Synlett 2018; 29(04): 433-439
DOI: 10.1055/s-0036-1590951
cluster
© Georg Thieme Verlag Stuttgart · New York

Investigating the Enantiodetermining Step of a Chiral Lewis Base Catalyzed Bromocycloetherification of Privileged Alkenes

Dietrich Böse
,
University of Illinois at Urbana-Champaign, Department of Chemistry, 600 S Mathews Ave., Urbana, IL 61801, USA   Email: sdenmark@illinois.edu
› Author Affiliations
We are grateful to the National Institutes of Health (R01 GM085235) for financial support.
Further Information

Publication History

Received: 19 September 2017

Accepted after revision: 13 October 2017

Publication Date:
13 November 2017 (online)

 


Published as part of the Cluster Alkene Halofunctionalization

Abstract

The development of catalytic, enantioselective halofunctionalizations of unactivated alkenes has made significant progress in recent years. However, the identification of generally applicable catalysts for wide range of substrates has yet to be realized. A detailed understanding of the reaction mechanism is essential to guide the formulation of a truly general catalyst. Herein, we present our investigations on the enantiodetermining step of a Lewis base catalyzed bromocycloetherification that provides important insights and design criteria.


#

Electrophilic functionalization, in particular halofunctionalization of alkenes, is one of the basic reactions in organic synthesis and has developed over the years from simple dihalogenation reactions to substrate-directed diastereoselective reactions and enantioselective halofunctionalisations.[2] However, catalytic, enantioselective variants emerged only in the past few years and the field has attracted significant attention as illustrated the appearance of several review articles in the last few years.[3]

In this context, these laboratories have focused on the development of the concept of Lewis base activation of Lewis acids to effect catalysis with main-group elements.[4] It has been already demonstrated that this concept can serve as a basis for the development of enantioselective Lewis base catalysis, e.g., for electrophilic seleno- and thiofunctionalizations.[5] Further investigations have demonstrated that Lewis bases such as triphenylphosphine sulfide (1), thiophosphoramide 2, and selenophosphoramide 3 act as efficient catalysts for racemic bromo- and iodolactonizations of olefinic acids 4 to stereoselectively form brominated five- and six-membered (5 and 6) lactones via the intermediacy of bromiranium ions i (Scheme [1]).[6] Catalytic, enantioselective bromoetherifications using chiral Brønsted acids have also been achieved.[7]

Zoom Image
Scheme 1 Lewis base catalyzed bromolactonization via bromiranium ion formation

Successful enantioselective halofunctionalizations therefore depend on chemical and configurational stability of haliranium ions. In 2010, work from these laboratories demonstrated that an inverse relationship exists between chemical and stereochemical stability of such haliranium ions.[8] The experiments involved the generation of enantiomerically enriched haliranium ions (chloriranium and bromiranium) by means of solvolysis followed by a nucleophilic trapping. Whereas chloriranium ions show the lowest chemical stability, their enantioselective formation and nucleophilic opening proceeds without loss of enantiomeric purity. With the more stable bromiranium ions an erosion of enantiomeric purity was observed. This is caused by an alkene-to-alkene exchange mechanism as was first demonstrated by Brown.[9] These observations have an important implication for the catalytic formation and capture of these ions. In the case of chloriranium ions the enantioselectivity can be controlled only during their formation. In contrast, reactions involving bromiranium ions may be controlled by either a dynamic asymmetric transformation with a chiral catalyst or by catalyst suppression of racemization to achieve high selectivity control over the overall process.[4a]

Zoom Image
Scheme 2 Chiral tetrahydrothiophene 8 catalyzed enantioselective bromocyclization of 1,3-diols and racemic bromocycloetherification of simple olefinic alcohol 10a using N-bromosuccinimide (NBS) and chloroacetic acid

In 2014 Yeung et al. reported an interesting example of a chiral Lewis base catalyzed enantioselective bromocycloetherification of olefinic 1,3-diols 7 using chiral tetrahydrothiophenes 8 as the catalyst.[10] It was striking that only symmetrical 1,3-diols such as 7 are viable substrates to form cyclic ethers 9 enantio- and diastereoselectively (Scheme [2]). On the basis of the proposed mechanism, there is no reason to expect that simple alcohols such as 10 should not undergo the same transformation.[11] Therefore, we attempted the enantioselective bromocycloetherification of the simple alcohol 10 using catalyst 8 and were surprised to find that this reaction delivered only racemic product 11 (Scheme [2]).

On the basis of these results, it was plausible to argue that the formation of a bromiranium ion might not be the enantiodetermining step of this transformation. Instead, it seems possible that this process might proceed through an enantiotopic group discrimination mechanism, in which the alkoxy hypobromite formation is the stereodetermining first step. This hypobromite then reacts with the olefin intramolecularly, forming a bromiranium ion which is then captured by a nucleophilic attack of one of the alcohol groups. This hypothesis would explain why alcohol 10 cyclizes to the racemic product 11 because an achiral alkoxy hypobromite is formed, thus rendering the following reaction steps unselective.

Zoom Image
Scheme 3 Proposed mechanistic pathways for an enantioselective bromocycloetherification desymmetrization of olefinic 1,3-diols with a enantiotopic group differentiating hypobromite ii formation as the stereodetermining step (pathway A) and an enantioselective bromiranium ion iii formation as the stereodetermining step (pathway B).

To gain insight into the reaction mechanism, racemic, monoprotected alcohol 12 would be subjected to the bromocycloetherification reaction conditions. The goal of this experiment was to distinguish between the two possible reaction mechanisms. In principle, the non-racemic bromocycloetherification can proceed by an enantiotopic group differentiating alkoxy hypobromite formation (pathway A) or by an enantioselective bromiranium ion formation (pathway B) as the stereodetermining step (Scheme [3]).

In the case of an enantioselective bromocycloetherification through a stereodetermining hypobromite formation (pathway A) the first step would set the initial stereogenic center at C-2. The following intramolecular bromiranium ion formation, which sets the stereogenic center at C-4, and intramolecular nucleophilic capture should proceed with high diastereoselectivity as it is observed for diol 7. Thus, an enantioselective formation of alkoxy hypobromite ii would not only set the absolute, but also the relative configuration of 13, this pathway should deliver the product as an enantioenriched single diastereomer at 50% conversion. However, at 100% conversion, diastereomerically enriched but racemic product 13 would be expected (Scheme [3]).

If the bromocycloetherification of alcohol rac-12 is proceeding by an enantioselective bromiranium ion iii formation (Scheme [3], pathway B), then the product mixture of 13 and 14 should be composed of two enantioenriched diastereoisomers. In such case the enantioselectivity would be controlled by the catalyst, whereas the diastereoselectivity would be dictated by the substrate. At this point it is assumed that the similarity of the two functional groups (OH vs. OTBS) and their distance to the newly formed bromiranium ion should lead to low diastereoselection.

The bromocycloetherification of racemic, monoprotected diol rac -12, under the conditions shown in Scheme [4], gave after full conversion a 41:59 mixture of two diastereoisomers (13/14) as determined by 1H NMR analysis.[12] After removal of the TBS group by treatment with TBAF (see Supporting Information for details), the relative and absolute configurations were assigned by comparison of 1H NMR and HPLC data to previous experiments and to previously published results by Yeung et al. [10] [11] Both diastereoisomers 13 and 14 were formed with an enantiomeric ratio of 60:40, which was also determined after the TBS-group cleavage.

Zoom Image
Scheme 4 Mechanistic probe reaction set up to investigate the enantiodetermining step of the Lewis base catalyzed bromocycloetherification

The initial bromiranium ion formation can fundamentally occur with four different rates k1–k4, which define the enantiomeric and diastereomeric outcome of the reaction and are represented by the concentrations of isomers IIV.

Zoom Image
Scheme 5 Mechanistic analysis for an enantioselective bromocycloetherification with stereodetermining bromiranium ion formation (pathway B)

The enantiomeric composition of the diastereoisomers 13 and 14 is then given through: e.r. (13) = k2/k4, and e.r. (14) = k1/k3. The diastereomeric ratio is defined through: d.r. (13/14) = (k2 + k4)/(k1 + k3) (Scheme [5]). Since the starting material is racemic, the sum of isomers I and III should be equal to the sum of isomers II and IV. The concentration of all isomers can be individually calculated by multiplying the enantiomeric ratios with the diastereomeric ratios, respectively, as shown in Table [1].

Table 1 Enantiomeric and Diastereomeric Ratios of the Isomers I-IV

Isomer

e.r.

d.r.

e.r. × d.r.

[I]

0.6

0.59

0.354

[II]

0.4

0.59

0.236

[III]

0.4

0.41

0.164

[IV]

0.6

0.41

0.246

[I] + [III] = 0.354 + 0.164 = 0.518

[II] + [IV] = 0.236 + 0.246 = 0.482

This result shows that the observed ratios are in good agreement (0.52 ≈ 0.48) with a bromocycloetherification mechanism based on an enantioselective bromiranium ion formation (pathway B) as depicted in Scheme [3]. A possible racemization by an olefin-to-olefin interchange of bromiranium ions does not interfere with the drawn conclusions.

Therefore, the hypobromite formation can be ruled out as the productive mechanism for an enantioselective bromocycloetherification via an enantiotopic group discrimination process (pathway A). At the same time, the data provided in Table [1] is in good agreement with an enantioselective bromiranium ion formation (pathway B) as the enantiodetermining step. However, this conclusion still does not provide an explanation for why the simple alcohol 10 does not undergo an enantioselective bromocycloetherification. A possible explanation could be connected to the rate with which the intramolecular nucleophilic attack on the bromiranium ion takes place. If the attack is slower than the racemization of the bromiranium ion by olefin-to-olefin interchange, the product would be a racemic. Therefore, the reason for the observed enantioselectivity for substrate 7, or the lack of thereof in substrate 10, might arise from in the increased rate of cyclization owing to the Thorpe–Ingold effect in substrate 7a.[13] To test this hypothesis, a short substrate survey was conducted with three different simple alcohols 10, 15, and 17 (Scheme [6]).

Zoom Image
Scheme 6 Enantioselective bromocycloetherification of gem-dimethyl-containing olefinic alcohols

In contrast to the primary alcohol 10 which cyclized to form racemic product 1, tertiary alcohol 15 cyclized to form product 16 with an enantiomeric ratio of 64:36. This result further supports pathway B (chiral bromiranium ion formation as the enantiodetermining step) as the primary mechanism. Finally, neopentyl alcohol 17 (containing two methyl groups in the β-position) afforded cyclization product 18 with an enantiomeric ratio of 68:32. These observations clearly underline the fact that the Thorpe–Ingold effect plays a major role for the enantioselectivity of this type of reaction.[13]

Because substrate 17 is clearly viable, an additional optimization of reaction conditions was conducted (see Supporting Information for details). These investigations showed that the reaction conditions employed were indeed suitable for achieving high conversion. In a recent study, Yeung and his group investigated the influence of catalyst structure, temperature, addition sequence of components, catalyst loading, and MsOH additive on the outcome of the bromocycloetherification of olefinic 1,3-diols.[11] However, we also found that the enantioselectivities observed in the bromocycloetherification are strongly dependent on the water content of the solvent used. All experiments described in this study were conducted in dichloromethane freshly taken from a solvent-drying system. However, rigorously dried dichloromethane (using highly activated molecular sieves) led to reduced enantioselectivities. This surprising observation implied an unexpected role for water as the reaction medium, something not accounted for in any mechanistic rationalization.

Therefore, dichloromethane with varying water content was prepared and tested in the enantioselective bromocycloetherification (Table [2]). It was very surprising to find that the highest enantioselectivity was observed with dichloromethane saturated with water. An explanation for this behavior is obscure at this time.

Table 2 Influence of Water Content on the Enantioselectivity of the Lewis Base Catalyzed Bromocycloetherification of 17

Entry

Water content (μg/mL)a

Source

Conversion (%)b

e.r.c

1

   0

dried with 4Å MS

100

53:47

2

   8

fresh from SDS

100

68:32

3

  48

water added

100

68:32

4

 112

water added

100

70:30

5

 416a

commercial bottle

100

74:26

6

1985a

saturated with water

100

74:26

aDetermined by Karl-Fischer titration.

b Determined by 1H-NMR analysis of the crude reaction mixture.

c Determined by CSP-HPLC.

Table 3 Bromocycloetherification of 17 Catalyzed by Chiral Tetrahydrothiophenes

Entry

Catalyst

Conversion (%)a

e.r.b

1

 8

100

74:26

2

19

100

49:51

a Determined by 1H-NMR analysis of the crude reaction mixture.

b Determined by CSP-HPLC.

With the optimal substrate and the optimized reaction conditions in hand a second catalyst survey was conducted (Table [3]).[14] For all further experiments dichloromethane with a water content >500 μg/mL was used.

For these experiments, two different C2 -symmetric tetrahydrothiophenes were tested. These results, together with similar results published by Yeung et al.,[11] clearly indicate that a tetrahydrothiophene core structure alone in the catalyst is not sufficient for an enantioselective reaction. The primary difference between these catalyst structures is the presence of the phenolic ethers in catalyst 8 which is absent in catalyst 19. Thus, it is possible that a second Lewis basic coordinating side in the catalyst's structure is necessary for observable enantioselectivities.

To test this hypothesis, a new family of catalysts was envisioned that could incorporate the additional coordinating group into the structure. Chiral thiophosphoramides and selenophosphoramides were identified as these functional groups proved to be effective catalysts for these types of transformations.[6] To enable introduction of the second coordinating site, a number of bisimidazoline-based catalysts 20 and 21 was prepared in which the bridging carbon could be functionalized with different substituents.

The evaluation of the enantioselective bromocycloetherification of 17 began with thiophosphoramides 20af which were ineffective as Lewis base catalysts for the reaction (Table [4], entries 1–6). All thiophosphoramides 20 gave very low conversions (less than 28%) and none provided any enantioselection.

Table 4 Survey of Seleno- and Thiophosphoramides as Chiral Catalysts

Entry

Catalyst

R1

R2

E

Conversion (%)a

e.r.b

 1

20a (R)

C3H7

CH(CH3)2

S

 22

50:50

 2

20b (R)

C3H7

C2H4OCH3

S

  0

 3

20c (R)

CH2OCH3

CH3

S

 28

50:50

 4

20d (R)

CH2OCH3

CH(CH3)2

S

  0

 5

20e (S)

C4H4OCH3

CH3

S

  0

 6

20f (R)

CH3

–(CH2)5

S

<10

50:50

 7

21a (S)

CH3

CH3

Se

100

49:51

 8

21b (S)

CH3

CH(CH3)2

Se

100

38:62

 9

21c (R)

C3H7

CH3

Se

100

49:51

10

21d (R)

C3H7

CH(CH3)2

Se

100

62:38

11

21e (R)

C3H7

C2H4OCH3

Se

100

52:48

12

21f (R)

CH2OCH3

CH3

Se

100

57:43

13

21g (S)

CH2OCH3

CH(CH3)2

Se

 95

49:51

14

21h (S)

CH2OCH3

(R)-CH(CH3)Ph

Se

100

49:51

15

21i (S)

CH2OCH3

(S)-CH(CH3)Ph

Se

100

47:53

16

21k (R)

C2H4OCH3

CH3

Se

100

41:59

17

21l (R)

C2H4OCH3

CH(CH3)2

Se

100

21:79

a Determined by 1H-NMR analysis of the crude reaction mixture.

b Determined by CSP-HPLC.

Next, chiral selenophosphoramides 21al were investigated. The selenophosphoramides were considerably more effective catalysts than the thiophosphoramides and led to a clean and full conversion in almost all cases. Additionally, several catalysts showed moderate to good enantioselectivities. The results obtained with catalysts 21a vs. 21c and 21b vs. 21d (Table [4], entries 7–10) clearly show that the steric effect of the groups attached to the backbone of the catalysts (i.e., methyl vs. propyl) did not play a critical role for the reactivity or enantioselectivity. On the other hand, the steric effect of the groups attached to the external nitrogen (methyl vs. isopropyl, Table [4], entries 16 and 17) does have a major influence on the enantioselectivity. This trend is visible with almost all catalysts explored in this study. Most interestingly, catalysts 21k and 21l, with a methoxyethyl group attached to the backbone, afforded the highest selectivities, while maintaining very high reactivity. These results clearly support the hypothesis that an additional coordination side in the structure of the catalysts plays an important role for the stabilization of the intermediate bromiranium ions, preventing them from a racemization via an olefin-to-olefin transfer as shown in Scheme [7]. However, we cannot rule out the possibility of a dynamic, kinetic asymmetric transformation in which the catalyst–bromiranium ion assembly undergoes equilibration, though if that were operative, then enantioselectivity should be observed with substrate 10.

Zoom Image
Scheme 7 Mechanistic rationale for a suppressed olefin-to-olefin isomerization through a stabilization of the intermediate bromiranium ion by a Lewis base catalyst with an additional coordination side in the catalyst´s structure

In conclusion, we have shown that bromiranium ion formation is most likely the enantiodetermining step in the Lewis base catalyzed enantioselective bromocycloetherification of Yeung’s substrate 7. We have also been able to identify that fast nucleophilic attack on the bromiranium ion and the presence of water is the key for high enantiomeric ratios observed. Two possible strategies to overcome the intrinsic low configurational stability of bromiranium ions were identified. First the Thorpe–Ingold effect, which leads to an increased cyclization rate, can be applied to achieve modest enantioselectivities. Second, stabilization of the bromiranium ion through an additional donating group in the catalyst's structure can effectively suppress the olefin-to-olefin interchange racemization. To our knowledge this strategy has so far not been explored in other designed catalysts, even if first examples of bifunctional Lewis base catalysts have been already published.[15] So far neither strategy alone is effective enough to provide good enantioselectivities. It is hoped that the mechanistic insights presented here will influence the future development of a truly rationally designed and general Lewis base catalyst which is capable of effecting a broad spectrum of enantioselective halofunctionalizations of unactivated olefins.


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Supporting Information

  • References and Notes

  • 1 New current address: Dietrich Böse, Boehringer Ingelheim RCV GmbH & Co KG, Dr.-Boehringer-Gasse 5-11, 1121 Vienna, Austria; e-mail: dietrich.boese@boehringer-ingelheim.com.
    • 2a Dowle MD. Davies DI. Chem. Soc. Rev. 1979; 8: 171
    • 2b Chen G. Ma S. Angew. Chem. Int. Ed. 2010; 49: 8306
    • 2c Murai K. Matsushita T. Nakamura A. Fukushima S. Shimura M. Fujioka H. Angew. Chem. Int. Ed. 2010; 49: 9174
    • 2d Nakatsuji H. Sawamura Y. Sakakura A. Ishihara K. Angew. Chem. Int. Ed. 2014; 53: 6974
    • 2e Hennecke U. Müller CH. Fröhlich R. Org. Lett. 2011; 13: 860
    • 3a French AN. Bissmire S. Wirth T. Chem. Soc. Rev. 2004; 33: 354
    • 3b Snyder SA. Treitler DS. Brucks AP. Aldrichimica Acta 2011; 44: 27
    • 3c Hennecke U. Chem. Asian J. 2012; 7: 456
    • 3d Tan CK. Zhou L. Yeung Y.-Y. Synlett 2011; 1335
    • 3e Gieuw MH. Ke Z. Yeung Y.-Y. Chem. Rec. 2017; 17: 287
    • 4a Denmark SE. Kuester WE. Burk MT. Angew. Chem. Int. Ed. 2012; 51: 10938
    • 4b Beutner GL. Denmark SE. In Inventing Reactions . Vol. 44. Goossen LJ. 2013: 55
    • 5a Denmark SE. Chi HM. J. Am. Chem. Soc. 2014; 136: 3655
    • 5b Denmark SE. Eklov BM. Yao PJ. Eastgate MD. J. Am. Chem. Soc. 2009; 131: 11770
    • 5c Denmark SE. Jaunet A. J. Am. Chem. Soc. 2013; 135: 6419
    • 5d Denmark SE. Jaunet A. J. Org. Chem. 2014; 79: 140
  • 6 Denmark SE. Burk MT. Proc. Nat. Acad. Sci. 2010; 107: 20655
  • 7 Denmark SE. Burk MT. Org. Lett. 2012; 14: 256
  • 8 Denmark SE. Burk MT. Hoover AJ. J. Am. Chem. Soc. 2010; 132: 1232
    • 9a Brown RS. Nagorski RW. Bennet AJ. McClung RE. D. Aarts GH. M. Klobukowski M. McDonald R. Santarsiero BD. J. Am. Chem. Soc. 1994; 116: 2448
    • 9b Neverov AA. Brown RS. J. Org. Chem. 1996; 61: 962
    • 9c Brown RS. Acc. Chem. Res. 1997; 30: 131
  • 10 Ke Z. Tan CK. Chen F. Yeung Y.-Y. J. Am. Chem. Soc. 2014; 136: 5627
  • 11 Ke Z. Tan CK. Liu Y. Lee KG. Z. Yeung Y.-Y. Tetrahedron 2016; 72: 2683
  • 12 Experimental Procedures: Enantioselective Bromocycloetherification of 2-{[(tert-butyldimethylsilyl)oxy] methyl}-4-phenylpent-4-en-1-ol (12) A stock solution of 2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-phenylpent-4-en-1-ol (rac-12) (30 mg/1.0 mL) in CH2Cl2 was added (1.0 mL, 0.1 mmol) to cyclic sulfide 8 (0.01 mmol, 0.1 equiv) in a septum sealed sample vial at 20 °C. The solution was cooled to –78 °C, and a second stock solution of chloroacetic acid in CH2Cl2 (0.1 M, 1.0 mL, 0.1 mmol, 1.0 equiv) was added. After 10 min at this temperature a stock solution of NBS (0.1 M, 1.0 mL, 0.10 mmol, 1.0 equiv) was slowly added. After 13 h 1 mL of a stock solution of NaBH4 in EtOH (50 mg/5 mL) was added. Then the reaction was slowly warmed to 0 °C (over approx. 2 h). Then 1 mL of H2O and 1 mL of hexanes (HPLC grade) were added, and the mixture was stirred at 20 °C for 15 min. After phase separation, the organic phase was filtered through a plug of MgSO4 and Celite and evaporated using a stream of nitrogen. The residue was dissolved in CDCl3 and a 1H NMR spectrum was collected to estimate conversion and product distribution. The diastereomeric ratio was found to be 13/14 = 41:59. Then the products were dissolved in THF (2 mL) at 20 °C and TBAF was added (95 mg, 0.3 mmol, 3.0 equiv). The reaction was stirred at 20 °C until full conversion was observed by TLC analysis (hexanes/EtOAc, 90:10). After 2.5 h 10 mL of diethyl ether were added, and the mixture was washed with sat. aq NH4Cl solution (1 × 10 mL). The organic layer was dried over MgSO4, filtered, and evaporated. Purification by column chromatography (hexanes/EtOAc, 90:10) yielded the pure products as a diastereomeric mixture. HPLC analysis revealed that both diastereoisomers were formed with an enantiomeric ratio of 60:40
  • 13 Jung ME. Piizzi G. Chem. Rev. 2005; 105: 1735
  • 14 For all screening experiments CH2Cl2 with a water content of >500 μg/mL was applied. A stock solution (0.12 M) of 2,2-dimethyl-4-phenylpent-4-en-1-ol (17) in CH2Cl2 (0.25 mL, 0.03 mmol) was added to the indicated Lewis base (0.003 mmol, 0.1 equiv) in a septum-sealed sample vial at 20 °C. The solution was cooled to –78 °C, and a second stock solution of chloroacetic acid (CAA) in CH2Cl2 (0.12 M, 0.25 mL, 0.03 mmol, 1.0 equiv) was added. After 10 min at this temperature a stock solution of NBS (0.12 M, 0.25 mL, 0.03 mmol, 1.0 equiv) was slowly added. After 18 h 1 mL of a stock solution of NaBH4 in EtOH (50 mg/5 mL) was added. Then the reaction was slowly warmed to 0 °C (over approx. 2 h). Then 1 ml of H2O and 1 mL of hexanes (HPLC grade) were added, and the mixture was stirred at 20 °C for 15 min. After phase separation, the organic phase was filtered through a plug of MgSO4 and Celite and evaporated using a stream of nitrogen. The residue was dissolved in CDCl3 and a 1H NMR spectrum was collected to estimate conversion and product distribution (d.r.). HPLC analysis was used to establish the enantioselectivities. HPLC: 18 t R = 8.2 min; ent-18 t R = 8.8 min (Chiralcel OJH, hexanes/2-propanol; 99:01, 0.4 mL/min, 220 nm, 20 °C). 1H NMR (500 MHz, CDCl3): δ = 0.89 (s, 3 H), 1.21 (s, 3 H, 1′′-H), 2.25 (d, J = 12.8 Hz, 1 H, 3-Ha), 2.35 (d, J = 12.8 Hz, 1 H, 3-Hb), 3.63 (s, 2 H, 1′-H), 3.66 (d, J = 8.2 Hz, 1 H, 5-Ha), 3.82 (d, J = 8.3 Hz, 1 H, 5-Hb), 7.24–7.33 (m, 1 H), 7.37 (dd, J = 8.6, 6.9 Hz, 2 H), 7.43–7.48 (m, 2 H, PhH). 13C NMR (125 MHz, CDCl3): δ = 27.0, 27.1, 40.8, 43.5, 51.9, 80.6, 86.0, 125.7, 127.3, 128.3, 144.7.
  • 15 Yu S.-N. Li Y.-L. Deng J. Adv. Synth. Catal. 2017; 359: 2499

  • References and Notes

  • 1 New current address: Dietrich Böse, Boehringer Ingelheim RCV GmbH & Co KG, Dr.-Boehringer-Gasse 5-11, 1121 Vienna, Austria; e-mail: dietrich.boese@boehringer-ingelheim.com.
    • 2a Dowle MD. Davies DI. Chem. Soc. Rev. 1979; 8: 171
    • 2b Chen G. Ma S. Angew. Chem. Int. Ed. 2010; 49: 8306
    • 2c Murai K. Matsushita T. Nakamura A. Fukushima S. Shimura M. Fujioka H. Angew. Chem. Int. Ed. 2010; 49: 9174
    • 2d Nakatsuji H. Sawamura Y. Sakakura A. Ishihara K. Angew. Chem. Int. Ed. 2014; 53: 6974
    • 2e Hennecke U. Müller CH. Fröhlich R. Org. Lett. 2011; 13: 860
    • 3a French AN. Bissmire S. Wirth T. Chem. Soc. Rev. 2004; 33: 354
    • 3b Snyder SA. Treitler DS. Brucks AP. Aldrichimica Acta 2011; 44: 27
    • 3c Hennecke U. Chem. Asian J. 2012; 7: 456
    • 3d Tan CK. Zhou L. Yeung Y.-Y. Synlett 2011; 1335
    • 3e Gieuw MH. Ke Z. Yeung Y.-Y. Chem. Rec. 2017; 17: 287
    • 4a Denmark SE. Kuester WE. Burk MT. Angew. Chem. Int. Ed. 2012; 51: 10938
    • 4b Beutner GL. Denmark SE. In Inventing Reactions . Vol. 44. Goossen LJ. 2013: 55
    • 5a Denmark SE. Chi HM. J. Am. Chem. Soc. 2014; 136: 3655
    • 5b Denmark SE. Eklov BM. Yao PJ. Eastgate MD. J. Am. Chem. Soc. 2009; 131: 11770
    • 5c Denmark SE. Jaunet A. J. Am. Chem. Soc. 2013; 135: 6419
    • 5d Denmark SE. Jaunet A. J. Org. Chem. 2014; 79: 140
  • 6 Denmark SE. Burk MT. Proc. Nat. Acad. Sci. 2010; 107: 20655
  • 7 Denmark SE. Burk MT. Org. Lett. 2012; 14: 256
  • 8 Denmark SE. Burk MT. Hoover AJ. J. Am. Chem. Soc. 2010; 132: 1232
    • 9a Brown RS. Nagorski RW. Bennet AJ. McClung RE. D. Aarts GH. M. Klobukowski M. McDonald R. Santarsiero BD. J. Am. Chem. Soc. 1994; 116: 2448
    • 9b Neverov AA. Brown RS. J. Org. Chem. 1996; 61: 962
    • 9c Brown RS. Acc. Chem. Res. 1997; 30: 131
  • 10 Ke Z. Tan CK. Chen F. Yeung Y.-Y. J. Am. Chem. Soc. 2014; 136: 5627
  • 11 Ke Z. Tan CK. Liu Y. Lee KG. Z. Yeung Y.-Y. Tetrahedron 2016; 72: 2683
  • 12 Experimental Procedures: Enantioselective Bromocycloetherification of 2-{[(tert-butyldimethylsilyl)oxy] methyl}-4-phenylpent-4-en-1-ol (12) A stock solution of 2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-phenylpent-4-en-1-ol (rac-12) (30 mg/1.0 mL) in CH2Cl2 was added (1.0 mL, 0.1 mmol) to cyclic sulfide 8 (0.01 mmol, 0.1 equiv) in a septum sealed sample vial at 20 °C. The solution was cooled to –78 °C, and a second stock solution of chloroacetic acid in CH2Cl2 (0.1 M, 1.0 mL, 0.1 mmol, 1.0 equiv) was added. After 10 min at this temperature a stock solution of NBS (0.1 M, 1.0 mL, 0.10 mmol, 1.0 equiv) was slowly added. After 13 h 1 mL of a stock solution of NaBH4 in EtOH (50 mg/5 mL) was added. Then the reaction was slowly warmed to 0 °C (over approx. 2 h). Then 1 mL of H2O and 1 mL of hexanes (HPLC grade) were added, and the mixture was stirred at 20 °C for 15 min. After phase separation, the organic phase was filtered through a plug of MgSO4 and Celite and evaporated using a stream of nitrogen. The residue was dissolved in CDCl3 and a 1H NMR spectrum was collected to estimate conversion and product distribution. The diastereomeric ratio was found to be 13/14 = 41:59. Then the products were dissolved in THF (2 mL) at 20 °C and TBAF was added (95 mg, 0.3 mmol, 3.0 equiv). The reaction was stirred at 20 °C until full conversion was observed by TLC analysis (hexanes/EtOAc, 90:10). After 2.5 h 10 mL of diethyl ether were added, and the mixture was washed with sat. aq NH4Cl solution (1 × 10 mL). The organic layer was dried over MgSO4, filtered, and evaporated. Purification by column chromatography (hexanes/EtOAc, 90:10) yielded the pure products as a diastereomeric mixture. HPLC analysis revealed that both diastereoisomers were formed with an enantiomeric ratio of 60:40
  • 13 Jung ME. Piizzi G. Chem. Rev. 2005; 105: 1735
  • 14 For all screening experiments CH2Cl2 with a water content of >500 μg/mL was applied. A stock solution (0.12 M) of 2,2-dimethyl-4-phenylpent-4-en-1-ol (17) in CH2Cl2 (0.25 mL, 0.03 mmol) was added to the indicated Lewis base (0.003 mmol, 0.1 equiv) in a septum-sealed sample vial at 20 °C. The solution was cooled to –78 °C, and a second stock solution of chloroacetic acid (CAA) in CH2Cl2 (0.12 M, 0.25 mL, 0.03 mmol, 1.0 equiv) was added. After 10 min at this temperature a stock solution of NBS (0.12 M, 0.25 mL, 0.03 mmol, 1.0 equiv) was slowly added. After 18 h 1 mL of a stock solution of NaBH4 in EtOH (50 mg/5 mL) was added. Then the reaction was slowly warmed to 0 °C (over approx. 2 h). Then 1 ml of H2O and 1 mL of hexanes (HPLC grade) were added, and the mixture was stirred at 20 °C for 15 min. After phase separation, the organic phase was filtered through a plug of MgSO4 and Celite and evaporated using a stream of nitrogen. The residue was dissolved in CDCl3 and a 1H NMR spectrum was collected to estimate conversion and product distribution (d.r.). HPLC analysis was used to establish the enantioselectivities. HPLC: 18 t R = 8.2 min; ent-18 t R = 8.8 min (Chiralcel OJH, hexanes/2-propanol; 99:01, 0.4 mL/min, 220 nm, 20 °C). 1H NMR (500 MHz, CDCl3): δ = 0.89 (s, 3 H), 1.21 (s, 3 H, 1′′-H), 2.25 (d, J = 12.8 Hz, 1 H, 3-Ha), 2.35 (d, J = 12.8 Hz, 1 H, 3-Hb), 3.63 (s, 2 H, 1′-H), 3.66 (d, J = 8.2 Hz, 1 H, 5-Ha), 3.82 (d, J = 8.3 Hz, 1 H, 5-Hb), 7.24–7.33 (m, 1 H), 7.37 (dd, J = 8.6, 6.9 Hz, 2 H), 7.43–7.48 (m, 2 H, PhH). 13C NMR (125 MHz, CDCl3): δ = 27.0, 27.1, 40.8, 43.5, 51.9, 80.6, 86.0, 125.7, 127.3, 128.3, 144.7.
  • 15 Yu S.-N. Li Y.-L. Deng J. Adv. Synth. Catal. 2017; 359: 2499

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Scheme 1 Lewis base catalyzed bromolactonization via bromiranium ion formation
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Scheme 2 Chiral tetrahydrothiophene 8 catalyzed enantioselective bromocyclization of 1,3-diols and racemic bromocycloetherification of simple olefinic alcohol 10a using N-bromosuccinimide (NBS) and chloroacetic acid
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Scheme 3 Proposed mechanistic pathways for an enantioselective bromocycloetherification desymmetrization of olefinic 1,3-diols with a enantiotopic group differentiating hypobromite ii formation as the stereodetermining step (pathway A) and an enantioselective bromiranium ion iii formation as the stereodetermining step (pathway B).
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Scheme 4 Mechanistic probe reaction set up to investigate the enantiodetermining step of the Lewis base catalyzed bromocycloetherification
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Scheme 5 Mechanistic analysis for an enantioselective bromocycloetherification with stereodetermining bromiranium ion formation (pathway B)
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Scheme 6 Enantioselective bromocycloetherification of gem-dimethyl-containing olefinic alcohols
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Scheme 7 Mechanistic rationale for a suppressed olefin-to-olefin isomerization through a stabilization of the intermediate bromiranium ion by a Lewis base catalyst with an additional coordination side in the catalyst´s structure