Convergent Asymmetric Synthesis of a Renin Inhibitor: A Highly

Article pubs.acs.org/OPRD

Convergent Asymmetric Synthesis of a Renin Inhibitor: A Highly Efficient Construction Method of Three Stereogenic Centers Makoto Michida,* Yoshihiro Takayanagi, Makoto Imai, Yukito Furuya, Kenichi Kimura, Takafumi Kitawaki, Hiroshi Tomori, and Hisaki Kajino Process Technology Research Laboratories (PTRL), Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan S Supporting Information *

ABSTRACT: An improved asymmetric synthesis of renin inhibitor DS-8108b (1) is described. This compound consists of three intermediates: 4-aminoadamantan-1-ol, ketopiperazine, and chiral lactone which contains three stereogenic centers. Especially, the chiral lactone is a key intermediate, and development of a scalable synthetic method was required, considering the quality, speed, and manufacturing cost. We established a scalable synthetic method of 1 from 4,6-O-benzylidene-D-glucose for early clinical studies. Furthermore, a highly efficient synthetic route of the chiral lactone for manufacturing was also successfully developed from n-butyryl chloride via Evans stereoselective alkylation, followed by stereoselective bromolactonization. In addition, a unique and highly efficient conversion protocol was developed from α-bromo-N-(2-nitrobenzenesulfonyl)amide to apparent rearranged diamine derivatives with a sequential aziridination−substitution reaction in one-pot.

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amino acids8 often employed as a chiral pool in early-stage synthesis. This approach is highly reliable methodology because it can fix the configuration in advance; however, it is often problematic when expensive chiral materials are used. On the other hand, highly efficient asymmetric reactions can be powerful tools for cost-effective synthesis, although it often requires much time for optimization of the reaction conditions and quality control, especially in stereoisomers. Among these reactions, halolactonization drew our interest. This reaction is one of the most efficient methods for the synthesis of chiral γbutyrolactones because two, new asymmetric carbons can be constructed directly from one asymmetric carbon by 1,3asymmetric induction with high stereoselectivity.9,10 Herein, we describe the establishment of a practical synthesis of 1, from a glucose derivative as the chiral pool, which has been successfully scaled up to produce multikilograms of active pharmaceutical ingredient (API), and the development of a further efficient synthetic method by drastic route change with highly stereoselective asymmetric reactions.

INTRODUCTION The renin−angiotension−aldosterone system (RAAS) is well established as an endocrine system in regulating blood pressure and extracellular fluid volume. In the RAAS, renin has an important role in the control of blood pressure,1 and its direct inhibitors are expected to not only treat hypertension but also prevent disorders in organs such as the heart and kidney.2 Significant research efforts have developed several novel renin inhibitors, such as MK-8141,3 VTP-27999,4 and aliskiren.5 In particular, aliskiren has recently received marketing approval and was launched as the first orally active renin inhibitor. On the other hand, our medicinal research group discovered DS-8108b (1) as a new drug candidate of a direct renin inhibitor (Figure 1),6 that has entered human clinical

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RESULTS AND DISCUSSION The initial medicinal chemistry route to 1 is outlined in Scheme 1.11 The route to 1 is a 15-step sequence combining the three key intermediates such as chiral aziridine 8, 4-(2-chlorophenyl)2,2-dimethylpiperazin-2-one (9),12 and commercially available trans-4-aminoadamantan-1-ol (12). The key intermediate 5 was constructed by Evans asymmetric alkylation of 2 with allyl bromide 3, and subsequent Shi’s asymmetric epoxidation of 4. Then 5 was derived to 2-nitrobenzensulfonyl (nosyl: Ns) aziridine 8 under Mitsunobu condition, and a ring-opening reaction with 9 to afford the adduct 10. After replacement of the protecting group, lactone ring cleavage with 12,

Figure 1. Chemical structure of DS-8108b (1).

trials as an epochal drug that is more active, efficient and safer than previous hypotensive agents. Therefore, the development of scalable and efficient synthetic method is required for clinical studies. Since 1 has three asymmetric carbons, it should be considered how to construct them steadily. When applying to large-scale synthesis, several approaches should be planned depending on the circumstances: for example, the use of commercially available chiral compounds such as sugars7 or © 2013 American Chemical Society

Received: August 13, 2013 Published: October 17, 2013 1430

dx.doi.org/10.1021/op400219y | Org. Process Res. Dev. 2013, 17, 1430−1439

Organic Process Research & Development

Article

Scheme 1. Medicinal chemistry route

deprotection of the Boc group, and treatment with fumaric acid afforded 1 in 12.6% overall yield. This synthetic method was suitable for early toxicological studies; however, it would not be suitable for large-scale production due to the following issues: (i) the requirement for several chromatographic purifications, (ii) the use of thiophenol which has a strong odor, and (iii) replacement of the protecting group (from Ns to Boc). Our retrosynthetic approach for kilogram-scale deliveries is outlined in Scheme 2. The same as the medicinal route, late-

Scheme 3. Early-stage synthesis of 1

Scheme 2. Retrosynthetic approach to 1

Lactone ring cleavage of 10 with 12 gave 15 in 73% yield. Importantly, it was confirmed that this lactone-opening reaction is an equilibrium between 10 and 15.13 Therefore, 3 equiv of 12 were used to suppress the reverse reaction. In the final step, deprotection of the Ns group was conducted steadily when 1decanethiol14 was employed instead of thiophenol to avoid the foul-smelling issue. After recrystallization, pure crystals of 1 were given in good yield. As a result, we established an earlystage synthetic method of 1. This method does not need the protecting group displacement, the use of thiophenol, or chromatography purifications. In order to develop a scalable method of 7, we tried to establish the first-generation supply route from 4,6-Obenzylidene-D-glucose 16 as a starting material, expecting to avoid chromatography purifications by isolating the crystalline intermediates as shown in Scheme 4. α,β-Unsaturated

stage ring-opening reactions of bicyclic intermediate 8 would be appropriate for a convergent synthesis. Then to solve the issues of the medicinal route, we planned several approaches as follows: (1) establishment of a concise practical route to 1 by avoiding the protecting group replacement and the use of thiophenol for Ns group deprotection, (2) development of a scalable synthetic method for 7 without silica gel column treatment. An initial scalable multikilogram synthesis of 1 has been developed that is summarized in Scheme 3. Chiral alcohol 7 was converted into aziridine 8 via mesylation following cyclization under Schotten−Baumann condition, then substituted with 9 to give 10 as crystalline solid in 89% yield. 1431



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Scheme 4. Early-stage synthesis of 7

Scheme 5. New strategy for the synthesis of aziridine 8

Table 1. Stereoselective alkylation of various chiral auxiliaries

a

entry

R

material

product

HPLC area % of 26a

2R : 2S ratio

1 2 3

Ph iPr Bn

24a 24b 24c

26a 26b 26c

78.23 88.31 70.58

96:4 98:2 97:3

Calculated the sum of (2R)-26 and (2S)-26.

Actually, early-stage multikilogram manufacturing was conducted using this method without chromatography. Although this route proved to be a scalable method, we had concerns over the long-term economic viability of the synthetic route. Most notably, construction of the three asymmetric carbon centers in a highly efficient manner is expected to be highly demanding. New Strategy for the Synthesis of Chiral Intermediate. We explored various new synthetic routes to 7; however, a promising route was not found. Instead of 7, we focused on aziridine 8 as an alternative target intermediate (Scheme 5). In conventional routes, 14 was cyclized to form 8 from the 5position. On the other hand, if an aziridine ring can be cyclized from the opposite side, 23 is expected to be an alternative precursor of 8. 23 is thought to be prepared by Evans

carboxylic acid 19 was exclusively obtained as a crystalline solid by oxidative cleavage of 16, Wittig reaction with 17, and hydrolysis. Although this route relied on stereoselective hydrogenation of 19, the selectivity was not sufficient (dr = 67:33); however, when 20 was isolated as dicyclohexylamine (DCHA) salt, the undesired isomer was removed effectively (60% yield from 19, dr = 95.0:5.0). An upgrade of 20 was carried out by acetone slurry in high recovery (91% yield, dr = 98.5:1.5). By using pure 20, esterification and subsequent mesylation was carried out to give 21 in 91% yield. Azidation of 21 was carried out by in situ prepared ammonium azide to give 22 in moderate yield. Reduction of the azide group of 22 and subsequent nosylation proceeded smoothly. Following acid hydrolysis of benzylidene acetal, the deprotected diol was cyclized spontaneously to afford the target chiral lactone 7. 1432



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moved to the next step. We challenged direct bromolactonization of 32 (Table 2).19 When we investigated bromolactonization of 32 using extracted solution, desired bromolactone 23 was given in poor yield with high stereoselectivity, and bromohydrins 33 were also observed with high stereoselectivity (entry 1). Surprisingly, when a catalytic amount of Et3N was added to the reaction mixture, 33 was immediately cyclized to form 23 as well (entry 2). Likewise, when reactions were carried out in various solvents and then treated with a base (entries 3−5), 33 was completely converted to 23, and AcOEt gave the best results. When the organic phase was not treated with a base, 33 remained unchanged. We examined the reaction mechanism and stereoselectivity as shown in Figure 2. This reaction mechanism is considered to be as follows: (1) bromolactonization takes place to form iminium intermediate A (stereoselectivity is determined in this step),20 then (2) hydrolyzed intermediate B is cleaved via two competing pathways (paths a and b). 33 is easily cyclized under basic conditions to afford 23 eventually in high yield with good stereoselectivity. To synthesize azirizine 8, cyclization of 23 was investigated (Table 3). Various reaction conditions were tried, 8 was given in moderate yield only when an excess amount of NaH was used in MeCN under highly diluted condition (entry 1). Furthermore, the yield of 8 was decreased along with the concentration of the reaction solution (entries 2 and 3). On the other hand, when the reactions were conducted in high concentration conditions, dimeric byproduct 34 increased.21 This result indicates that 8 is highly reactive and nucleophilic addition had occurred by 23. As a result, we could not find practical aziridination conditions from 23 to 8.

stereoselective alkylation followed by stereoselective bromolactonization. On the basis of this working hypothesis, this synthetic route has a great potential to be a more efficient route if the stereoselectivities of these reactions are favorable. To synthesize the chiral substrate for bromolactonization, diastereoselective alkylation of butylic amides 24a−24c having Evans chiral auxiliary with 1,4-dibromo-2-butene 2515 were tried (Table 1). Stereoselective alkylation reactions were carried out by using 1.1 equiv of LHMDS as a base, and 2 equiv of 25 to avoid the formation of an overalkylated compound.16 When the alkylation reaction having (S)-phenyl oxazolizinone 24a was carried out at −50 to −40 °C, 26a was obtained in good selectivity (entry 1). We also tested other chiral auxiliaries such as (S)-benzyl- 24b and (S)-isopropyl oxazolizinone 24c; however, the stereoselectivities were almost the same level (entries 2 and 3) and overalkylated byproducts were suppressed not more than 5%. Consequently, (S)-phenyl oxazolidinone was selected as appropriate auxiliary by considering the cost and physical properties of the intermediates shown in Table 1. Next, we tried a one-pot reaction of acylation and the stereoselective alkylation shown in Scheme 6. LiH was employed as an inexpensive base. Following stereoselective alkylation, the same result was obtained in one pot (75.9% reaction yield from 27, dr = 96:4).17 Scheme 6. One-pot procedure of acylation−stereoselective alkylation

Next, we tried a different approach to the problem. Considering the reactivity of 8, we devised direct conversion from 23 into 10 in the presence of 9 (Table 4). We expected that generated 8 to immediately react with nucleophile 9 which is supposed to be more nucleophilic than 23. On the basis of this hypothesis, we examined direct conversion from 23 into 10 under various conditions. When the reaction was tried in the presence of 1.5 equiv of 9 and potassium carbonate was used as a base, undesired side product 34 was remarkably suppressed in low level and the desired 10 was obtained as main product (entry 1). In the case when sodium carbonate was used, the reaction did not proceed (entry 2). Interestingly, when a small amount of water was added, the reaction proceeded smoothly with suppressing 34 even if 9 was decreased to 1.1 equiv (entries 3 and 4). After crystallization from 2-propanol, the desired 10 was obtained in 67.4% net yield from 30-HCl as crystalline solid.22 At this point, 7.5% of diastereomer of 10 was contained; however, it was completely removed by crystallization in the following step. The final route is summarized in Scheme 9. The quality of 10 through the new route is relatively low because it contains 7.5% of diastereomer which was derived from 23 diastereomer. The diastereomer was difficult to be removed by crystallization at this point. Fortunately, the diastereomer was completely

Then we encountered issues regarding the next step. It was confirmed that approximately 1 equiv of unreacted 25 could not be separated by general workup (i.e., separation, evaporation, crystallization) except for column chromatography because 25 and 26a have similar reactivities and solubilities. To solve this critical problem, we moved forward to the next step, expecting the separation of these corresponding products. In order to convert allylic bromides into amines, Delépine’s protocol18 was employed by using hexamethylene tetramine (HMTA) as an inexpensive nitrogen source (Scheme 7). 25 and 26a were converted to the corresponding ammonium salts 28 and 29, respectively. After acidic hydrolysis, undesired diamine which was derived from 25 was completely removed as diamine 31 by separation to the aqueous phase even under basic condition, and then 30 was isolated as the HCl salt in 63% yield from 27. 30 was easily nosylated to 32 using 2-nitrobenzensulfonyl chloride (NsCl) under Schotten−Baumann conditions (Scheme 8). After disposal of the aqueous layer, we then 1433



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Scheme 7. Separation process of 25 and 26a

removed in subsequent step as the corresponding diastereomer of 15 by the original crystallization method to afford highly pure 15 in almost the same yield and quality toward the earlystage synthesis. Furthermore, the equivalence in the quality of 1 was also confirmed including enantiomer of 1 by the same steps as shown in Scheme 9.23

Scheme 8. Sequential nosylation−bromolactonization of 30HCl

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CONCLUSION We have demonstrated scalable syntheses for renin inhibitor (1) and key chiral intermediates. Our early-stage synthetic method accomplished avoidance of chromatographic separation steps. Furthermore, we have also developed highly efficient construction of chiral intermediate 23 which has three stereogenic centers by Evans-stereoselective alkylation and subsequent direct bromolactonization. We also developed a new approach for the efficient synthesis of common intermediate 10 from 23 with apparently rearrangement via sulfonyl aziridine in one pot. This new efficient method is also chromatography free, and quite cost effective. Finally, we decreased the reaction steps from 18 to 10 steps compared with the early-stage synthetic method, and overall yield was also increased from 8% to 24% .

Table 2. Screening results of the stereoselective bromolactonization entry 1 2b 3

b

4b 5b

solvents AcOEt/ H2O AcOEt/ H2O MeCN/ H2O THF/ H2O toluene/ H2O

ratio of 23 (R,S,R): (R,R,S)a

(R,S,R)33 (%)

(R,R,S)33 (%)

55.03

4.28

(R,S,R)23 (%)

(R,R,S)23 (%)

27.71

2.74

85.93

6.89

92.6:7.4

0

0

76.13

13.73

84.7:15.3

0

0

63.10

7.96

88.8:11.2

0

0

71.13

7.03

91.0:9.0

0

0

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EXPERIMENTAL SECTION All reagents and solvents were commercially available and used without further purification. All reactions were performed in an atmosphere of nitrogen. 1H NMR spectra were recorded with TMS as an internal standard. HPLC was performed using Shimadzu LC-10AD systems. All the yields were calculated as gross yield unless otherwise noted. All diastereomeric ratios and reaction yields were analyzed by HPLC. Analytical conditions are described below. HPLC Conditions. Condition A. Column: L-Column ODS (4.6 i.d. × 250 mm); eluent: (a) 0.1% trifluoroacetic acid, (b) MeCN, flow rate: 1.0 mL/min, Temperature: 40 °C, Gradient: (b/a) 30/70 (0 min) − 30/70 (0−5 min) − 80/20 (5−20 min) − 80/20 (20−35 min), UV detection at 210 nm, 24c: 19.2 min, 26c major (S,2R): 27.9 min, 26c minor (S,2S): 28.3 min, 28: 7.5 min, 30:6.8 min.

a

Calculated by HPLC area %. bThe organic phase was treated with catalytic amount of Et3N after separation.

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Figure 2. Plausible reaction mechanism of stereoselective bromolactonization.

Table 3. Cyclization of 23a

min, 10 major (1S,2S,4R): 22.2 min, 10 minor (1R,2R,4R): 21.6 min, 15 major (2R,4S,5S): 11.6 min, 15 minor (2R,4R,5R): 12.2 min. Early-Stage Synthesis. N-{(1S)-2-[4-(2-Chlorophenyl)2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide (10). To the solution of N-{(1S)-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]-2-hydroxyethyl}-2-nitrobenzenesulfonamide (7) (6.00 kg, 16.74 mol) in isopropyl acetate (60 L) was added methanesulfonyl chloride (1.36 L, 17.58 mol) maintaining the temperature below 10 °C, and the reaction mixture was stirred under a nitrogen atmosphere at 0−5 °C for 2.5 h. After water (12 L) was added, the aqueous layer was removed. Water (12 L) and potassium carbonate (2.78 kg, 21.10 mol) were added at 3−5 °C to the organic layer. The biphasic mixture was stirred vigorously under a nitrogen atmosphere at 25−30 °C for 16 h. After the layers were separated, the organic layer was washed twice with 5% aqueous sodium chloride (18 L × 2), and the layers were separated. To the organic layer was added 9 (4.00 kg, 16.74 mol), and the mixture was stirred under a nitrogen atmosphere at 70−73 °C for 3 h. After cooling to 30 °C, the

HPLC area % entry

MeCN vol

8

34

reaction yieldb (%)

1 2 3

100 50 10

79.25 71.76 45.03

6.03 10.48 24.58

79.6 64.4 48.8

a Purified material was used (by column chromatography). bYields were quantified by HPLC area.

Condition B. Column: L-Column ODS (4.6 i.d. × 250 mm); eluent: (a) 0.1% trifluoroacetic acid, (b) MeCN, flow rate: 1.0 mL/min., Temperature: 40 °C, Gradient: (b/a) 40/60 (0 min) − 60/40 (0−25 min) − 80/20 (25−30 min), UV detection at 210 nm, 23 major (R,S,R): 17.5 min, 23 minor (R,R,S): 17.7 Table 4. Direct conversion from 23a to 10

HPLC area %b entry

9 (equiv)

1 2 3 4

1.5 1.5 1.5 1.1

base (equiv) K2CO3 (2) Na2CO3 (2) Na2CO3 (2) Na2CO3 (2) isolated crystal

solvent

10 (%)

10 diastereomer (%)c

34 (%)

MeCN (10) MeCN (10) MeCN/H2O (10/0.5) MeCN/H2O (10/0.5)

75.92 3.44 78.58 83.32 (75.2)d 90.26

4.18 0.11 7.41 6.29 7.47

4.46 0.21 0.67 1.23 0.30

a

Extracted AcOEt solution of 23 was used. bThe peaks of residual 9 and 27 were not calculated. cThe configuration of 10 diastereomer is the correspondence with (R,R,S)-23 dReaction yield was calculated by HPLC area from 30-HCl. 1435



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Scheme 9. Endgame

filtrated, washed with isopropyl acetate (26 L), and dried under vacuum to aconstant weight at 50 °C to give 15 (8.11 kg, 72.8%, 97.43 area %, Assay: 96.3%) as a light yellowish white solid.1H NMR (500 MHz, DMSO-d6) a mixture of rotamer: δ 0.74 (t, 3H, J = 7.4 Hz), 0.98 (s, 3H), 1.02−1.03 (m, 3H), 1.16−1.24 (m, 3H), 1.28−1.39 (m, 3H), 1.54−1.59 (m, 4H), 1.65−1.67 (m, 2H), 1.83−1.89 (m, 4H), 1.97 (br s, 1H), 2.17− 2.21 (m, 0.5H), 2.36−2.42 (m, 2H), 2.48−2.56 (m, 2H), 2.76− 2.80 (m, 0.5H), 2.98−3.28 (m, 5H), 3.59 (br s, 1H), 3.80 (br d, 1H, 7.4 Hz), 4.39 (s, 1H), 4.72 (br d, 1H, J = 5.7 Hz), 7.22− 7.25 (m, 1H), 7.36−7.44 (m, 2H), 7.54−7.56 (m, 1H), 7.83− 7.88 (m, 2H), 7.97−8.01 (m, 1H), 8.14−8.16 (m, 1H). 13C NMR (500 MHz, DMSO-d6) a mixture of rotamer: δ 11.69, 18.98, 19.24, 19.30, 21.59, 21.65, 26.04, 29.10, 29.88, 29.92, 29.94, 33.41, 33.45, 36.42, 40.27, 43.22, 44.49, 44.56, 45.34, 50.75, 50.77, 52.12, 52.40, 52.51, 60.05, 65.51, 128.35, 128.37, 129.30, 129.31, 129.35, 129.42, 130.13, 132.42, 133.88, 133.90, 139.10, 147.20, 165.51, 165.54, 174.08. HRMS (ESI) exact mass calcd for C36H49ClN5O8S (M + H) 746.2990, found: 746.3021. (2R,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5oxopiperazin-1-yl]-2-ethyl-4-hydroxy-N-[(2S,5S)-5-hydroxyadamantan-2-yl]hexanamide Monofumarate Dihydrate (1). 1-Decanethiol (4.44 L, 21.44 mol) and water (0.80 L) were added to a mixture of 15 (8.00 kg, 10.72 mol) and potassium carbonate (4.44 kg, 32.16 mol) in acetone 40 L, and stirred under a nitrogen atmosphere at 45−50 °C for 17 h. After the reaction mixture was cooled to 25 °C, ethyl acetate (40 L) and water (24 L) were added. After the layers were separated, the organic layer was washed with 20% aqueous sodium chloride (24 L), and the layers were again separated. After acetone (16 L) and activated carbon (0.40 kg) were added to the organic layer, the suspension was stirred at 25−30 °C for 1 h, then filtrated and washed with acetone (24 L). The filtate was warmed to 40−50 °C, and then fumaric acid (1.24 kg, 10.72 mol) was added at 40−50 °C. After the slurry was stirred at 40−50 °C for 1 h, and cooled to 30 °C, the resultant slurry was

reaction mixture was concentrated under reduced pressure to approximately 18 L. Isopropyl alcohol (18 L) was added at 40− 50 °C to the resulting solution. After confirmation to change the slurry, additional isopropyl alcohol (42 L) was poured at 40−45 °C for over 0.5 h, and the mixture was stirred at 30−40 °C for 12 h. The slurry was cooled to 0−5 °C, and stirred at 2− 5 °C for 3 h. The solid product was filtrated, washed with isopropyl alcohol (12 L), and dried under vacuum to a constant weight at 50 °C to give 10 (8.65 kg, 89.2%, 99.17 area %, Assay: 98.7%) as a yellow solid. 1H NMR (500 MHz, CDCl3) a mixture of rotamers: δ 1.04 (br t, 3H, J = 7.4 Hz), 1.07 (br s, 3H), 1.17 (br s, 3H), 1.56−1.60 (m, 1H), 1.84−1.90 (m, 1H), 2.15 (br s, 0.5H), 2.55−2.91 (m, 4.5H), 3.11−3.30 (m, 3H), 3.63 (br s, 1H), 4.89 (br s, 1H), 5.56 (br s, 0.5H), 5.92 (br s, 0.5H), 7.12−7.20 (m, 1H), 7.26−7.34 (m, 2H), 7.45 (br d, 1H, J = 8.0 Hz), 7.79 (br s, 2H), 7.94 (br s, 1H), 8.17 (br d, 1H, J = 7.4 Hz). 13C NMR (500 MHz, CDCl3) a mixture of rotamer: δ 11.51, 19.35, 19.70, 23.07, 24.59, 25.37, 28.93, 29.21, 40.61, 49.50, 50.53, 52.24, 52.80, 53.05, 54.20, 55.40, 60.45, 60.69, 64.45, 67.64, 125.72, 125.93, 128.13, 128.59, 129.02, 129.45, 130.41, 130.66, 132.04, 132.18, 133.40, 134.11, 138.54, 165.40, 178.97. HRMS (ESI) exact mass calcd for C26H32ClN4O7S (M + H) 579.1680, found: 579.1689. (2R,4S,5S)-6-[4-(2-Chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-2-ethyl-4-hydroxy-N-(5-hydroxyadamantan-2-yl)5-{[(2-nitrophenyl)sulfonyl]amino}hexanamide (15). The mixture of 10 (8.63 kg, 14.90 mol), 4-aminoadamantan-1-ol (12) (7.48 kg, 44.70 mol), triethylamine (0.62 L, 4.47 mmol) and 2-hydroxypyridine (0.33 kg, 3.43 mol) in ethyl acetate (43 L) was stirred under nitrogen at 75−78 °C for 70 h. After cooling to 40 °C, 5% aqueous sodium chloride (26 L) was added. After the layers were separated, the organic layer was washed with 5% aqueous citric acid (26 L) and then the layers were separated. After the organic layer was seeded with 15 (5 g) at 45−50 °C, the clear solution turned into the slurry, and then isopropyl acetate (86 L) was poured into the slurry at 40− 55 °C. The resulting slurry was stirred at 30−40 °C for 15 h, 1436



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stirred at 30 °C for 16 h, filtrated, washed with 98% aqueous acetone (24 L), and dried under vacuum to a constant weight at 50 °C to give crude 1 (6.50 kg, 85.0%, 99.89 area %, Assay: 99.1%) as a white solid. Purification of 1. To a solution of acetone (28L) and water (5 L) was added crude 1 (6.48 kg, 4.54 mol), and the slurry was stirred under nitrogen at 40−50 °C for 6 h. After acetone (65 L) was poured into the slurry at 40−50 °C for over 0.5 h, the mixture was stirred at 40−50 °C for 1 h, and then cooled to 30 °C. After stirring at 30 °C for 16 h, the slurry was cooled to 0− 5 °C. The resulting slurry was stirred at 0−5 °C for 3 h, filtrated, washed with 98% aqueous acetone (19 L), and dried under vacuum to a constant weight at 50 °C to give DS-8108b (1) (6.30 kg, 97.0%, 99.84 area %, Assay: 99.5%) as a white solid. 1H NMR (500 MHz, CD3OD) a mixture of rotamer: δ 0.95 (t, 3H, J = 7.4 Hz), 1.26−1.31 (m, 6H), 1.48−1.68 (m, 5H), 1.75−1.77 (m, 4H), 1.82−1.98 (m, 5H), 2.07 (br s, 1H), 2.11 (br s, 2H), 2.52 (dd, 0.6H, J = 3.7, 13.7 Hz), 2.65−2.79 (m, 1.8H), 2.91−2.96 (m, 0.6H), 3.13−3.21 (m, 1H), 3.26− 3.65 (m, 5H), 3.97 (br s, 1H), 6.68 (s, 2H), 7.32−7.42 (m, 3H), 7.54−7.55 (m, 1H), 7.87 (d, 1H, J = 7.4 Hz). 13C NMR (500 MHz, CD3OD) a mixture of rotamer: δ 12.17, 17.92, 20.12, 22.49, 24.83, 28.01, 31.13, 31.26, 31.38, 35.14, 35.24, 37.80, 45.18, 45.37, 45.47, 45.51, 45.99, 50.21, 50.76, 53.18, 54.01, 54.44, 54.46, 54.74, 54.88, 61.92, 67.86, 68.32, 68.52, 129.51, 129.67, 130.25, 130.48, 130.98, 131.56, 131.65, 133.30, 133.36, 136.29, 139.88, 140.12, 168.76, 168.89, 171.42, 177.69. Anal. Calcd for C34H53ClN4O10: C 57.25; H 7.49; N; 7.89; Cl; 4.97. Found: C 57.27; H 7.48; N 7.86; Cl 4.89. (2E)-4,6-O-benzylidene-2,3-dideoxy-2-ethyl-D-erythro-hex2-enonic acid (19). To a solution of 4,6-O-benzylidene-Dglucopyranose (55.0 kg, 205.00 mol) and potassium bicarbonate (61.6 kg, 615.00 mol) in water (278 L) was added sodium periodate (100.9 kg, 471.50 mol) in water (830 L), maintaining the temperature at 30−40 °C, and the reaction mixture was stirred for 2 h. After cooling to 25−30 °C, ethyl acetate (275 L) and ethyl 2-(triphenyl-λ5-phosphanylidene)butanoate (81.0 kg, 215.25 mol) was added, and reaction mixture was stirred for 14 h at 25−30 °C. After the reaction, the heterogeneous mixture was filtered and washed with ethyl acetate (165 L), and then the filtrate was separated. The organic layer was washed with water (276 L), and the aqueous layer was removed. The organic layer was concentrated under reduced pressure to approximately 110 L. Ethanol (440 L) was added and the mixture concentrated again to approximately 330 L. NaOH (5 N, 97.2 kg, 410.00 mol) was added, and the reaction mixture was stirred for 3 h at 30−35 °C. The reaction mixture was concentrated to approximately 115 L, then water (444 L) was added and filtered, and the filtrate was washed with water (167 L). Then the filtrate was washed with methylisobutylketone (275 L), and then washed two times with methylisobutylketone (135 L) from the aqueous layer to remove triphenylphosphine oxide. Methanol (55 L) was added to the aqueous layer, then conc. HCl (35.2 kg) was added to adjust the pH to 5.0. The slurry was stirred at 25−30 °C for 12 h. The slurry was cooled to 0−5 °C, and stirred at 2−5 °C for 3 h. The solid product was filtrated, washed with 20% aqueous methanol (165 L), and dried under vacuum to a constant weight at 40 °C to give 19 (40.7 kg, 69.7%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 1.12 (t, 3H, J = 7.6 Hz), 2.41− 2.57 (m, 2H), 3.69−3.82 (m, 2H), 4.37 (dd, 1H, J = 4.3, 10.4 Hz), 4.46 (t, 1H, J = 8.6 Hz), 5.58 (s, 1H), 6.80 (d, 1H, J = 8.6 Hz), 7.33−7.40 (m, 3H), 7.48−7.50 (m, 2H).13C NMR (500

MHz, CDCl3): δ 14.17, 21.04, 65.07, 70.76, 78.61, 100.99, 126.14, 128.34, 129.15, 137.16, 137.89, 138.76, 171.75. Anal. Calcd for C15H18O5: C 64.74; H 6.52. Found: C 64.74; H 6.46. N-Cyclohexylcyclohexanamine-4,6-O-benzylidene-2,3-dideoxy-2-ethyl-D-ribo-hexonic Acid (20). To a solution of 19 (40.7 kg, 146.25 mol) and 5% Pd/C(AD) (50% wet, 12.2 kg) in ethanol (407 L) was added ammonium formate (27.7 kg, 438.75 mol) and cyclohexylamine (14.5 kg, 146.25 mol), then the mixture was stirred at 40 °C. Ammonium formate (23.0 kg, 292.5 mol) was added, maintaining the temperature below 45 °C, and the reaction mixture was stirred at 40−45 °C for 10 h. The resulting slurry was filtrated and washed with ethanol (122 L); to the filtrate was added water (204 L). The solution was concentrated to approximately 204 L under reduced pressure, and ethyl acetate (285 L) was added, then the mixture was concentrated again to approximately 204 L. After concentration, ethyl acetate (407 L) and 10% NaCl(aq) (436 kg) were added, and then 5 N HCl (34.9 kg) was added to adjust pH = 4.0, followed by separation of the layers. After the organic layer was washed twice with 10% NaCl(aq) (349 kg), and 20% NaCl(aq) (139 kg) then concentrated to 204 L. Ethyl acetate (407 L) was added and then concentrated to 204 L. Acetone (488 L) was added then concentrated again to 204 L. Acetone (366 L) and dicyclohexylamine (26.5 kg, 146.25 mol) were added and warmed to 35 °C, seeded with 20 (20.4 g) and warmed to 50 °C and stirred for 2 h. The temperature of the slurry mixture was gradually cooled (1 °C/min) to 0−5 °C, and then stirred for 2 h. The resulting slurry was filtered and washed with acetone (204 L), and dried under vacuum to a constant weight at 40 °C to give crude 20 (40.5 kg, 59.8%, dr = 95.0:5.0) as a white solid. Upgrade of 20. Crude 20 (40.5 kg) was added to acetone (406 L), warmed to 50 °C, and stirred for 16 h. Then the temperature of slurry mixture was gradually cooled (1 °C/min) to 0−5 °C and then stirred for 2 h. The resulting slurry was filtered, washed with acetone (81 L), and dried under vacuum to a constant weight at 40 °C to give pure 20 (35.8 kg, 90.7%, dr = 98.5: 1.5) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.95 (t, 3H, J = 7.6 Hz), 1.12−1.30 (m, 7H), 1.38−1.56 (m, 5H), 1.65−1.82 (m, 8H), 2.00−2.01 (m, 4H), 2.08−2.17 (m, 1H), 2.42−2.48 (m, 1H), 2.90−2.98 (m, 2H), 3.50−3.62 (m, 3H), 4.27−4.31 (m, 1H), 5.43 (s, 1H), 7.30−7.38 (m, 3H), 7.46−7.50 (m, 2H).13C NMR (500 MHz, CDCl3): δ 12.04, 24.80, 25.28, 27.46, 29.54, 29.63, 37.12, 46.47, 52.65, 66.76, 71.79, 82.95, 101.02, 126.14, 128.24, 128.80, 138.12, 182.16. Anal. Calcd for C27H43NO5: C 70.25; H 9.39; N; 3.03. Found: C 70.09; H 9.43; N 3.12. Methyl 4,6-O-Benzylidene-2,3-dideoxy-2-ethyl-5-O-(methylsulfonyl)-D-ribo-hexonate (21). To a solution of 20 (35.5 kg, 76.90 mol) in ethyl acetate (355 L) was added 5% citric acid aqueous solution (402 kg), the mixture was stirred, and then the layers were separated. After the organic layer was washed with water (181 L), and aqueous layer was extracted with ethyl acetate (178 L). The organic layers were combined, and then concentrated to 107 L. Dimethyl acetamide (178 L) was added and then concentrated to 200 L. Sodium bicarbonate (9.7 kg, 115.35 mol) and methyl iodide (15.3 kg, 107.71 mol) were heated to 60−65 °C and stirred for 8 h. After reaction completion, toluene (355 L) and water (180 L) were added, and the layers were separated. The organic layer was washed with water (182 L) and then concentrated to 142 L. The solution was cooled to 0−5 °C, and methanesulfonyl chloride (9.7 kg, 84.59 mol) was added. Triethylamine (10.1 kg, 99.97 1437



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mol) was added dropwise to maintain the temperature 0−5 °C, and stirred for 1 h. After reaction completion, 1H-HCl (36.2 kg) was added, and the layers were separated. The organic layer was washed with 5% NaHCO3(aq) (36.8 kg) and washed again with water (36 L). Isopropyl alcohol (355 L) was added, and concentrated to 132 L. Then isopropyl alcohol (220 L) was added, and concentrated to 107 L in twice and adjust to 284L, and 21 (35.5 g) was seeded to the solution at 20−25 °C and stirred for 2 h. Then the mixture was cooled to −10 °C, stirred for 2 h, the resulting slurry was filtered and washed with isopropyl alcohol (71 L), and dried under vacuum to a constant weight at 40 °C to give 21 (26.22 kg, 91.2%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 0.92 (t, 3H, J = 7.8 Hz), 1.52− 1.62 (m, 1H), 1.65−1.78 (m, 2H), 2.21−2.28 (m, 1H), 2.68− 2.75 (m, 1H), 3.10 (s, 3H), 3.64 (s, 3H), 3.73−3.82 (m, 2H), 4.50−4.56 (m, 2H), 5.47 (s, 1H), 7.33−7.40 (m, 3H), 7.44− 7.46 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 11.60, 26.08, 33.60, 38.52, 42.01, 51.53, 68.70, 71.66, 76.91, 101.13, 126.03, 128.26, 129.13, 136.88, 175.97. HRMS (ESI) exact mass calcd for C17H25O7S (M + H) 373.1321, found: 373.1329. Methyl 5-Azido-4,6-O-benzylidene-2,3,5-trideoxy-2-ethylL-xylo-hexonate (22). The mixture of tetrabutylammonium chloride (18.43 kg, 66.32 mol), sodium azide (12.90 kg, 198.96 mol) in dimethyl acetamide (50 L) was stirred under nitrogen at 85−90 °C for 4 h. Then 21 (24.7 kg, 66.32 mol) and dimethyl acetamide (37 L) were added and stirred at 85−90 °C for 72 h. After reaction completion, the reaction mixture was cooled to 20−25 °C, then toluene (124 L) and water (124 L) were added, and the layers were separated. The aqueous layer was extracted with toluene (124 L), and the organic layers were combined and washed twice with water (124 L). Active carbon (4.9 kg) was added and stirred at 20−25 °C for 2 h and then filtered and washed with toluene (50 L). The filtrate was concentrated to 50 L. Isopropyl alcohol (247 L) was added and concentrated to 100 L twice. The resulting slurry was stirred at 20−25 °C for 2 h, filtrated, washed with isopropyl acetate (50 L), and then dried under vacuum to a constant weight at 30 °C to give 22 (13.80 kg, 63.6%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.91 (t, 3H, J = 7.8 Hz), 1.55−1.74 (m, 2H), 1.87−2.06 (m, 2H), 2.66−2.74 (m, 1H), 2.89 (s, 1H), 3.69 (s, 3H), 4.00 (ddd, 1H, J = 2.0, 2.9, 9.8 Hz), 4.20 (dd, 1H, J = 2.0, 11.7 Hz), 4.49 (d, J = 13.7 Hz), 5.55 (s, 1H), 7.33−7.41 (m, 3H), 7.48−7.51 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 11.44, 26.11, 34.42, 42.31, 51.56, 56.26, 70.82, 77.85, 102.14, 126.21, 128.32, 129.15, 137.55, 176.33. HRMS (ESI) exact mass calcd for C16H22N3O4 (M + H) 320.1610, found: 320.1629. N-{(1S)-1-[(2S,4R)-4-Ethyl-5-oxotetrahydrofuran-2-yl]-2hydroxyethyl}-2-nitrobenzenesulfonamide (7).6 The mixture of 22 (13.78 kg, 43.15 mol) and 5% Pd/C (50% wet, 2.1 kg) in cyclopentylmethyl ether (138 L) was stirred under hydrogen at 15−20 °C for 3 h. The reaction mixture was filtered and washed with cyclopentylmethyl ether (69 L). Water (14 L) was added to the filtrate, and the mixture was cooled to 0−5 °C. 2Nitrobenzenesulfonyl chloride (14.32 kg, 64.73 mol), triethylamine (13.14 kg, 129.45 mol), and water (55 L) were added and stirred at 20−25 °C for 18 h. After reaction completion, the layers were separated. The organic layer was washed with 10% citric acid (68.9 kg), and 20% NaCl(aq) (68.8 kg); then the organic layer was concentrated to 69 L. Concentrated HCl(aq) (21.1 kg, 56.1 mol) was added, and stirred for 20 h. The mixture was cooled to 0−5 °C, water (69 L) and ethyl acetate (138 L) were added, and then the layers were separated. The

organic layer was washed twice with 20% Na2S2O5 (82.5 kg), washed again with 10% NaCl (69.9 kg), and then concentrated to 96 L. Cyclopentylmethyl ether (138 L) was added and concentrated to 69 L. The resulting slurry was stirred at 20−25 °C for 3 h and then cooled to 0−5 °C and stirred for 3 h. The slurry was filtrated, washed with cyclopentylmethyl ether (27 L), and then dried under vacuum to a constant weight at 40 °C to give 7 (12.16 kg, 80.0%, dr = >99.9: 0.1) as a white solid. (4S)-3-[(2R,4E)-6-Amino-2-ethylhex-4-enoyl]-4-phenyl-1,3oxazolidin-2-one hydrochloride (30-HCl). To a solution of nbutyryl chloride (16.3 g, 0.153 mol) and (4S)-4-phenyl-1,3oxazolidin-2-one (27) (25.0 g, 0.153 mol) in THF (200 mL) was added lithium hydride (2.0 g, 90% assay, 0.226 mol) at 0− 25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. The reaction mixture was then cooled to −78 °C, LHMDS in THF solution (161 mL, 1.0 M, 0.161 mol) was added for over 0.5 h to maintain the temperature below −60 °C, and the mixture stirred for 0.5 h. trans-Dibromobutene (65.3 g, 0.306 mol) in THF (100 mL) was added and stirred at −40 °C for at least 6 h until completion by HPLC analysis. After the reaction was complete, a solution of aqueous HCl (170 mL, 2 M, 0.340 mol) was added, warmed to 20−25 °C, and stirred for 0.5 h. The layers were then separated, and the aqueous layer was extracted with isopropyl acetate (100 mL). Then the organic layers were combined and washed with 10% aqueous NaHCO3 (50 mL) and 20% NaCl (50 mL). Diastereomeric ratio of 26a was 96:4 (analyzed by HPLC condition A). To a combined solution of 26a, was added in one portion at 20−25 °C hexamethylene tetramine (70.9 g, 0.506 mol) and stirred for at least 1 h until completion by HPLC analysis. After reaction completion, a solution of conc. HCl (210 mL, 12 M, 2.520 mol) was added and stirred for 1 h, and then the layers were separated. The aqueous layer was washed with isopropyl acetate (100 mL); obtained was 30 hydrochloride aqueous solution (30 assay yield: 71.8% from 27). The aqueous layer was concentrated to remove the containing THF. Then water (150 mL) and isopropyl acetate (500 mL) were added and cooled to 0−5 °C. NaHCO3 was added to the mixture until the pH was >9, and the layers were separated. HCl (2 M, 60 mL) was added to the organic layer and stirred at 20−25 °C for 1 h, NaHCO3 was added again to the mixture until the pH was >9, then separated. The organic layer was warmed to70−75 °C, water (1.9 mL) and HCl/AcOEt (4 M, 0.320 mol) was added and stirred for 2 h, then cooled to 20−25 °C. The resulting slurry was further stirred for 14 h, then filtered and washed with isopropyl acetate (50 mL). The wet crystal was dried under vacuum at 40−45 °C to give 34.82 g of 30-HCl as a crystalline solid [62.6% from 27 (analyzed by HPLC condition A) ] 1H NMR (500 MHz, DMSO-d6): δ 8.24 (br, 2H), 7.61−7.36 (m, 2H), 7.31−7.26 (m, 3H), 5.59−5.53 (m, 1H), 5.49−5.43 (m, 2H), 4.74 (t, J = 8.0 Hz, 1H), 4.13−4.11 (m, 1H), 3.73−3.68 (m, 1H), 3.26−3.19 (m, 2H), 2.31−2.26 (m, 1H), 2.13−2.07 (m, 1H), 1.61−1.52 (m, 1H), 1.49−1.41 (m, 1H), 0.82 (t, J = 7.5 Hz, 1H), 13C NMR (500 MHz, DMSO-d6): δ 174.18, 153.51, 139.89, 132.89, 128.77, 127.95, 125.77, 124.60, 69.93, 57.15, 43.05, 40.14, 33.71, 23.39, 11.33 Improved Synthesis: Preparation of 10 from 30-HCl. The solution of NaHCO3 (1.09 g, 12.99 mmol) and water (10 mL) was added to a mixture of 30-HCl (2.0 g, 5.90 mmol), 2nitrobenzenesulfonyl chloride (1.33 g, 5.90 mmol), and AcOEt (20 mL) at 20−25 °C. The reaction mixture was stirred at 20− 25 °C for 3 h. The layers were then separated, and water (10 mL) was added to the organic layer. DBH (0.928 g, 3.54 mmol) 1438



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was added into the mixture at 0−5 °C, and stirred for 2 h. The reaction was quenched by adding 10% Na2S2O3 (2 mL), and the layers were separated. A catalyst amount of Et3N (0.03 g, 0.30 mmol) was added to the organic layer, and stirred for 0.5 h at 20−25 °C. Then the solution was concentrated under reduced pressure until approximately 6 mL. MeCN (20 mL) was added to the mixture and then concentrated twice to 6 mL to afford 23 MeCN solution. Then 9 was added into the solution, and heated to 80−85 °C. Na2CO3 (1.56 g, 14.76 mmol) and water (1 mL) were added and stirred for 1 h. The reaction mixture was cooled to 20−25 °C, 5% NaCl solution (10 mL) was added, and the layers were separated. Then the solution was concentrated under reduced pressure until approximately 6 mL remained. IPA (20 mL) was added to the mixture and then concentrated twice to 20 mL at 50 °C. 10 was crystallized during the concentration, then stirred for 12 h at 0−5 °C. The resulting slurry was filtered and washed with IPA (10 mL). The wet crystal was dried under vacuum at 40− 45 °C to give 2.63 g of 10 as a crystalline solid [76.6% gross yield from 30-HCl as a diastereo mixture (dr = 92.5:7.5) Net yield of major isomer: 67.4% from 30-HCl (analyzed by HPLC condition B) ].

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(11) Nakamura, Y.; Fujimoto, T.; Ogawa, Y.; Namiki, H.; Suzuki, S.; Asano, M.; Sugita, C.; Mochizuki, A.; Miyazaki, S.; Tamaki, K.; Nagai, Y.; Inoue, S.; Nagayama, T.; Kato, M.; Chiba, K.; Takasuna, K.; Nishi, T. Bioorg. Med. Chem. 2013, 21, 3175−3196. (12) Nakamura, Y.; Sugita, C.; Meguro, M.; Miyazaki, S.; Tamaki, K.; Takahashi, M.; Nagai, Y.; Nagayama, T.; Kato, M.; Suemune, H.; Nishi, T. Bioorg. Med. Chem. Lett. 2012, 22, 4561−4566. (13) Confimation of the reverse reaction: 8% of 10 was oberved from pure 15 in the same reaction condition. (14) Node, M.; Kumar, K.; Nishide, K.; Ohsugi, S.; Miyamoto, T. Tetrahedron Lett. 2001, 42, 9207−9210. (15) (a) Li, Y.; Zhou, F.; Forsyth, C. J. Angew. Chem., Int. Ed. 2007, 46, 279−282. (b) Gant, T. G.; Shahbaz, M. M. U.S. Pat. Appl. Publ. 2010/0124550, 20, May, 2010 (16) Overalkylated compound was not isolated. Molecular weight ((ESI) m/z 519 [M + 1]) was confirmed by LC−MS spectral analysis.

(17) The reaction yield was quantified from 27 by HPLC area. (18) Albert, T. B.; Vasu, D.; Jane, K. Organic Syntheses 1963, 43, 6−9. (19) Yamaguchi, Y.; Menear, K.; Cohen, N. C.; Mah, R.; Cumin, F.; Schnell, C.; Wood, J. M.; Maibaum, J. Bioorg. Med. Chem. Lett. 2009, 19, 4863−4867. (20) Chiral auxiliary was not affected the stereoselectivity in bromolactonization because high stereoselectivities were also observed even in the case of achiral dialkylamides. (See Supporting Information.) (21) Dimeric byproduct was not isolated. Molecular weight ((ESI) m/z 761 and 763 [M + 1]) was confirmed by LC−MS spectral analysis.

ASSOCIATED CONTENT

S Supporting Information *

This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Zaman, M. A.; Oparil, S.; Calhoun, D. A. Nat. Rev. Drug Discovery 2002, 1, 621−636. (2) Remuzzi, G.; Perico, N.; Macia, M.; Ruggenenti, P. Kidney Int. 2005, 68, S57−S65. (3) Bezençon, O.; Bur, D.; Weller, T.; Richard-Bildstein, S.; Remeň, L.; Sifferlen, T.; Corminboeuf, O.; Grisostomi, C.; Boss, C.; Prade, L.; Delahaye, S.; Treiber, A.; Strickner, P.; Binkert, C.; Hess, P.; Steiner, B.; Fischli, W. J. Med. Chem. 2009, 52, 3689−3702. (4) Jia, L.; Simpson, R. D.; Yuan, J.; Xu, Z.; Zhao, W.; Cacatian, S.; Tice, C. M.; Guo, J.; Ishchenko, A.; Singh, S. B.; Wu, Z.; McKeever, B. M.; Bukhtiyarov, Y.; Johnson, J. A.; Doe, C. P.; Harrison, R. K.; McGeehan, G. M.; Dillard, L. W.; Baldwin, J. J.; Claremon, D. A. ACS Med. Chem. Lett. 2011, 2, 747−751. (5) Maibaum, J.; Stutz, S.; Göschke, R.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Rahuel, J.; Baum, H. P.; Cohen, N. C.; Schnell, C. R.; Fuhrer, W.; Gruetter, M. G.; Schilling, W.; Wood, J. M. J. Med. Chem. 2007, 50, 4832−4844. (6) Nakamura, Y.; Fujimoto, T.; Ogawa, Y.; Sugita, C.; Miyazaki, S.; Tamaki, K.; Takahashi, M.; Matsui, Y.; Nagayama, T.; Manabe, K.; Mizuno, M.; Masubuchi, N.; Chiba, K.; Nishi, T. ACS Med. Chem. Lett. 2012, 3, 754−758. (7) (a) Wascholowski, V.; Giannis, A. Angew. Chem., Int. Ed. 2006, 45, 827−830. (b) Nishii, Y.; Higa, T.; Takahashi, S.; Nakata, T. Tetrahedron lett. 2009, 50, 3597−3601. (8) (a) Liang, N.; Datta, A. J. Org. Chem. 2005, 70, 10182−10185. (b) Gu, W.; Silverman, R. B. J. Org. Chem. 2011, 76, 8287−8293. (9) Tamaru, Y.; Mizutani, M.; Furukawa, Y.; Kawamura, S.; Yoshida, Z.; Yanagi, K.; Minobe, M. J. Am. Chem. Soc. 1984, 106, 1079−1085. (10) Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fässler, A. Tetrahedron Lett. 2000, 41, 10091−10094.

(22) Net yield was calculated by the assay of 10 and gross of 30-HCl (Assay of 30-HCl was not confirmed). (23) Regarding the enantiopurity, purification effects have not been confirmed yet in each intermediate (30-HCl, 10, 15).

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Convergent Asymmetric Synthesis of a Renin Inhibitor: A Highly

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