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Abstract: The acid-catalyzed alkene-aldehyde condensation, known as the Prins reaction, is reviewed. Lewis acids, or-
ganic acids and supported catalysts have been reported to assist both the Prins acyclic reaction and the Prins cyclization.
Acetals and oxocarbenium ions (generated from aldehydes and alcohols) have been described as reacting systems in the
Prins reaction. Prins cyclizations have been used to form mainly five- and six-membered rings, albeit formation of seven
to nine rings have been described. The Prins reaction (and cyclization) has been developed as a key strategic element in
the total synthesis of different natural products.
1. INTRODUCTION R2 R2
R4 R4
The Prins reaction is an important carbon-carbon bond R3 R3
R1 or R1
forming reaction consisting in the acid-catalyzed condensa-
tion of aldehydes with alkenes. The outcome of the reaction OH OH
depends on the substrate structure and the reaction condi- 2a 2b
tions, resulting in a variety of products, such as 1,3-diols,
1,3-dioxanes or unsaturated alcohols [1]. The carbenium ion
R2 R2
1, generated by addition of the olefin to the activated car- R1 R2 R4 R4
bonyl compound, can be initially considered as the interme- + R3 Nu R3
R1 R1
diate for this stepwise reaction, which can eliminate a proton H
giving an unsaturated alcohol 2 or can add water producing OH Y OH
O 1
the corresponding diol 3 (Y = OH). Moreover, other nucleo- 3
philic species (such as, acetate or chloride) present in the R3 R4 R3R4CO
reaction medium can react with the cationic intermediate.
Neighboring-group stabilization assistance has been pro- R2
posed in some cases to explain the anti stereoselectivity, but R4
this is not a general behavior and the outcoming stereochem- R3
R1
istry also depends on the reactants and reaction conditions.
O O
Alternatively, the reaction of the intermediate 1 with an ex-
cess of the carbonylic reagent produces the dioxane 4 R4 R3
(Scheme 1). 4
The carbonyl-ene reaction is closely related to the Prins [Nu = H2O, Cl-, AcOH, ...]
reaction, producing an unsaturated alcohol. When the reac- Scheme 1.
tion is performed thermally, a concerted mechanism is in-
volved and the corresponding homoallylic alcohol 2b is R1 R1
formed in a single step (Scheme 2) [2]. However, when us- OH
H
ing a Lewis acid to activate the carbonyl compound, the re- O
action does not proceed through either a concerted mecha- R3
nism (pericyclic reaction) or a simple stepwise mechanism R4 R4
R3 R2
(with a cation intermediate like in a formal Prins reaction), R2
but rather through a more complex stepwise mechanism [3]. 2b
Albeit the use of this carbon-carbon bond forming reac- Scheme 2.
tion in organic synthesis has been restricted in some cases
due to the operating conditions required and the fact that it 2. CLASSICAL PRINS REACTION
often yields a complex mixture of products, it is one of the 2.1. Catalysis by a Lewis or An Organic Acid
most effective reactions for the synthesis of tetrahydropyran
The Prins-type reaction of different aldehydes and termi-
and dioxane moieties. Since the last review on this topic [4]
nal olefins in the presence of alkoxytrimethylsilane and un-
there are important advances and applications in the Prins
der mild conditions, using a catalytic system consisting in a
reaction that are worthy to be taken into account, so we will
mixture of trimethylsilyl chloride, tin(II) chloride and lith-
consider herein the literature from 1977 to 2005. ium perchlorate to give homoallylic alcohol derivatives 5-9
was described (Scheme 3) [5] any other side product not
*Address correspondence to this author at the Departamento de Química being reported using this protocol. The same catalytic system
Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 (SnCl2-TMSCl-LiClO4) allowed the use of the corresponding
Alicante, Spain; Tel: (+34) 965 903548; Fax: (+34) 965903549; E-mail:
yus@ua.es aldehyde dimethylacetals and olefins to obtain the same
O R3 OR4 R2
SnCl2 TMSCl (10 mol%)
+ R3
R1 H R4OTMS, LiClO4 R1
R2
OR' 5-9
R
5 (71%): R = Ph; R' = Me
6 (58%): R = Ph(CH2)2; R' = Me
OR'
products, in this case alkoxytrimethylsilane being not neces- one formed (75/25 trans/cis-25 diastereomeric ratio) what
sary for the reaction to proceed. The authors suggested [6] can be explained by the preferred carbenium ion transition
the formation of an intermediate type 10 which then reacts state 26, where the aromatic group adopts a pseudoequatorial
with the alkene. position (Scheme 5).
O O O O
(CH2O)n, 13 (10 mol%)
Ph Ph + Ph
dioxane
(88%; dr = 75/25) trans-25 cis-25
H
ArOF2B O O
Me
Ph
H
26
Scheme 5. O O
R2
R3 (CH2O)n, Bi(OTf)3 (5 mol%)
R2
acetonitrile, reflux, 4-10 h R3
R 1 R1
14-18, 25, 27
O O O O O O
O O O SiMe3
R2
InBr3 (10 mol%), (CH2O)n O
R3 R1
R1 [bmim]PF6, 25 °C, 3-10 h R2 SnCl4
R3
14-17, 25, 27, 30, 32-36 O
O O O O O
SiMe3
(R)-37
R2
R2 R1 R3
R' (R)-37, CH2Cl2
R R R1 R3
14 (91%): R = H 25 (89%, 1:9 cis/trans): R = H; R' = Me -97 °C, 5 or 12 h SiMe3
O
15 (91%): R = Me 30 (90%, 1:9 cis/trans): R = H; R' = Ph 38-41
16 (85%): R = Cl 32 (85%, 1:9 cis/trans): R = OMe; R' = Me
17 (85%): R = OMe
O O O O R
O
O SiMe3 SiMe3
O O
38 (74%, 81% ee): R = Me 40 (75%,77% ee)
39 (80%, 84% ee): R = Ph
27 (87%) 33 (88%) 34 (85%)
O O
R
Cl
n SiMe3 SiMe3
O O
35 (49%, 90 ˚C): n = 4
41 (92%, 73% ee) 42 : R = Me
36 (55%; 90 ˚C): n = 6
43 : R = Ph
Scheme 8. Scheme 10.
Cl
Cl Cl Cl Cl Cl
CCl3CN, BCl3 BCl3
R1
CH2Cl2, -78 °C R1 N CH2Cl2, r.t. R1 CN
44-48 49-53
44 (90%), 49 (60%): R1 = (CH2)5CH3
45 (90%), 50 (60%): R1 = (CH2)3CH3
46 (90%), 51 (60%): R1 = CH2CH(CH3)2
47 (92%), 52 (60%): R1 = C(CH3)2CH2CH3
48 (44%), 53 (60%): R1 = Bn
Scheme 11.
R2 Cl O R2 O
CCl3CN, BCl3
+
R1 R1 CCl3 R1 CCl3
CH2Cl2, -78 °C R2
54a-60a 54b-60b
yield, which can be increased using an excess of the alde- Other transition metals such as ruthenium [16], nickel
hyde (Scheme 13) [15]. In addition, not only the Prins adduct [17], zinc [18], or tungsten [19] were reported as catalysts
was formed through the carbocationic intermediate 63, but for the reaction of dienes and activated alkenes with alde-
also the hetero Diels-Alder (D-A) product (Scheme 14). hydes. Albeit, in some cases, typical Prins reaction products
Consequently, when a non-concerted mechanism is involved, were formed, organometallic reagents are involved in these
the pyran derivatives (64-69) were formed by a triflic acid- processes, acting as nucleophiles toward the carbonyl com-
catalyzed Prins reaction of aldehydes with dienes followed pounds.
by nucleophilic attack of the oxygen to the allylic carboca- As commented before, the variety of possible products in
tion 63 (Scheme 15). the Prins reaction is one of the main drawbacks of this pro-
Ph
R O
HOTf (1 mol%) O O
+
Ph H R
toluene, r.t., 16 h Ph
(3 eq.)
61-62
61 (85%): R = H
62 (60%): R = Me
Scheme 13.
O
+
R H
R O
H H
O O R H OH O O
R R R R
63
Hetero D-A
product
R
O O
R
Prins reaction
product
Scheme 14.
930 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
O R2 R3 HOTf (1 mol%) R2
O
+
R1 H toluene, r.t., 16 h
R1 R3
64-69
O O
MeO
R
64 (72%): R = H 68 (45%)
65 (65%): R = Me O
66 (68%): R = Cl
67 (40%): R = NO2
69 (85%)
Scheme 15.
OR2 TMSOTf (1 eq.), CH2Cl2 OR2
PhMe2Si +
R1 OR2 R1
But N But
70 71-78
R
R
71 (88%): R = H, R' = Me 74 (40%): R = CO2Et, R' = Et
72 (61%): R = NO2, R' = Me 75 (43%): R = C CH, R' = Et
73 (59%): R = CHO, R' = Et 76 (60%): R = CH2OMe, R' = Me
77 (79%): R = CH2Br, R' = Me
78 (68%): R = CH2Cl, R' = Me
Scheme 16.
cedure, but the methodology becomes more interesting if the ylsilane terminated Prins reaction was prepared by Brad-
evolution of the cation intermediate can be controlled, for dock’s group with the aim of improving the atom economy
instance by an adjacent group. In this approach to solve the of the mentioned methodology [23]. Thus, tetrakis[(2-
problem, Braddock presented the use of the silylmethylcy- vinylcyclopropyl)methyl]silane (90), which was synthesized
clopropane functionality to terminate the Prins reaction [20]. as a mixture of all possible diastereoisomers starting from
Thus, the reaction of 1-phenyldimethylsilylmethyl-2-vinyl tetraallylsilane, was tested in the standard procedures previ-
cyclopropane (70) with different acetals under the influence ously commented in Schemes 16 and 18, giving the diene
of TMSOTf proceeded smoothly to provide skipped dienes ether 71 in 65% yield or the alcohol 79 in 22% yield, respec-
71-78 with exclusive E-geometry regardless of the initial tively. This reagent seems to transfer three substituents when
cis/trans configuration of the starting cyclopropane (Scheme using the protocol described in Scheme 16 but only one of
16). The authors suggested a stereoelectronic control due to the vinylcyclopropane groups participates in the reaction
the stabilization of the intermediate Prins cation by the adja- with the aldehyde under the reaction conditions shown in
cent cyclopropyl ring in a conformation where the alkyl Scheme 18. The reaction occurred under the same stereoelec-
chain orientates itself anti to that ring. Then, the silicon moi- tronic control than when using the reagent 70 and products
ety directed the collapse leading to the (E)-alkene, independ- with E-configuration were obtained.
ently of the cyclopropane configuration (Scheme 17) [21].
Afterward, Braddock and coworkers showed that under the
influence of dimethylaluminium chloride, aldehydes (instead R2O
R1 OR2
of acetals) could be used in the cyclopropylmethylsilane H
terminated Prins reaction to generate the corresponding die- H
nes [22]. Thus, unsaturated alcohols 79-89 were isolated R1
H
after reaction of 1-phenyldimethylsilyl-2-vinyl cyclopropane PhMe2Si
H
(70) with 2 equivalents of an aldehyde and Me2AlCl in di-
chloromethane at low temperature (Scheme 18). A novel
tetrafunctionalized silicon reagent for the cyclopropylmeth- Scheme 17.
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 931
O OH
Me2AlCl (2 eq.)
PhMe2Si +
R1 H CH2Cl2, -78 °C R1
70 (2 eq.) 79-89
OH OH
Cl
R
79 (88%): R = H 82 (83%)
80 (90%): R = Cl
81 (80%): R = NO2 OH
R OH R
85 (80%): R = (CH2)5CH3
86 (73%): R = (CH2)8CH3
87 (84%): R = Pri
83 (38%): R = Cl 88 (53%): R = But
84 (42%): R = NO2 89 (54%): R = CO2Et
Scheme 18.
O O
R'
R R
14 (91%): R = H 25 (95%): R = H; R' = Me
16 (83%): R = Cl 32 (97%): R = OMe; R' = Me
28 (15%): R = NO2 93 (98%): R = OMe; R' = Pr
91 (94%): R = F
92 (78%): R = Br O O O O
MeO O
HO O
94 (94%) 95 (97%)
Scheme 19.
932 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
R3
R2 O O
R3CHO (2 eq.), Lewatit
R3
R2
toluene, 20-40 °C, 12-192 h
R1 R1
96-107
R R
O O O O
R R
MeO
96 (90%): R = Me 102 (88%): R = Me
97 (76%): R = Et 103 (70%): R = Et
98 (78%): R = (CH2)4CH3 104 (69%): R = (CH2)4CH3
99 (94%): R = Ph 105 (90%): R = Ph
100 (88%): R = 3-ClC6H4 106 (81%): R = 3-ClC6H4
101 (76%): R = 2-FC6H4 107 (78%): R = 2-FC6H4
Scheme 20.
[26]. The catalytic activity of the resin remained unchanged the Ce3+–montmorillonite, which could be recycled at least
after the reaction and could be reused many times without three times without losing its effectiveness. The protocol
regeneration. Generally, the cross linkage of the resins has using the Ce3+–montmorillonite allowed to obtain the di-
no significant influence in the outcome of the reaction, but oxanes 16 (79%), 25 (61%), 27 (40%) and 32 (99%, with
for the Lewatit gel resins yields decrease regularly when the 9:91 cis/trans ratio). Other aldehydes were also used under
proportion of divinylbenzene increases [27]. The same these conditions and using the Fe3+–montmorillonite, giving
methodology was extended to other aldehydes allowing the the corresponding products 108-111 (Scheme 21).
preparation of substituted 1,3-dioxanes 96-107, which are Zeolites were also active as catalysts for the Prins reac-
hardly accessible by using inorganic acids (Scheme 20) [28]. tion, the beta (75) zeolite being the most effective and selec-
R1
O O
R1CHO (2 eq.), Fe3+-mont
R1
toluene, 80 °C, 12 h
Scheme 21.
OH O O
(CH2O)n, catalyst OH
+ +
CHCl3, 60 °C, 2 h OH
112 113 114
Scheme 22.
Uemura and coworkers described the Prins reaction of tive one [30]. Thus, different styrene derivatives, such as
styrenes with paraformaldehyde or 1,3,5-trioxane in toluene styrene, trans--methylstyrene and -methylstyrene, were
at 80 ºC in the presence of cation-exchanged montmorillo- reacted with paraformaldehyde in the presence of the men-
nite [29]. Among the 21 examined Mn+–montmorillonites, tioned zeolite to produce exclusively the corresponding 1,3-
the corresponding Ce3+ and Fe3+ ones revealed to be quite dioxanes 14 (40%), 25 (50%) and 27 (32%), respectively.
effective, giving the dioxane 14 in 90% and 93% yield re- Reusable Lewis acid catalysts were prepared by anchor-
spectively. The regeneration of the catalyst was studied with ing tin chloride on quaternary ammonium chloride function-
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 933
OH
O
O
O
O
MeO OMe
OMe
132
R1 R1 R1
O[Al] OH
R2 (CH2O)n, Me2AlCl R2 R2
CH2Cl2, 0 °C
R3 R5 R3 R5 R3 R5
R4 R4 R4
133 135
134
135a (95%): R1 = H, R2 = H, R3 = H, R4 = H, R5 = H
135b (88%): R1 = H, R2 = H, R3 = OMe, R4 = OMe, R5 = H
135c (62%): R1 = H, R2 = H, R3 = OMe, R4 = OMe, R5 = OMe
135d (38%): R1 = H, R2 = H, R3-R4 = OCH2O, R5 = H
135e (82%): R1 = OMe, R2 = OMe, R3 = H, R4 = H, R5 = H
135f (25%): R1-R2 = OCH2O, R3 = H, R4 = H, R5 = H
Scheme 26.
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 935
O OH
HO O
H O
136a (4β-H)
136b (4α-H)
R1 O OH R1
R2 R2
H Me2AlCl
+
R 1 OMs MsO R1
2 2
R 137 R
137a (93%): R1 2
= H, R = H
137b (60%): R1 = OMe, R2 = Br
Scheme 27.
(CH2O)n, MCM-41 OH
AcO
toluene, 90 °C OAc
138
146
Scheme 28.
The effectiveness of the catalyst (R)-37 was proved in the o-geranylphenol with the catalyst under the conditions de-
enantioselective cyclization of polyprenoids. The reaction of scribed in Scheme 10 gave the trans-fused tricyclic com-
OTBDMS OTBDMS
(CH2O)n, Me2AlCl
ClCH2CH2Cl, -10 °C
OH
MeO MeO
139 140
OTBDMS OTBDMS
(CH2O)n, Me2AlCl
ClCH2CH2Cl, -10 °C
MeO MeO OH
141 142
Scheme 29.
OH CO2Me
143
(CH2O)n, Me2AlCl
CH2Cl2, -80 to 15 °C
OPiv OH OPiv
144 145
Scheme 30.
936 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
SiMe3
HO
(R)-37 O
CH2Cl2, -97 °C O
H
147 (27%, 54% ee)
Scheme 31.
pound 147 as the major diastereomer (up to 54% ee) dioxane derivative 153 in 41% yield, as a single diastereo-
(Scheme 31) [12]. mer. However, significant amounts of by-products were
A novel, stereoselective Prins reaction of the chiral alky- formed in the course of the reaction. Changing the solvent to
lidene morpholinone derivative 152, prepared from (1R,2S)- acetic acid was beneficial for the reaction, and so compound
ephedrine and 3-methyl-2-oxobutanoic acid, was employed 152 reacted with paraformaldehyde in the presence of a cata-
in the synthesis of (S)-pantolactone (148). Aqueous formal- lytic amount of sulfuric acid to provide compound 153 in
dehyde reacted with compound 152 in dioxane at 80 ºC, un- 72% yield (Scheme 32) [50]. Other ,-dialkyl -hydroxy -
der sulfuric acid catalysis, giving the corresponding 1,3- butyrolactones (149-151), analogues of pantolactone, were
prepared employing this stereoselective Prins reaction as the
O O key step [51].
The cyclopropylmethylsilane terminated Prins reaction
O O
OH OH using the silicon-centred tetrafunctionalized reagent 90 was
also utilized in the synthesis of Lyngbic acid (154) with a
complete control of the 4E-olefin geometry [23].
148 149
O
O OMe O
O
OH O
OH OH
154
150 151
3. PRINS CYCLIZATIONS
Ph Ph
3.1. Five Membered Rings Formation
N N Some catalysts (i.e. Me2AlCl, Et2AlCl, EtAlCl2, SnCl4,
(CH2O)n
O O TiCl4) were studied in the cyclization of olefinic aldehydes
O O (such as 155) by an internal Prins and/or ene mechanism to
AcOH, 80 °C O
afford five-membered rings giving a mixture of products
O 156-158. Although tin(IV) chloride and dimethylaluminum
152 153 (72%) chloride were considered superior for the cyclization proc-
ess, titanium(IV) chloride gave mainly chlorhydrins (157)
Scheme 32. (Scheme 33) [52].
Cl
catalyst OH
n n n
OH + n OH +
CHO
m
R
m m m
Cl
catalyst n
OH
n n n
CHO + +
OH OH R
m m m m
A route to substituted tetrahydrofurans was described by If the cationic intermediate structure is suitable, a pinacol
Mikami and coworkers performing a Lewis acid-promoted rearrangement can be the terminating step of a Prins cycliza-
Prins reaction between a bishomoallyl silyl ether (159) and tion. Consequently, the tandem Prins-pinacol reaction was
methyl glyoxylate, the cationic intermediate 160 being developed as a useful family of reactions for forming five-
trapped by internal attack of the silyloxy group, giving the membered rings, as depicted in Scheme 35, a new approach
corresponding products 161-165 (Scheme 34). Among the for the stereocontrolled preparation of substituted tetrahydro-
screened silyl protecting groups, the less bulky but relatively furans being reported. Thus a diastereomeric mixture of
stable dimethyl(isopropyl)silyl was found to be the best of compounds 166 (prepared by acid-catalyzed condensation of
choice. The observed selectivity in the reaction, independ- the corresponding aldehyde and a diol) was treated with tin
ently of the substituent position, could be reasonably ex- tetrachloride at low temperature to give the corresponding 3-
plained by the transition state 160 [53]. A lactonization proc- acyltetrahydrofurans 167 in good yields, bearing substituents
ess was reported to terminate the Prins reaction when a car- R1, R3 and R2CO in cis-position (Scheme 36). The authors
boxyl group was present in the structure [54]. suggested the existence of an equilibrium between the allyl-
[Si] MeO2C OH
R2 R4 R4
O R3
MeO2CCHO, SnCl4 (1 eq.)
R1 O
R1 OSiR3 R1 O R4
CH2Cl2, -78 °C
R3 R2
MeO SnCl4 R2
O R3
159
160 161-165
MeO2C OH
MeO2C MeO2C OH MeO2C
OH OH
O
O O O
Pri
R
161 (48%) 162 (67%) 163 (64%: R = Me) 165 (44%)
(91% stereoselectivity) (75/25 : cis/trans) (80/20 : cis/trans) (77/23 : cis/trans)
164 (56%: R = Pri)
(89/11 : cis/trans)
Scheme 34. Y
XR
Y XR Y XR
Prins pinacol
HO HO
O
Scheme 35.
O
R2 R2
O SnCl4 (2-4 eq.)
R3
O CH2Cl2, -78 to -23 °C R1 R3
R1 166 O
167
167a (77%): R1 = Me, R2 = Me, R3 = Me
167b (76%): R1 = Me, R2 = Me, R3 = Et
167c (81%): R1 = Me, R2 = Me, R3 = Pri
167d (92%): R1 = Me, R2 = Me, R3 = CH2CH2Ph
167e (60%): R1 = Me, R2 = Me, R3 = CH=CH2
167f (66%): R1 = Me, R2 = Me, R3 = Ph
167g (82%): R1 = Me, R2 = Bu, R3 = Me
R2
OSnCl4-
R2 R2
R1 O SnCl4 O SnCl4
R3
-Cl4SnO R3 O R1 O R3
R1
168 166 169
Scheme 36.
938 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
O
R2 R2
O SnCl4 (2-4 eq.) n
n R1
CH2Cl2, -78 to -23 °C R1
O O
H
170 171
R3Si R1 O O
O R2 R2
R1 R1
SnCl4 (1.1 eq.) RuO4
2 OMe O
R
CH2Cl2, -78 to -23 °C MeCN/H2O
n
n H n H
MeO OMe
173 174
172
174a (69%): n = 1, R3Si = TMS, R1 = Me, R2 = H
174b (62%): n = 1, R3Si = TMS, R1 = Me, R2 = Me
174c (58%): n = 1, R3Si = TBDMS, R1 = H, R2 = H
174d (62%): n = 2, R3Si = TMS, R1 = Me, R2 = H
174e (55%): n = 7, R3Si = TMS, R1 = Me, R2 = H
Scheme 38.
carbenium ion 168 (which would regenerate the starting car- best accomplished under the same conditions (1.1 eq. of
bonyl component and produce an enone product) and the SnCl4 in dichloromethane at -78 ºC), the annulated products
oxocarbenium ion 169 (which would give Prins cyclization), being produced as mixtures of methoxy epimers (173) that
the cyclization rate being high enough to form tetrahydro- were directly oxidized with RuO4 to the diones 174 (Scheme
furan products in good yields (Scheme 36) [55]. Similar de- 38) [59]. The reaction of compounds 172 is believed to occur
rivatives 170, obtained from the corresponding cyclic cis- by a 6-endo Prins cyclization of the oxocarbenium ion inter-
diols, underwent the same transformation to form the subse-
quent bicyclic furanones 171 (Scheme 37) [56]. In contrast, OMe OMe
isomeric cyclic trans-diols reacted directly with the aldehyde OTMS
under acid-catalysis giving the corresponding bicyclic prod- OMe TMSOTf
ucts.
CH2Cl2, 23 °C
The Prins-pinacol synthesis of acyltetrahydrofuran de-
R1 O
rivatives using isomerically pure allylic diols was also inves- R1 175
tigated by Overman’s research group. Thus, in the anti series 176-178
(acetals type 166 were prepared form anti-diols), the stereo- OMe OMe
chemical outcome of the reaction was found to depend dra-
matically on the nucleophilicity of the alkene and the size of
OMe
the allylic substituent (R2 in 166). On the other hand, in the
syn series (acetals prepared from syn-diols) a single stereoi-
somer (having a cis relationship between the acyl group and O But O But O
the C2 and C5 ring substituents) was preferentially formed
176 (82%) 177 (70%) 178 (70%)
for all the investigated substrates [57]. Additionally, 2,2-
disubstituted 1,3-dioxanes (from the condensation of allylic
OMe
diols with unsymmetrical ketones) were also subjected to the
same protocol (SnCl4 in dichloromethane at low tempera- a
b
ture) to obtain the corresponding 2,2-disubstituted 4-acyl- R1
tetrahydrofurans [58]. OTMS
Other olefinic acetal systems were studied in order to ex- 179
pand the scope of the Prins-pinacol synthesis of carbocyclic
ring products. The transformation of compounds 172 was Scheme 39.
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 939
OH
O R1 OH
SiMe3
R 1 BF3-OEt2 R 1
H CbzN +
NHCbz CH2Cl2, -10 °C NHCbz
SiMe3
O R1
CAN or CTAN O
SnBu3 MeCN/CH2Cl2, 25 °C
R1
SiMe3
O R1
Ph
OH R1COR2, TMSOTf
SiMe3 R2
Ph Et2O, -78 °C
·
Scheme 41.
As shown in Scheme 41, allylsilyl [63] and propargylsilyl 186 (87%) 187 (72%) 188 (84%)
[64] moieties were described to give five-membered cycliza-
tion when condensing with carbonyl or acetal groups in the Scheme 42.
940 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
R1 = R2 = H R1 = R2 = H
R1 = CO2Et, R2 = Me R1 = Me, R2 = H Cl
R1 = H, R2 = Me
H
HO Cl HO
produced. The authors pointed out an ene mechanism for
these latter processes [66]. 201 (93%) 202 (63%)
(Trifluoromethyl)decalin derivatives (such as 194) were
prepared from the corresponding (cyclohexenyl)propyl
trifluromethyl ketones by the same methodology [67]. Re- A diastereoselective synthesis of cis and trans 3,4-
garding to other decalin derivatives (compounds of type disubstituted piperidines (204 and 205, respectively) from
195), they were achieved as a single trans fused diastereo- simple acyclic precursors 203 was reported by Snaith and
mer by treating the corresponding 5-cyclodecenone with coworkers. The trans compounds (205) were preferentially
trifluoroacetic acid [68]. Additionally, trifluroacetic acid was formed when the cyclization was catalyzed by methyl alumi-
efficiently used to catalyze a Prins cyclization [69] of enol num dichloride in refluxing chloroform. In contrast, the Prins
ethers 196 to provide a mixture of tetrahydropyrans 197 and cyclization of 203 catalyzed by hydrochloric acid at low
198 after ester ethanolysis under basic conditions (Scheme temperatures afforded selectively the cis-compunds 204
44) [70]. Using Lewis acids such as TiCl4, TiBr4, SnBr4 as (Scheme 46) [72].
catalysts, the corresponding 4-halotetrahydropyrans were Cyclopropylvinylic aldehydes of type 206 suffered the
obtained, but with lower chemical yield (ca. 65%) and selec- same cyclization described above for systems 180, but pro-
tivity. ducing the corresponding 4-chloro-1-butenylcyclohexanol
CO2Et CO2Et
O 1 O R1
R
O R1 1) TFA (10 eq.), CH2Cl2, rt
EtO2C +
2) K2CO3, EtOH
OH OH
196
197 198
197a/198a (85%, 91/9): R1 = (CH2)5CH3
197b/198b (77%, 95/5): R1 = Ph
197c/198c (58%, 50/50): R1 = CH2OBn
197d/198a (66%, 57/43): R1 = CH2OTBDPS
197e/198e (78%, 91/9): R1 = CH2CH2Bn
197f/198f (72%, 91/9): R1 = CH=CH2
197g/198g (42%, 80/20): R1 = C C TMS
Scheme 44.
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 941
Ts Ts Ts
N N N
MeAlCl2 (1 eq.), CHCl3, reflux
+
R1 or HCl (3 eq.), CH2Cl2, -78 °C R1 R1
O OH OH
R1 R1 R1
203
204 205
204a/205a (>95%, 8/92, MeAlCl2): R1 = H
(>95%, 95/5, HCl): R1 = H
204b/205b (70%, 22/78, MeAlCl2): R1 = Me
(86%, 98/2, HCl): R1 = Me
204c/205c (75%, 30/70, MeAlCl2): R1-R1 = (CH2)2
(78%, 90/10, HCl): R1-R1 = (CH2)2
204d/205d (78%, 7/93, MeAlCl2): R1-R1 = (CH2)3
(81%, 89/11, HCl): R1-R1 = (CH2)3
204e/205e (81%, 25/75, MeAlCl2): R1-R1 = (CH2)4
(74%, 80/20, HCl): R1-R1 = (CH2)4
Scheme 46.
derivatives 207 in good yields and with cis-selectivity of ,-unsaturated -hydroxy aldehydes 208 with tert-
(Scheme 47) [62]. The use of a mixture of Zn and TMSCl butyldimethylsilyl triflate (TBSOTf) and a hindered base
was reported also to catalyze this type of cyclization [73]. (such as 2,6,di-tert-butyl-4-methylpyridine: DBMP) afforded
products 209 in 84-92% yield via a double cyclization
(Scheme 48) [74]. The reaction presumably goes through the
silylated intermediate 210, which is attacked by the double
TiCl4 (1.1 eq.) X bond to produce the tertiary carbocation 211. This cation is
X CHO Cl then trapped by the alcohol group giving the second cycliza-
CH2Cl2, -78 °C OH tion process (Scheme 48).
206 207 Differently substituted tetrahydropyrans (THPs) can be
prepared in the course of a Prins type cyclization starting
207a (74%): X = CH2
from homoallylic acetals, the generated carbocation at C4
207b (76%): X = NTs being trapped by nucleophilic species. Thus, acetals 212
207c (82%): X = C(CO2Et)2 were treated with titanium tetrachloride to give the corre-
Scheme 47. sponding 4-chloro-2-substituted tetrahydropyrans 213
(Scheme 49) [75]. The reaction seemed to be very selective,
Jung and coworkers reported an intramolecular Prins thus the 2-methoxyethoxymethyl (MEM) ether derived from
double cyclization with high diastereoselectivity. Treatment (E)-3-hexenol (214) cyclized under these conditions to pro-
TBSO H
R3
R1 CHO
TBSOTf (1.5 eq.) O
R2 OH R2
R3 DBMP (2 eq.), CH2Cl2
208 209 R1
TBSO H TBSO H
R3 R3
OH OH
R2 R2
R1 R1
210 211
209a (89%): R1 = R2 = R3 = Me
209b (84%): R1 = R2 = Me, R3 = Et
209c (92%): R1 = H, R2 = Ph, R3 = Me
Scheme 48.
942 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
R2 R3
R2 R3 R4 R5
TiCl4 (2 eq.) O
+ R5
R1O OR1 HO CH2Cl2, 0 or 22 ˚C
Cl R4
218 219
220
220a (97%): R1 = (CH2)2OMe, R2 = R3 = R4 = R5 = H
220b (98%): R1 = (CH2)2OMe, R2 = R3 = R4 = H, R5 = Et
220c (93%): R1 = (CH2)2OMe, R2 = Me, R3 = R4 = R5 = H
220d (99%): R1 = (CH2)2OMe, R2 = Me, R3 = R4 = H, R5 = Et
220e (85%): R1 = OMe, R2 = R3 = R4 = Me, R5 = H
220f (77%): R1-R1 = (CH2)2, R2-R3 = (CH2)5, R4 = R5 = H
220g (99%): R1-R1 = (CH2)2, R2-R3 = (CH2)5, R4 = Me, R5 = H
220h (98%): R1-R1 = (CH2)2, R2-R3 = (CH2)4, R4 = R5 = H
220i (96%): R1-R1 = (CH2)2, R2-R3 = (CH2)4, R4 = Me, R5 = H
Scheme 50.
R2 R2
O
OH OMe
InCl3 X
O
OMe R1
R2 CHCl3, 23 °C
1 R2
R O
228 232
Nu O
R1 O OMe R1 O
R2 R2
R1
O R2
O O
229 230 231
232a (55%): X = OMe, R1 = H, R2 = Me
232b (54%): X = OMe, R1 = R2 = H
Scheme 54. 232c (30%): X = OMe, R1 = R2 = Me
944 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
OH O
OH O
Sc(OTf)3 (5 mol%)
+ +
R1 H CHCl3, reflux
R1 O R1 O
Scheme 55.
OMe
MeO
OH O In(OTf)3 (5 mol%), anisole
+ +
R1 H [bmim]PF6, 23 °C
R1 O R1 O
1
238a/239a (79%, 51/49): R = Ph 238 239
238b/239b (71%, 54/46): R1 = 4-FC6H4
238c/239c (70%, 54/46): R1 = 4-ClC6H4
238d/239d (79%, 73/27): R1 = 4-MeOC6H4
238e/239e (46%, 53/47): R1 = 4-MeC6H4
238f/239f (60%, 57/43): R1 = 4-(NC)C6H4
238g/239g (68%, 58/42): R1 = 4-(O2N)C6H4
238h/239h (73%, 67/33): R1 = CHEt2
238i/239i (50%, 49/51): R1 = But
Scheme 56.
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 945
240
240a (71%): X = Cl, R1 = Et
240b (76%): X = Br, R1 = Et
240c (82%): X = I, R1 = Et
240d (74%): X = Cl, R1 = Ph
240e (82%): X = Br, R1 = Ph
240f (82%): X = I, R1 = Ph
240g (77%): X = Cl, R1 = CH=CHCH2CH3
240h (82%): X = Br, R1 = CH=CHCH2CH3
240i (83%): X = I, R1 = CH=CHCH2CH3
240j (94%): X = Cl, R1 = (CH2)2Ph
240k (83%): X = Br, R1 = (CH2)2Ph
240l (86%): X = I, R1 = (CH2)2Ph
Scheme 57.
Me OH Me O
O CF3SO3H or SnCl4
Ph + Ph
R1 H MeNO2, -25 °C
OH O R1
245 246
246a (73%,TfOH): R1 = Me
(66%, SnCl4): R1 = Me
246b (61%,TfOH): R1 = Ph
(76%, SnCl4): R1 = Ph
246c (68%,TfOH): R1 = But
(76%, SnCl4): R1 = But
246d (81%,TfOH): R1 = (CH2)2Ph
(65%, SnCl4): R1 = (CH2)2Ph
Scheme 61.
MeO
OH
O 1) TFA, CH2Cl2
OH
+
OMe R1 H 2) K2CO3, MeOH
R1 O
1
247a (66%, >99% ee): R = (CH2)2Ph 247
247b (81%, >99% ee): R1 = 4-MeOC6H4
Scheme 62.
Since oxocarbenium ions are the main intermediates for the C4 position of the tetrahydropyran. The homopropargylic
the Prins cyclizations, -acetoxy ethers are useful substrates -acetoxy ether 251 yielded the corresponding dihydropyran
in order to generate this ionic species, because the acetate under the same reaction conditions but with low selectivity
group is solvolyzed regioselectively upon treatment with a (only 24% of the DHP), the major isomer being a tetrahydro-
Lewis acid, so they can react with unsaturated carbon-carbon furan derivative resulting from a 5-exo-dig cyclization [105].
bonds to produce a Prins cyclization. Rychnovsky showed Acetoxyalkoxyacetic esters (compounds of type 248 with R2
that -acetoxy ethers 248, prepared easily from the related = CO2 Me) were also cyclized under the influence of tin tet-
esters [103], are appropiate starting materials to prepare THP rachloride [106].
units via the Prins route. Treatment of compound 248 with a
Lewis acid [i.e. TiCl4 or trifluoroacetic anhydride (TFAA)]
produced an oxocarbenium ion, which subsequently cyclized R1
to give the all-cis-tetrahydropyrans 249, after trapping the R2 OAc
carbocation intermediate by a nucleophile (Scheme 63)
[104]. In addition, -acetoxy ethers type 250 with an aro- O Ph O
matic ring instead of an olefin behaved similarly and were Cl
transformed into the corresponding isochroman derivatives OAc
with excellent yields. Other catalytic systems were able to 250 251
promote the cyclization process: tin tetrabromide (dichloro-
methane at -78 ºC) or boron trifluoride (acetic acid/hexanes R1 = Me, R2 = H
at 0 ºC), introduced a bromine or a fluorine, respectively, at R1 = H, R2 = (CH2)5CH3
252 Nu
Prins oxonia-Cope R1 R1
O a O
X R2 R2 X
b H
H
Prins 259 all-cis-THP
R1 O R2 R1 O R2
Scheme 66.
253 254
The former mechanistic feature of the Prins cyclization
has brought interesting consequences. An oxonia-Cope Prins
Scheme 64.
(OCP) process was described to prepare tetrahydropyrans
(S)-255 with a Lewis acid (i.e. SnBr4) provided a low enan- with quaternary carbon centers, synthetic targets that were
tioenriched product 258, which indicates that the first gener- normally not accessible by Prins cyclization strategies [112].
ated oxocarbenium 256 suffers rapidly an oxonia-Cope rear- As shown in Scheme 67, -acetoxy ethers 260 were treated
rangement producing the achiral intermediate 257, which with TMSOTf to generate the oxocarbenium 261, which
after cyclization gives the final racemic compound 258 should be in rapid equilibrium with the ion 262 via an oxo-
(Scheme 65) [108,109]. nia-Cope process. At that point, the silyl enol ether present in
OAc
L.A. 1) Prins
1 O 1 O R1 O
R R 2) Nu
(S)-255 (S)-256 chiral 258
oxonia-Cope
1) Prins
R1 O 2) Nu R1 O
257 racemic 258
achiral intermediate
Scheme 65.
Another interesting aspect of the Prins cyclization is its the molecule played its role, as the best nucleophile, and
selectivity to yield the corresponding all-cis tetrahydropyran. through the chair-like transition state formed the final prod-
A rationale for this result was set forth by the computational uct 263.
work of Alder and coworkers [110], who suggested that the A very interesting tandem reaction is the Mukaiyama al-
initial Prins cyclization of an oxocarbenium ion through a dol-Prins (MAP) cyclization [113]. Unsaturated enol ethers
chair-like transition state would lead to the tetrahydropyranyl 264 coupled with aldehydes in the presence of titanium bro-
cation 259. This intermediate increased its stability due to mide to yield 4-bromo tetrahydropyran derivatives 265
the delocalizaton (specifically, bonds a and b and the lone (Scheme 68). In all these experiments, compound 265 was
pair on oxygen are in alignment with the empty p orbital, obtained as a ca. 1:1 mixture of diastereomers at the alco-
creating a six-electron system in the equatorial plane of the holic stereogenic center, but the selectivity for the equatorial
ring), which gave an optimal geometry that placed the C4 bromide was >95:5. The MAP cyclization was also de-
hydrogen in a pseudoaxial geometry, thereby favoring the
scribed to be effective with ketones [114].
nucleophilic trapping from an equatorial trajectory (Scheme
66). Rychnovsky developed an axial-selective Prins cycliza- If the alkene moiety bears a silyl substitutent, after occur-
tions, where the nucleophile (bromine) attacks from the other ring the Prins cyclization the reaction can be terminated by
side as shown in Scheme 66. The reaction of a compound of elimination of the silyl group, giving an unsaturation. Ac-
type 255 with TMSBr gave a substitution of the acetate to cording to this protocol, acetal-vinylsilane systems 266 un-
form the corresponding -bromo ether, which then provided derwent Prins cyclization, using TiCl4 or SnCl4 as the Lewis
948 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
O
Bn R1 R1
OTBS
R2
O Bn
O
R2
263
Scheme 67.
Br
O Ph OH
TiBr4 (2 eq.), 2,6-DTBMP
+
Ph O R1 H CH2Cl2, -78 °C O R1
264
265
265a (53%): R1 = Ph
265b (74%): R1 = But
265c (78%): R1 = Pri
265d (82%): R1 = cyclohexyl
265e (80%): R1 = (CH2)2Ph
265f (70%): R1 = (CH2)2OTBDPS
265g (75%): R1 = (CH2)2OBn
Scheme 68.
acid catalyst, the subsequent silyl elimination producing the dihydrothiapyrans 270 and the tetrahydropyridines 271 were
expected dihydropyran derivatives 267 (Scheme 69) [115]. obtained, in the latest case the selectivity being unexpectedly
trans [117]. Silyl ethers related to alcohols 268 were also
R2 employed in the condensation with aldehydes to provide
R2 OMEM
R1
R1 TiCl4 (3 eq.) or SnCl4 (5 eq.) OH
O InCl3 (1 eq.)
TMS CH2Cl2, -20 °C O R2
266 267 + CH2Cl2, 23 °C
R1 H TMS R2 O R1
267a (78%): R1 = Br, R2 = H
268 269
267b (83%): R1 = (CH2)3Ph, R2 = H
269a (39%): R1 = Ph, R2 = H
267c (71%): R1 = R2 = H
269b (88%): R1 = CH2Ph, R2 = H
267d (65%): R1 = H, R2 = Me
269c (86%): R1 = 4-O2NC6H4, R2 = H
Scheme 69.
269d (54%): R1 = 4-F3CC6H4, R2 = H
The reaction of 4-trimethylsilyl-3-buten-1-ols 268 with 269e (72%): R1 = cyclohexyl, R2 = H
aldehydes under mild Lewis acid conditions gave substituted 269f (50%): R1 = CH2Ph, R2 = Me
dihydropyrans 269 in excellent yields (Scheme 70) [116]. 269g (60%): R1 = 4-O2NC6H4, R2 = Me
Sulfur- and nitrogen-containing analogues of 268 were pre- 269h (69%): R1 = cyclohexyl, R2 = Me
pared and used in the Prins cyclization under the same react-
ing conditions depicted in Scheme 70, so the corresponding Scheme 70.
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 949
O TMS InCl3
2 +
R1 H SnBu3 CH2Cl2, 23 °C R1 O R1
274 275
TFA
NaHCO3 (aq. sol.)
R1
[Si] O
R1CHO
Ph [Si] Ph
H
277 278
279a (78%): R1 = Ph
279b (72%): R1 = Pr
279c (61%): R1 = 4-MeOC6H4
279d (60%): R1 = 4-O2NC6H4
279e (65%): R1 = CH=CHPh
Scheme 72.
950 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
O
Ce(NO3)3·6H2O (10 mol%) OH
O
NaO3SOC12H25, H2O, 23 °C O
TMS
OH TMSOTf ·
TMS
Et2O, -78 °C
O Ph
O OH · TMSOTf
+
R1 H R2 Et2O, -78 °C R1 O R2
Scheme 73.
O
AlX3 (1 eq.)
+
R1 H OH CH2Cl2, 0 °C O
R1
280
280a (78%): X = Cl, R1 = Pr
280b (65%): X = Br, R1 = Pri
Scheme 74.
Baylis-Hillman adducts with formaldehyde in the presence The cyclic acetal 285 gave the bicyclic product 286 in
of sulfuric acid was also reported [125]. good yield through a cyclization process induced by tin tet-
Different acetals were also used as oxocarbenium inter- rachloride (Scheme 77) [129]. As described previously, an-
mediate precursors. Thus, the acetoxyalkoxyacetic ester 281 other reaction catalyzed by tin tetrachloride was the Prins-
cyclized under tin tetrachloride catalysis forming the corre- pinacol procedure, where starting from the compound 287
sponding tetrahydrooxepine 282 in moderate yield (Scheme the formation of the seven membered ring 12-oxatricyclo
75) [106]. Mixed acetals 283 had the same behavior under [6.3.1.02,7]dodecane 288 ocurred (Scheme 77) [130].
Lewis acid catalysis (either SnCl4 or EtAlCl2) and the corre-
sponding seven membered heterocycles 284 were isolated OMe
(Scheme 76) [126]. The same authors reported the cycliza-
SnCl4 (1 eq.)
tion of 5-alkenyl or 6-alkenyl acetals using tin tetrachloride O O Cl
as Lewis acid, forming the eight- [127] or nine-membered CH2Cl2, -78 °C Me
ring ethers, respectively [128]. TMS TMS
285 286 (82%)
Cl OTES CHO
H
MeO O SnCl4 (1 eq.)
O SnCl4 (2 eq.) O
CO2Me CO2Me CH2Cl2, 0 °C
CH2Cl2, -70 °C H
AcO O
287 288 (81%)
281 282 (43%)
Scheme 77.
Scheme 75.
Cl Silylated homoallenyl alcohols were reported to give
seven and eight membered cyclization in the presence of
O
TMSOTf, so a diastereoselective synthesis of oxabicycles
SnCl4 or EtAlCl2 (3 eq.) was carried out (Scheme 78) [131]. Nevertheless, as com-
R2 R1 R2
CH2Cl2, -78 °C
O mented before, this reaction can be considered as a Sakurai-
MeO R1
Hosomi reaction [24].
283 284
284a (66%): R1 = (CH2)2Ph, R2 = H 3.4. Prins Cyclization in Synthesis
284b (75%): R1 = Me, R2 = (CH2)2Ph Yohimbane derivatives (289) were synthesized using a
Prins cyclization reaction (Scheme 79). The reaction was
Scheme 76.
carried out with HCl as catalyst finding that depending on
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 951
m m
O
m
TMSOTf
n O n
HO O
Et2O, -78 °C
H
n
· ·
TMS TMS
m = 1-3, n = 1, 2
Scheme 78.
N N
H H X
N HCl N
H H H H
solvent
H H
R1 R1
O OH
X = OH, R1 = H 289
X = Cl, R1 = CO2Me
Scheme 79.
O O
O O
O OH
Me
THF/AcOH/TFA/H2O
Me Me
H H OH
AcO AcO
H H
290
Scheme 80.
the solvent, a hydroxyl group (performing the reaction in acetal derived from 2-hydroxymethyl-3-buten-1-ol in order
water) or chlorine (in acetone) was included in the product as to prepare an intermediate for the synthesis of (±)-talaro-
nucleophile [132]. mycin B [139].
The steroid derivative 290 was obtained as a mixture of An intramolecular oxidative Prins cyclization was per-
isomers by a mild acid catalyzed intramolecular Prins cycli- formed on the alcohol 300 with pyridinium chlorochromate
zation (Scheme 80) [133]. The same cyclization process was in dichloromethane producing the tricyclic ketone 301 in
used in the preparation of steroid intermediates which were 67% yield during the synthesis of (±)-isocycloseychellene
afterwards coupled to give cephalostatin 1 (291) [134]. The (302), which is related to the natural sesquiterpene seychel-
unsaturated aldehyde 292 (or its 13 isomer) underwent a lene (Scheme 82) [140]. In the synthesis of the sesquiterpene
Prins reaction on treatment with a Lewis acid (such as SnCl4 , (±)--isocomene, a Prins cyclization was also the key step,
ZnBr2 or BF3·OEt2) to give the corresponding 16-halo- so the tricyclic intermediate 304 was formed by treating the
genated homoestrone derivatives 293 chemoselectively bicyclic aldehyde 303 with titanium tetrachloride [141]. In
[135]. Bridged steroids with hormonal activity were also the course of the synthesis of a related (–)-anisatin com-
prepared by this methodology, so compound 294 was ob- pound, the tricyclic derivative 306 was prepared from the
tained by treatment of the aldehyde 295 with zinc iodide enol ether 305, which under acidic catalysis gave the corre-
[136], and the steroid 296 was achieved from compound 297 sponding aldehyde and then cyclization [142]. A similar
in the presence of titanium tetrachloride [137]. process was used to cyclize the enol ether 307 during the
Spiroketals are structural elements present in several synthesis of cis--irone (308) [143].
natural compounds and antibiotics. The pheromone compo- Molybdenum and tungsten catalysts were used in the cy-
nent of the female olive fly Dacus oleae 299 was prepared clization of citronellal and other related unsaturated alde-
from the compound 298, which was obtained from the corre- hydes. Depending on the surrounding ligands of the metal
sponding unsaturated acetal by a Prins cyclization (Scheme the cyclization of citronellal (309) gave either a mixture of
81) [138]. The same group applied this methodology to an two diastereomers of isopulegol (310) or a mixture of the
952 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
Me OH
Me O
HO
Me
O OH
Me
N
OH
H
N
Me
O
Me O O 291
Me OH OH
Me Me
13 O
H H H H 16
X
H H
MeO MeO
293
292
X = F, Cl, Br or I
HO O
OAc OAc
H H
MeO MeO
294 295
OAc OAc
Me O Me
HO
AcO AcO
Cl
296 297
OH
O
BF3·OEt2 O
O CCl3
OH
CCl3CH2OH
O O O
298 299
Scheme 81.
PCC
CH2Cl2
OH O
cyclic diols 311 [144]. A stereoselective preparation of l- Phorboxazoles A and B are very interesting targets in to-
isopulegol was reported by using zinc halides as catalysts tal synthesis due to their high anticancer activity, tetrahydro-
(70% yield and 94% of the expected isomer) [145]. On the pyran rings being present in their structures, so different
other hand, scandium triflate was also found to be an effi- segments of these compounds were synthesized by a Prins
cient catalyst for the cyclization of citronellal [146]. cyclization. Thus, the C20-C26 segment of phorboxazole A
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 953
Cl
OH
O O OH OH
303 304 OH
OH
OMe 309 310 311
OBn OAc
O
26 O OTBDPS
OBn
20
AcO
Me
Me OTBDPS
312 313
OAc OBn
N
Br
19 O O
Cl
O
O
BnO
3
TsO
314 315
O O OAc 18 Br
O 25 OTBDPS 16
OBn
O
23
316 317
954 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
HO
AcO
O
HO
OH
AcO
319 OR1
318 1
R = H, Ac
OBn R1 O O
O HO2C O
CO2Me Me
OH
320 321 322
R1 = Me, Pri, CH=CHCH3
Boc (CH2)7CH3
N OBn TIPSO
O
326 327
HO O
OTBS O OMe
OTBS H O
323 324 N H
OMe N
OH
Leucascandrolide A (325) was isolated from the sponge n
Leucascandra cavelolata and shows potent cytotoxicity O n OR1
O
against P388 cancer cells. The aldehyde 326 and the enol
ether 327 were used as building blocks to produce most of 328a n = 0 329a n = 0, R1 = H, Me
the leucascandrolide A skeleton by a Mukaiyama aldol-Prins 328b n = 1 329b n = 1, R1 = H, Me
cyclization [113]. In the total synthesis of (+)-dactylolide a
cyclization to a tetrahydropyran ring from an allyl silane
derivative was used [158].
The norlapachol amino derivative 328a was cyclized un- cyclic and carbocyclic natural products, an interesting ac-
der formic acid catalysis to the corresponding 1-aza-anthra- count on this topic having been recently published [161].
quinones 329a, which exhibit molluscicidal activity [159].
4. CONCLUSIONS
The intramolecular Prins reaction of the corresponding lapa-
chol amino derivative 328b gave the expected azepine de- The Prins reaction is a very interesting route to form car-
rivatives 329b [160]. bon-carbon bonds. New and different acid catalysts (Lewis
acids, organic acids, solid-supported catalysts) have been
Pinacol terminated Prins cyclizations have been em-
studied in order to control the outcome of the reaction. In
ployed as key steps in the stereocontrolled synthesis of oxa-
combination with other reactions (such as pinacol rear-
The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 955
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