. M.; Mart´ın, J. D. J. Org. Chem. 1996, 61,
3003. Mori, Y. Chem. Eur. J. 1997, 3, 849.
(4) Leeuwenburgh, M. A.; Overkleeft, H. S.; Van der Marel, G. A.; Van
Boom, J. H. Synlett 1997, 1263. Leeuwenburgh, M. A.; Kulker, C.;
Duynstee, H. I.; Overkleeft, H. S.; Van der Marel, G. A.; Van Boom, J. H.
Tetrahedron 1999, 55, 8253. Leeuwenburgh, M. A.; Kulker, C.; Overkleeft,
H. S.; Van der Marel, G. A.; Van Boom, J. H. Synlett 1999, 1945.
(5) Rainier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310. Oguri,
H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405.
Maeda, K.; Oishi, T.; Oguri, H.; Hirama, H. Chem. Commun. 1999, 1063.
Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372.
(6) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993, 34,
4831.
metathesis mediated synthesis of cis- and trans-fused bicyclic
(B) as well as tricyclic ether systems. Some years ago, Lee
et al.6 revealed that â-(alkynyloxy)acrylates could be con-
verted into monocyclic ethers via tributyltin radical mediated
cyclization and subsequent acidic destannylation. It occurred
to us that this interesting two-step methodology could be
10.1021/ol0000408 CCC: $19.00 © 2000 American Chemical Society
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of transforming C (n ) 1) into a tricyclic ether system via
an iterative process.
In the first instance, the transformation of the known7
perbenzylated R-1,2-anhydro-D-glucose 3 (Scheme 2) into
proceeded with virtually complete stereoselectivity to give
the â-propargyl-C-glucoside 8.9 Subjection of the corre-
sponding Michael adduct 9 to the same two-step procedure
mentioned for the conversion of 5 into 7 gave the expected
trans-fused pyranopyran 11 as the single diastereoisomer in
71% over the two steps.
The high stereoselectivity and acceptable yield of the
radical cyclization of 9 was an incentive to explore the
feasibility of converting the known11 partially protected
methyl R-D-glucoside 12 (Scheme 3) into the trans-fused
Scheme 2a
Scheme 3a
a Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2;
(b) PPh3, CBr4, CH2Cl2, 82%-83% (two steps); (c) t-BuLi, THF,
-50 °C, 76% 13a, 92% 13c; (d) DDQ, H2O, CH2Cl2, 79% 14a,
77% 14b, 77% 14c, 88% 14d; (e) ethyl propiolate, NMM, CH2Cl2,
94% 15a, 99% 15b, 97% 15c, 96% 15d; (f) I2, imidazole, toluene,
92% 16, 78% 19; (g) HCCLi ethylenediamine complex, DMSO,
74% 13b, 82% 13d; (h) H2, PtO2, EtOAc/hexanes; (i) LiAlH4, THF,
0 °C, 76% (two steps).
a Reagents and conditions: (a) NaCCH, ZnCl2, THF, 0 °C to
room temperature, 85%; (b) ethyl propiolate, NMM, CH2Cl2, 98%
5, 95% 9; (c) Bu3SnH, AIBN, added over 5 h, toluene, 80 °C, 59%
6, 72% 10; (d) p-TsOH, CH2Cl2, 97% 7, 99% 11; (e) Bu3SnCHd
CdCH2, n-BuLi, then ZnCl2, then 3, -50 °C to room temperature,
72%.
five- to eight-membered bicyclic ethers 20a-d (Table 1).
Accordingly, 12 was subjected to Dess-Martin oxidation12
and the resulting aldehyde was transformed into alkyne 13a
the respective cis-5,6- and trans-6,6-bicyclic ethers 7 and
11 was explored. To this end, 3 was treated with sodium
acetylide in the presence of zinc chloride to give exclusively
the R-ethynyl-C-glucoside 4.8,9 Hetero-Michael addition of
4 to ethyl propiolate under the influence of N-methylmor-
pholine gave the sugar-derived â-(alkynyloxy)acrylate 5 in
83% yield based on 3. The radical cyclization of 5 by syringe
pump addition of Bu3SnH and AIBN in toluene at 80 °C
led to the isolation of cis-fused 5,6-bicyclic vinylstannane
derivative 6 in a yield of 59%. Acidic destannylation of 6
afforded in near quantitative yield 7, the stereochemistry of
which was firmly established by NOESY spectroscopy. On
the other hand, the trans-fused 6,6-bicyclic ether system 11
was also readily accessible from 3 by the following sequence
of reactions. Ring opening of epoxide 3 with allenyllithium,
generated in situ by transmetalation of allenyltributyltin10
with n-butyllithium, under the influence of zinc chloride
Table 1. Formation of Five- through Eight-Membered Rings
(7) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661.
(8) Leeuwenburgh, M. A.; Timmers, C. M.; Van der Marel, G. A.; Van
Boom, J. H.; Mallet, J.-M.; Sinay¨, P. G. Tetrahedron Lett. 1997, 38, 6251-
6254.
(9) Details on the synthesis of this and related C-glycosides from R-1,2-
anhydrosugars will be reported soon.
a Conditions: (a) 2 equiv of Bu3SnH and 0.25 equiv of AIBN, added
over 5 h to the acrylate in toluene at 80 °C, followed by stirring for 10 h;
(b) 1.5 equiv of p-TsOH, CH2Cl2, 1.5 h. b Overall isolated yield of the
cyclization and destannylation. c Bu3SnH and AIBN were added over 24
h.
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Org. Lett., Vol. 2, No. 9, 2000

via a slightly modified two-step Corey-Fuchs procedure.13,14
Removal of the p-methoxybenzyl (MPM) group in 13a with
DDQ was followed by hetero-Michael addition of alkynol
14a to afford five-membered ring precursor 15a in an overall
yield of 47% from 12. The corresponding six-membered ring
precursor 15b was also readily accessible by treatment of
primary iodide 16, prepared by reaction of 12 with I2/PPh3/
imidazole in toluene, with lithium acetylide ethylenediamine
complex. Subsequent deprotection of HO-4 in the resulting
13b and hetero-Michael addition of 14b afforded â-(alkyn-
yloxy)acrylate 15b. On the other hand, known15 ethyl
D-gluco-oct-6-enuronate 17 served as the starting compound
for the 7,6- and 8,6-bicyclic ether precursors 15c and 15d.
Thus, selective hydrogenation of the double bond in 17 under
the influence of platinum(IV) oxide followed by reduction
of the saturated ester with lithium aluminum hydride gave
alcohol 18 (76%, two steps). Transformation of 18 into the
corresponding aldehyde and sequential dibromoolefination
and elimination yielded alkyne 13c in 76% over the three
steps. Intermediate alkyne 13d was prepared from alcohol
18 by executing the earlier mentioned two-step protocol (cf.
12 f 13b) in an overall yield of 64%. Deprotection of 13c
and 13d at the 4-positions and installation of the acrylate
functionalities yielded 15c and 15d, respectively.
Scheme 4a
a Reagents and conditions: (a) O3; NaBH4, MeOH/CH2Cl2 (7:
1), -70 °C to room temperature, 92%; (b) TBSOTf, i-Pr2EtN,
CH2Cl2, 0 °C, 89%; (c) LiAlH4, Et2O, 0 °C, 91%; (d) Dess-Martin
periodinane, pyridine, CH2Cl2; (e) CBr4, PPh3, CH2Cl2, 86% (two
steps); (f) n-BuLi, THF, -50 °C, 92%; (g) TBAF, THF, 91%; (h)
ethyl propiolate, NMM, CH2Cl2, 99%; (i) Bu3SnH, AIBN, added
over 5 h, toluene, 80 °C, 90%; (j) p-TsOH, CH2Cl2, 97%.
The results of the ensuing tributyltin radical mediated
cyclizations of 15a-d and subsequent acidic destannylations
to afford compounds 20a-d are summarized in Table 1. First
of all, it is of interest to note that the formation of the trans-
5,6 bicyclic ether 20a proceeded more efficiently than the
cis-5,6 system 7. This may be explained by taking into
consideration that the acrylate moiety in 15a, in contrast to
acrylate 5, adopts a more favorable equatorial conformation.
It is also evident that there is a dramatic drop in yield going
from the seven- to eight-membered rings (20c to 20d). In
this particular case, the desired product 20d could only be
isolated in 8% yield and the major product proved to be the
result of hydrostannylation of the triple bond (60-70%).
Prolonging the time of addition (i.e., from 5 to 24 h) of Bu3-
SnH and AIBN in order to suppress quenching of the
intermediate vinylic radical by Bu3SnH only led to a slight
increase in the yield of 20d.
process, giving equatorial alcohol 21 as the sole isomer, as
evidenced by NOESY spectroscopy. Temporary protection
of the newly formed secondary alcohol with a tert-butyldi-
methylsilyl (TBS) group and reduction of the ester in 22,
followed by oxidation and a Corey-Fuchs procedure, gave
alkyne 23 in 64% yield over the five steps. Fluoride-ion
mediated desilylation and reaction of alkynol 24 with ethyl
propiolate furnished bicyclic â-(alkynyloxy)acrylate 25,
cyclization and destannylation of which afforded homoge-
neous tricyclic ether 26 in an overall yield of 87%.
In summary, an efficient method for the preparation of
functionalized fused ethers of various ring sizes by radical
cyclization of sugar-derived â-(alkynyloxy)acrylates is pre-
sented. The versatility of this approach is highlighted by the
iterative expansion of 20b to give 26 in an overall yield of
48% over 10 steps and nicely complements recently reported
related radical cyclization protocols.16 At present, we are
studying in detail whether an appropriately protected sugar
can be extended at both the reducing and nonreducing end.
An additional merit of the radical cyclization process is
the formation of an exocyclic double bond. The latter feature
offers the opportunity to install an equatorially oriented
hydroxyl group, thus opening the way for an iterative radical
cyclization process. The feasibility of this concept is
demonstrated in the conversion of bicyclic 20b into the
tricyclic system 26 (Scheme 4). In this respect, it was
gratifying to establish that subjection of 20b to ozonolysis
and in situ reduction of the intermediate ozonide with sodium
borohydride was a highly efficient and stereoselective
Acknowledgment. We thank Fons Lefeber for recording
the 2D-NMR spectra, Hans van den Elst for the mass spectra,
and Han Peeters (University of Amsterdam) and Peter van
Veelen for the high-resolution mass measurements.
Supporting Information Available: General experimen-
tal procedures for the acrylation, radical cyclization, and
acidic destannylation. Full characterization data for com-
pounds 7, 11, 20a-d, and 26. This material is available free
of charge via the Internet at http://pubs.acs.org.
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OL0000408
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(14) Butylation of the methylene of the MPM group was observed when
n-BuLi instead of t-BuLi was used.
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1994, 35, 129. Evans, P. A.; Roseman, J. D. J. Org. Chem. 1996, 61, 2252.
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