S. J. Gharpure, L. N. Nanda, M. K. Shukla
SHORT COMMUNICATION
delivered bromides 6a,b. Regioselective cyclopropane ring Hagen’s gland lactones in 12 steps from readily available
opening of bromides 6a,b by using nBu3SnH and AIBN in starting materials. The key steps involved in this synthesis
refluxing benzene furnished dihydrofuran derivatives 5a,b were the enantioselective organocatalytic direct α-oxyamin-
in good yields. Base-catalyzed hydrolysis of esters 5a,b fol- ation of an aldehyde, a highly regio- and stereoselective in-
lowed by iodolactonization of resultant acids 3a,b by using tramolecular cyclopropanation of vinylogous carbonates,
iodine and NaHCO3 in THF/H2O yielded iodolactones and facile regioselective radical ring opening of the cyclo-
4a,b (Scheme 4). The structures of 4a,b were deduced by propane moiety. Further efforts using DACs in the synthesis
their spectroscopic data. The stereochemistries of the vari- of lactone-based natural products are underway in our lab-
ous stereocenters were further unambiguously ascertained oratory and will be reported in due course.
by single-crystal X-ray diffraction analysis of iodolactone
4b (Figure 2).[11]
Experimental Section
(3aR,5R,6aR)-5-Butyltetrahydrofuro[3,2-b]furan-2(5H)-one (1a): A
solution of iodolactone 4a (28.0 mg, 0.09 mmol), nBu3SnH (35 µL,
0.13 mmol), and a catalytic amount of AIBN (3.0 mg, 0.02 mmol)
in benzene (4 mL) was heated at reflux for 2 h. The reaction mix-
ture was cooled, diluted with ether (15 mL) and washed success-
ively with 1% aq. NH4OH, water, and brine and dried (anhyd.
Na2SO4). Purification by column chromatography (silica gel; ethyl
acetate/hexanes, 1:3) furnished 1a (0.014 g, 88%) as a colourless
liquid. Rf = 0.4 (EtOAc/hexanes, 1:5). [α]2D3 = +39.5 (c = 1.00,
CHCl ). IR (neat): ν = 2929, 2862, 1774, 1462, 1401, 1342, 1175,
˜
3
1146, 1061, 1030, 976, 946, 904, 833, 733 cmϪ1 1H NMR (400
.
Scheme 4. Completion of the synthesis of Hagen’s gland lactones
1a and 1b. Reagents and conditions: (a) LiAlH4, THF, –78 °C,
20 min. (88% for 7a, 83% for 7b); (b) PPh3, CBr4, pyridine,
CH2Cl2, r.t., 36 h, (80% for 6a, 78% for 6b); (c) nBu3SnH, AIBN,
benzene, reflux, 2 h, (88% for 5a, 82% for 5b); (d) LiOH, EtOH/
H2O, r.t., overnight (81% for 3a, 99% for 3b); (e) I2, NaHCO3,
THF/H2O, r.t., 2 h, (75% for 4a, 92% for 4b); (f) nBu3SnH, AIBN,
benzene, reflux, 2 h (88% for 1a, 92% for 1b).
MHz, CDCl3): δ = 5.11 (t, J = 4.8 Hz, 1 H), 4.81 (t, J = 5.6 Hz, 1
H), 4.10–4.00 (m, 1 H), 2.76 (ABX, J = 18.8, 6.4 Hz, 1 H), 2.64
(ABX, J = 18.8, 0.0 Hz, 1 H), 2.37 (ABX, J = 14.0, 4.8 Hz, 1 H),
1.70–1.55 (m, 4 H), 1.55–1.45 (m, 1 H), 1.40–1.25 (m, 2 H), 0.90
(t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, DEPT): δ
= 176.17 (C), 85.08 (CH), 78.42 (CH), 77.48 (CH), 38.97(CH2),
36.79 (CH2), 34.52 (CH2), 28.31(CH2), 22.78 (CH2), 14.09 (CH3)
ppm. HRMS (ESI): calcd. for C10H16O3Na [M + Na]+ 207.0997;
found 207.0995.
(3aR,5R,6aR)-5-Hextetrahydrofuro[3,2-b]furan-2(5H)-one (1b): Re-
duction of iodolactone 4b (26.0 mg, 0.07 mmol) by using nBu3SnH
(42 µL, 0.15 mmol) and a catalytic amount of AIBN (5.0 mg,
0.03 mmol) in refluxing benzene (5 mL), as described for 1a fol-
lowed by purification by column chromatography (silica gel; ethyl
acetate/hexanes, 1:3) furnished 1b (0.015 g, 92%) as a colourless
liquid. Rf = 0.6 (EtOAc/hexanes, 1:4). [α]2D3 = +31.0 (c = 1.00,
CHCl ). IR (neat): ν = 2928, 2859, 1783, 1463, 1400, 1344, 1295,
˜
3
1259, 1173, 1150, 1065, 1038, 959, 930, 898, 833 cmϪ1 1H NMR
.
(400 MHz, CDCl3): δ = 5.11 (t, J = 4.7 Hz, 1 H), 4.81 (t, J =
5.5 Hz, 1 H), 4.10–4.00 (m, 1 H), 2.76 (ABX, J = 18.8, 6.4 Hz, 1
H), 2.64 (ABX, J = 18.8, 0.0 Hz, 1 H), 2.37 (ABX, J = 14.0, 4.8 Hz,
1 H), 1.70–1.55 (m, 1 H), 1.55–1.20 (m, 10 H), 0.88 (t, J = 6.7 Hz,
Figure 2. ORTEP diagram for iodide 4b.
Finally, reductive removal of the iodine under radical
conditions by using nBu3SnH and AIBN in refluxing ben-
zene furnished Hagen’s gland lactones 1a,b in 88 and 92% 3 H) ppm. 13C NMR (100 MHz, CDCl3, DEPT): δ = 76.20 (C),
85.08 (CH), 78.40 (CH), 77.48 (CH), 38.94 (CH2), 36.78 (CH2),
34.82 (CH2), 31.84 (CH2), 29.36 (CH2), 26.12 (CH2), 22.67 (CH2)
14.19 (CH3) ppm. HRMS (ESI): calcd. for C12H20O3Na
[M + Na]+ 235.1310; found 235.1313.
yield, respectively. The structures of 1a,b were confirmed by
comparison of the 1H and 13C NMR spectroscopic data
of the synthetic sample with those reported for the natural
product.[2b] The enantiomeric excess values of 1a,b were
measured by using chiral GC and were found to be consis-
tent with 97 and 96%ee, respectively. The optical rotation
data for lactones 1a {[α]D = +39.5 (c = 1.0, CHCl3)} and
1b {[α]D = +31.0 (c = 1.0, CHCl3)} were found to be consis-
tent with those reported earlier.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data along with
1
copies of the H and 13C NMR spectra for all new compounds.
Acknowledgments
We thank the Department of Science and Technology (DST) and
the Council of Scientific and Industrial Research (CSIR), New
Delhi, for financial support. We thank Mr. Ramkumar of the X-
Conclusions
In conclusion, we have developed a new concise enantio-
and diastereoselective total synthesis of the cis isomers of ray facility in the Department of Chemistry, IIT Madras, for col-
6634 Eur. J. Org. Chem. 2011, 6632–6635
www.eurjoc.org
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