Diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres

Tetrahedron: Asymmetry 23 (2012) 1633–1639

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Diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres Takehiro Yamagishi a,⇑, Atsushi Kinbara a, Noriko Okubo a, Shunpei Sato a, Haruhiko Fukaya b a b

School of Pharmacy, Ohu University, 31-1 Tomita-machi, Misumidou, Kooriyama, Fukushima 963-8611, Japan School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 31 August 2012 Accepted 25 October 2012

The diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres in protected form was achieved by starting from optically active 1,1-diethoxyethyl(aminomethyl)phosphinate. Our methodology involves diastereoselective a-alkylation and b0 -alkylation of phosphinate derivatives with an asymmetric center at the phosphorus atom. Ó 2012 Elsevier Ltd. All rights reserved.

1. Introduction Several studies have demonstrated that the synthesis of peptides with phosphinyl dipeptide isosteres (PDIs) 1 can be a very effective approach for the development of highly potent and selective inhibitors of aspartic proteases and Zn metalloproteases (Fig. 1).1 PDIs contain the metabolically stable phosphinic moiety, NH2XaaW[P(O)OHCH2]XaaOH, which mimics the tetrahedral transition state of a scissile peptide bond during enzymatic hydrolysis. The stereochemistry of PDIs significantly affects their biological activities and the peptide derivatives of 1, which possess stereochemistry analogous to dipeptides composed of natural Lamino acids and which show relatively good inhibitory activity compared to those of other diastereomers.2 Recent studies of zinc metalloprotease inhibitors by Dive et al. have reported that the stereochemistry at the b0 -position of PDIs influences the inhibitor’s ability to discriminate between each protease enzyme. Thus, peptides containing 1 caused the inhibition of angiotensin-converting enzyme (ACE), endothelin-converting enzyme-1 (ECE-1), and neprilysin (NEP), while peptides derived from diastereomer 10 were dual inhibitors of ACE and ECE-1, but did not inhibit NEP.3

Therefore, isomers 1 and 10 needed to be prepared in order to investigate protease inhibitors. Proline amino acid mimetics (Pro-Xaa type PDIs) have shown utility in medicinal chemistry. The Pro-Phe PDIs have been developed as potent and selective inhibitors of angiotensin-converting enzyme 2 (ACE2),4 and as a useful scaffold for protease inhibitor development because of their restricted conformation that minimizes entropy upon enzyme binding, which can enhance activity.5 However, a lack of reliable synthetic methods6 and a review of the literature revealed that Pro-Xaa type PDIs have not been prepared in a stereocontrolled manner. Herein we focus on a concise, stereoselective synthesis of Pro-Phe PDI 2 and its diastereomer 20 (Fig. 2).

O N H

P O OH Bn 2

O OH

N H

P O

OH OH Bn 2'

Figure 2. Structure of Pro-Phe PDIs 2 and 20 .

R1 H2N

P O

PDIs

R1

O OH OH R2

H2N

O P

O

1

OH OH R2 1'

Figure 1. Structures of PDIs 1 and 10 .

⇑ Corresponding author. Tel./fax: +81 24 932 9212. E-mail address: [email protected] (T. Yamagishi). 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2012.10.019

Racemic PDIs were successfully prepared in protected form 7 in a highly stereocontrolled manner starting from ethyl 1,1-diethoxyethyl(aminomethyl)phosphinate 37,8 (Scheme 1). In this method, the a-substituent (R1) of the PDI was introduced via stereoselective alkylation of the phosphorus-stabilized carbanion generated from 3.7,9 The b0 -substituent (R2) was also incorporated stereoselectively via alkylation of the lithium enolates generated from 6, which was prepared via conversion of 4 into the stereodefined H-phosphinate 5 and its stereospecific Michael reaction with tert-butyl acrylate.8 This method involved tight control of the two stereogenic centers at the a- and b0 -positions under the influence of the phosphorus chirality. The preparation of optically active 3 with an asymmetric

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O

Ph N

P

Ph

R1

LHMDS R1X

Me OEt

N

OEt

OEt

O

Ph

P

Ph

1

R

R

1

O PG

N H

O O

P

H

PG

N H

P

OEt 5

O-t-Bu

OEt 6

PG=Ts, Trs R1

LHMDS R2X

OEt

OEt OEt dr: up to 10:1

4

3

Me

O O

PG

N H

P

O-t-Bu R2

OEt

PG=Ts; R1=R 2=Bn; dr=4.0:1

7

PG=Trs; R1=R 2=Bn; dr=21:1

Scheme 1. Stereocontrolled synthesis of racemic PDIs in protected form.

center at the phosphorus atom was accomplished using the requisite chiral building block leading to PDIs with defined absolute configuration, via resolution with (S)-phenylethylamine10 or the lipase-catalyzed acyl transfer reaction of 1,1-diethoxyethyl(hydroxymethyl)phosphinate.11 In an effort to extend the scope of this synthetic methodology to PDIs, optically active Pro-Phe PDIs were synthesized in protected form. Herein we report the details of our investigation.

ever, the formation of the desired alkylation product did not occur, and starting material (RP)-3 was recovered (entry 1). When the reaction temperature was increased from 78 to 20 °C, (RP)-3 disappeared within 6 h, as verified by TLC, affording products (RP)-14 and (RP)-140 in 66% yield in a ratio of 5.7:1 (entry 2). When the reaction was conducted at 0 °C, the reaction time decreased from 6 to 3 h, giving (RP)-14 and (RP)-140 in 66% yield with a ratio of 6.0:1 (entry 3). Reaction at room temperature resulted in a decrease in the diastereomeric ratio (entry 4). In studies on alkylation reactions of lithium enolates, LiCl has proven to be a useful additive for enhancing reactivity and influencing diastereoselectivity by changing the aggregated states.13 When a similar a-alkylation of (RP)-3 was attempted using LiCl as an additive at 0 °C, the selectivity was slightly improved to 7.1:1, although the chemical yield decreased to 46% (entry 5). Although the product (RP)-14 was obtained as a mixture with the minor isomer (RP)-140 , the corresponding alcohol (RP)-15, prepared by desilylation with TBAF, could be isolated by silica gel column chromatography. X-ray crystallographic analysis of one of the diastereomers, racemic 15 was performed (Fig. 3), which revealed the relative stereochemistry of optically active (RP)-15. Table 1 a-Alkylation of (RP)-3 with 13 LHMDS I O

Ph

2. Results and discussion

N

P

Ph

The P-chiral (RP)-3 was readily prepared from racemic 1,1-diethoxyethyl(hydroxymethyl)phosphinate 8 according to a previously reported procedure (Scheme 2).11 Treatment of 8 with isopropenyl acetate in the presence of lipase AK (Pseudomonas fluorescens) and molecular sieves 3 Å (MS 3 Å) in hexane at room temperature afforded acetate (SP)-9 and alcohol (RP)-8 in 50% and 40% yields, respectively. A good enantiomeric ratio (E) was observed (E = 82) with (SP)-9 obtained with 88% ee while (RP)-8 was obtained with excellent enantiomeric purity (99% ee). After (RP)-8 was converted into tosylate (RP)-10, treatment with benzylamine at 80 °C under solvent-free conditions afforded (RP)-11. Hydrogenolytic removal of the benzyl group followed by formation of the imine with benzophenone furnished (RP)-3. O Me HO

OEt

O a

OEt

P

AcO

OEt

8

Me

O OEt

P OEt

+

HO

OEt

50% (88% ee)

(RP)- 8

O

b TsO

O

Me

P

c OEt

BnHN

OEt

OEt

OEt

O d

H 2N

P OEt (R P)-12

OEt OEt

(RP)- 11

(RP)-10 Me OEt OEt

e

O

Ph N Ph

P OEt

TBAF (92%)

a

Me

P

Me OEt OEt

(R P)-3

Scheme 2. Preparation of (RP)-3. Reagents and conditions: (a) isopropenyl acetate, lipase AK, MS 3 Å, hexane, rt, 19 h; (b) TsCl, Et3N, CH2Cl2, rt, 90%; (c) BnNH2, 80 °C, 75%; (d) H2, Pd(OH)2-C, MeOH, rt, 97%; (e) Ph2CO, toluene, reflux, 77%.

With the requisite chiral building block (RP)-3 in hand, its aalkylation with electrophile 13 was examined (Table 1). After treatment of (RP)-3 with LHMDS in THF at 78 °C, the resulting carbanion was treated with 1312 at the same temperature. How-

O N

Ph

b

40% (99% ee)

THF

OR

OEt

(R P)- 8

(S P)-9

E=82

OEt OEt

OEt

Ph

OEt

OEt

13

(RP)-3

Me

P

OTBDPS

Me

c

OR

Me

P OEt

OEt

N

+

OEt

Ph

(RP)-14

: R=TBDPS

(RP)-15

: R=H

Entry

Temp (°C)

1 2 3 4 5c

78 78 to 20 78 to 0 78 to rt 78 to 0

O

Ph

TBAF

P OEt (RP)-14'

Me OEt OEt : R=TBDPS

(RP)-15' : R=H

Time (h)

Yielda (%)

1 6 3 1 3

0 66 66 80 46

Dr (14:140 )b — 5.7:1 6.0:1 2.4:1 7.1:1

Combined yield of (RP)-14 and (RP)-140 . Determined by 31P NMR (121 MHz, CDCl3) analysis of the crude products. 2 equiv of LiCl was used as an additive.

The stereoselectivity in the present a-alkylation can be produced through the anion intermediate A bearing a planar sp2 carbanionic carbon,14 in which the lithium atom is coordinated with a phosphinyl oxygen and a nitrogen atom (Fig. 4). The approach of the electrophile from the side of the 1,1-diethoxyethyl group was hindered by this bulky moiety, therefore, access to the electrophile occurred preferentially from the opposite side of the 1,1diethoxyethyl group to give (RP)-14 as the product, which is consistent with a previously proposed model.7 After establishing good conditions for the a-alkylation of (RP)-3 and verifying the product stereochemistry, the conversion of (RP)15 into the target molecule was attempted (Scheme 3). Hydrogenolysis of (RP)-15 with 10% Pd–C followed by tosylation of the resulting amine in the presence of pyridine gave N-tosyl amide (RP)-16. After transformation into mesylate (RP)-17, it was exposed to K2CO3 in DMF at room temperature, causing cyclization that proceeded to give pyrrolidine (RP)-18 in 92% yield. Removal of

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Figure 3. ORTEP drawing of racemic 15.

Li

Ph R

Ph O N

O Me

Ph N

Me

R-I

OEt OEt

OEt

R-I

OEt EtO

P

Ph

OEt

(RP)-14

H A

R=TBDPSO(CH2)3

Figure 4. Proposed model for diastereoselectivity in the alkylation of (RP)-3.

OH

OH

O Me

Ph N Ph

P

O

a,b OEt

Ts

OEt

OEt

N H

Me

P OEt

(RP)-15

OEt OEt

(R P)-16 OMs O Me

O Me

c Ts

N H

P

d OEt

OEt OEt

N

P

Ts

OEt OEt

(R P)- 17

adduct (SP)-20 in 95% yield. Upon treatment of (SP)-20 with LHMDS (3 equiv) and then benzyl bromide (3 equiv) in THF at 78 °C, b0 alkylation occurred to give (SP)-21 and (SP)-210 in 81% yield. The diastereoselectivity ratio was determined to be 1:4.8 by 31P NMR analysis of the crude products, while the inversed stereoselection favoring the formation of (SP)-210 was observed as compared with the b0 -benzylation of NH-tosyl amide 6 (4.0:1 diastereoselectivity, Scheme 1).8 When product (SP)-210 was treated with LHMDS and then D2O at 78 °C, deuterium incorporation was not observed. This result indicated that the b0 -alkylation of (SP)-20 might not be accompanied by the abstraction of an a-proton. Stereochemical assignment of (SP)-210 based upon NMR spectra and X-ray analysis, was attempted, but was unsuccessful. To confirm the relative configuration and find a possible selective synthesis of the corresponding diastereomer, the preparation of one of the diastereomers, racemic 21 was examined. As shown in Scheme 1, the diastereoselective b0 -alkylation of the lithium enolate generated from compound 6 bearing an acidic NH proton was already established, giving product 7 whose stereochemistry had also been established. Thus, b0 -alkylation of the related compound, followed by pyrrolidine construction, should lead to 21 with a defined relative configuration. Transformation of the racemic alcohol 16 into TBDPS ether 22, which was subjected to deprotection of the 1,1-diethoxyethyl moiety with TMSCl and EtOH, gave H-phosphinate 23 in 71% yield (Scheme 4). When 23 was treated with t-butyl acrylate in the presence of t-BuOMgBr, the desired Michael reaction proceeded sluggishly to afford adduct 24 in low yield (33%) and the recovery of 23. A sluggish reaction was also observed in the b0 -alkylation of 24 with LHMDS and benzyl bromide, giving 25 in poor yield (20%) although producing relatively good diastereoselectivity (5.7:1). While the exact reason for the low yield in these steps remains unclear, it might be due to the bulky TBDPS group of the substrates hindering their reactivity. Removal of the silyl group with TBAF furnished alcohol 26, which was converted into pyrrolidine 21 through sequential mesylation and cyclization with the N-tosyl amide moiety. The 1H and 31P NMR spectra of 21 were consistent with those of the minor isomer (SP)-21 prepared in Scheme 3, but not the major isomer (SP)-210 . Thus, the diastereoselection in the b0 -alkylation of (SP)-20 was different from those of substrates 6 and 24 bearing an acidic NH proton. The reason for this inverse stereochemical outcome is currently under investigation. Although the sequence shown in Scheme 4

OEt OR O

(R P)-18 Ts O

O e

N

P

Ts

N

OEt

P

O N Ts

O O-t-Bu

+

Bn

N Ts

(SP)-21

OEt

N H

H

OTBDPS O

d

O-t-Bu

O Ts

N H

P

OEt

Bn

O-t-Bu Bn

OEt 25

24

dr=5.7:1

OH

(SP)-21:(SP)-21'=1:4.8

O

O O

the 1,1-diethoxyethyl moiety by TMSCl and EtOH15 gave H-phosphinate (SP)-19, which underwent Michael addition to t-butyl acrylate in the presence of t-BuOMgBr as a basic reagent,16 affording

P 23

P

(SP)-21'

Scheme 3. Preparation of (SP)-21 from (RP)-15. Reagents and conditions: (a) H2, Pd–C, MeOH, rt; (b) TsCl, pyridine, CH2Cl2, rt, 62% for two steps; (c) MsCl, Et3N, CH2Cl2, rt, 86%; (d) K2CO3, DMF, rt, 92%; (e) TMSCl, EtOH, CH2Cl2, rt, 84%; (f) tBuOMgBr, t-butyl acrylate, THF, 0 °C, 95%; (g) LHMDS, BnBr, THF, 78 °C, 81%.

N H

OEt

O

O-t-Bu

0

Ts

OEt

OTBDPS O Ts

P

b OEt

22 : R=TBDPS

c

O

P OEt

a

(SP)-20

O

O

16 : R=H

O-t-Bu

OEt

Ts

P OEt

O

f

H

(S P)-19

g

N H

OTBDPS

Me

Ts

N H

P OEt 26

O

f,g

e O-t-Bu Bn

N

P

Ts

OEt

O-t-Bu Bn

21

Scheme 4. Preparation of racemic 21 from 16. Reagents and conditions: (a) TBDPSCl, imidazole, DMF, rt, 98%; (b) TMSCl, EtOH, CH2Cl2, rt, 71%; (c) t-BuOMgBr, t-butyl acrylate, THF, 0 °C, 33%; (d) LHMDS, BnBr, THF, 78 °C, 20%; (e) TBAF, THF, rt, 84%; (f) MsCl, Et3N, CH2Cl2, rt; (g) K2CO3, DMF, rt, 46% for two steps.

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needs further optimization, it might be useful for the diastereoselective synthesis of optically active (SP)-21. 3. Conclusions In conclusion, a new method for the preparation of optically active Pro-Phe PDIs in a protected form has been developed; optically active Pro-Phe PDIs have not been prepared in a diastereoselective manner. Our method relied upon the diastereoselective a-alkylation of optically active 1,1-diethoxyethyl(aminomethyl)phosphinate to construct a pyrrolidine moiety, and b0 -alkylation utilizing an asymmetric center at the phosphorus atom. The other diastereomer of the Pro-Phe PDIs derivative could be selectively prepared as a racemate through a procedure involving b0 -alkylation and subsequent pyrrolidine formation. The synthesis of their peptide derivatives and their evaluation as protease inhibitors are under investigation. 4. Experimental All melting points were obtained on a Yanagimoto micro-melting point apparatus and are uncorrected. IR spectra were recorded on a JASCO FTIR-4100 instrument. Optical rotations were measured with a JASCO P-1020 polarimeter. Mass spectra were measured on a JEOL JMS-MS700 V instrument by FAB+. X-ray crystal data were collected by a Mac-Science DIP Image plate diffractometer. NMR spectra were obtained on a JEOL JNM-AL300 instrument. The chemical shift data for each signal on 1H NMR are given in units of d relative to CHCl3 (d = 7.26) for CDCl3 solution. For 13C NMR spectra, the chemical shifts in CDCl3 are recorded relative to the CDCl3 resonance (d = 77.0). The chemical shifts of 31P are recorded relative to external 85% H3PO4 (d = 0) with broad-band 1H decoupling. 4.1. (1R,RP)-Ethyl 1,1-diethoxyethyl{1-[(diphenylmethylene)amino]4-tert-butyl(diphenyl)silyloxybutyl}phosphinate (RP)-14 and (1S,RP)isomer (RP)-140 To a stirred solution of (RP)-3 (201 mg, 0.50 mmol), prepared according to our previously reported method,11 in THF (1.5 mL) was added a 1.0 M THF solution of LHMDS (0.75 mL, 0.75 mmol) at 78 °C. After stirring for 30 min at the same temperature, a solution of 13 (318 mg, 0.75 mmol) in THF (1 mL) was added to the mixture and stirred for 3 h at 0 °C. The mixture was diluted with aqueous saturated NH4Cl solution and extracted with Et2O. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/AcOEt = 5:1 to 1:1) to give a mixture of (RP)-14 and (RP)-140 (231 mg, 66%) in a ratio of 6.0:1. Pale yellow oil; 1H NMR (300 MHz, CDCl3) d: 7.64–7.25 (20H, m), 4.31–4.16 (2H, m), 3.96–3.85 (1H, m), 3.75–3.55 (6H, m), 2.22–2.12 (2H, m), 1.76–1.66 (1H, m), 1.58 (3H, d, J = 11.0 Hz), 1.41–1.30 (1H, m), 1.26 (3H, t, J = 7.1 Hz), 1.14 (3H, t, J = 7.0 Hz), 1.13 (3H, t, J = 7.0 Hz), 1.02 (9H, s); 31P NMR (122 MHz, CDCl3) d: 41.76 (major isomer), 42.34 (minor isomer); IR (neat) 1109, 1028 cm1; MS m/z 700 (MH+); HRMS calcd for C41H55NO5PSi: 700.3587 (MH+). Found: 700.3569. 4.2. (1R,RP)-Ethyl 1,1-diethoxyethyl{1-[(diphenylmethylene)amino]4-hydroxybutyl}phosphinate (RP)-15 and (1S,RP)-isomer (RP)-150 To a solution of the mixture of (RP)-14 and (RP)-140 (5.90 g, 8.40 mmol) in THF (25 mL) was added a 1.0 M THF solution of TBAF (16.8 mL, 16.8 mmol) at 0 °C and the mixture was stirred for 3 h at room temperature. The mixture was poured into H2O and

extracted with AcOEt. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/ AcOEt = 1:1 to CHCl3/AcOEt = 1:5) to give (RP)-15 (3.06 g, 79%) and (RP)-150 (494 mg, 13%). (RP)-15: White crystals; mp 87– 1 90 °C; ½a27 D ¼ þ29:25 (c 0.18, CHCl3); H NMR (300 MHz, CDCl3) d: 7.64–7.27 (10H, m), 4.31–4.16 (2H, m), 3.97 (1H, dt, J = 3.8, 9.5 Hz), 3.76–3.53 (6H, m), 2.20–2.12 (2H, m), 1.78–1.64 (1H, m), 1.59 (3H, d, J = 11.2 Hz), 1.52–1.37 (1H, m), 1.33 (3H, t, J = 7.0 Hz), 1.17 (3H, t, J = 7.0 Hz), 1.15 (3H, t, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) d: 139.4–128.0 (aromatic), 102.2 (d, JCP = 134.2 Hz), 63.1 (d, JCP = 96.3 Hz), 62.3, 62.1 (d, JCP = 7.4 Hz), 57.8 (2 carbons), 30.1 (d, JCP = 11.8 Hz), 26.9, 20.8 (d, JCP = 11.8 Hz), 16.7 (d, JCP = 5.0 Hz), 15.5, 15.2; 31P NMR (122 MHz, CDCl3) d: 42.16; IR (neat) 3386, 1158, 1024 cm1; MS m/z 462 (MH+); HRMS calcd for C25H37NO5P: 462.2409 (MH+). Found: 462.2407. (RP)-150 : 1 Pale yellow oil; ½a27 D ¼ 16:4 (c 0.21, CHCl3); H NMR (300 MHz, CDCl3) d: 7.67–7.23 (10H, m), 4.27–4.18 (2H, m), 4.02 (1H, dt, J = 2.2, 6.3 Hz), 3.77–3.50 (6H, m), 2.20–2.10 (2H, m), 1.68–1.56 (1H, m), 1.42–1.32 (1H, m), 1.36 (3H, d, J = 11.0 Hz), 1.27 (3H, t, J = 7.0 Hz), 1.11 (3H, t, J = 7.1 Hz), 1.06 (3H, t, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3) d: 139.2–127.9 (aromatic), 101.7 (d, JCP = 136.7 Hz), 62.2 (d, JCP = 7.4 Hz), 62.1, 61.0 (d, JCP = 94.4 Hz), 58.3 (d, JCP = 4.3 Hz), 57.4 (d, JCP = 6.8 Hz), 29.9 (d, JCP = 12.4 Hz), 27.0, 20.4 (d, JCP = 11.8 Hz), 16.8 (d, JCP = 5.0 Hz), 15.3, 15.1; 31P NMR (122 MHz, CDCl3) d: 42.61; IR (neat) 3381, 1151, 1027 cm1; MS m/z 462 (MH+); HRMS calcd for C25H37NO5P: 462.2409 (MH+). Found: 462.2407. 4.3. (1R⁄,RP⁄)-Ethyl 1,1-diethoxyethyl{1-[(diphenylmethylene)amino]4-hydroxybutyl}phosphinate 15 Colorless plates; mp 90–91 °C. The 1H NMR spectrum was identical to that of (RP)-15. Crystallographic data (excluding structure factors) for the structures herein have been deposited with Cambridge Crystallographic Data Center as supplementary publication numbers CCDC 882508. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: [email protected]). 4.4. (1R,RP)-Ethyl 1,1-diethoxyethyl(1-{[(4-methylphenyl)sulfonyl] amino}-4-hydroxybutyl)phosphinate (RP)-16 To a solution of (RP)-15 (797 mg, 1.72 mmol) in MeOH (30 mL) was added 10% Pd–C (103 mg) and stirred for 12 h at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated to give a residue. To a solution of this residue in CH2Cl2 (2.4 mL) were added pyridine (0.14 mL, 1.72 mmol) and a solution of TsCl (295 mg, 1.55 mmol) in CH2Cl2 (2.4 mL) at 0 °C and the mixture was stirred for 12 h at room temperature. The mixture was poured into H2O and extracted with CHCl3. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/AcOEt = 1:1 to CHCl3/MeOH = 40:1) to give (RP)-16 1 (481 mg, 62%). Colorless oil; ½a27 H D ¼ 18:2 (c 0.08, CHCl3); NMR (300 MHz, CDCl3) d: 7.77 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 6.10 (1H, dd, J = 4.4, 8.8 Hz), 4.22–4.09 (2H, m), 4.00–3.89 (1H, m), 3.75–3.43 (6H, m), 2.42 (3H, s), 1.89–1.59 (4H, m), 1.51 (3H, d, J = 11.7 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.222 (3H, t, J = 7.1 Hz), 1.218 (3H, t, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3) d: 143.2–127.0 (aromatic), 102.4 (d, JCP = 140.4 Hz), 62.5 (d, JCP = 7.4 Hz), 62.1, 58.6 (d, JCP = 5.0 Hz), 58.0 (d, JCP = 7.4 Hz), 49.8 (d, JCP = 91.9 Hz), 28.7 (d, JCP = 5.6 Hz), 27.3, 21.5, 19.8 (d, JCP = 12.4 Hz), 16.5 (d, JCP = 5.6 Hz), 15.4, 15.1; 31P NMR

T. Yamagishi et al. / Tetrahedron: Asymmetry 23 (2012) 1633–1639

(122 MHz, CDCl3) d: 42.07; IR (neat) 3103, 1332, 1156, 1028 cm1; MS m/z 452 (MH+); HRMS calcd for C19H35NO7PS: 452.1872 (MH+). Found: 452.1884. 4.5. (1R,RP)-Ethyl 1,1-diethoxyethyl(1-{[(4-methylphenyl)sulfonyl]amino}4-methanesulfonyloxybutyl)phosphinate (RP)-17 To a solution of (RP)-16 (713 mg, 1.58 mmol) in CH2Cl2 (3.2 mL) were added Et3N (0.31 mL, 2.24 mmol) and a solution of MsCl (0.15 mL, 1.92 mmol) in CH2Cl2 (3.2 mL) at 0 °C and the mixture was stirred for 1 h at room temperature. The mixture was poured into H2O and extracted with AcOEt. After the combined extracts were washed with brine and dried over MgSO4, removal of the solvent gave a residue, which was purified by column chromatography (Hexane/AcOEt = 1:1 to AcOEt) to give (RP)-17 (728 mg, 86%). White crystals; mp 99–101 °C; 1 ½a27 D ¼ þ6:4 (c 0.10, CHCl3); H NMR (300 MHz, CDCl3) d: 7.77 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 5.62 (1H, dd, J = 7.4, 7.4 Hz), 4.19–4.01 (4H, m), 3.82–3.57 (5H, m), 2.98 (3H, s), 2.43 (3H, s), 2.05–1.75 (4H, m), 1.45 (3H, d, J = 11.7 Hz), 1.25 (3H, t, J = 7.0 Hz), 1.22 (3H, t, J = 7.0 Hz), 1.20 (3H, t, J = 7.0 Hz); 13 C NMR (75 MHz, CDCl3) d: 143.5–127.0 (aromatic), 102.7 (d, JCP = 142.9 Hz), 69.5, 62.5 (d, JCP = 7.5 Hz), 58.9 (d, JCP = 4.3 Hz), 58.0 (d, JCP = 6.8 Hz), 50.0 (d, JCP = 89.5 Hz), 37.3, 26.9, 25.5 (d, JCP = 6.8 Hz), 21.5, 19.3 (d, JCP = 11.2 Hz), 16.5 (d, JCP = 5.6 Hz), 15.4, 15.1; 31P NMR (122 MHz, CDCl3) d: 40.75; IR (neat) 3114, 1335, 1159, 1025 cm1; MS m/z 530 (MH+); HRMS calcd for C20H37NO9PS2: 530.1647 (MH+). Found: 530.1679. 4.6. (1R,RP)-Ethyl 1,1-diethoxyethyl{[1-(4-methylphenyl)sulfonyl]2-pyrrolidinyl}phosphinate (RP)-18 To a solution of (RP)-17 (727 mg, 1.37 mmol) in DMF (8.2 mL) was added K2CO3 (947 mg, 6.85 mmol) and the mixture was stirred for 12 h at room temperature. The mixture was poured into H2O and extracted with Et2O. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/ AcOEt = 1:1 to AcOEt) to give (RP)-18 (546 mg, 92%). Colorless oil; 1 ½a27 D ¼ 82:5 (c 0.05, CHCl3); H NMR (300 MHz, CDCl3) d: 7.78 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 4.39 (1H, ddd, J = 3.8, 3.8, 9.7 Hz), 4.29–4.12 (2H, m), 3.89–3.69 (4H, m), 3.55 (1H, ddd, J = 4.6, 8.1, 12.3 Hz), 3.40 (1H, ddd, J = 7.8, 7.8, 12.3 Hz), 2.43 (3H, s), 2.24–2.13 (1H, m), 2.00–1.80 (1H, m), 1.80–1.36 (2H, m), 1.72 (3H, d, J = 11.5 Hz), 1.32 (3H, t, J = 7.0 Hz), 1.24 (6H, t, J = 7.0 Hz); 13 C NMR (75 MHz, CDCl3) d: 143.9–127.8 (aromatic), 102.0 (d, JCP = 137.3 Hz), 62.0 (d, JCP = 6.8 Hz), 58.3 (d, JCP = 5.0 Hz), 58.0 (d, JCP = 7.4 Hz), 56.5 (d, JCP = 103.7 Hz), 49.2, 25.8, 24.0, 21.5, 20.3 (d, JCP = 12.4 Hz), 16.6 (d, JCP = 5.0 Hz), 15.5, 15.2; 31P NMR (122 MHz, CDCl3) d: 41.25; IR (neat) 1348, 1158, 1030 cm1; MS m/z 434 (MH+); HRMS calcd for C19H33NO6PS: 434.1766 (MH+). Found: 434.1761. 4.7. (1R,SP)-Ethyl {[1-(4-methylphenyl)sulfonyl]-2-pyrrolidinyl} phosphinate (SP)-19 To a solution of (RP)-18 (114 mg, 0.26 mmol) in CH2Cl2 (2.6 mL) was added TMSCl (0.23 mL, 1.79 mmol) and EtOH (0.11 mL) at room temperature. After stirring for 2 h at the same temperature, the mixture was concentrated to give a residue, which was purified by column chromatography (AcOEt) to give (SP)-19 (70 mg, 84%). 1 White crystals; mp 91–92 °C; ½a27 D ¼ 109:0 (c 0.19, CHCl3); H NMR (300 MHz, CDCl3) d: 7.73 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.1 Hz), 7.31 (1H, d, J = 573.5 Hz), 4.27–4.10 (2H, m), 3.82– 3.79 (1H, m), 3.44 (1H, ddd, J = 5.1, 7.0, 10.3 Hz), 3.28–3.23 (1H, m), 2.43 (3H, s), 2.28–2.21 (1H, m), 2.08–1.98 (1H, m), 1.80–1.71

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(1H, m), 1.59–1.52 (1H, m), 1.38 (3H, t, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3) d: 144.2–127.7 (aromatic), 63.0 (d, JCP = 7.5 Hz), 57.0 (d, JCP = 119.9 Hz), 49.4 (d, JCP = 2.5 Hz), 25.3 (d, JCP = 1.9 Hz), 25.0 (d, JCP = 1.2 Hz), 21.5, 16.3 (d, JCP = 5.6 Hz); 31P NMR (122 MHz, CDCl3) d: 35.77; IR (neat) 1345, 1157, 1030 cm1; MS m/z 318 (MH+); HRMS calcd for C13H21NO4PS: 318.0929 (MH+). Found: 318.0913. 4.8. (1R,SP)-tert-Butyl 3-[ethoxy(1-{[(4-methylphenyl)sulfonyl]2-pyrrolidinyl})phosphoryl]propanoate (SP)-20 To a stirred solution of (SP)-19 (244 mg, 0.77 mmol) and tert-butyl acrylate (138 mg, 1.08 mmol) in THF (3.2 mL) was added a solution of t-BuOMgBr in THF (1.2 mL) at 0 °C, prepared from t-BuOH (57 mg, 0.77 mmol) and a 1.10 M THF solution of MeMgBr (0.70 mL, 0.77 mmol) in situ. After stirring for 4 h at the same temperature, to the mixture was slowly added H2O and extracted with AcOEt. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/AcOEt = 1:1 to AcOEt) to give (SP)-20 (324 mg, 95%). Colorless oil; ½a29 D ¼ 68:3 (c 0.27, CHCl3); 1H NMR (300 MHz, CDCl3) d: 7.73 (2H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 4.20–4.00 (3H, m), 3.47–3.37 (2H, m), 2.70–2.62 (2H, m), 2.44 (3H, s), 2.41–2.27 (2H, m), 1.46 (9H, s), 1.32 (3H, t, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) d: 171.7, 144.1–127.6 (aromatic), 80.8, 61.8 (d, JCP = 6.8 Hz), 57.4 (d, JCP = 116.2 Hz), 49.5, 28.1, 28.0 (d, JCP = 3.1 Hz), 25.3, 24.6, 21.6, 21.2 (d, JCP = 91.3 Hz), 16.7 (d, JCP = 5.6 Hz); 31P NMR (122 MHz, CDCl3) d: 53.14; IR (neat) 1728, 1348, 1156, 1032 cm1; MS m/z 446 (MH+); HRMS calcd for C20H33NO6PS: 446.1766 (MH+). Found: 446.1788. 4.9. (1R,SP,2R)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methylphenyl) sulfonyl]-2-pyrrolidinyl})phosphoryl]propanoate (SP)-210 To a stirred solution of (SP)-20 (120 mg, 0.27 mmol) in THF (3.4 mL) was added a 1.06 M THF solution of LHMDS (0.76 mL, 0.81 mmol) at 78 °C. After stirring for 30 min at the same temperature, BnBr (0.10 mL, 0.81 mmol) was added to the mixture and stirred for 2 h at the same temperature. The mixture was diluted with an aqueous saturated NH4Cl solution and extracted with AcOEt. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/ AcOEt = 1:1 to 1:5) to give a mixture of (SP)-21 and (SP)-210 (117 mg, 81%). The major isomer (SP)-210 was isolated by preparative TLC (CHCl3/AcOEt = 1:3). Colorless oil; ½a29 D ¼ 72:8 (c 0.24, CHCl3); 1H NMR (300 MHz, CDCl3) d: 7.73 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.27–7.19 (5H, m), 4.19–3.98 (3H, m), 3.50–3.34 (2H, m), 3.18–3.11 (1H, m), 3.04 (1H, dd, J = 5.5, 13.4 Hz), 2.89 (1H, dd, J = 9.2, 13.4 Hz), 2.54–2.41 (1H, m), 2.44 (3H, s), 2.22–2.06 (2H, m), 1.96–1.88 (1H, m), 1.67– 1.46 (2H, m), 1.34–1.27 (3H, m), 1.30 (9H, s); 13C NMR (75 MHz, CDCl3) d: 173.2 (d, JCP = 5.0 Hz), 144.0–126.4 (aromatic), 80.6, 61.0 (d, JCP = 6.8 Hz), 57.0 (d, JCP = 114.3 Hz), 49.6, 41.8 (d, JCP = 3.7 Hz), 40.3 (d, JCP = 12.4 Hz), 27.9 (d, JCP = 89.4 Hz), 27.8, 25.1, 24.4, 21.4, 16.6 (d, JCP = 5.0 Hz); 31P NMR (122 MHz, CDCl3) d: 51.99; IR (neat) 1724, 1348, 1156, 1032 cm1; MS m/z 536 (MH+); HRMS calcd for C27H39NO6PS: 536.2236 (MH+). Found: 536.2259. 4.10. (1R⁄,RP⁄)-Ethyl 1,1-diethoxyethyl(1-{[(4-methylphenyl)sulfo nyl]amino}-4-tert-butyl{diphenyl}silyloxybutyl)phosphinate 22 To a solution of 16 (1.01 g, 2.23 mmol) in DMF (2 mL) were added a solution of imidazole (318 mg, 4.68 mmol) in

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DMF (4 mL) and a solution of TBDPSCl (673 mg, 2.45 mmol) in DMF (4 mL) and the mixture was stirred for 12 h at room temperature. The mixture was poured into H2O and extracted with Et2O. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/AcOEt = 2:1 to 1:2) to give 22 (1.51 g, 98%). White crystals; mp 121–122 °C; 1 H NMR (300 MHz, CDCl3) d: 7.75–7.20 (14H, m), 5.50–5.43 (1H, m), 4.22–4.09 (2H, m), 3.92–3.80 (1H, m), 3.79–3.59 (4H, m), 3.53–3.39 (2H, m), 2.33 (3H, s), 1.95–1.43 (4H, m), 1.50 (3H, d, J = 11.5 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.22 (3H, t, J = 7.1 Hz), 1.19 (3H, t, J = 7.1 Hz), 1.00 (9H, s); 13C NMR (75 MHz, CDCl3) d: 143.1–126.9 (aromatic), 102.5 (d, JCP = 140.4 Hz), 63.4, 62.3 (d, JCP = 7.5 Hz), 58.8 (d, JCP = 4.3 Hz), 57.9 (d, JCP = 7.4 Hz), 50.6 (d, JCP = 89.9 Hz), 29.0 (d, JCP = 6.8 Hz), 27.3, 26.7, 21.4, 19.8 (d, JCP = 11.8 Hz), 19.1, 16.5 (d, JCP = 4.9 Hz), 15.4, 15.1; 31P NMR (122 MHz, CDCl3) d: 41.39; IR (neat) 3135, 1336, 1159, 1027 cm1; MS m/z 690 (MH+); HRMS calcd for C35H53NO7PSSi: 690.3050 (MH+). Found: 690.3080. 4.11. (1R⁄,SP⁄)-Ethyl (1-{[(4-methylphenyl)sulfonyl]amino}-4tert-butyl{diphenyl}silyloxybutyl)phosphinate 23 To a solution of 22 (1.51 g, 2.19 mmol) in CH2Cl2 (6.6 mL) were added TMSCl (0.42 mL, 3.28 mmol) and EtOH (0.5 mL) at room temperature. After stirring for 3 h at the same temperature, the mixture was concentrated to give a residue, which was purified by column chromatography (Hexane/AcOEt = 1:1 to 0:1) to give 23 (899 mg, 71%). White crystals; mp 141– 142 °C; 1H NMR (300 MHz, CDCl3) d: 7.74–7.24 (14H, m), 6.90 (1H, d, J = 558.7 Hz), 5.30–5.20 (1H, m), 4.17–4.07 (2H, m), 3.53–3.46 (3H, m), 2.37 (3H, s), 1.92–1.88 (1H, m), 1.69–1.50 (2H, m), 1.45–1.40 (1H, m), 1.32 (3H, t, J = 7.1 Hz), 1.02 (9H, s); 13C NMR (75 MHz, CDCl3) d: 143.4–126.9 (aromatic), 63.1 (d, JCP = 7.4 Hz), 62.4, 51.6 (d, JCP = 109.9 Hz), 28.0 (d, JCP = 9.9 Hz), 26.7, 23.2, 21.4, 19.0, 16.2 (d, JCP = 6.2 Hz); 31P NMR (122 MHz, CDCl3) d: 33.91; IR (neat) 3066, 1333, 1158, 1051 cm1; MS m/ z 574 (MH+); HRMS calcd for C29H41NO5PSSi: 574.2212 (MH+). Found: 574.2218. 4.12. (1R⁄,SP⁄)-tert-Butyl 3-[ethoxy(1-{[(4-methylphenyl)sulfonyl]amino}4-tert-butyl{diphenyl}silyloxybutyl)phosphoryl]propanoate 24 To a stirred solution of 23 (597 mg, 1.04 mmol) and tert-butyl acrylate (187 mg, 1.46 mmol) in THF (4 mL) were added a solution of t-BuOMgBr in THF (2.2 mL) at 0 °C, prepared from t-BuOH (77 mg, 1.04 mmol) and 0.99 M THF solution of MeMgBr (1.05 mL, 1.04 mmol) in situ. After stirring for 7 h at the same temperature, to the mixture was slowly added H2O and extracted with AcOEt. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/AcOEt = 1:1) to give 24 (237 mg, 33%). White crystals; mp 117–118 °C; 1H NMR (300 MHz, CDCl3) d: 7.72–7.20 (14H, m), 5.35–5.25 (1H, m), 4.13–4.03 (2H, m), 3.64–3.42 (3H, m), 2.51 (1H, dd, J = 7.7, 7.7 Hz), 2.47 (1H, dd, J = 7.6, 7.6 Hz), 2.33 (3H, s), 2.02–1.83 (3H, m), 1.59–1.31 (3H, m), 1.45 (9H, s), 1.26 (3H, t, J = 7.1 Hz), 1.00 (9H, s); 13C NMR (75 MHz, CDCl3) d: 171.5 (d, JCP = 14.2 Hz), 143.0–126.7 (aromatic), 80.7, 62.8, 61.4 (d, JCP = 6.8 Hz), 51.4 (d, JCP = 106.8 Hz), 28.5 (d, JCP = 8.7 Hz), 28.0, 27.7 (d, JCP = 3.7 Hz), 26.7, 24.8, 21.3, 21.0 (d, JCP = 91.3 Hz), 19.0, 16.5 (d, JCP = 5.6 Hz); 31 P NMR (122 MHz, CDCl3) d: 52.37; IR (neat) 3070, 1726, 1326, 1155, 1024 cm1; MS m/z 702 (MH+); HRMS calcd for C36H53NO7PSSi: 702.3050 (MH+). Found: 702.3057.

4.13. (1R⁄,SP⁄,2S⁄)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methyl phenyl)sulfonyl]amino}-4-tert-butyl{diphenyl}silyloxybutyl)phos phoryl]propanoate 25 To a stirred solution of 24 (140 mg, 0.20 mmol) in THF (2.5 mL) was added a 1.06 M THF solution of LHMDS (0.57 mL, 0.60 mmol) at 78 °C. After stirring for 30 min at the same temperature, BnBr (71 lL, 0.60 mmol) was added to the mixture and stirred for 3 h at the same temperature. The mixture was then diluted with aqueous saturated NH4Cl solution and extracted with AcOEt. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by column chromatography (Hexane/AcOEt = 3:1 to 1:1) to give 25 (32.3 mg, 20%). Colorless oil; 1H NMR (300 MHz, CDCl3) d: 7.73–7.13 (19H, m), 5.55–5.38 (1H, m), 4.13–3.98 (2H, m), 3.59–3.51 (1H, m), 3.44– 3.40 (2H, m), 3.10–2.94 (1H, m), 2.88–2.74 (2H, m), 2.33 (3H, s), 2.14–1.74 (4H, m), 1.60–1.37 (2H, m), 1.32 (9H, s), 1.25 (3H, t, J = 7.0 Hz), 1.00 (9H, s); 13C NMR (75 MHz, CDCl3) d: 173.7, 143.4–126.5 (aromatic), 80.9, 63.0, 61.7 (d, JCP = 6.8 Hz), 52.9 (d, JCP = 103.7 Hz), 42.0 (d, JCP = 4.3 Hz), 40.2 (d, JCP = 11.8 Hz), 28.7 (d, JCP = 8.0 Hz), 28.3 (d, JCP = 88.8 Hz), 27.8, 26.8, 25.6, 21.4, 19.1, 16.5 (d, JCP = 5.6 Hz); 31P NMR (122 MHz, CDCl3) d: 50.85; IR (neat) 3055, 1719, 1365, 1156, 1029 cm1; MS m/z 792 (MH+); HRMS calcd for C43H59NO7PSSi: 792.3519 (MH+). Found: 792.3539. 4.14. (1R⁄,SP⁄,2S⁄)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methyl phenyl)sulfonyl]amino}-4-hydroxybutyl)phosphoryl]propanoate 26 To a solution of 25 (70.5 mg, 0.09 mmol) in THF (1.6 mL) was added a 1.0 M THF solution of TBAF (0.27 mL, 0.27 mmol) and the mixture was stirred for 1 h at room temperature. The mixture was poured into H2O and extracted with AcOEt. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by preparative TLC (CHCl3/MeOH = 30:1) to give 26 (41.3 mg, 84%). Colorless oil; 1 H NMR (300 MHz, CDCl3) d: 7.77 (2H, d, J = 8.1 Hz), 7.30–7.12 (7H, m), 6.88–6.67 (1H, m), 4.10–4.04 (2H, m), 3.67–3.45 (2H, m), 3.12–2.96 (2H, m), 2.93–2.77 (2H, m), 2.40 (3H, s), 2.20–1.95 (2H, m), 1.72–1.46 (4H, m), 1.31 (9H, s), 1.27 (3H, t, J = 7.0 Hz); 13 C NMR (75 MHz, CDCl3) d: 173.5, 143.4–126.5 (aromatic), 81.0, 62.1, 61.8 (d, JCP = 6.2 Hz), 52.4 (d, JCP = 106.8 Hz), 42.0 (d, JCP = 4.3 Hz), 40.2 (d, JCP = 13.0 Hz), 28.4 (d, JCP = 8.0 Hz), 28.2 (d, JCP = 89.4 Hz), 27.8, 26.0, 21.5, 16.5 (d, JCP = 5.6 Hz); 31P NMR (122 MHz, CDCl3) d: 52.26; IR (neat) 3271, 2975, 1723, 1331, 1153, 1030 cm1; MS m/z 554 (MH+); HRMS calcd for C27H41NO7PS: 554.2341 (MH+). Found: 554.2365. 4.15. (1R⁄,SP⁄,2S⁄)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methyl phenyl)sulfonyl]-2-pyrrolidinyl})phosphoryl]propanoate 21 To a solution of 26 (41.3 mg, 0.07 mmol) in CH2Cl2 (0.25 mL) were added Et3N (15 lL, 0.11 mmol) and a solution of MsCl (10.3 mg, 0.09 mmol) in CH2Cl2 (0.5 mL) at 0 °C and the mixture was stirred for 1 h at room temperature. The mixture was poured into H2O and extracted with CHCl3. After the combined extracts were washed with brine and dried over MgSO4, removal of the solvent gave a residue. To a solution of this residue in DMF (1.5 mL) was added K2CO3 (51.8 mg, 0.37 mmol) and the mixture was stirred for 6 h at room temperature. The mixture was poured into H2O and extracted with AcOEt. The combined extracts were washed with brine and dried over MgSO4. Removal of the solvent gave a residue, which was purified by preparative TLC (AcOEt) to give 21 (18.6 mg, 46%). Colorless oil; 1H NMR (300 MHz, CDCl3)

T. Yamagishi et al. / Tetrahedron: Asymmetry 23 (2012) 1633–1639

d: 7.72 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.28–7.19 (5H, m), 4.19–4.06 (2H, m), 4.00 (1H, ddd, J = 3.7, 3.7, 9.3 Hz), 3.49–3.32 (2H, m), 3.23–3.12 (1H, m), 3.06 (1H, dd, J = 5.7, 13.4 Hz), 2.91 (1H, dd, J = 9.2, 13.4 Hz), 2.43 (3H, s), 2.39–2.32 (2H, m), 2.11– 1.88 (2H, m), 1.76–1.45 (2H, m), 1.33–1.25 (3H, m), 1.30 (9H, s); 13 C NMR (75 MHz, CDCl3) d: 173.7 (d, JCP = 5.0 Hz), 144.0–126.3 (aromatic), 80.5, 61.2 (d, JCP = 7.4 Hz), 58.5 (d, JCP = 114.9 Hz), 49.4, 42.2 (d, JCP = 4.3 Hz), 40.4 (d, JCP = 12.4 Hz), 28.1 (d, JCP = 89.4 Hz), 27.8, 25.2, 24.5, 21.5, 16.7 (d, JCP = 5.6 Hz); 31P NMR (122 MHz, CDCl3) d: 51.11; IR (neat) 1722, 1347, 1157, 1031 cm1; MS m/z 536 (MH+); HRMS calcd for C27H39NO6PS: 536.2236 (MH+). Found: 536.2259. Acknowledgment The authors thank Ohu University for their generous financial support. References 1. For reviews, see: (a) Collinsová, M.; Jirácek, J. Curr. Med. Chem. 2000, 7, 629; (b) Yiotakis, A.; Geogiadis, D.; Matziari, M.; Makaritis, A.; Dive, V. Curr. Org. Chem. 2004, 8, 1135; (c) Mucha, A.; Kafarski, P.; Berlicki, Ł. J. Med. Chem. 2011, 54, 5955. 2. For selected examples, see: (a) Manzenrieder, F.; Frank, A. O.; Huber, T.; Dorner-Ciossek, C.; Kessler, H. Bioorg. Med. Chem. 2007, 15, 4136; (b) Vassiliou, S.; Xeilari, M.; Yiotakis, A.; Grembecka, J.; Pawelczak, K.; Kawel, P.; Mucha, A. Bioorg. Med. Chem. 2007, 15, 3187; (c) Makaritis, A.; Georgiadis, D.; Dive, V.; Yiotakis, A. Chem. Eur. J. 2003, 9, 2079. 3. Jullien, N.; Makritis, A.; Georgiadis, D.; Beau, F.; Yiotakis, A.; Dive, V. J. Med. Chem. 2010, 53, 208. 4. Mores, A.; Matziari, M.; Beau, F.; Ciniasse, P.; Yiotakis, A.; Dive, V. J. Med. Chem. 2008, 51, 2216. 5. Nasopoulou, M.; Georgiadis, D.; Matziari, M.; Dive, V.; Yiotakis, A. J. Org. Chem. 2007, 72, 7222.

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6. For selected examples of stereoselective syntheses of PDIs, see: (a) Bartley, D. M.; Coward, J. K. J. Org. Chem. 2005, 70, 6757; (b) Liu, X.; Hu, X. E.; Tian, X.; Mazur, A.; Ebetino, F. H. J. Organomet. Chem. 2002, 646, 212–222; (c) Cristau, H.J.; Coulombeau, A.; Genevois-Borella, A.; Pirat, J.-L. Tetrahedron Lett. 2001, 42, 4491; (d) Chen, H.; Noble, F.; Mothe, A.; Meudal, H.; Coric, P.; Danascimento, S.; Roques, B. P.; George, P.; Fournie-Zaluski, M.-C. J. Med. Chem. 2000, 43, 1398; (e) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989, 32, 1652; (f) Parsons, W. H.; Patchett, A. A.; Bull, H. G.; Schoen, W. R.; Taub, D.; Davidson, J.; Combs, P. L.; Springer, J. P.; Gadebusch, H.; Weissberger, B.; Valiant, M. E.; Mellin, T. N.; Busch, R. D. J. Med. Chem. 1988, 31, 1772; A method to separate inidividual phosphinic dipeptide stereoisomers using HPLC was reported, see: (g) Mucha, A.; Lammerhofer, M.; Lindner, W.; Pawelczak, M.; Kafarski, P. Bioorg. Med. Chem. Lett. 2008, 18, 1550. 7. Yamagishi, T.; Haruki, T.; Yokomatsu, T. Tetrahedron 2006, 62, 9210. 8. Yamagishi, T.; Ichikawa, H.; Haruki, T.; Yokomatsu, T. Org. Lett. 2008, 10, 4347. 9. Yuan et al. independently reported on the preparation of 4 and the related compounds by addition of phosphorus nucleophiles to imines, see: (a) Zhang, D.; Yuan, C. Chem. Eur. J. 2008, 14, 6049; (b) Zhang, D.; Yuan, C. Chem. Eur. J. 2009, 15, 4088. 10. Haruki, T.; Yamagishi, T.; Yokomatsu, T. Tetrahedron: Asymmetry 2007, 18, 2886. 11. Yamagishi, T.; Mori, J.; Haruki, T.; Yokomatsu, T. Tetrahedron: Asymmetry 2011, 22, 1358. 12. (a) Swindell, C. S.; Patel, B. P. Tetrahedron Lett. 1987, 28, 5275; (b) Hanessian, S.; Bennani, Y. L.; Delorme, D. Tetrahedron Lett. 1990, 31, 6461. 13. For LiCl-mediated reactions of lithium enolates with electrophiles, see: (a) Seebach, D.; Grunder, H.; Shoda, S.-I. Helv. Chim. Acta 1991, 74, 197; (b) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656; (c) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496; (d) Lee, J.; Choi, W. B.; Lynch, J. E.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 3679. 14. Similar working models for the asymmetric alkylation of phosphorusstabilized carbanions were proposed by Denmark and Hanessian, respectively. See: (a) Denmark, S. E.; Chen, C.-T. J. Org. Chem. 1994, 59, 2922; (b) Denmark, S. E.; Chen, C.-T. J. Am. Chem. Soc. 1995, 117, 11879; (c) Ref. 12b.; (d) Hanessian, S.; Bennani, Y. L. Tetrahedron Lett. 1990, 31, 6465; (e) Hanessian, S.; Bennani, Y. L.; Hervé, Y. Synlett 1993, 35. 15. (a) Baylis, E. K. Tetrahedron Lett. 1995, 36, 9385; (b) Froestl, W.; Mickel, S. J.; Hall, R. G.; von Sprecher, G.; Strub, D.; Baumann, P. A.; Brugger, F.; Gentsch, C.; Jaekel, J.; Olpe, H-R.; Rihs, G.; Vassout, A.; Waldmeier, P. C.; Bittiger, H. J. Med. Chem. 1995, 38, 3297. 16. Han, L.-B.; Zhao, C.-Q. J. Org. Chem. 2005, 70, 10121.