1.3. Prins Cyclization
1.3.7. Miscellaneous Prins Cyclization Reactions
Chapter 1 Multicomponent and Prins Cyclization Reactions
35 tetrahydrofuranoid lipids from red algae of the genus Luurenciu has been developed by Overman and co-workers.92 The total synthesis of (±)-trans-kumausyne from rac-170 was accomplished in 13 steps and >5% overall yield. The central step is the convenient formation of (±)-hydrobenzofuranone (169) on a large scale, and with complete stereocontrol, from the acid-catalyzed condensation of 1 -vinylcyclopentanediol (167) and a- (benzy1oxy)acetaldehyde (168). Starting with the chiral, nonracemic (lS,2R) diol (167), (-)- hydrobenzofuranone (169) was also available in good enantiomeric purity. (Scheme 1.3.56).
Scheme 1.3.56.
Oveman was the first to present synthesis enantiomer of citreoviral (175), in 16 steps and 2.4% overall yield. Moreover, the key step was the synthesis 3-acyltetrahydrofuran (174) from condensation of (171) with dimethyl ketal (172) in the presence of TMSOTf at -30 °C
Scheme 1.3.57.
in CH2Cl2 in 88% yield with a separable mixture of acetals (173). Compound (173) could be converted efficiently to (174) by exposure to SnCl4 at -78 °C in CH2Cl2 (Scheme 1.3.57).93
Chapter 1 Multicomponent and Prins Cyclization Reactions
36 Scheme 1.3.58.
Yadav and co-workers95 developed a Prins cyclization of a silicon-stabilized homoallyl cation formed from a cyclopropyl carbinol that was vicinally substituted by a silylmethyl function.
The reaction was applied to the synthesis of 2,4,6-trisubstituted tetrahydropyran rings in good to excellent yields. As illustrated in Scheme 1.3.59, butyraldehyde reacted with (178) in the
Scheme 1.3.59.
presence of trifluoroacetic acid in CH2Cl2 at -30 °C to furnish compound (179) in 72% yield as a single isomer. The reaction introduces three stereogenic centers in the product.
Yu and co-workers developed an intramolecular Prins type cyclization of cyclopropylvinylic aldehydes (180) promoted by TiCl4 under mild reaction conditions to form cis-cyclic products
Scheme 1.3.60.
(181) in high yield (Scheme 1.3.60).96
Loh and co-workers98 established new type Prins cyclization, as shown in Scheme 1.3.61. The reaction involves the Mukaiyama-Aldol reaction in presence of TiBr4, silyl enol ether (183) with acetal (182) via an oxocarbenium intermediate (185), which upon trapping by an alkene functionality in an intramolecular Prins cyclization fashion, gives bridged bicyclic ring system (184).
HOPh TBDPS
CH3CH2CH2CHO Trifluoroacetic Acid CH2Cl2, -30 oC
72%
O TBDPS
Ph OH 178
179
TsN O
TsN
OH H Cl
H TiCl4 (1.1 equiv.)
CH2Cl2, -78 - 0 oC 180 82%
181 N
Ot-Bu
C8H17 O t-BuLI, THF BF3.Et2O O
OTBS
N Ot-Bu C8H17 O
OTBS HO
H O InCl3 CH2Cl2 0 oC, 1h
84%
O O
62% OTBS 176
177
TH-961_06612201
Chapter 1 Multicomponent and Prins Cyclization Reactions
37
EtO OEt
+
H
OTIPS TiBr4 CH2Cl2, -78 oC
30 min., 76-90% OEt
Br TIPSO
H
H OTIPS TiBr4
TIPS O Prins Cyclization
TIPSO OEt
Br 182 183
185
184
OEt OEt
Cyclization involving allenes: Loh et al.98 showed an efficient Prins cyclization of carboalkoxyl allenic alcohols with aldehyde. As depicted in Scheme 1.3.62, In(OTf)3
Scheme 1.3.61.
catalyzed the cyclization of carboalkoxyl allenic alcohol (186) in the presence of TMSBr to give 2,6-trans dihydropyrans (187) in 68% yield and high diastereoselectivity.
Scheme 1.3.62.
Similarly, fluorinated 2,6-trans dihydropyrans were synthesized via BF3.
Et2O promoted Prins cyclization of allenic alcohols (188) with aldehydes (189). Various 2,6-trans fluorodihydropyrans (190) were synthesized in moderate to good yields with excellent diastereoselectivities (Scheme 1.3.63).99
Scheme 1.3.63.
i-PrO
TMS
OH O
+ PhCH2CH2CHO BF3.OEt2
O F TMS i-PrO
O CH2Cl2, 0 oC
3 h, 78%
dr 89 : 11 Ph 188
189
190 n-BuOOC
TMS
OH
+ PhCHO
In(OTf)3 (10 mol%) TMSBr (1.2 equiv)
O
n-BuOOC Ph
Br TMS CH2Cl2, 0 oC
2.5 h
dr 99 : 168%
186 187
TH-961_06612201
Chapter 1 Multicomponent and Prins Cyclization Reactions
38 1.3.8. Cyclization involving Homopropargylic alcohol
More recently, Martin has also explored the synthetic potential of cyclization involving homopropargylic alcohols.100 Reactions of homopropargylic alcohol (191) and aldehyde (192) mediated by anhydrous FeCl3 or FeBr3 led to 4-halo-2-alkyl-5,6-dihydro-2H- pyrans (193) in yields ranging from 30 to 98%. Optimization of the experimental conditions has established that the best source of halide anion was TMSX in the presence of 7 mol % of the iron catalyst FeX3 (Scheme 1.3.64). The cyclization could also be mediated with InCl3 and
InBr3, but the times of
reaction were much
longer and the yields
were slightly
lower.
Scheme 1.3.64.
The reaction also catalyzed by Fe(acac)3 to construct the chloro, bromo and iodo heterocycles (194), by the suitable combination of iron(III) source, the corresponding trimethylsilyl halide and the solvent, in high yields (Scheme 1.3.65).101
Scheme 1.3.65.
Epoxides (196) which function as aldehyde equivalent undergo cyclization with homopropargylic alcohols (195) in the presence of zirconium tetrachloride under mild conditions to afford the corresponding dihydropyran derivatives (197) in excellent yields under mild conditions (Scheme 1.3.66).102
Y R
+R1O H
Y R1 R
X Fe(acac)3, (7 mol%)
X = Cl, Br, I; Y = O, NTs
TMSX, CH2X2
194
OH
R +
O R
Cl
O ZrCl4
DCM, rt, 65-80%
195 196 197
OH + H
O
O FeX3 X
TMSX CH2Cl2, rt
X = Cl, 24 h 80%
X = Br, 2 h 73%
191 192
193
TH-961_06612201
Chapter 1 Multicomponent and Prins Cyclization Reactions
39 Scheme 1.3.66.
The silylated secondary homopropargylic alcohols (198) undergo smooth coupling with aldehydes (199) in the presence of molecular iodine under mild reaction conditions to produce 4-iododihydropyrans (200) in good yields.103 This method is highly stereoselective, affording cis-dihydropyrans exclusively (Scheme 1.3.67).
Scheme 1.3.67.
Tandem gold- or platinum-promoted cycloisomerization/Prins cyclization leading to bridged bicyclic tetrahydropyran has been devised by Barluenga and co-workers.104 As for example, homoallylic alkynol (201) led to bicylic ether (202) in 92–94% yield (Scheme 1.3.68).
Scheme 1.3.68.
3-Furanylidenes and 3-pyranylidens having cis-2,5 and cis-2,6 substitution were synthesized from terminally substituted alkynyl alcohols (203) with various aldehydes (204) via Prins- type cyclization.105 Those 3-furanylidenes and 3-pyranylidenes (205) underwent hydrolysis to give the corresponding 3-acyl-substituted products having all-cis-configured isomers, such as
CH2Cl2, rt 1.5 h, 85%
O
I H
O BnO +
OH TMS
I2 BnO
TMS
198 199
200
OH 2 mol% MLn ConditionsMeOH
O MeO
MLn Conditions Yield(%) [PtCl2(cod)] 65 oC, 12 h 95 PtCl4 65 oC, 0.5 h 96 AuCl3 rt, 1 h 94
201 202
TH-961_06612201
Chapter 1 Multicomponent and Prins Cyclization Reactions
40 2,3,5-trisubstituted tetrahydrofurans and 2,3,6-trisubstituted tetrahydropyrans (206) (Scheme 1.3.69).
Scheme 1.3.69.