LETTER
▌713
Stereoselective Synthesis of Dioxolanes and Oxazolidines via a Desymmetrization Acetalization/Michael Cascade letter
David M. Rubush, Tomislav Rovis* Stereoselective Synthesis of Dioxolanes and Oxazolidines
Colorado State University, Department of Chemistry, Fort Collins, CO 80523, USA Fax +1(970)4911801; E-mail: [email protected] Received: 04.10.2013; Accepted after revision: 02.01.2014
Key words: acetals, desymmetrization, Michael addition, stereoselective synthesis, cascade catalysis
Cyclic acetals and aminals are important structural motifs which are found in sugars, alkaloids and pharmaceuticals.1 They are also utilized in the synthesis of chiral ligands and auxiliaries.2 Accordingly, the development of viable stereoselective routes to these compounds is important. The catalytic asymmetric synthesis of acetals and aminals is challenging because formation of the hemiacetal intermediate and acetal/aminal product are both reversible. Most enantioenriched acetals are prepared using chiral starting materials or stoichiometric chiral reagents but recent development in chiral hydrogen bond catalysts has opened the door for success in this area.3–6 The synthesis of cyclic acetals can be achieved via an acetalization/oxa-Michael cascade involving aldehydes and γ-hydroxy α,β-unsaturated carbonyl compounds. Although 1,3-dioxanes can be synthesized in high diastereoselectivity through this method, the analogous 1,3dioxolanes have been more challenging.7,8 Matsubara re• previous work (Rovis10): O
O
O
O
chiral phosphoric acid
R2 R1
R1
OOH
OH O
O
H R1
R2
racemic
O O
O
90–96% ee
• this work: O
O
O R2
R1
OH
H R1
O O R2
Scheme 1 Acetalization/oxa-Michael cascade
SYNLETT 2014, 25, 0713–0717 Advanced online publication: 10.02.20140936-52141437-2096 DOI: 10.1055/s-0033-1340669; Art ID: ST-2013-S0937-L © Georg Thieme Verlag Stuttgart · New York
R2
cently synthesized 1,3-dioxolanes and 1,3-oxazolidines using a quinidine-derived bifunctional thiourea catalyst, proceeding in excellent enantioselectivity but modest to low diastereoselectivity.9 We previously reported that a chiral SPINOL-derived phosphoric acid catalyst could catalyze the synthesis of 1,2,4-trioxanes in high enantioselectivity and diastereoselectivity via a dynamic kinetic resolution of the peroxyhemiacetal intermediate (Scheme 1).10 We envisioned a similar approach to the stereoselective synthesis of 1,3-dioxolanes. Table 1 Optimization of Reaction Conditionsa O
O
O
catalyst (10 mol%) H Me
OH
i-PrCHO (2a), CH2Cl2 23 °C, 12–24 h
Me
O
3aa i-Pr (major)
1a
H
+
O
Me
O O 3aa' i-Pr (minor)
Catalyst
Yield (%)
drb
1
Amberlyst-15
93
1:1
2
TsOH
88
1.6:1
3
F3CSO3H
50
1.6:1
4
H3PO4
85
1.9:1
5
(+)-CSA
90
2.2:1
6
HClaq
67
2.2:1
7
TFA
77
14:1
8
Me2PO2H
90
14:1
9
PhPO3H2
71
17:1
10
Ph2PO2H
92
>20:1
11c
Ph2PO2H
91
>20:1
d
Ph2PO2H
85
17:1
(PhO)2PO2H
87
1.5:1
Entry
12 13
a Reaction conditions: quinol 1 (1 equiv), i-PrCHO (1.25 equiv), 0.25 M. b Diastereoselectivity was determined by 1H NMR of unpurified reaction mixture. c Ph2PO2H (5 mol%) was used in dichloroethane (DCE) at 45 °C. d Ph2PO2H (10 mol%) was used with H2O (10 equiv).
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Abstract: The desymmetrization of p-quinols using a Brønsted acid catalyzed acetalization/Michael cascade was achieved in high yields and diastereoselectivities for aldehydes and imines. Use of a chiral Brønsted acid allowed for the synthesis of 1,3-dioxolane and 1,3-oxazolidine products in modest enantioselectivity.
LETTER
D. M. Rubush, T. Rovis O
O
O
O 2 R2 Me
OH
Me
OH
O
Me
O
3a R2 O H
O
Me
O
O
R2
H
O
Me
O
O
t-Bu
i-Pr 3aa, 91% yield >20:1 dr
3ab, 84% yield >20:1 dr
O
3ac, 89% yield
O
O
H Me
O
O H
Me
H
DCE, 45 °C
O 4a
1a
Ph2PO2H (10 mol%)
H
O
O
Me
O
H O
Me
O
O
Cy 3ad, 75% yield >20:1 dr
3ae, 95% yield >20:1 dr
O
O
O
H Me
3af, 83% yield >20:1 dr
H
O O
In addition to aldehydes and ketones, imines were found to be competent partners for the formal [3+2] cycloaddition.
H
O
Me
O
Me
O
Ph
10).12 By increasing the temperature to 45 °C and using dichloroethane (DCE) as a solvent, we were able to decrease the reaction time and reduce the catalyst loading to 5 mol% while still maintaining excellent diastereoselectivity (entry 11). When excess water was added to the reaction while using diphenylphosphinic acid, the diastereoselectivity decreased to 17:1 (entry 12). This indicates that moderately dry conditions are preferred to prevent epimerization. Our optimized reaction conditions were applied to a variety of aldehydes (Scheme 2).13 Paraformaldehyde as well as sterically hindered aliphatic aldehydes all provided the 1,3-dioxolane products in good yields and high diastereoselectivity. Alkenes, alkynes, thioethers and protected alcohols are tolerated under the reaction conditions. Aryl aldehydes and acetone participated in the reaction but lower yields were obtained. The lower yields for the aromatic aldehydes, and acetone can be attributed to the less thermodynamically favorable hemiacetal/hemiketal formation.14 The high diastereoselectivity was tolerant to substitution on the quinol including ethers and multiple tetrasubstituted stereocenters (Scheme 3).
O
OTIPS
SMe O
O 3ag, 74% yield >20:1 dr
3ah, 71% yield 14:1 dr
O
3ai, 84% yield >20:1 dr
O
Ph2PO2H (10 mol%) R2
O
R2 R1
H Me
O O
H Me
O
Me
O
Me
H
3ak, 63% yield >20:1 dr
O
We initiated our investigation by exploring the reaction of p-methylquinol11 1 with isobutyraldehyde. A screen of Brønsted acid catalysts demonstrated that Amberlyst-15, p-toluenesulfonic acid (TsOH), (+)-camphorsulfonic acid (CSA), CF3SO3H, H3PO4, and HClaq all afford desired dioxolane 3/3′ in modest to good yield but poor diastereoselectivity ranging from 1:1 to 2.2:1 (Table 1, entries 1–6). Both trifluoroacetic acid (TFA) and dimethylphosphinic acid improved the selectivity to 14:1. Switching to a bulkier catalyst, phenylphosphonic acid, further improved the selectivity to 17:1 but the catalyst’s low solubility diminished the yield. Implementing the larger and more soluble catalyst diphenylphosphinic acid improved both the yield and the diastereoselectivity to >20:1 favoring 3aa (entry Synlett 2014, 25, 713–717
O H
O
O
O
i-Pr
3al, 18% yield
Scheme 2 Aldehyde substrate scope (dr indicates stereochemistry at acetal with respect to ring juncture; dr at ring juncture is >20:1 cis)
i-Pr
Me Me Me
O
Br 3aj, 26% yield >20:1 dr
O 3
Me Et
O
R1
OH
O
O O
R2
1
H
O
R2
i-PrCHO (2a), DCE, 45 °C
O i-Pr
3ba, 84% yield >20:1 dr
i-Pr
MeO
3ca, 68% yield >20:1 dr
3da, 74% yield >20:1 dr
Scheme 3 Quinol substrate scope (dr indicates stereochemistry at acetal with respect to ring juncture; dr at ring juncture is >20:1 cis) Table 2 Mechanistic Studies O
O
H Me
O O 3aa
O
H
acid (10 mol%) CH2Cl2, 23 °C, 48 h
i-Pr
Me
O 3aa
H
+
O i-Pr
Me
O O
3aa'
Entry
Initial dr of 3aa
Catalyst
1
20:1
Amberlyst-15
4:1
2
1:1
Ph2PO2H
1:1
3
20:1
Ph2PO2H
20:1
i-Pr
Product dr
© Georg Thieme Verlag Stuttgart · New York
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714
LETTER
715
Stereoselective Synthesis of Dioxolanes and Oxazolidines
N-Alkyl and N-aryl imines afforded the desired 1,3-oxazolidine products in good yields and high diastereoselectivity (Scheme 4). In order to better understand the reaction we subjected single diastereomer 3aa to the conditions with Amberlyst15 (Table 2). The 1,3-dioxolane was slowly epimerized to a 4:1 ratio over two days using Amberlyst-15. Both the 1:1 mixture of diastereomers and the major diastereomer were not changed when they were individually subjected to diphenylphosphinic acid. This suggests that the diastereoselectivities observed with diphenylphosphinic acid are a product of kinetic control in the acetalization/cyclization.
After improving the diastereoselectivity, expanding the scope and exploring the reaction mechanism, we hoped to render the reaction enantioselective with the use of a chiral Brønsted acid. Isobutyraldehyde and quinol 1a were screened with a variety of chiral catalysts (Table 3). Using the TRIP phosphoric acid catalyst A the product could be obtained in 35% ee at –78 °C. While the 9-anthracenyl catalyst B showed very little enantioselectivity, the triphenylsilyl-substituted catalyst gave a small improvement to 41% ee. The SPINOL-derived phosphoric acid D gave a promising 45% ee at room temperature but unfortunately the reaction was very slow at –78 °C. Chiral thiourea catalyst E and squaramide cat-
O
O catalyst (10 mol%) H
Me
i-PrCHO (2a), 4 Å MS CH2Cl2, 24 h
OH
1a
Me
O O 3aa
i-Pr
i-Pr i-Pr SiPh3 i-Pr
O P O
O
O
O
O
P
OH i-Pr
P
OH
O
O OH
O SiPh3
A
C
B
i-Pr i-Pr
F3C CF3
i-Pr i-Pr F3C
NH
i-Pr O
O
NH
O
NH
O S
P OH O i-Pr
NH N N
N i-Pr D
H
i-Pr E
OMe
H
F
Entry
Catalyst
1
A
23
89
9:1
10
2
A
–78
69
>20:1
35
3
B
–78
71
>20:1
11
4
C
–78
63
>20:1
41
5
D
23
26
>20:1
45
6
D
–78
20:1 dr
6ab, 73% yield >20:1 dr
6ac, 76% yield >20:1 dr
Scheme 4 Imine substrate scope (dr indicates stereochemistry at acetal with respect to ring juncture; dr at ring juncture is >20:1 cis)
alyst F showed no improvement over the phosphoric acid catalysts. The enantioselective synthesis of a 1,3-oxazolidine was also investigated using quinol 1a (Scheme 5). The best result came with catalyst A which gave the product in 32% yield and 53% ee. The more hindered catalyst D only produced a trace amount of desired oxazolidine 6ac. O
O NAr2
A (10 mol%)
H
Ar DCE, 4 Å MS, 23 °C Me
N
+ 1
Me
OH 1a
5c
32% yield, >20:1 dr 53% ee
OMe
O
6ac
NO2
Scheme 5 Enantioselective synthesis of 1,3-oxazolidine 6ac
In summary, we have developed a diastereoselective synthesis of 1,3-dioxolanes and 1,3-oxazolidines via a diphenyl phosphinic acid catalyzed acetalization/oxa-Michael cascade. The reaction tolerates a variety of aliphatic and aryl aldehydes as well as imines. Employing chiral phosphoric acids allows for the synthesis of 1,3-dioxolane and 1,3-oxazolidine products in modest enantioselectivity.
Acknowledgment We are grateful to NIGMS (GM72586) for generous support for this research.
Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.SonrmfIupgitSa
Synlett 2014, 25, 713–717
(1) (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617. (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406. (c) Mavragani, C. P.; Moutsopoulos, H. M. Clinic Rev. Allerg. Immunol. 2007, 32, 287. (d) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669. (2) (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem. Int. Ed. 1996, 35, 2708. (b) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159. (c) Agami, C.; Couty, F. Eur. J. Org. Chem. 2004, 677. (3) (a) Frauenrath, H.; Philipps, T. Angew. Chem., Int. Ed. Engl. 1986, 25, 274. (b) Frauenrath, H.; Reim, S.; Wiesner, A. Tetrahedron: Asymmetry 1998, 9, 1103. (c) Burke, S. D.; Müller, N.; Beaudry, C. M. Org. Lett. 1999, 1, 1827. (d) Fletcher, S. J.; Rayner, C. M. Tetrahedron Lett. 1999, 40, 7139. (e) Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553. (f) Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J. 2001, 7, 945. (4) For examples of organocatalytic asymmetric acetal synthesis, see: (a) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130, 15787. (b) Čorić, I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132, 8536. (c) Čorić, I.; Müller, S.; List, B. J. Am. Chem. Soc. 2010, 132, 17370. (d) Čorić, I.; List, B. Nature (London) 2012, 483, 315. (e) Sun, Z.; Winschel, G. A.; Borovika, A.; Nagorny, P. J. Am. Chem. Soc. 2012, 134, 8074. (f) Kim, J. H.; Čorić, I.; Vellalath, S.; List, B. Angew. Chem. Int. Ed. 2013, 52, 4474. (5) Nagano, H.; Katsuki, T. Chem. Lett. 2002, 31, 782. (6) For examples of organocatalytic asymmetric aminal formation, see: (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b) Liang, Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem. Commun. 2007, 4477. (c) Li, G.-L.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216. (d) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130, 15786. (e) Rueping, M.; Antonchick, A. P.; Sugiono, E.; Grenader, K. Angew. Chem. Int. Ed. 2009, 48, 908. (7) (a) Jefford, C. W.; Jaggi, D.; Kohmoto, S.; Boukouvalas, J. Helv. Chim. Acta 1984, 67, 2254. (b) Jefford, C. W.; Rossier, J. C.; Kohmoto, S.; Boukouvalas, J. Synthesis 1985, 29. (c) Jefford, C. W.; Jaggi, D.; Boukouvalas, J.; Kohmoto, S. J. Am. Chem. Soc. 1983, 105, 6497. (d) Jefford, C. W.; Kohmoto, S.; Boukouvalas, J.; Burger, U. J. Am. Chem. Soc. 1983, 105, 6498. (8) For examples of diastereoselective cyclic acetal syntheses by intramolecular oxy-Michael addition via hemiacetal formation, see: (a) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446. (b) Watanabe, H.; Machida, K.; Itoh, D.; Nagatsuka, H.; Kitahara, T. Chirality 2001, 13, 379. (c) Redondo, M. C.; Ribagorda, M.; Carreño, M. C. Org. Lett. 2010, 12, 568. (d) Evans, P. A.; Grisin, A.; Lawler, M. J. J. Am. Chem. Soc. 2012, 134, 2856. (9) (a) Asano, K.; Matsubara, S. Org. Lett. 2012, 14, 1620. (b) Okamura, T.; Asano, K.; Matsubara, S. Chem. Commun. 2012, 48, 5076. (c) Fukata, Y.; Miyaji, R.; Okamura, T.; Asano, K.; Matsubara, S. Synthesis 2013, 45, 1627. (d) Fukata, Y.; Asano, K.; Matsubara, S. Chem. Lett. 2013, 42, 355. (10) Rubush, D. M.; Morges, M. A.; Rose, B. J.; Thamm, D. H.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 13554. (11) (a) Carreño, M. C.; González-López, M.; Urbano, A. Angew. Chem. Int. Ed. 2006, 45, 2737. (b) Barradas, S.; Carreño, M. C.; González-López, M.; Latorre, A.; Urbano, A. Org. Lett. © Georg Thieme Verlag Stuttgart · New York
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716
LETTER
Stereoselective Synthesis of Dioxolanes and Oxazolidines
disappeared by TLC (6–48 h). In some cases the reaction was heated to 45 °C. The reaction was concentrated in vacuo. Flash column chromatography (10–20% hexanes– EtOAc) of the resulting clear or yellow residue gave the analytically pure product in high diastereoselectivity as a white solid or clear oil. Some products decompose slowly upon treatment with SiO2 (via acetal hydrolysis) so fast column chromatography is optimal. (14) Gómez-Bombarelli, R.; González-Pérez, M.; Pérez-Prior, M. T.; Calle, E.; Casado, J. J. Phys. Chem. A 2009, 113, 11423.
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2007, 9, 5019. (c) Barradas, S.; Urbano, A.; Carreño, M. C. Chem. Eur. J. 2009, 15, 9286. (12) The stereochemistry of the 1,3-dioxolane was confirmed using nuclear Overhauser effect (NOE) experiments on the minor diastereomer. (13) A 1.5 dram vial was charged with a magnetic stir bar, 4-methyl-4-hydroxycyclohexa-2,5-dienone (1; 0.25 mmol, 1.0 equiv), diphenylphosphinic acid (18 mg, 0.025 mmol, 0.1 equiv), aldehyde/imine (0.31 mmol, 1.25 equiv), and 1,2dichloroethane or CH2Cl2 (1.0 mL, 0.25 M). The vial was then sealed and stirred at r.t. until the starting material
717
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 713–717
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▌713
Stereoselective Synthesis of Dioxolanes and Oxazolidines via a Desymmetrization Acetalization/Michael Cascade letter
David M. Rubush, Tomislav Rovis* Stereoselective Synthesis of Dioxolanes and Oxazolidines
Colorado State University, Department of Chemistry, Fort Collins, CO 80523, USA Fax +1(970)4911801; E-mail: [email protected] Received: 04.10.2013; Accepted after revision: 02.01.2014
Key words: acetals, desymmetrization, Michael addition, stereoselective synthesis, cascade catalysis
Cyclic acetals and aminals are important structural motifs which are found in sugars, alkaloids and pharmaceuticals.1 They are also utilized in the synthesis of chiral ligands and auxiliaries.2 Accordingly, the development of viable stereoselective routes to these compounds is important. The catalytic asymmetric synthesis of acetals and aminals is challenging because formation of the hemiacetal intermediate and acetal/aminal product are both reversible. Most enantioenriched acetals are prepared using chiral starting materials or stoichiometric chiral reagents but recent development in chiral hydrogen bond catalysts has opened the door for success in this area.3–6 The synthesis of cyclic acetals can be achieved via an acetalization/oxa-Michael cascade involving aldehydes and γ-hydroxy α,β-unsaturated carbonyl compounds. Although 1,3-dioxanes can be synthesized in high diastereoselectivity through this method, the analogous 1,3dioxolanes have been more challenging.7,8 Matsubara re• previous work (Rovis10): O
O
O
O
chiral phosphoric acid
R2 R1
R1
OOH
OH O
O
H R1
R2
racemic
O O
O
90–96% ee
• this work: O
O
O R2
R1
OH
H R1
O O R2
Scheme 1 Acetalization/oxa-Michael cascade
SYNLETT 2014, 25, 0713–0717 Advanced online publication: 10.02.20140936-52141437-2096 DOI: 10.1055/s-0033-1340669; Art ID: ST-2013-S0937-L © Georg Thieme Verlag Stuttgart · New York
R2
cently synthesized 1,3-dioxolanes and 1,3-oxazolidines using a quinidine-derived bifunctional thiourea catalyst, proceeding in excellent enantioselectivity but modest to low diastereoselectivity.9 We previously reported that a chiral SPINOL-derived phosphoric acid catalyst could catalyze the synthesis of 1,2,4-trioxanes in high enantioselectivity and diastereoselectivity via a dynamic kinetic resolution of the peroxyhemiacetal intermediate (Scheme 1).10 We envisioned a similar approach to the stereoselective synthesis of 1,3-dioxolanes. Table 1 Optimization of Reaction Conditionsa O
O
O
catalyst (10 mol%) H Me
OH
i-PrCHO (2a), CH2Cl2 23 °C, 12–24 h
Me
O
3aa i-Pr (major)
1a
H
+
O
Me
O O 3aa' i-Pr (minor)
Catalyst
Yield (%)
drb
1
Amberlyst-15
93
1:1
2
TsOH
88
1.6:1
3
F3CSO3H
50
1.6:1
4
H3PO4
85
1.9:1
5
(+)-CSA
90
2.2:1
6
HClaq
67
2.2:1
7
TFA
77
14:1
8
Me2PO2H
90
14:1
9
PhPO3H2
71
17:1
10
Ph2PO2H
92
>20:1
11c
Ph2PO2H
91
>20:1
d
Ph2PO2H
85
17:1
(PhO)2PO2H
87
1.5:1
Entry
12 13
a Reaction conditions: quinol 1 (1 equiv), i-PrCHO (1.25 equiv), 0.25 M. b Diastereoselectivity was determined by 1H NMR of unpurified reaction mixture. c Ph2PO2H (5 mol%) was used in dichloroethane (DCE) at 45 °C. d Ph2PO2H (10 mol%) was used with H2O (10 equiv).
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Abstract: The desymmetrization of p-quinols using a Brønsted acid catalyzed acetalization/Michael cascade was achieved in high yields and diastereoselectivities for aldehydes and imines. Use of a chiral Brønsted acid allowed for the synthesis of 1,3-dioxolane and 1,3-oxazolidine products in modest enantioselectivity.
LETTER
D. M. Rubush, T. Rovis O
O
O
O 2 R2 Me
OH
Me
OH
O
Me
O
3a R2 O H
O
Me
O
O
R2
H
O
Me
O
O
t-Bu
i-Pr 3aa, 91% yield >20:1 dr
3ab, 84% yield >20:1 dr
O
3ac, 89% yield
O
O
H Me
O
O H
Me
H
DCE, 45 °C
O 4a
1a
Ph2PO2H (10 mol%)
H
O
O
Me
O
H O
Me
O
O
Cy 3ad, 75% yield >20:1 dr
3ae, 95% yield >20:1 dr
O
O
O
H Me
3af, 83% yield >20:1 dr
H
O O
In addition to aldehydes and ketones, imines were found to be competent partners for the formal [3+2] cycloaddition.
H
O
Me
O
Me
O
Ph
10).12 By increasing the temperature to 45 °C and using dichloroethane (DCE) as a solvent, we were able to decrease the reaction time and reduce the catalyst loading to 5 mol% while still maintaining excellent diastereoselectivity (entry 11). When excess water was added to the reaction while using diphenylphosphinic acid, the diastereoselectivity decreased to 17:1 (entry 12). This indicates that moderately dry conditions are preferred to prevent epimerization. Our optimized reaction conditions were applied to a variety of aldehydes (Scheme 2).13 Paraformaldehyde as well as sterically hindered aliphatic aldehydes all provided the 1,3-dioxolane products in good yields and high diastereoselectivity. Alkenes, alkynes, thioethers and protected alcohols are tolerated under the reaction conditions. Aryl aldehydes and acetone participated in the reaction but lower yields were obtained. The lower yields for the aromatic aldehydes, and acetone can be attributed to the less thermodynamically favorable hemiacetal/hemiketal formation.14 The high diastereoselectivity was tolerant to substitution on the quinol including ethers and multiple tetrasubstituted stereocenters (Scheme 3).
O
OTIPS
SMe O
O 3ag, 74% yield >20:1 dr
3ah, 71% yield 14:1 dr
O
3ai, 84% yield >20:1 dr
O
Ph2PO2H (10 mol%) R2
O
R2 R1
H Me
O O
H Me
O
Me
O
Me
H
3ak, 63% yield >20:1 dr
O
We initiated our investigation by exploring the reaction of p-methylquinol11 1 with isobutyraldehyde. A screen of Brønsted acid catalysts demonstrated that Amberlyst-15, p-toluenesulfonic acid (TsOH), (+)-camphorsulfonic acid (CSA), CF3SO3H, H3PO4, and HClaq all afford desired dioxolane 3/3′ in modest to good yield but poor diastereoselectivity ranging from 1:1 to 2.2:1 (Table 1, entries 1–6). Both trifluoroacetic acid (TFA) and dimethylphosphinic acid improved the selectivity to 14:1. Switching to a bulkier catalyst, phenylphosphonic acid, further improved the selectivity to 17:1 but the catalyst’s low solubility diminished the yield. Implementing the larger and more soluble catalyst diphenylphosphinic acid improved both the yield and the diastereoselectivity to >20:1 favoring 3aa (entry Synlett 2014, 25, 713–717
O H
O
O
O
i-Pr
3al, 18% yield
Scheme 2 Aldehyde substrate scope (dr indicates stereochemistry at acetal with respect to ring juncture; dr at ring juncture is >20:1 cis)
i-Pr
Me Me Me
O
Br 3aj, 26% yield >20:1 dr
O 3
Me Et
O
R1
OH
O
O O
R2
1
H
O
R2
i-PrCHO (2a), DCE, 45 °C
O i-Pr
3ba, 84% yield >20:1 dr
i-Pr
MeO
3ca, 68% yield >20:1 dr
3da, 74% yield >20:1 dr
Scheme 3 Quinol substrate scope (dr indicates stereochemistry at acetal with respect to ring juncture; dr at ring juncture is >20:1 cis) Table 2 Mechanistic Studies O
O
H Me
O O 3aa
O
H
acid (10 mol%) CH2Cl2, 23 °C, 48 h
i-Pr
Me
O 3aa
H
+
O i-Pr
Me
O O
3aa'
Entry
Initial dr of 3aa
Catalyst
1
20:1
Amberlyst-15
4:1
2
1:1
Ph2PO2H
1:1
3
20:1
Ph2PO2H
20:1
i-Pr
Product dr
© Georg Thieme Verlag Stuttgart · New York
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714
LETTER
715
Stereoselective Synthesis of Dioxolanes and Oxazolidines
N-Alkyl and N-aryl imines afforded the desired 1,3-oxazolidine products in good yields and high diastereoselectivity (Scheme 4). In order to better understand the reaction we subjected single diastereomer 3aa to the conditions with Amberlyst15 (Table 2). The 1,3-dioxolane was slowly epimerized to a 4:1 ratio over two days using Amberlyst-15. Both the 1:1 mixture of diastereomers and the major diastereomer were not changed when they were individually subjected to diphenylphosphinic acid. This suggests that the diastereoselectivities observed with diphenylphosphinic acid are a product of kinetic control in the acetalization/cyclization.
After improving the diastereoselectivity, expanding the scope and exploring the reaction mechanism, we hoped to render the reaction enantioselective with the use of a chiral Brønsted acid. Isobutyraldehyde and quinol 1a were screened with a variety of chiral catalysts (Table 3). Using the TRIP phosphoric acid catalyst A the product could be obtained in 35% ee at –78 °C. While the 9-anthracenyl catalyst B showed very little enantioselectivity, the triphenylsilyl-substituted catalyst gave a small improvement to 41% ee. The SPINOL-derived phosphoric acid D gave a promising 45% ee at room temperature but unfortunately the reaction was very slow at –78 °C. Chiral thiourea catalyst E and squaramide cat-
O
O catalyst (10 mol%) H
Me
i-PrCHO (2a), 4 Å MS CH2Cl2, 24 h
OH
1a
Me
O O 3aa
i-Pr
i-Pr i-Pr SiPh3 i-Pr
O P O
O
O
O
O
P
OH i-Pr
P
OH
O
O OH
O SiPh3
A
C
B
i-Pr i-Pr
F3C CF3
i-Pr i-Pr F3C
NH
i-Pr O
O
NH
O
NH
O S
P OH O i-Pr
NH N N
N i-Pr D
H
i-Pr E
OMe
H
F
Entry
Catalyst
1
A
23
89
9:1
10
2
A
–78
69
>20:1
35
3
B
–78
71
>20:1
11
4
C
–78
63
>20:1
41
5
D
23
26
>20:1
45
6
D
–78
20:1 dr
6ab, 73% yield >20:1 dr
6ac, 76% yield >20:1 dr
Scheme 4 Imine substrate scope (dr indicates stereochemistry at acetal with respect to ring juncture; dr at ring juncture is >20:1 cis)
alyst F showed no improvement over the phosphoric acid catalysts. The enantioselective synthesis of a 1,3-oxazolidine was also investigated using quinol 1a (Scheme 5). The best result came with catalyst A which gave the product in 32% yield and 53% ee. The more hindered catalyst D only produced a trace amount of desired oxazolidine 6ac. O
O NAr2
A (10 mol%)
H
Ar DCE, 4 Å MS, 23 °C Me
N
+ 1
Me
OH 1a
5c
32% yield, >20:1 dr 53% ee
OMe
O
6ac
NO2
Scheme 5 Enantioselective synthesis of 1,3-oxazolidine 6ac
In summary, we have developed a diastereoselective synthesis of 1,3-dioxolanes and 1,3-oxazolidines via a diphenyl phosphinic acid catalyzed acetalization/oxa-Michael cascade. The reaction tolerates a variety of aliphatic and aryl aldehydes as well as imines. Employing chiral phosphoric acids allows for the synthesis of 1,3-dioxolane and 1,3-oxazolidine products in modest enantioselectivity.
Acknowledgment We are grateful to NIGMS (GM72586) for generous support for this research.
Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.SonrmfIupgitSa
Synlett 2014, 25, 713–717
(1) (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617. (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406. (c) Mavragani, C. P.; Moutsopoulos, H. M. Clinic Rev. Allerg. Immunol. 2007, 32, 287. (d) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669. (2) (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem. Int. Ed. 1996, 35, 2708. (b) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159. (c) Agami, C.; Couty, F. Eur. J. Org. Chem. 2004, 677. (3) (a) Frauenrath, H.; Philipps, T. Angew. Chem., Int. Ed. Engl. 1986, 25, 274. (b) Frauenrath, H.; Reim, S.; Wiesner, A. Tetrahedron: Asymmetry 1998, 9, 1103. (c) Burke, S. D.; Müller, N.; Beaudry, C. M. Org. Lett. 1999, 1, 1827. (d) Fletcher, S. J.; Rayner, C. M. Tetrahedron Lett. 1999, 40, 7139. (e) Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553. (f) Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J. 2001, 7, 945. (4) For examples of organocatalytic asymmetric acetal synthesis, see: (a) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130, 15787. (b) Čorić, I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132, 8536. (c) Čorić, I.; Müller, S.; List, B. J. Am. Chem. Soc. 2010, 132, 17370. (d) Čorić, I.; List, B. Nature (London) 2012, 483, 315. (e) Sun, Z.; Winschel, G. A.; Borovika, A.; Nagorny, P. J. Am. Chem. Soc. 2012, 134, 8074. (f) Kim, J. H.; Čorić, I.; Vellalath, S.; List, B. Angew. Chem. Int. Ed. 2013, 52, 4474. (5) Nagano, H.; Katsuki, T. Chem. Lett. 2002, 31, 782. (6) For examples of organocatalytic asymmetric aminal formation, see: (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b) Liang, Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem. Commun. 2007, 4477. (c) Li, G.-L.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216. (d) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130, 15786. (e) Rueping, M.; Antonchick, A. P.; Sugiono, E.; Grenader, K. Angew. Chem. Int. Ed. 2009, 48, 908. (7) (a) Jefford, C. W.; Jaggi, D.; Kohmoto, S.; Boukouvalas, J. Helv. Chim. Acta 1984, 67, 2254. (b) Jefford, C. W.; Rossier, J. C.; Kohmoto, S.; Boukouvalas, J. Synthesis 1985, 29. (c) Jefford, C. W.; Jaggi, D.; Boukouvalas, J.; Kohmoto, S. J. Am. Chem. Soc. 1983, 105, 6497. (d) Jefford, C. W.; Kohmoto, S.; Boukouvalas, J.; Burger, U. J. Am. Chem. Soc. 1983, 105, 6498. (8) For examples of diastereoselective cyclic acetal syntheses by intramolecular oxy-Michael addition via hemiacetal formation, see: (a) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446. (b) Watanabe, H.; Machida, K.; Itoh, D.; Nagatsuka, H.; Kitahara, T. Chirality 2001, 13, 379. (c) Redondo, M. C.; Ribagorda, M.; Carreño, M. C. Org. Lett. 2010, 12, 568. (d) Evans, P. A.; Grisin, A.; Lawler, M. J. J. Am. Chem. Soc. 2012, 134, 2856. (9) (a) Asano, K.; Matsubara, S. Org. Lett. 2012, 14, 1620. (b) Okamura, T.; Asano, K.; Matsubara, S. Chem. Commun. 2012, 48, 5076. (c) Fukata, Y.; Miyaji, R.; Okamura, T.; Asano, K.; Matsubara, S. Synthesis 2013, 45, 1627. (d) Fukata, Y.; Asano, K.; Matsubara, S. Chem. Lett. 2013, 42, 355. (10) Rubush, D. M.; Morges, M. A.; Rose, B. J.; Thamm, D. H.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 13554. (11) (a) Carreño, M. C.; González-López, M.; Urbano, A. Angew. Chem. Int. Ed. 2006, 45, 2737. (b) Barradas, S.; Carreño, M. C.; González-López, M.; Latorre, A.; Urbano, A. Org. Lett. © Georg Thieme Verlag Stuttgart · New York
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716
LETTER
Stereoselective Synthesis of Dioxolanes and Oxazolidines
disappeared by TLC (6–48 h). In some cases the reaction was heated to 45 °C. The reaction was concentrated in vacuo. Flash column chromatography (10–20% hexanes– EtOAc) of the resulting clear or yellow residue gave the analytically pure product in high diastereoselectivity as a white solid or clear oil. Some products decompose slowly upon treatment with SiO2 (via acetal hydrolysis) so fast column chromatography is optimal. (14) Gómez-Bombarelli, R.; González-Pérez, M.; Pérez-Prior, M. T.; Calle, E.; Casado, J. J. Phys. Chem. A 2009, 113, 11423.
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2007, 9, 5019. (c) Barradas, S.; Urbano, A.; Carreño, M. C. Chem. Eur. J. 2009, 15, 9286. (12) The stereochemistry of the 1,3-dioxolane was confirmed using nuclear Overhauser effect (NOE) experiments on the minor diastereomer. (13) A 1.5 dram vial was charged with a magnetic stir bar, 4-methyl-4-hydroxycyclohexa-2,5-dienone (1; 0.25 mmol, 1.0 equiv), diphenylphosphinic acid (18 mg, 0.025 mmol, 0.1 equiv), aldehyde/imine (0.31 mmol, 1.25 equiv), and 1,2dichloroethane or CH2Cl2 (1.0 mL, 0.25 M). The vial was then sealed and stirred at r.t. until the starting material
717
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Synlett 2014, 25, 713–717
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