Synthesis of (tetrahydrofiiranyl)tetrahydrofurans via radical cyclization of bis(-alkoxyacrylates)

Article abstract of DOI:10.1039/a908456h

Radical cyclizations of bis(-alkoxyacrylates) obtained from. (3R, 4R)- and mes0-l, 6-dibromohexane-3, 4-diol proceed to form a C2-symmetric and a nieso (tetrahydrofuranyl)tetrahydrofuran derivative. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a908456h

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Synthesis of (tetrahydrofuranyl)tetrahydrofurans via radical
cyclization of bis(ꢀ-alkoxyacrylates)
Eun Lee*, Ho Young Song and Hee Jo Kim
Department of Chemistry, College of Natural Sciences, Seoul National University,
Seoul 151-742, Korea
Received (in Cambridge, UK) 16th August 1999, Accepted 26th October 1999
Radical cyclizations of bis(ꢀ-alkoxyacrylates) obtained
from (3R,4R)- and meso-1,6-dibromohexane-3,4-diol
proceed to form a C2-symmetric and a meso (tetrahydro-
furanyl)tetrahydrofuran derivative.
β-Alkoxyacrylates are excellent precursors for stereoselective
preparation of cis-2,5-substituted tetrahydrofurans and cis-2,6-
substituted tetrahydropyrans via radical cyclizations.1 Fused
oxacycles may be prepared from double cyclizations; radical
cyclizations of the bis(β-alkoxyacrylate) 2 obtained from
(2S,3S)-1,4-bis(phenylseleno)butane-2,3-diol led to the form-
ation of the cis-fused C2-symmetric 2,6-dioxabicyclo[3.3.0]-
octane derivative 3,2 which served as a key intermediate in the
formal total synthesis of (Ϫ)-kumausallene (Scheme 1).3 Aside
Scheme 2 a) TBSCl, imidazole, cat. DMAP, DMF, r.t. 1 h; b)
HCCCO2Me, N-methylmorpholine (NMM), DCM, r.t. 4 h; c) conc.
HCl, MeOH, r.t. 30 min; d) CBr4, Ph3P, DCM, r.t. 30 min; e) 2.4 eq.
Bu3SnH, 0.2 eq. AIBN, benzene (0.025 M), reflux, 5 h (syringe pump,
4 h).
alkoxyacrylate) 11 was obtained following the known three
step sequence of reactions from 10, and it was transformed into
the meso-(tetrahydrofuranyl)tetrahydrofuran derivative 125 in
high yield under the standard conditions (Scheme 3). The pre-
Scheme 1 a) 2.5 eq. Bu3SnH, 0.25 eq. AIBN, benzene (0.02 M), reflux,
5 h (syringe pump, 4 h).
from its ascetic beauty, we were intrigued by the efficacy of the
double radical cyclization strategy for fused oxacycles like 3,
which called for further investigations.
meso-Erythritol (5) served as the starting point in the
attempted synthesis of the trans-fused meso isomer of 3. The
diol 6 was obtained via selective TBS protection of the primary
hydroxy groups of 5, which was then converted into the corre-
sponding bis(β-alkoxyacrylate). Deprotection of the TBS
groups and primary bromide substitution with carbon tetra-
bromide–triphenylphosphine led to the formation of the bis-
(β-alkoxyacrylate) 7. When the substrate 7 was allowed to react
with tributylstannane under high dilution conditions, a high
yield of the tetrahydrofuranyl product 84 was obtained. Appar-
ently, thermodynamic bias against the trans-fused bicyclo-
[3.3.0]octane systems prevented the second radical cyclization
step necessary for the bicycle formation (Scheme 2).
We then turned our attention to the bishomo analogues of
the substrates 2 and 7. Diethyl trans-hex-3-enedioate (9) was
reduced with lithium aluminium hydride, and the resulting
trans-hex-3-ene-1,6-diol was converted into the epoxide, from
which the meso diol 10 was obtained via aqueous acid treatment
and TBS protection of the 1,6-hydroxy groups. The bis(β-
Scheme 3 a) LAH, ether, 0 ЊC; b) MCPBA, DCM, 0 ЊC, 1 h; aq. H2SO4,
r.t. 12 h; c) TBSCl, imidazole, DMF, r.t. 30 min; d) HCCCO2Me, NMM,
DCM, r.t. 3 h; e) conc. HCl, MeOH, r.t. 10 min; f) CBr4, Ph3P, DCM,
r.t. 1 h; g) 2.4 eq. Bu3SnH, 0.2 eq. AIBN, benzene (0.025 M), reflux, 5 h
(syringe pump, 4 h).
dominant formation6 of the product 12 attests to the complete
dominance of the 5-exo mode of radical cyclization over the
alternative 6-exo mode, which would have generated a (tetra-
hydropyrano)tetrahydropyran product.
Next, trans-hex-3-ene-1,6-diol (13) was converted into the
bis(TBS) ether, and it was subjected to the Sharpless asym-
metric dihydroxylation conditions to provide the diol 14 in
84% ee.7 The preparation of the bis(β-alkoxyacrylate) 15 from
14 proceeded without incident. When the substrate 15 was
allowed to react with tributylstannane under high dilution
J. Chem. Soc., Perkin Trans. 1, 1999, 3395–3396
This journal is © The Royal Society of Chemistry 1999
3395

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Y.-S. Cho, H.-S. Cheon and Y. H. Chong, Tetrahedron Lett., 1997,
38, 7757.
2 In this case, a small amount of the minor product 4 was also
obtained.
3 E. Lee, S.-K. Yoo, H. Choo and H. Y. Song, Tetrahedron Lett., 1998,
39, 317.
1
4 H-NMR (300 MHz, CDCl3) δ 1.28 (d, 3H, J = 6.5 Hz), 1.90–1.95
(m, 1H), 2.17–2.19 (dd, 1H, J = 5.4, 1.6 Hz), 2.55 and 2.68 (AB of
ABX, JAB = 15.6 Hz, JAX = 6.7 Hz, JBX = 6.1 Hz), 3.70 (s, 6H), 4.06–
4.09 (m, 1H), 4.40 (m, 1H), 4.50 (m, 1H), 5.17 (d, 1H, J = 12.7 Hz),
7.51 (d, 1H, J = 12.7 Hz); 13C-NMR (75 MHz, CDCl3) δ 19.69,
37.54, 39.98, 51.18, 51.78, 74.33, 79.83, 86.18, 97.81, 160.70, 167.87,
171.06; MS (EI, relative intensity) 258 (Mϩ, 3), 157 (86), 83 (100).
1
5 H-NMR (300 MHz, CDCl3) δ 1.56–1.66 (m, 2H), 1.73–1.83 (m,
2H), 1.91–2.11 (m, 4H), 2.47 and 2.61 (AB of ABX, JAB = 15.2 Hz,
JAX = 6.9 Hz, JBX = 6.4 Hz), 3.68 (s, 6H), 3.80–3.86 (m, 2H), 4.24–
4.33 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 27.59, 30.79, 40.68,
51.55, 75.70, 81.34, 171.63; MS (CI, relative intensity) 287 (Mϩ1,
100), 255 (26), 213 (20); HRMS (CI) calcd for C14H23O6 287.1495,
found 287.1493.
Scheme 4 a) TBSCl, imidazole, DCM; b) AD-mix-β, MeSO2NH2,
NaHCO3, t-BuOH–H2O (1:1), 0 ЊC; c) HCCCO2Me, NMM, DCM,
r.t.; d) conc. HCl, MeOH, r.t.; e) CBr4, Ph3P, DCM, r.t.; f) 2.4 eq.
Bu3SnH, 0.2 eq. AIBN, benzene (0.025 M), reflux, 5 h (syringe pump,
4 h).
6 A trace amount of a minor (presumably epimeric) product was
obtained.
7 Sharpless asymmetric dihydroxylation of trans-1,6-dibromo-
hex-3-ene, obtained from trans-hex-3-ene-1,6-diol via mesylation
and bromide substitution, provided 74% yield of (3R,4R)-1,6-
dibromohexane-3,4-diol in high enantiomeric excess (>98%).
Reaction of this diol with ethyl propiolate was a little sluggish, and
gave 40% yield of the corresponding bis(β-alkoxyacrylate). Radical
cyclization produced ethyl ester analogues of 16 and 17 in 72% and
6% yield, respectively.
conditions, the C2-symmetric (tetrahydrofuranyl)tetrahydro-
furan 168 and the C2-symmetric (tetrahydropyrano)tetrahydro-
pyran 179 were obtained in 66% and 6% yield, respectively
(Scheme 4). In this case, the 6-exo cyclization competes with the
favored 5-exo cyclization, albeit ineffectively.
The present results show that radical cyclization strategy may
provide an effective alternative in the synthesis of multi-
oxacyclic motifs of current interest.10 Further efforts in these
laboratories towards synthesis of oxacyclic natural products
and functional molecular systems will be reported in due
course.
8 [α]D28 Ϫ8.9 (c 1.8, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 1.56–1.78
(m, 4H), 1.86–1.96 (m, 2H), 2.01–2.12 (m, 2H), 2.47 and 2.73 (AB of
ABX, JAB = 15.4 Hz, JAX = 6.3 Hz, JBX = 7.2 Hz), 3.68 (s, 6H), 3.80–
3.87 (m, 2H), 4.25–4.34 (m, 2H); 13C-NMR (75 MHz, CDCl3)
δ 27.59, 30.94, 40.48, 51.50, 75.78, 81.55, 171.68; MS (CI, relative
intensity) 287 (M ϩ 1, 100), 255 (86), 213 (21); HRMS (CI) calcd for
C14H23O6 287.1495, found 287.1499.
9 [α]D26 Ϫ14.9 (c 0.62, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 1.32–1.44
(m, 2H), 1.54–1.71 (m, 4H), 1.84–1.94 (m, 2H), 2.41 and 2.58 (AB of
ABX, JAB = 15.3 Hz, JAX = 7.3 Hz, JBX = 5.7 Hz), 3.39 (br, 2H), 3.71
(s, 6H), 3.74–3.85 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 25.69,
29.17, 41.29, 51.56, 71.34, 73.82, 171.97; MS (CI, relative intensity)
287 (M ϩ 1, 77), 255 (100), 213 (34); HRMS (CI) calcd for C14H23O6
287.1495, found 287.1491.
This research was supported by the Korea Research Found-
ation (98-015-D00178) and the Korea Science and Engineering
Foundation (95-0501–06-01-3).
Notes and references
10 (a) U. Koert, Synthesis, 1995, 115; (b) Many of the more recent
references on the synthesis of Annonaceous acetogenins may be
found in A. Sinha, S. C. Sinha, S. C. Sinha and E. Keinan, J. Org.
Chem., 1999, 64, 2381.
1 (a) E. Lee, J. S. Tae, C. Lee and C. M. Park, Tetrahedron Lett., 1993,
34, 4831; (b) E. Lee, J. S. Tae, Y. H. Chong, Y. C. Park, M. Yun and
S. Kim, Tetrahedron Lett., 1994, 35, 129; (c) E. Lee and C. M. Park,
J. Chem. Soc., Chem. Commun., 1994, 293; (d) E. Lee, J.-w. Jeong and
Y. Yu, Tetrahedron Lett., 1997, 38, 7765; (e) E. Lee, C. M. Park and
J. S. Yun, J. Am. Chem. Soc., 1995, 117, 8017; ( f ) E. Lee, S.-K. Yoo,
Communication 9/08456H
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J. Chem. Soc., Perkin Trans. 1, 1999, 3395–3396