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Stereoselective Synthesis of Functionalized 2,3‐dihydrobenzofurans, 

1‐benzopyrans and 1‐benzoxepines by Phenoxide ion‐mediated 
Carbocyclization
Subal Kumar Dinda, Sajal Kumar Das and Gautam Panda
Medicinal and Process Chemistry Division 
Central Drug Research Institute, CSIR, Lucknow‐226001
E‐mail: gautam_panda@cdri.res.in

Introduction Synthesis of functionalized 1-benzoxepines


OH OH OBn OBn
a b c d
2,3-Dihydrobenzofuran, 1-benzopyran and 1-benzoxepine derivatives are R R R R
CHO CO2Et CO2Et CHO
ubiquitous in natural products as well as in large number of unnatural 25a-c 26a-c 27a-c 28a-c
OBn OBn OBn a, R= 4-OMe,
molecules. Owing to their wide range of biological properties, they have e OH f CO2Et b, R= 2-OMe,
R R R c, R= H
attracted considerable attention of organic and medicinal chemists. CO2Et CO2Et O
29a-c 30a-c OH 31a-c O SO2

Scheme 3. Reagents and conditions: (a) Ph3P=CHCO2Et, dry CH2Cl2, rt, 1 h, 26a (96%),
O
O
2-Aminomethyl chroman derivatives and
2-azaheterocyclylmethyl chroman derivatives
26b (95%) and 26c (95%). (b)(i) H2, 10% Pd-C, EtOAc, 8 h. (ii) BnBr, anhyd. K2CO3, dry
actone, reflux, 4 h, 27a (90%), 27b (87%) and 27c (91%); for combined two steps. (c)
OHC O O DIBAL-H, dry toluene, -78oC, 1 h, 28a (95%), 28b (94%) and 28c (95%). (d)
X OH
O
1, (R)-(-)-Tremetone 2, Fomannoxin
2-Alkyl chroman
derivatives
R * R * Ph3P=CHCO2Et, dry CH2Cl2, rt, overnight, 29a (80%), 29b (82%) and 29c (77%). (e) AD-
O O
mix-β , MeSO2NH2, t-BuOH/H2O (1:1), 0oC, 24 h, 30a (95%), 30b (94%) and 30c (88%).
Enantiomerically pure Versatile
intermediate
(f) (i) SOCl2, Et3N, dry CH2Cl2, 0oC, 20 min. (ii) RuCl3, NaIO4, MeCN-H2O(1:9), 0oC, 10 h,
O O X= Leaving group. O 31a (84%), 31b (87%) and 31c (85%); for combined two steps.
H
O MeO O
O S O
N N
H H
OH MeO O O CO 2Et OH
6. Repinotan OBn O
3, Rotenone 4, Deoxypsorospermin F CO2Et O
R a CO 2Et
R OH R
O H OH O O
N 31a-b O SO2 32a and 34b 33a and 35b not formed
H
HO 32a, R= 4-OMe, 33a, R= 4-OMe,
N
5, Heliannuol G 34b, R= 2-OMe 35b, R= 2-OMe,
7. Sarizotan
OH
Figure 1. Some natural products containing Figure 2. Medicinally important 2-substituted OBn
CO2Et O
CO 2Et
O
2-substituted 2,3-dihydrobenzofuran moiety. benzopyran derivatives a OH
CO2Et
O
31c O SO2
36c (major) 37c (minor)
36c:37c= 4:1
HO HO
OH
Scheme 4. Reagents and conditions: (a) (i) H2, 10%Pd-C, EtOAc, 8 h. (ii) anhyd. K2CO3,
O
O
dry acetone, rt, 8h. (iii) 20% H2SO4, THF, rt, overnight, 32a (70%), 34b (72%) and 36c
8, Heliannuol B OH 9, Heliannuol C
(60%) and 37c (15%); for combined three steps.
R OH
O OH
O
HO 12 HO
OH CO2Et O
O
O a
O
OH OH
10, Heliannuol D OH 11, Heliannuol H OH
MeO MeO
Figure 3. Selected natural products 8-11 and our designed target molecules 12 containing 1- 32a 38a
benzoxepine ring system.
Scheme 5. Reagents and conditions: (a) MeMgI, dry THF, 0oC-reflux, 3h, 38a (88%); for
combined two steps.
Synthesis of 2,3-dihydrobenzofurans (Scheme 1)
R R R R
Synthesis of 2-hydroxymethyl chromans (Scheme 6)
R
OH OBn OBn OBn OBn
a b c d e OH OBn OBn OBn OBn
a b c d e
CHO CO2Et
CHO CHO OH OH
13a,b 14a,b 15a,b 16a,b 17a,b R R R R CHO R CO 2Et
39a,b 40a,b 41a,b 42a,b 43a,b
a, R= -OMe a, R= -OMe
R R b, R= -H OH b, R= -H
R R R
OBn OH O i OBn O OH O
O OH g O h O O OBn f g h OH
f
O
OH R OH R
OH OH OTs R
19a,b 20a,b R O 46a,b 47a,b
18a,b 21a,b 22a,b 44a,b 45a,b

Scheme 1. Reagents and conditions: (a) BnBr, anhyd. K2CO3, dry acetone, reflux, 4 h, 14a (85%), 14b Scheme 6. Reagents and conditions: (a) BnBr, anhyd. K2CO3, dry acetone, reflux, 4 h, 40a
(85%). (b) (i) CH3OCH2Ph3P+Cl-, LHMDS, dry THF, 0oC-rt, 3 h. (ii) 1.5 (N) HCl, THF, reflux, 3 h, (95%), 40b (96%). (b) (i) 9-BBN, dry THF, rt, 4 h. (ii) 30% H2O2, NaOH, reflux, 2 h, 41a
15a (70%), 15b (71%); based on two steps. (c) Ph3P=CHCO2Et, dry CH2Cl2, rt, overnight, 16a (81%), (94%), 41b (96%). (c) PCC, dry CH2Cl2, 0oC-rt, 5 h, 42a (76%), 42b (72%). (d)
16b (75%). (d) DIBAL-H, dry toluene, 0oC-rt, 2 h, 17a (95%), 17b (94%). (e) L-(+)-DIPT, Ti(OiPr)4, Ph3P=CHCO2Et, dry CH2Cl2, rt, overnight, 43a (80%), 43b (77%). (e) DIBAL-H, dry toluene,
TBHP, CH2Cl2, 4 Å MS, -25oC, 18 h, 18a (85%), 18b (88%). (f) (i) 10% Pd-C, ethyl acetate, H2, 2 h. 0oC-rt, 4 h, 44a (96%), 44b (95%) (f) D(-)-DIPT, Ti(OiPr)4, TBHP, dry CH2Cl2, 4 Å MS, -25oC,
(ii)10% NaOH solution saturated with NaCl, 0oC, 3 h, 19a (80%), 19b (78%); based on two steps. (g) 18 h, 45a (88%), 45b (90%). (g) (i) 10% Pd-C, ethyl acetate, H2, 2 h. (ii) 10% NaOH solution
TsCl, anhyd. Et3N, dry CH2Cl2, 0oC, overnight, 20a (75 %), 20b (77%). (h) (i) LiAlH4, dry THF, 0oC- saturated with NaCl, 0oC, 3 h, 46a (83%), 46b (84%); based on two steps. (h) (i) NaIO4,
rt, 3 h. (ii) PDC, dry CH2Cl2, 0oC-rt, 24 h, 21a (68%), 21b (66%); based on last two steps. (i) MeOH-H2O, 0oC, 2 h. (ii) NaBH4, MeOH, 0oC-rt, 0.5 h, 47a (87%), 47b (89%); based on two
CH3Ph3P+I-, t-BuOK, dry THF, 0oC-rt, 12 h, 22a (78%), 22b (75%). steps.

Synthesis of 4-(2,3-dihydrobenzofuran-2-yl)-2- Conclusion


methylbut-3-en-2-ols (Scheme 2) ‰ Asymmetric synthesis of 2,3-dihydrobenzofuran and 1-
R R R
benzopyran nuclei have been developed employing Sharpless
O OH
a O CO2Et b O OH asymmetric epoxidation and phenoxide ion-mediated
OH intramolecular epoxide ring opening reactions.[1]
19a,b 23a,b 24a,b a, R= -OMe
b, R= -H

Scheme 2. Reagents and conditions: (a) (i) NaIO4, MeOH-H2O, 0oC, 2 h. (ii) Ph3P=CHCO2Et, dry ‰ Further, Sharpless asymmetric dihydroxylation on suitable α,β-
CH2Cl2, rt, overnight, 23a (85%), 23b (87%); based on two steps. (b) MeMgI, dry ether, 0oC- unsaturated esters and phenoxide ion-directed intramolecular 7-
reflux, 4 h, 24a (94%), 24b (93%); based on two steps. endo-tet carbocyclization of syn-2,3-dihydroxy ester-derived cyclic
References sulphates were used to synthesize 2,3-disubstituted 1-
benzoxepines.[2]
[1] S K Dinda, S K Das and G Panda, Synthesis, 2009, 1886-1896.
[2] S K Das, S K Dinda and G Panda, Eur. J. Org. Chem., 2009, 204-207.