Brønsted Base Catalyzed Conjugate Addition of β-Acylvinyl Anion Equivalents to α,β-Unsaturated Ketones

Abstract

A Brønsted base catalyzed addition reaction of allyl sulfones having a diethoxyphosphoryloxy group, which are new precursors of β-acylvinyl anion equivalents, with α,β-unsaturated ketones was developed. The reaction proceeded efficiently under the influence of a phosphazene base as the catalyst. This is a rare example of a catalytic addition reaction of β-acylvinyl anion equivalents. A preliminary study on an asymmetric variant was also conducted with a chiral bis(guanidino)iminophosphorane catalyst.

Carbon–carbon bond-forming reactions using umpolung carbanions and their equivalents as nucleophiles are powerful tools for the construction of complex molecular structures that are otherwise difficult to access. Both an acyl anion and a homoenolate are representative umpolung carbanions (Figure [1]). The fact that the application of these carbanions and their equivalents to reactions with various electrophiles has been intensively studied for several decades emphasizes the importance of the strategy utilizing the inversion of the innate reactivity of a functional group, namely, umpolung, in organic synthesis.[1] [2] On the other hand, a β-acylvinyl anion is also an umpolung carbanion. The carbon–carbon bond-forming reactions of the equivalent of this carbanion permit the direct introduction of a versatile enone unit into a molecule used as an electrophile. However, the reactions of β-acylvinyl anions have been sparsely studied.[3] In particular, to the best of our knowledge, the catalytic generation of β-acylvinyl anions and their equivalents under the influence of a Brønsted base and their application to carbon–carbon bond-forming reactions as nucleophiles have never been pursued.[4]

We have previously developed a Brønsted base catalyzed addition reaction of homoenolate equivalents in which allylic alcohols having a diethoxyphosphoryl group at the α-position are used as precursors of homoenolate equivalents (Scheme [1a]).[5] In the reaction, α-oxygenated allyl anions, generated through deprotonation and a subsequent [1,2]-phospha-Brook rearrangement,[6] react with electrophiles at the γ-position to provide alkenyl phosphates. The adducts are then converted by solvolysis into ketones, which are the formal adducts of homoenolates with electrophiles. We envisioned that a methodology involving the regioselective addition of α-oxygenated allyl anion might be applicable to the development of a catalytic addition of β-acylvinyl anion equivalents. Specifically, we expected that the addition reaction of α-oxygenated allyl anions having a leaving group as a γ-substituent would provide adducts that are convertible into the formal adducts of β-acylvinyl anion equivalents through solvolysis (Scheme [1b]). Based on this concept, allyl sulfone 1 having a diethoxyphosphoryloxy group was designed as a new precursor of a β-acylvinyl anion equivalent. We report herein a Brønsted base catalyzed conjugate addition of allyl sulfones 1 to α,β-unsaturated ketones 2 (Scheme [1c]). In this report, the conversion of the adducts into enones and the preliminary results of the investigation of asymmetric addition are also described.

We began our investigation by screening the reaction conditions for the conjugate addition reaction of the allyl sulfone 1a as an initial pronucleophile with chalcone (2a). Treatment of 1a with 2a in the presence of 10 mol% P2-tBu (pK _BH ⁺ = 21.5 in DMSO)[7] in toluene at room temperature for three hours resulted in the formation of the desired adduct 3aa in 91% NMR yield as a mixture of diastereomers (dr = 65:35) (Table [1], entry 1). Screening of Brønsted bases revealed that a high basicity of the catalyst is essential to promote the reaction (entries 2–5). The reaction with Brønsted bases having higher basicity than P2-tBu, such as P4-tBu (pK _BH ⁺ = 30.3), tBuOK, or KHMDS, proceeded smoothly to provide 3aa in comparable yields to that given by P2-tBu (entries 2–4). In contrast, the use of less-basic P1-tBu (pK _BH ⁺ = 15.7) resulted in the recovery of 1a (entry 5). As regards solvents, various types of solvents were applicable, although THF was less effective than the other solvents tested (entries 6–9). Finally, the yield of 3aa was slightly improved by increasing the reaction concentration from 0.1 M to 0.2 M, giving 3aa in 92% isolated yield (entry 10).[8]

Table 1 Screening of Reaction Conditions^a

Entry	Base	Solvent	Yieldb of 3aa (dr)
1	P2-tBu	toluene	91% (65:35)
2	P4-tBu	toluene	87% (60:40)
3	tBuOK	toluene	80% (69:31)
4	KHMDS	toluene	84% (63:37)
5	P1-tBu	toluene	<1% (–)
6	P2-tBu	DMF	83% (62:38)
7	P2-tBu	CH3CN	90% (60:40)
8	P2-tBu	THF	56% (73:27)
9	P2-tBu	Et2O	88% (64:36)
10c	P2-tBu	toluene	94%d (55:45)

^a Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), base (0.01 mmol), solvent (1.0 mL), rt, 3 h.

^b Yields are based on ¹H NMR analysis of the crude reaction mixture, unless otherwise noted. 1,3-Benzodioxole was used as an internal standard. The diastereomeric ratio was determined by ¹H NMR analysis of the crude reaction mixture.

^c Toluene (0.50 mL).

^d 92% isolated yield.

With the optimized conditions in hand, we investigate the substrate scope. First, allyl sulfones 1 having various aryl groups at the γ-position were tested (Scheme [2]). The reaction of ortho- and para-tolyl-substituted 1b and 1e proceeded without any problem to provide the corresponding adducts 3ba and 3ea in good yields. Allyl sulfones 1c and 1d having an electron-donating methoxy group and an electron-withdrawing chloro group, respectively, at the ortho-position both underwent the reaction smoothly to give the corresponding products 3ca and 3da in good yields. In contrast, the reactivity of allyl sulfones 1f and 1g having a methoxy group and a chloro group, respectively, at the para-position was found to be rather low, although the reason for this is not clear at this stage. In the case of 1f, the yield of 3fa increased on changing the solvent from toluene to DMF. On the other hand, 1g did not undergo the reaction even after screening of catalysts and solvents. In this case, the starting material 1g was recovered. 2-Furyl-substituted 1h was applicable to this reaction, providing 3ha in 78% isolated yield.

Next, the scope of the α,β-unsaturated ketones was screened (Scheme [3]). Chalcone derivatives 2b–h having various aryl groups on the carbonyl carbon or at the β-position gave the corresponding adducts in moderate to good yields. In addition, 2i, possessing an alkyl substituent at the β-position, and cyclic enones 2j and 2k were found to be suitable electrophiles, and the corresponding products were obtained in high yields. On the other hand, the use of α,β-unsaturated esters resulted in no reaction.

The transformation of the adducts into enones was then examined. Treatment of 3aa with sodium ethoxide in ethanol, which was found to be suitable for the cleavage of the diethoxyphosphoryl group in our previous study, resulted in the formation of a complex mixture of products, presumably because of the instability of 3aa and/or the products under the highly basic conditions. On the other hand, a combination of KF and ethanol was found to be effective in affording the desired enone. Specifically, treatment of 3aa with five equivalents of KF in ethanol at 40 °C provided the (E)-enone 4 in 73% yield (Scheme [4]).[9]

Finally, a catalytic enantioselective addition of 1a was attempted. In this study, the chiral bis(guanidino)iminophosphorane (M)-5, which was developed by our group,[10] was chosen as a chiral Brønsted base catalyst, as it possesses high basicity relative to P2-tBu.[11] After a brief screening of reaction conditions and electrophiles, the reaction of 1a with α,β-unsaturated acylimidazole 6 was found to proceed with moderate enantioselectivity (Scheme [5]).[12] [13] Although a further improvement of the stereoselectivity is required, this preliminary result demonstrates a good potential for the development of catalytic enantioselective reactions with the newly developed β-acylvinyl anion equivalents.

In conclusion, we have developed a catalytic addition reaction of allyl sulfones having a diethoxyphosphoryloxy group, which are new precursors of β-acylvinyl anion equivalents, with α,β-unsaturated ketones by using phosphazene base P2-tBu as a Brønsted base catalyst. This is a rare example of a catalytic addition reaction of a β-acylvinyl anion equivalent. A preliminary study with a chiral bis(guanidino)iminophosphorane catalyst suggested the good potential of the newly developed methodology in asymmetric synthesis.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes


For selected reviews on umpolung reactivity, see:
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• 8 Diethyl (1Z)-6-Oxo-1,4,6-triphenyl-3-(phenylsulfonyl)hex-1-en-1-yl phosphate (1aa): Typical Procedure for the Brønsted Base Catalyzed Addition of Allyl Sulfones 1 to Chalcone Derivatives 2nChalcone (2a, 25 mg, 0.12 mmol) and a 2.0 M solution of P2-tBu in THF (5.0 μL, 0.010 mmol) were sequentially added to a solution of 1a (41 mg, 0.10 mmol) in toluene (0.50 mL), and the mixture was stirred at rt for 3 h. The reaction was quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude mixture was purified by column chromatography [silica gel, hexane–EtOAc (1:1)] to give a yellow oil; yield: 57 mg (0.092 mmol, 92%; dr = 55:45).nIR (ATR): 2981, 1681, 1594, 1448, 1273, 1141, 1087, 1080, 1022, 975, 744, 690 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 0.98 (td, J = 7.2, 0.6 Hz, 3 H), 1.15 (td, J = 7.2, 0.6 Hz, 3 H), 3.51 (dd, J = 17.4, 9.0 Hz, 1 H), 3.58–3.93 (m, 4 H), 3.96 (dd, J = 17.4, 4.8 Hz, 1 H), 4.43 (m, 1 H), 4.96 (dd, J = 10.8, 6.6 Hz, 1 H), 5.72 (dd, J = 10.8, 1.2 Hz, 1 H), 7.19–7.57 (m, 16 H), 7.78 (d, J = 7.2 Hz, 2 H), 7.91 (d, J = 7.2 Hz, 2 H); δ (minor diastereomer) = 0.96 (td, J = 7.2, 0.6 Hz, 3 H), 1.17 (td, J = 7.2, 0.6 Hz, 3 H), 3.58–3.93 (m, 5 H), 4.06 (dd, J = 17.4, 5.4 Hz, 1 H), 4.56 (m, 1 H), 4.92 (dd, J = 10.8, 6.6 Hz, 1 H), 5.14 (dd, J = 10.8, 1.2 Hz, 1 H), 6.96 (d, J = 7.2 Hz, 2 H), 7.14 (t, J = 7.2 Hz, 1 H), 7.19–7.57 (m, 12 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 2 H), 7.97 (d, J = 7.2 Hz, 2 H).¹³C NMR (150 MHz, CDCl₃): δ = 15.70 (d, J = 7.2 Hz), 15.75 (d, J = 7.2 Hz), 15.9 (d, J = 7.2 Hz), 39.4, 40.1, 42.0, 43.8, 64.4 (d, J = 5.7 Hz), 64.6 (d, J = 5.7 Hz), 65.7, 67.3, 107.3 (d, J = 7.2 Hz), 108.9 (d, J = 7.2 Hz), 125.9, 126.9, 127.1, 128.06, 128.08, 128.12, 128.2, 128.3, 128.37, 128.41, 128.6, 128.7, 129.3, 129.4, 129.6, 132.86, 132.94, 133.2, 133.3, 134.2, 134.3, 136.8, 136.9, 138.8, 139.1, 139.8, 141.3, 150.6 (d, J = 8.6 Hz), 151.8 (d, J = 8.7 Hz), 197.5, 197.6; ³¹P NMR (243 MHz, CDCl₃): δ (major diastereomer) = –6.8; δ (minor diastereomer) = –6.5; HRMS (ESI): m/z [M⁺] calcd for C₃₄H₃₅O₇PS: 618.1841; found 618.1841.
• 9 (2E)-1,4,6-Triphenylhex-2-ene-1,6-dionenTo a flask containing KF (15 mg, 0.25 mmol) was added a solution of 3aa (31 mg, 0.050 mmol) in EtOH (0.5 mL). The resulting mixture was warmed to 40 °C, stirred for 17 h, and then cooled to rt. The reaction was quenched with sat. aq NH₄Cl, and the product was extracted with CH₂Cl₂. The combined organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude mixture was purified by column chromatography [silica gel, hexane–EtOAc (4:1)] to give a white solid: 13 mg (0.037 mmol, 73%); mp 139.0–141.0 °C.nIR (ATR): 3082, 3059, 3025, 2883, 1678, 1668, 1611, 1488, 1448, 1371, 1252, 1187, 1001, 748, 697 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 3.52 (dd, J = 17.4, 6.0 Hz, 1 H), 3.58 (dd, J = 17.4, 7.8 Hz, 1 H), 4.43 (ddd, J = 7.8, 7.2, 6.0 Hz, 1 H), 6.88 (dd, J = 15.0, 1.2 Hz, 1 H), 7.21 (dd, J = 15.0, 7.2 Hz, 1 H), 7.24–7.27 (m, 1 H), 7.31–7.36 (m, 4 H), 7.44 (dd, J = 7.8, 7.8 Hz, 2 H), 7.47 (dd, J = 7.8, 7.8 Hz, 2 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.85 (dd, J = 7.8, 1.8 Hz, 2 H), 7.95 (dd, J = 7.8, 1.2 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 44.4, 45.5, 64.1, 64.6, 109.7, 124.6, 125.7, 126.6, 127.7, 128.1, 128.2, 128.4, 128.6, 128.7, 132.5, 138.0, 142.4, 142.9, 153.1, 191.3. HRMS (ESI): m/z [M⁺] calcd for C₂₄H₂₀O₂: 340.1463; found: 340.1463.
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• 12 Diethyl (1Z)-4-Methyl-6-(1-methyl-1H-imidazol-2-yl)-6-oxo-1-phenyl-3-(phenylsulfonyl)hex-1-en-1-yl phosphate (7)nA 0.50 M solution of KHMDS in toluene (40 μL, 0.020 mmol), 1a (41 mg, 0.10 mmol), and 6 (18 mg, 0.12 mmol) were sequentially added at one-minute intervals to a solution of (M)-5·HCl (10 mg, 0.011 mmol) in toluene (1.0 mL), and the mixture was stirred for 1 h at rt. The reaction was then quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was initially purified by column chromatography [silica gel, hexane–EtOAc (1:2 to 1:3)] then further purified by preparative HPLC to give the major diastereomer as a yellow oil; yield: 36 mg (0.065 mmol, 65%; dr 94:6; 56% ee); [α]_D ²².⁰ +20.9 (c 1.82, CHCl₃).HPLC: DAICEL Chiralcel OD-3, 2.1 × 150 mm (hexane–i-PrOH, 85:15, 1.0 mL/min, λ = 254 nm, 30 °C): T _r = 12.7 min (major), 14.5 min (minor). IR (ATR): 2971, 1680, 1443, 1410, 1258, 1145, 1013, 980, 912, 724, 693 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 1.13 (t, J = 7.2 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H), 1.19 (d, J = 6.0 Hz, 3 H), 3.34–3.41 (m, 2 H), 3.69–3.74 (m, 1 H), 3.81–3.97 (m, 4 H), 3.99 (s, 3 H), 4.51 (dd, J = 10.8, 3.0 Hz, 1 H), 5.68 (d, J = 10.8 Hz, 1 H), 7.02 (s, 1 H), 7.12 (s, 1 H), 7.32–7.37 (m, 5 H), 7.51 (dd, J = 7.8, 7.8 Hz, 2 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ (major diastereomer) = 15.88 (d, J = 5.7 Hz), 15.90 (d, J = 7.2 Hz), 19.8, 28.6, 36.1, 41.7, 64.4 (d, J = 5.9 Hz), 64.6 (d, J = 5.7 Hz), 66.5, 106.5 (d, J = 7.2 Hz), 126.1, 126.9, 128.3, 128.7, 128.87, 128.93, 129.5, 133.3, 134.3, 139.0, 143.1, 152.3 (d, J = 8.7 Hz), 190.8. ³¹P NMR (243 MHz, CDCl₃): δ (major diastereomer) = 6.5; δ (minor diastereomer) = 6.6. HRMS (ESI): m/z [M⁺] calcd for C₂₇H₃₃N₂O₇PS: 560.1746; found: 560.1744.
• 13 The reaction of 1a with 2a was attempted, but 3aa was obtained in only a low enantiomeric excess (~20% ee).

Corresponding Author

Publication History

Received: 27 January 2022

Accepted after revision: 16 April 2022

Accepted Manuscript online:
16 April 2022

Article published online:
09 June 2022

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• References and Notes


For selected reviews on umpolung reactivity, see:
• 1a Seebach D. Angew. Chem. Int. Ed. 1979; 18: 239
  CrossrefSearch in Google Scholar
• 1b Enders D, Niemeier O, Henseler A. Chem. Rev. 2007; 107: 5606
  CrossrefPubMedSearch in Google Scholar
• 1c Bugaut X, Glorius F. Chem. Soc. Rev. 2012; 41: 3511
  CrossrefPubMedSearch in Google Scholar
• 1d Flanigan DM, Romanov-Michailidis F, White NA, Rovis T. Chem. Rev. 2015; 115: 9307
  CrossrefPubMedSearch in Google Scholar
• 2a Brehme R, Enders D, Fernandez R, Lassaletta JM. Eur. J. Org. Chem. 2007; 5629
  Crossref
• 2b Hoppe D. Synthesis 2009; 43
  Thieme Connect
• 2c Nithiy N, Rosa D, Orellana A. Synthesis 2013; 45: 3199
  Thieme ConnectSearch in Google Scholar
• 2d Menon RS, Biju AT, Nair V. Chem. Soc. Rev. 2015; 44: 5040
  CrossrefPubMedSearch in Google Scholar
• 2e Nikolaev A, Orellana A. Synthesis 2016; 48: 1741
  Thieme ConnectSearch in Google Scholar
• 2f Ohmiya H. ACS Catal 2020; 10: 6862
  CrossrefSearch in Google Scholar

For a review, see:
• 3a Chinchailla R, Nájera C. Chem. Rev. 2000; 100: 1891 For selected examples, see
  CrossrefPubMedSearch in Google Scholar
• 3b Katritzky AR, Manju K, Gramova AV, Steel PJ. J. Org. Chem. 2004; 69: 6018
  CrossrefPubMedSearch in Google Scholar
• 3c Sasaki M, Takeda K. Org. Lett. 2004; 6: 4849
  CrossrefPubMedSearch in Google Scholar
• 3d Lechuga-Eduardo H, Zarza-Acuña E, Romero-Ortega M. Tetrahedron Lett. 2017; 58: 3234
  CrossrefSearch in Google Scholar

For examples of NHC catalysis, see:
• 4a Fischer C, Smith SW, Powell DA, Fu GC. J. Am. Chem. Soc. 2006; 128: 1472
  CrossrefPubMedSearch in Google Scholar
• 4b Wu Y, Yao W, Pan L, Zhang Y, Ma C. Org. Lett. 2010; 12: 640
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  CrossrefPubMedSearch in Google Scholar
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• 7 Schwesinger R, Schlemper H, Hasenfratz C, Willaredt J, Dambacher T, Breuer T, Ottaway C, Fletschinger M, Boele J, Fritz H, Putzas D, Rotter HW, Boldwell FG, Satish AV, Ji G.-Z, Peters EM, Peters K, von Schnering HG, Walz L. Liebigs Ann. 1996; 1055
  Crossref
• 8 Diethyl (1Z)-6-Oxo-1,4,6-triphenyl-3-(phenylsulfonyl)hex-1-en-1-yl phosphate (1aa): Typical Procedure for the Brønsted Base Catalyzed Addition of Allyl Sulfones 1 to Chalcone Derivatives 2nChalcone (2a, 25 mg, 0.12 mmol) and a 2.0 M solution of P2-tBu in THF (5.0 μL, 0.010 mmol) were sequentially added to a solution of 1a (41 mg, 0.10 mmol) in toluene (0.50 mL), and the mixture was stirred at rt for 3 h. The reaction was quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude mixture was purified by column chromatography [silica gel, hexane–EtOAc (1:1)] to give a yellow oil; yield: 57 mg (0.092 mmol, 92%; dr = 55:45).nIR (ATR): 2981, 1681, 1594, 1448, 1273, 1141, 1087, 1080, 1022, 975, 744, 690 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 0.98 (td, J = 7.2, 0.6 Hz, 3 H), 1.15 (td, J = 7.2, 0.6 Hz, 3 H), 3.51 (dd, J = 17.4, 9.0 Hz, 1 H), 3.58–3.93 (m, 4 H), 3.96 (dd, J = 17.4, 4.8 Hz, 1 H), 4.43 (m, 1 H), 4.96 (dd, J = 10.8, 6.6 Hz, 1 H), 5.72 (dd, J = 10.8, 1.2 Hz, 1 H), 7.19–7.57 (m, 16 H), 7.78 (d, J = 7.2 Hz, 2 H), 7.91 (d, J = 7.2 Hz, 2 H); δ (minor diastereomer) = 0.96 (td, J = 7.2, 0.6 Hz, 3 H), 1.17 (td, J = 7.2, 0.6 Hz, 3 H), 3.58–3.93 (m, 5 H), 4.06 (dd, J = 17.4, 5.4 Hz, 1 H), 4.56 (m, 1 H), 4.92 (dd, J = 10.8, 6.6 Hz, 1 H), 5.14 (dd, J = 10.8, 1.2 Hz, 1 H), 6.96 (d, J = 7.2 Hz, 2 H), 7.14 (t, J = 7.2 Hz, 1 H), 7.19–7.57 (m, 12 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 2 H), 7.97 (d, J = 7.2 Hz, 2 H).¹³C NMR (150 MHz, CDCl₃): δ = 15.70 (d, J = 7.2 Hz), 15.75 (d, J = 7.2 Hz), 15.9 (d, J = 7.2 Hz), 39.4, 40.1, 42.0, 43.8, 64.4 (d, J = 5.7 Hz), 64.6 (d, J = 5.7 Hz), 65.7, 67.3, 107.3 (d, J = 7.2 Hz), 108.9 (d, J = 7.2 Hz), 125.9, 126.9, 127.1, 128.06, 128.08, 128.12, 128.2, 128.3, 128.37, 128.41, 128.6, 128.7, 129.3, 129.4, 129.6, 132.86, 132.94, 133.2, 133.3, 134.2, 134.3, 136.8, 136.9, 138.8, 139.1, 139.8, 141.3, 150.6 (d, J = 8.6 Hz), 151.8 (d, J = 8.7 Hz), 197.5, 197.6; ³¹P NMR (243 MHz, CDCl₃): δ (major diastereomer) = –6.8; δ (minor diastereomer) = –6.5; HRMS (ESI): m/z [M⁺] calcd for C₃₄H₃₅O₇PS: 618.1841; found 618.1841.
• 9 (2E)-1,4,6-Triphenylhex-2-ene-1,6-dionenTo a flask containing KF (15 mg, 0.25 mmol) was added a solution of 3aa (31 mg, 0.050 mmol) in EtOH (0.5 mL). The resulting mixture was warmed to 40 °C, stirred for 17 h, and then cooled to rt. The reaction was quenched with sat. aq NH₄Cl, and the product was extracted with CH₂Cl₂. The combined organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude mixture was purified by column chromatography [silica gel, hexane–EtOAc (4:1)] to give a white solid: 13 mg (0.037 mmol, 73%); mp 139.0–141.0 °C.nIR (ATR): 3082, 3059, 3025, 2883, 1678, 1668, 1611, 1488, 1448, 1371, 1252, 1187, 1001, 748, 697 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 3.52 (dd, J = 17.4, 6.0 Hz, 1 H), 3.58 (dd, J = 17.4, 7.8 Hz, 1 H), 4.43 (ddd, J = 7.8, 7.2, 6.0 Hz, 1 H), 6.88 (dd, J = 15.0, 1.2 Hz, 1 H), 7.21 (dd, J = 15.0, 7.2 Hz, 1 H), 7.24–7.27 (m, 1 H), 7.31–7.36 (m, 4 H), 7.44 (dd, J = 7.8, 7.8 Hz, 2 H), 7.47 (dd, J = 7.8, 7.8 Hz, 2 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.85 (dd, J = 7.8, 1.8 Hz, 2 H), 7.95 (dd, J = 7.8, 1.2 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 44.4, 45.5, 64.1, 64.6, 109.7, 124.6, 125.7, 126.6, 127.7, 128.1, 128.2, 128.4, 128.6, 128.7, 132.5, 138.0, 142.4, 142.9, 153.1, 191.3. HRMS (ESI): m/z [M⁺] calcd for C₂₄H₂₀O₂: 340.1463; found: 340.1463.
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• 11 The pK _BH ⁺ of an achiral bis(guanidino)iminophosphorane possessing a backbone similar to (M)-5 was reported to be 26.8 in THF, see: Kolomeitsev, A. A; Koppel, I. A.; Rodima, T.; Barten, J.; Lork, E.; Röschenthaler, G.-V.; Kaljurand, I.; Kütt, A.; Koppel, I.; Mäemets, V.; Leito, I. J. Am. Chem. Soc. 2005, 127, 17656.
• 12 Diethyl (1Z)-4-Methyl-6-(1-methyl-1H-imidazol-2-yl)-6-oxo-1-phenyl-3-(phenylsulfonyl)hex-1-en-1-yl phosphate (7)nA 0.50 M solution of KHMDS in toluene (40 μL, 0.020 mmol), 1a (41 mg, 0.10 mmol), and 6 (18 mg, 0.12 mmol) were sequentially added at one-minute intervals to a solution of (M)-5·HCl (10 mg, 0.011 mmol) in toluene (1.0 mL), and the mixture was stirred for 1 h at rt. The reaction was then quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was initially purified by column chromatography [silica gel, hexane–EtOAc (1:2 to 1:3)] then further purified by preparative HPLC to give the major diastereomer as a yellow oil; yield: 36 mg (0.065 mmol, 65%; dr 94:6; 56% ee); [α]_D ²².⁰ +20.9 (c 1.82, CHCl₃).HPLC: DAICEL Chiralcel OD-3, 2.1 × 150 mm (hexane–i-PrOH, 85:15, 1.0 mL/min, λ = 254 nm, 30 °C): T _r = 12.7 min (major), 14.5 min (minor). IR (ATR): 2971, 1680, 1443, 1410, 1258, 1145, 1013, 980, 912, 724, 693 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 1.13 (t, J = 7.2 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H), 1.19 (d, J = 6.0 Hz, 3 H), 3.34–3.41 (m, 2 H), 3.69–3.74 (m, 1 H), 3.81–3.97 (m, 4 H), 3.99 (s, 3 H), 4.51 (dd, J = 10.8, 3.0 Hz, 1 H), 5.68 (d, J = 10.8 Hz, 1 H), 7.02 (s, 1 H), 7.12 (s, 1 H), 7.32–7.37 (m, 5 H), 7.51 (dd, J = 7.8, 7.8 Hz, 2 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ (major diastereomer) = 15.88 (d, J = 5.7 Hz), 15.90 (d, J = 7.2 Hz), 19.8, 28.6, 36.1, 41.7, 64.4 (d, J = 5.9 Hz), 64.6 (d, J = 5.7 Hz), 66.5, 106.5 (d, J = 7.2 Hz), 126.1, 126.9, 128.3, 128.7, 128.87, 128.93, 129.5, 133.3, 134.3, 139.0, 143.1, 152.3 (d, J = 8.7 Hz), 190.8. ³¹P NMR (243 MHz, CDCl₃): δ (major diastereomer) = 6.5; δ (minor diastereomer) = 6.6. HRMS (ESI): m/z [M⁺] calcd for C₂₇H₃₃N₂O₇PS: 560.1746; found: 560.1744.
• 13 The reaction of 1a with 2a was attempted, but 3aa was obtained in only a low enantiomeric excess (~20% ee).

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