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Stereochemistry of PdII-Catalyzed THF Ring Formation of Epsilon-Hydroxy Allylic Alcohols and Synthesis of 2,3,5Trisubstituted and 2,3,4,5-Tetrasubstituted Tetrahydrofurans Yuki Murata, and Jun'ichi Uenishi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01154 • Publication Date (Web): 19 Jul 2016 Downloaded from http://pubs.acs.org on July 20, 2016
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The Journal of Organic Chemistry
Stereochemistry of PdII-Catalyzed THF Ring Formation of ε-Hydroxy Allylic Alcohols and Synthesis of 2,3,5-Trisubstituted and 2,3,4,5-Tetrasubstituted Tetrahydrofurans Yuki Murata, and Jun’ichi Uenishi* Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, 607-8412, Japan e-mail:
[email protected] H O O iPr ε H X Si iPr OH γ δ iPr Si O Y iPr X = H or OH Y = H or OH Z = H or Me
O O H cat. iPr 2 H X 5 Si PdCl2(MeCN)2 iPr OH Z THF, rt iPr Si O Y Z – H2O iPr
OH
cis-oxypalladation and syn-elimination
Z iPr iPr
O Si
O
O H X H
iPr Si
H
O Y
iPr
5-exo-trigonal product No 6-endo-trigonal product was formed.
ABSTRACT: PdII-Catalyzed ring formation of 2,3,5-trisubstituted tetrahydrofuran is described. Oxypalladation of a chiral ε−hydroxy allylic alcohol provides 5-alkenyl tetrahydrofuran ring in excellent yields via a 5-exo-trigonal process. Nine substrates including six secondary allylic alcohols and three primary allylic alcohols with or without an additional secondary hydroxy substituent at the γ-position
have
been
examined.
Their
2,2,4,4-tetraisopropyl-1,3,5,2,4-trioxadisilocane
ring.
structures The
are
restricted
stereochemistry
of
the
by
a
resulting
tetrahydrofuran products was determined by chemical transformation. The reaction mechanism is discussed based on the stereochemical results. The steps in the chiral allylic alcohol-directed or the nucleophilic alcohol-directed facial selection for the formation of the alkene-PdII-π-complex, the cis-oxypalladation, and a syn-elimination mechanism account for the observed stereochemistry of the reaction. 1 ACS Paragon Plus Environment
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INTRODUCTION Oxypalladation is an addition reaction of an oxygen functional group to an alkene promoted by a PdII-catalyst. The process has been utilized as a fundamental step in a variety of synthetically useful O-C bond formations. Numerous PdII-catalyzed oxygenetive transformation reactions have been used in organic synthesis.1 Particularly, the intramolecular oxypalladation reaction is important for the formation of oxygen rings.2 With respect to the synthesis of chiral oxygen heterocycles, the stereochemistry of oxypalladation becomes more important in enantioselective and diastereoselective oxygen ring formation.3 Many arguments related to the mechanism for the oxypalladation and aminopalladation have been proposed in the long history of the nucleopalladation reaction. Both cisand tran-additions have been proposed for inter- and intra-molecular nucleopalladation reactions (Scheme 1).4
SCHEME 1. Nucleopalladation to Alkene H NuH or Nu PdII
H H
PdII NuH
PdII
Nu
trans (anti)
H
PdII
NuH (from a front face)
NuH (from a back face) H
Nu
PdII
cis (syn)
or Nu PdII
H Nucleopalladation
Nu = O; oxypalladation N; azapalladation
The process of the reaction involves three steps; i) coordination of an alkene to the PdII–catalyst to form an alkene-PdII-π−complex; ii) oxypalladation to form the alkyl-PdII-σ-complex with a new O-C bond formation; and iii) reductive elimination to produce an alkene product with the formation of a 2 ACS Paragon Plus Environment
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Pd 0 species which is oxidized to regenerate the PdII-catalyst. The reaction mechanism has been discussed in terms of the results conducted under various reaction conditions with different PdII-catalysts, solvents, temperatures and oxidants. When an allylic alcohol is used as a substrate, this reaction becomes simpler. The dehydration reaction can proceed in the presence of a PdCl2(MeCN)2 catalyst at room temperature in THF without an oxidant, because the catalytic cycle works without the formation of Pd0-species under these mild conditions. We have studied the reaction of various allylic alcohol substrates and their stereochemistry.5 For example, as shown in Scheme 2, the PdII-catalyzed reaction of ε-hydroxy allylic alcohol (1) gave a chiral 2,5-substituted THF product bearing an alkenyl group at the 5-position in excellent yield with high diastereoselectivity (>20:1).6
SCHEME 2. Intramolecular Oxypalladation to Allylic Alcohol H R
ε
*
OH
γ
*
1 >99% ee either R or S
5
PdCl2(MeCN)2 (10 mol %) THF, 0 °C–rt – H2O
(5S,E)-2
20
:
δ
OH
H
*
2
R
O
>
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The Journal of Organic Chemistry
H R 2
O
*
1
H 5
(5R,E)-2
We have proposed a reaction mechanism (Scheme 3) that involves the chiral allylic alcohol-directed formation7 of the alkene-PdII-π−complex followed by ligand exchange to form another alkene-PdII-π−complex,
which
then
undergoes
cis-oxypalladation
leading
to
the
alkyl-PdII-σ-complex. Dissociation of the PdII-species furnished the major stereoisomer predominantly. The original chiral allylic hydroxy center was transmitted to the newly generated chiral center at the C-5 carbon. On the other hand, the minor stereoisomer may be produced from the initial alkene-PdII-π−complex via a trans-oxypalladation pathway.
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SCHEME 3. Proposed Mechanism of the Intramolecular Oxypalladation to Allylic Alcohol H O PdII
OH
cis-O-Pd
O H OH
– HX
PdII
PdII
syn-E
– PdX(OH)
(5S,E)-2
*
OH
OH
major isomer
Ligand exchange
(5R,E)-2 minor isomer
PdII
1
syn-E
OH directed coordination OH
PdII O
H trans-O-Pd
– PdX(OH)
O H OH PdII
– HX O-Pd = oxypalladation syn-E = syn-elimination
SCHEME 4. Synthesis of Dihydrobenzofuran by the Intramolecular Oxypalladation OH
OH
PdCl2(MeCN)2 (15 mol %)
O
O H
H
THF, rt 44% 93% ee
>99% ee
33% >99% ee
(S,E)-4
3
(R,Z)-4
H O PdII
O H OH
OH cis-O-Pd
PdII
– HX PdII
PdII
H O
syn-E
– PdX(OH)
(S,E)-4 (>27:1) OH
OH (R,Z)-4
3
PdII syn-E OH
H
O
PdII
cis-O-Pd – HX
– PdX(OH) O H PdII
OH
In contrast, the reaction of the phenol substrate 3 displayed quite different stereochemical results (Scheme 4).8 The reaction afforded (S,E)-4 as a major isomer in 44% yield with 93% ee through the same pathway as described in Scheme 3, while another isomer (R,Z)-4 was produced in 33% yield with 99% ee. The latter product had an opposite stereocenter with a (Z)-alkene. The phenol-directed opposite face recognition of the alkene-π-face, cis-oxypalladation and syn-elimination occurred. 4 ACS Paragon Plus Environment
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ε OH
OH
ε
X
OH
δ
δ
γ
γ
Type B X = C or N
Type A
sp2
atom at δ and ε position
H
ε δ
OH
O
H OH
ε O δ
γ
OH γ
OH
5-exo-trig. or
5-exo-trig. Type C
6-endo-trig.
Figure 1. Type of Substrates in Oxypalladation of ε-Hydroxy allylic Alcohol
Quite different stereochemical results were observed in 5-exo-trigonal cyclization for the two types of substrates, termed Type A and Type B (Figure 1). Type A had saturated carbons from the γ− to ε-positions and Type B had two sp2-hybridized atoms at the δ- and ε-positions. We were interested in substrates like Type C (Figure 1). Configurational restriction in Type C substrates by a ring might influence the stereochemical course of the cyclization reaction. Furthermore, if an additional hydroxy group is placed at the γ-position, either 5-exo-trigonal cyclization leading to 2,3,4,5-tetrasubstituted tetrahydrofuran or 6-endo-trigonal cyclization leading to 2,3,6-trisubstituted 3,6-dihydro-2H-pyran would be expected.9 Both of the tetrahydrofuran and 3,6-dihydro-2H-pyran are important moieties in biologically active natural products10,11 and C-nucleoside12. Based on this idea, we report here an intramolecular oxypalladation reaction of nine substrates 5 to 13 (Figure 2) and describe the stereochemistry of the products.
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H O iPr Si iPr O
H
O H X O
O iPr Si iPr O
OH
H
iPr Si iPr
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Y
OH
O H X H
iPr Si iPr
O
Y
5
X=Y=H
8 X=Y=H
6
X = OH, Y = H
9 X = OH, Y = H
7
X = H, Y = OH
10 X = H, Y = OH H
O iPr Si iPr O
OH
O H X H
iPr Si iPr
O
Y
11 X = Y = H 12 X = OH, Y = H 13 X = H, Y = OH
Figure 2. Substrates for Oxypalladation
RESULTS AND DISCUSSION Preparation of Precursors 5 to 13 for Cyclization We started the synthesis of these ε-hydroxy allylic alcohols from commercial D-pentose. Two hydroxy groups of D-2-deoxyribose, D-arabinose and D-ribose were protected with cyclic bis-silyl ethers to give 14, 15, and 16 by the reported procedure.13 Wittig reaction of 14, 15, and 16 with methyl (triphenylphosphoranylidene)acetate gave α,β−unsaturated esters 17, 18, and 19 in 74%, 81%, and 73% yields, respectively. These esters were reduced with DIBAL-H in CH2Cl2 to give allylic alcohols 5, 6, and 7 in 90%, 85%, and 88%, respectively (Scheme 5). SCHEME 5. Preparation of Precursors 5-7 for Cyclization iPr iPr
D-2-deoxyribose D-arabinose D-ribose
ref. 10
O
O
Si O iPr Si
H
X
O
Y
H
iPr
OH
Ph3PCHCOOMe (2 equiv) Benzene reflux, 1 h
14 X = Y = H 15 X = OH, Y = H 16 X = H, Y = OH
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H O O iPr Si H X iPr OH O Y iPr Si
COOMe
H O O iPr Si H X iPr OH O Y iPr Si
DIBAL (4 equiv) CH2Cl2 –78 °C 30 min
iPr
OH
iPr
17 X = Y = H
74%
5 X=Y=H
90%
18 X = OH, Y = H
81%
6 X = OH, Y = H
85%
19 X = H, Y = OH
73%
7 X = H, Y = OH
88%
For the synthesis of compounds 8 to 13, a diastereomeric pair of three allylic alcohols was prepared (Scheme
6).
The
first
step
was
a
Wittig
reaction
of
14,
15,
and
16
with
(triphenylphosphoranylidene)acetone which gave α,β−unsaturated ketones 20, 21, and 22 in 71%, 68%, and 70% yields, respectively. The resulting methyl ketones were reduced by NaBH4 in the presence of CeCl3·7H2O to give diastereomeric mixture of the secondary alcohols 8 and 11, 9 and 12, and 10 and 13, in 87%, 80%, and 91% yields, respectively. These diastereomeric alcohols were differentiated by kinetic acetylation catalyzed with Cal-B (Candida antartica lipase B; Novozyme 435). A mixture of alcohols 8 and 11 were treated with vinyl acetate in the presence of Cal-B for 3 days to provide the (R)-acetate 23 in 48% yield along with recovery of the (S)-alcohol 11 in 47% yield. Diastereomeric purities of both compounds were over >98%. (R)-Alcohol 8 was obtained in 91% yield by the reduction of 23 with LiAlH4. The same two steps afforded the diastereomeric alcohols 9 and 12, and 10 and 13 effectively with satisfactory yields and purities in the same manner described for the case of 8 and 11. SCHEME 6. Preparation of Precursors 8-13 for Cyclization H 14, 15 and 16
Ph3PCHCOMe (3 equiv) Benzene reflux, 1 h
O
iPr Si iPr O iPr Si iPr
O H X
O
H O
Y
20 X = Y = H
71%
21 X = OH, Y = H
68%
22 X = H, Y = OH
70%
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H O iPr Si iPr O
CeCl3 . 7H2O (3 equiv) NaBH4 (1.5 equiv) CH2Cl2, rt 30 min
OH
O H X H
iPr Si iPr
Y
O
Vinyl acetate (5 equiv) MS 4 Å Novozyme 435 (10 w/w%)
8 and 11 X = Y = H
87%
iPr2O, rt, 2-3 d
9 and 12 X = OH, Y = H 80% 10 and 13 X = H, Y = OH 91%
H O
iPr Si iPr O
(S)-alcohol
iPr Si iPr
O H X H
(4 equiv) Et2O, 0 °C
Y
O
LiAlH4
OAc
1h
11
47%
23 X = Y = H
48%
12
46%
24 X = OH, Y = H
42%
13
49%
25 X = H, Y = OH
46%
H O iPr Si iPr O iPr Si iPr
O H X H O
Y
OH
8
X=Y=H
93%
9
X = OH, Y = H
90%
10 X = H, Y = OH
85%
PdII-Catalyzed Cyclization First, we examined the cyclization of primary allylic alcohol 5. The reaction of 5 with 10 mol % of PdCl2(CH3CN)2 in THF at rt gave a mixture of the 5-vinyl substituted THF products, 2,5-trans-26 and 2,5-cis-26 in 89% yield (Scheme 7 and Table 1, entry 1). Although the products were not separable, the ratio was determined to be approximately 3:1 by the proton NMR spectrum. We examined other reaction conditions using other PdII-catalysts, solvents, and additives, which are summarized in Table 1. The reaction was completed after 2 h at 0 °C and in less than 1 min at 60 °C (entries 2 and 3). However, the chemical yields decreased a little and while the selectivity did not change much at 0 °C, but decrease at 60 °C. When 1 mol % of PdII-catalyst was employed, the reaction took 3 h (entry 4). No influence was observed when acetic acid was added to the reaction
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(entry 5). On the other hand, when triethylamine or its hydrochloride was used as an additive, no reaction occurred (entries 6 and 7). PdCl2 also catalyzed the reaction (entry 8). Other PdII-catalysts such as Pd(OAc)2, or PdCl2(PPh3)2 were not effective at all (entries 9 and 10). The use of Pd(OCOCF3)2 provided the cyclized product in 31% yield with a 2:1 ratio of isomers (entry 11). Methylene chloride and toluene could be used as a solvent (entries 12 and 13), however their chemical yields and selectivities were lower than those in THF. Polar solvents such as methanol or acetonitrile gave the product with poor yield and selectivity (entries 14 and 15). In summary, PdCl2(CH3CN)2 was found to be an appropriate catalyst for the reaction, and THF was the best solvent for this reaction.
SCHEME 7. PdII-Catalyzed Cyclization of 5 iPr iPr
O O
O
O iPr Si H iPr OH iPr Si O
H H O
iPr Si
H
iPr
89%
and
THF, rt, 10 min iPr
5
2,5-trans-26
iPr
PdCl2(MeCN)2 OH (10 mol %)
iPr
3 1
O
O
Si O
H
O
Si
:
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The Journal of Organic Chemistry
H H
H O
iPr Si
2,5-cis-26
iPr
Table 1. PdII-Catalyzed Cyclization of 5 entry
Pd-catalyst (mol %)
additive
solvent
temp (°C)
time
yield (%)
a
2,5-trans:2,5-cis
1
PdCl2(MeCN)2
10
–
THF
rt
10 min
89
77:23
2
PdCl2(MeCN)2
10
–
THF
0
2h
84
79:21
3
PdCl2(MeCN)2
10
–
THF
60
