and Diastereoselective Selenoetherification through Supramolecular

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Desymmetrizing Enantio- and Diastereoselective Selenoetherification through Supramolecular Catalysis JIE YANG SEE, Hui Yang, Yu Zhao, Ming Wah Wong, Zhihai Ke, and Ying-Yeung Yeung ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03510 • Publication Date (Web): 11 Dec 2017 Downloaded from http://pubs.acs.org on December 11, 2017

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ACS Catalysis

Desymmetrizing Enantio- and Diastereoselective Selenoetherification through Supramolecular Catalysis Jie Yang See,† Hui Yang,† Yu Zhao,† Ming Wah Wong,*,† Zhihai Ke,*,‡ Ying-Yeung Yeung*,†,‡ †

Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543

‡

Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China)

ABSTRACT: Selenofunctionalization is used for the introduction of aryl- or alkylseleno moieties, which can then be transformed into other functional groups (such as alkenes and carbonyls). However, asymmetric selenofunctionalization of unactivated olefins is often difficult to realize as aryl- and alkylseleno cations rapidly interchange between olefinic partners. Recently, it has been demonstrated that Lewis bases, assisted by Brønsted acids, induce high levels of enantioselectivity in selenocyclization reactions. The Brønsted acid serves as an activator for the reaction. In this work, we demonstrate an asymmetric selenoetherification and desymmetrization of olefinic 1,3-diols, driven by a unique chiral pairing between a C2-symmetric

ACS Paragon Plus Environment

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cyclic selenide catalyst and a chiral Brønsted acid. The resulting substituted tetrahydrofurans contain a phenylselenoether handle, and can be transformed into synthetically useful building blocks. A series of experimental and computational investigations suggest that the reaction proceeds via a supramolecular catalytic pathway.

KEYWORDS: Asymmetric catalysis, cyclic selenide, chiral phosphoric acids, Pummerer rearrangement, selenoetherification, tetrahydrofuran, mechanism


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ACS Catalysis

1. INTRODUCTION Selenofunctionalization

is

a

versatile

transformation

used

in

conjunction

with

halofunctionalization.1 It is used for the introduction of aryl- and alkylselenium moieties, which can then be transformed into other synthetically useful functionalities (e.g. aldehydes or olefins). For example, pioneering works by Tomoda, Déziel and Wirth demonstrated that stoichiometric amounts of chiral selenium reagents could be used for the preparation of chiral non-racemic selenium compounds.2 However, catalytic diastereo- and enantioselective pathways using achiral electrophilic selenium reagents have been hindered by the rapid racemization of the configurationally unstable seleniranium ion, even at low reaction temperatures.3,4 Recently, catalytic and asymmetric reactions of unactivated olefins have been accomplished with satisfactory levels of enantioselectivity. Denmark reported the union between a chiral Lewis basic sulfide catalyst and an achiral acid additive in the enantioselective selenoetherification reaction (Scheme 1a).3a Subsequently, Jacobsen demonstrated an achiral Lewis basic sulfide/chiral squaramide/mineral acid co-catalyst system in the cyclization of an olefinic phenol (Scheme 1b).3c In addition, our research group reported the first catalytic enantioselective selenolactonization of olefinic acids, using substoichiometric amount of (DHQD)2PHAL as the catalyst.3d Herein, we are pleased to report a novel approach to catalytic and desymmetrizing asymmetric selenoetherification based upon a cooperative chiral Lewis basic selenide/chiral Brønsted acid catalyst system (Scheme 1c). This was achieved by applying a co-catalyst system using a chiral C2-symmetric cyclic selenide and a chiral BINOL-derived phosphoric acid. Computational studies suggest that a supramolecular catalyst system might be involved in the catalytic cycle. The investigation used olefinic 1,3-diol 1 as the substrate. The cyclized product tetrahydrofuran


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2 bearing a hydroxyl moiety can be found in the structures of many pharmaceutically important intermediates.5 Moreover, the incorporation of a phenylselenoether handle enables additional transformations, which is complementary to the halide handle (vide infra).6

Scheme 1. Catalytic and enantioselective carbosulfenylation and selenoetherification


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ACS Catalysis

2. RESULTS AND DISCUSSION 2.1 Screening of Lewis basic chalcogens for catalytic activity in the desymmetrizing asymmetric selenoetherification of olefinic 1,3-diols Initial examination of the selenoetherification of olefinic 1,3-diol 1a was conducted using chalcogen-containing Lewis base catalysts

with electrophilic selenylating agent

N-

(phenylseleno)phthalimide (NPSP) (Table 1). A low reaction temperature (−78 °C) was expected to minimize the background reaction promoting the racemic pathway (Table 1, entry 1).

Table 1. Desymmetrizing asymmetric selenoetherification of 1aa

entry catalyst

acid coyield (%)b catalyst

drc

erd

1

-

-

N.R.

-

-

2

Ph3PS

-

N.R.

-

-

3

Ph3PSe

-

N.R.

-

-

4

Ph3PS

(R)-3a

27

86:14

49:51


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5

Ph3PSe

(R)-3a

72

91:9

50:50

6e

4a

-

10

90:10

57:43

7e

4a-S

-

68

90:10

50:50

8

4a

MsOH

63

86:14

50:50

9

4a

(S)-3a

85

93:7

55:45

10

4a

(R)-3a

67

93:7

63:37

11e

-

(S)-3a

N.R.

-

-

12e

-

(R)-3a

N.R.

-

-

a

Reactions were conducted using olefinic diol 1a (0.050 mmol), catalyst (0.005 mmol), acid co-catalyst (0.050 mmol), and NPSP (0.052 mmol) in CH2Cl2 (2 mL) at −78°C for 1 d. b Isolated yield. c Determined using 1H NMR. d Determined using chiral HPLC. e Reaction time was 4 d. N.R. = No Reaction. NPSP = N-phenylselenophthalimide. Utilizing either the Lewis basic sulfide or selenide alone was found to be ineffective in promoting the reaction (Table 1, entries 2 and 3). Conversely, pairing a catalytic amount of triphenylphosphine sulfide with (R)-BINOL-derived chiral phosphoric acid 3a was found to promote the reaction,3,6 affording 2a in 27% yield and 86:14 dr (Table 1, entry 4). Pairing (R)-3a with a softer Lewis base, such as triphenylphosphine selenide, resulted in a higher yield and slightly

enhanced

diastereoselectivity.

However,

both

of

these

cases

returned

no

enantioselectivity (Table 1, entries 4 and 5). Interestingly, when cyclic selenide catalyst 4a was used without a co-catalyst, 2a was obtained in 57:43 er, albeit in low yield of 10% (Table 1, entry 6). Employing cyclic sulfide catalyst 4a-S, the chalcogenide counterpart of 4a, increased the yield of the product 2a, but failed to exhibit any enantioselectivity under similar conditions (Table 1, entry 7). Catalyst 4a was investigated alongside several selected achiral and chiral Brønsted acids (Table 1, entries 8–10). It was found that the involvement of MsOH could enhance the reaction yield but no enantioselectivity was observed (Table 1, entry 8 vs 6). Cooperative catalysis using


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ACS Catalysis

cyclic selenide 4a and (S)-3a gave good yield and diastereoselectivity but only a slight improvement in the enantioselectivity (Table 1, entry 9). In contrast, one equivalent of (R)-3a greatly enhanced enantioselectivity (Table 1, entry 10). Based on these results, pairing the matching enantiomer of the Brønsted acid with the chiral C2-symmetric cyclic selenide appears to be crucial in achieving the selenoetherification in high enantio- and diastereoselectivities. To the best of our knowledge, this is the first example utilizing a chiral pair for asymmetric catalysis with respect to electrophilic selenofunctionalization.7 Control experiments were conducted using one equivalent of either (R)-3a or (S)-3a as the promoter. No desired product 2a was detected after 4 d (Table 1, entries 11 and 12). This further indicated that the enhanced enantioselectivity resulted from a synergistic relationship between the chiral selenide and chiral Brønsted acid. Next, we examined the reaction using a variety of chiral Lewis basic selenide catalysts. A survey on the cyclic selenide catalysts revealed that the addition of a bulky or electronwithdrawing substituent at the 4,4’-position8 of the phenyl ring of 4 had no significant effect on either the enantio- or diastereoselectivities (see SI, Table S2). Subsequently, investigations of 1,1’-BINOL-derived phosphoric acids 3 with a variety of substitutions at the 3,3’-positions revealed that (R)-3h containing anthryl substituents was the optimal co-catalyst. This system enabled 2a to be produced in 33% yield, >99:1 dr and 94:6 er (Table 2, entries 1–7). Increasing the reaction temperature improved reaction rates, but resulted in slightly reduced dr and er (Table 2, entry 8). Based on a plausible catalytic cycle of the selenoetherification reaction (vide infra), the acid co-catalyst should be regenerated after each cycle. Therefore, we postulated that the acid co-catalyst loading could be reduced to a substoichiometric amount and still promote the reaction at a reasonable reaction rate.3 To our


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delight, a loading of 15 mol % Brønsted acid (R)-3h co-catalyst was found to be sufficient in driving the reaction. Reducing the acid loading increased the reaction time; however, this system demonstrated good yield, and diastereo- and enantioselectivity in toluene (Table 2, entry 9).9

Table 2. Optimization of chiral phosphoric acida

entry

(R)-3, R, equiv

temp (oC)

yield (%)b

drc

erd

1

3b, Ph, 1

–78

74

90:10

62:38

2

3c, mesityl, 1

–78

42

96:4

83:17

3

3d, TRIP, 1

–78

42

90:10

61:39

4

3e, 2-naphthyl, 1

–78

36

86:14

70:30

5

3f, 4-Ph-C6H4, 1

–78

8

75:25

52:48

6

3g, Ph3Si, 1

–78

65

70:30

57:43

7

3h, 9-anthryl, 1

–78

33

>99:1

94:6

8

3h, 9-anthryl, 1

–63

95

96:4

90:10

9e

3h, 9-anthryl, 0.15

–63

98

98:2

92:8

a

Reactions were conducted using olefinic diol 1a (0.050 mmol), catalyst 4a (0.005 mmol), (R)-3, and NPSP (0.052 mmol) in toluene:CH2Cl2 (3:1 v/v, 2 mL) for 1 d. b Isolated yield. c Determined using 1H NMR. d Determined using chiral HPLC. e Toluene was used as the solvent and the reaction time was 4 d. TRIP = 2,4,6-triisopropylphenyl.


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ACS Catalysis

2.2 Substrate scope of the asymmetric selenoetherification of olefinic 1,3-diols and synthetic application A range of phenylseleno-functionalized tetrahydrofurans were synthesized from olefinic diols 1 under the optimal conditions (Table 3). Generally, good-to-excellent yields, dr and er, were obtained for the substrates with electron-withdrawing substituents (Table 3, entries 2–10). Particularly, 3-chloro-4-fluorophenyl substituted substrate 1h gave the corresponding cyclized product 2h in >99:1 dr and 98:2 er (entry 8). On the other hand, electron-rich substituted substrates 1k-1m returned good yields and dr but diminished enantioselectivity (entries 11-13), attributed to the enhanced rate of racemization of the seleniranium intermediate.3 While aryl substrates 1n and 1o with ortho-substitutions gave sluggish reaction potentially due to steric hindrance (entries 14 and 15), 2-naphthyl and 2-fluorophenyl substrates 1p and 1q still returned appreciable conversions (entries 16 and 17). Simple alkyl substituent led to good reactivity and dr but diminished enantioselectivity (entry 18). It is noteworthy that similar performance was observed when the reaction was conducted at a 0.5 mmol scale (entry 19). The absolute configuration of the phenylselenyl tetrahydrofuran product 2q was determined to be (3R,5R), based on an X-ray crystallographic study of its 3,5-dinitrobenzoyl ester derivative (Scheme 2).10 The configurations of the other products were assigned analogously. Unfortunately, the reaction was sluggish when using the substrate with a longer carbon backbone.11


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Table 3. Substrate scopea H OH O 4a (10 mol %), (R)-3h (15 mol %) NPSP, toluene OH R -63 oC, 4 d SePh

OH R 1a - m

2a - m b

c

entry substrate, R

yield (%)

dr

erd

1

1a, C6H5

98

98:2

92:8

2

1b, 3-Cl-C6H4

75

96:4

92.5:7.5

3

1c, 4-Cl-C6H4

92

94:6

94.5:5.5

4

1d, 2,4-F2-C6H3

72

97:3

95:5

5

1e, 4-CF3-C6H4

72

91:9

84:16

6

1f, 3-F-C6H4

77

96:4

90:10

7

1g, 4-CF3O-C6H4

96

93:7

81:19

8

1h, 3-Cl-4-F-C6H3

86

>99:1

98:2

9

1i, 3,4-F2-C6H3

64

90:10

97.5:2.5

10

1j, 4-F-3-Me-C6H3

99

95:5

91:9

11

1k, 4-tBu-C6H4

81

97:3

76:24

12

1l, 3-Me-C6H4

85

93:7

83:17

13

1m, 3-MeO-C6H4

86

93:7

64:36

14

1n, 2-Me-C6H4

N.R.

-

-

15

1o, 2-CF3O-C6H4

N.R.

-

-

16

1p, 2-naphthyl

61

90:10

78:22

17

1q, 2-F-C6H4

78

96:4

97:3

18

1r, Me

94

82:18

61:39

19e

1a, C6H5

84

94:6

90:10

a

Reactions were conducted using olefinic diol 1 (0.050 mmol), catalyst 4a (0.005 mmol), (R)3h (0.0075 mmol), and NPSP (0.052 mmol) in toluene at −63°C for 4 days. b Isolated yield. c Determined using 1H NMR. d Determined using chiral HPLC. NPSP = Nphenylselenophthalimide. e Reaction was conducted at 0.5 mmol scale.


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ACS Catalysis

Scheme 2. Derivatization of 2q and X-ray crystallographic analysis of 5 To further demonstrate the synthetic application of 2, the phenylselenoether handle of 2j was successfully derivatized into an aldehyde (Scheme 3). After masking the hydroxyl handle in 2j in the form of benzyl ether, the selenophenyl moiety was oxidized with meta-chloroperoxybenzoic acid (mCPBA) to afford selenoxide 7. Pummerer rearrangement of selenoxide 7 and subsequent treatment of ethanolic sodium hydroxide gave rise to aldehyde 9.12,13 Aldehyde 9 was obtained in 60% yield after the four-step synthetic sequence (2j→6→7→8→9), with no erosion of enantioselectivity.14


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Scheme 3. Conversion of 2j to 9 via Pummerer rearrangement A novel feature of the asymmetric selenoetherification reactions developed in the present study is the matching/mismatching effect exhibited in the co-catalysis. Several experiments were conducted in order to shed light on the mechanistic picture (Table 4). Under optimal conditions, the 4a/(S)-3h catalyst pair exhibited low reaction efficiency and enantioselectivity. This demonstrated the importance of using a matching pair of catalysts in the selenocyclization (Table 4, entries 1 and 2).15 In the other set of experimentation, the hydroxyl groups of 4a were masked in the form of 10. No reaction was observed when 10 mol% of 10 was used in the same selenocyclization reaction (Table 4, entries 1 and 3). This result suggests that the hydroxyl groups of 4a may play a crucial role in promoting the cyclization process with enantioselectivity. The use of Ph3PSe and (R)-3h provided the cyclized product 2a in 60% yield and 88:12 dr but with no enantioselectivity (Table 4, entry 4). This result is similar to the experiments indicated in


12

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ACS Catalysis

Table 1, entries 4 and 5, whereby the utilization of Lewis bases that bear no hydroxyl functionality (triphenylphosphine sulfide and selenide) in conjunction with phosphoric acid (R)3a achieved appreciable conversions but no enantioselectivity. We believe that NPSP might still be activated by the synergistic effect of triphenylphosphine sulfide/selenide and phosphoric acid in the selenocyclization process; Lewis basic triphenylphosphine sulfide/selenide might coordinate to the PhSe moiety in NPSP while phosphoric acid could protonate the phthalimide.3 However, a more complicated system that involve the hydroxyl group in 4a seems necessary to achieve the enantioselective selenoetherification reaction.


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Table 4. Control experimentsa

entry catalyst

acid coyield (%)b catalyst

drc

erd

1

4a

(R)-3h

84

94:6

92:8

2

4a

(S)-3h

and Diastereoselective Selenoetherification through Supramolecular

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