Asymmetric Synthesis of Silanediol Inhibitors for the Serine Protease

Apr 18, 2018 - Figure 1. Simplified depiction of the of serine protease cascade that .... we added a Boc group to the tosyl amide nitrogen of 20 under...
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Article Cite This: J. Org. Chem. 2018, 83, 5398−5409

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Asymmetric Synthesis of Silanediol Inhibitors for the Serine Protease Coagulation Cascade Enzyme FXIa Hoan Q. Duong† and Scott McN. Sieburth*,‡ †

Department of Chemistry, Hanoi National University of Education 136 Xuan Thuy Street, Cau Giay District, Hanoi, Vietnam Department of Chemistry, Temple University, 1901 North 13th Street, Philadelphia, Pennsylvania 19122, United States

‡

S Supporting Information *

ABSTRACT: Silanediol peptidomimetics have been prepared, designed to inhibit the serine protease enzyme Factor XIa (FXIa) for treatment of thrombosis without complete interruption of normal hemostasis. These Arg-[Si]-Ala analogues of the FXIa substrate (FIX) are the first silanediol dipeptide analogues to carry a basic guanidine group. Control of stereochemistry was accomplished using catalytic asymmetric hydrosilylation and addition of a silyllithium intermediate to the Davis−Ellman sulfinimine.

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INTRODUCTION Coagulation is a critical component of blood chemistry, intrinsic to maintaining the integrity of the circulatory system, and is therefore carefully regulated.1 Rapid response of coagulation to an injury is accomplished through a cascade of serine protease enzymes in which the proteases (e.g., Factor XIIa, Figure 1) cleave and activate other serine protease

Our silicon-based protease inhibitors employ silanediols embedded within a peptide or peptide-like structure.4 Biologically active organosilanes have been studied for more than half a century.5−13 The silanediol was conceived as a mimic of a hydrated carbonyl, anticipating that such a functional group, replacing a protease-targeted amide, would be recognized and held tightly at the enzyme active site, resulting in inhibition.4,14 Dialkylsilanediols, as nonhydrolyzable analogues of the tetrahedral intermediate of amide hydrolysis, have been found to be low nanomolar inhibitors of enzymes representing three of the four classes of protease enzymes (they have not yet been tested with cysteine proteases). These include inhibitors of angiotensin-converting enzyme (ACE) and thermolysin,15−19 both metalloproteases, the aspartic protease the HIV-1 protease,20 and the serine protease α-chymotrypsin.21 In all of these cases, the silanediol inhibitor was designed by analogy to previously described carbon- or phosphorus-based inhibitors of those enzymes. The importance of the coagulation cascade in an array of diseases,22 the potential for modulation by serine protease inhibition, and the fact that few small molecule inhibitors had yet been described made inhibition of Factor XIa of great interest.23−27 In addition, the polar amino acid sequence adjacent to the amide bond cleavage site would allow us to explore the use of our silanediol synthesis strategy in a challenging chemical environment. We describe here our design approach and construction of the FXIa inhibitor.

Figure 1. Simplified depiction of the of serine protease cascade that mediates a fast coagulation response the Factor XIa target.

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precursors (i.e., Factor XI → Factor XIa) that activate other serine proteases (FIX → FIXa, for example) and so on.2 While arresting blood flow (hemostasis) through coagulation (clotting) is obviously important, prevention of clotting can be a priority immediately following a stroke, for example. Stroke therapy with an anticoagulant that can also avoid hemorrhage would have an important advantage. It has been suggested that FIXa would be an optimal target for such a therapeutic species.3 © 2018 American Chemical Society

INHIBITOR DESIGN The substrate for Factor XIa is Factor IX, a 461 amino acid protein that contains a key disulfide bond. Transformation of Factor IX into its activated form Factor IXa involves two sequential amide bond cleavages, Figure 2. In both cases the Received: January 14, 2018 Published: April 18, 2018 5398

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

Article

The Journal of Organic Chemistry cleavage sites are flanked by an arginine residue and a lipophilic group. The Arg145-Ala146 amide is cleaved first, followed by Arg180-Val181.28

Scheme 2. Sulfinimine Synthesis

Figure 2. Two Factor XIa cleavage sites of Factor IX.

On the basis of the cleavage sites for FIXa, the silanediol dipeptide mimic 1 in Scheme 1 was chosen as our first target

Following oxidation of the alcohol with PCC, the pure aldehyde 6 could be isolated by distillation (60%).33 While the overall yield of this aldehyde was modest, the procedure was practical and could easily be used to prepare tens of grams of product. Condensation of the aldehyde with the Ellman and Davis (R)-sulfinamines gave the sulfinimines 7 and 8, respectively, both in 72% yield. With the two sulfinimines in hand, the requisite silyllithium precursors (S)-4 and 12 were synthesized, Scheme 3. We have

Scheme 1. Central Silanediol Dipeptide Mimic 1 and Its Synthetic Precursors

Scheme 3. Diphenylsilyllithium Precursor Syntheses

from which we could build inhibitors. This unit would carry the presumably critical guanidinyl propyl side chain and the simpler of the two lipophilic side chains, the methyl group of the alanine-192 residue. Cleavage of the Arg145−Ala146 amide is also the first proteolytic cleavage of the Factor IX activation pathway. The presence of the very polar guanidinium side chain was expected to make synthesis of 1 and its derivatives more challenging than previously prepared silanediol inhibitors, and therefore, this would be a good substrate with which to evaluate the preparative chemistry developed in our laboratory. Initially, this dipeptide mimic would be coupled with amino acids at the amine and acid ends to probe nearby substrate recognition sites. The target 1 was anticipated to be derived from 2 in which the silanediol is carried as an acid-labile and chemically robust diphenylsilyl moiety, where hydrolysis/deprotection of the silanediol would be the last step of enzyme inhibitor synthesis.4 The guanidine would be installed from an alcohol precursor. Intermediate 2 would be prepared by reacting a Davis−Ellman sulfinimine 329,30 with a silyllithium reagent derived from homochiral 4.31 Protocols originally developed by Nielsen and Skrydstrup for the addition of diphenylsilyllithium reagents to sulfinimines have been found to give complete control of the αaminosilane stereogenic center.32

previously described the intramolecular hydrosilylation of 9 using rhodium and the ferrotane ligand to produce 4 in greater than 90% enantiomeric excess.31 Racemic 12, a potential precursor to racemic 4 and a more easily synthesized test silane, could be prepared on a large scale and in a single step (80%) by radical hydrosilylation of methallyl alcohol 11 using diphenylsilane 10.34 Exploration of the synthetic pathways leading to the first derivatives of 1 was initially conducted with racemic 12, described below. Subsequent synthesis using enantiomerically pure 4 to give full control of the two stereogenic centers of 1 is then described and detailed in the Supporting Information. Starting with racemic silane 12, treatment with lithium led to formation of dianion 13 which, on addition of the Ellman sulfinimine 7, gave coupled product 14 as a 1:1 mixture of diastereomers in 59% yield, Scheme 4. Compound 14 has the complete carbon skeleton of the target 1; however, it carries two acid-labile protecting groups with selective hydrolysis of the sulfinamide the desired next step. Loss of the MOM group would yield an intermediate with two primary alcohols that might be difficult to differentiate chemically. Unfortunately, treatment of 14 with 1 equiv of HCl in dioxane, followed by acetyl chloride and triethylamine, resulted in a complex mixture. An easy workaround, albeit less desirable than selective hydrolysis of the sulfinamide of 14, was to first protect the

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INITIAL SURVEY OF THE SYNTHESIS ROUTE The requisite sulfinimines 7 and 8 were prepared from 1,4butanediol by protecting the diol with a methoxymethyl group followed by PCC oxidation, Scheme 2. Monoprotection of the diol suffered from the expected low selectivity, and distillation of the mixture gave a 53% yield of the desired monoprotected diol mixed with the doubly protected diol in a ratio of 9:1. 5399

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

Article

The Journal of Organic Chemistry Scheme 4. Ellman’s Sulfonamide Proved Difficult To Hydrolyze

Scheme 6. Unexpectedly Facile Cyclization of the Tosyl Amide

proceeded without incident. Mixing this mesylate with sodium azide in DMF, however, led to cyclization and formation of the proline-alanine-like structure 23. At 50 °C, this cyclization was complete within 20 min, and even in the absence of sodium azide the cyclization still occurred in DMF but required 6 h. Cyclization of 4-(mesyloxy)-1(N)-butylsulfonamide structures has been commonly performed, but in all cases these cyclizations involved the use of a base such as potassium carbonate.37−39 While this appears to be a very useful approach to proline-containing silanediol dipeptide analogues, it was not useful for the goals of this study. Returning to intermediate 20, we focused on exchanging the tosyl group for a Boc group, Scheme 7. Following the examples

primary alcohol of 14 with the very robust tert-butyldiphenylsilyl (TPS) group. The Hardinger protocol then gave 16 in high yield.35 Nevertheless, hydrolysis of the Ellman sulfonamide in 16 followed by acetylation gave the desired product 17 in low yield. Alternate chemistry was clearly desirable. Presented with these Ellman sulfoximine difficulties, we turned our attention to using the original Davis sulfoximine, Scheme 5.29 This path was pursued with the anticipation that

Scheme 7. Tosyl to Boc Conversion, Azide Introduction, and Acetylation of the Nitrogen

Scheme 5. Davis Sulfoximine-Derived 18 and Oxidation to a Tosyl Group

provided by Ragnarsson and Muir,40−42 we added a Boc group to the tosyl amide nitrogen of 20 under standard conditions: ditert-butyl dicarbonate with DMAP in acetonitrile. Despite the potential issues of steric interference from the adjacent alkyldiphenylsilyl substituent, this reaction proceeded in good yield and without difficulty, yielding 24 (89%). Reductive removal of the tosyl group using magnesium in methanol gave Boc-protected amine 25 in 90% yield. With 25 in hand, the MOM group was removed with BBr3, and the resulting alcohol was converted to a mesylate. Warming this mesylate with sodium azide in DMF gave the desired azide 26 in 52% yield for the three steps. The Boc group of 26 was easily removed using 4 M HCl in dioxane, and the resulting amine was converted to the acetamide 27 using acetyl chloride. The yield of 27 under these conditions was low, however (25%). Using identical Boc deprotection conditions followed by coupling with acetic acid using (dimethylamino)-N,Ndimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU) and 4-methylmorpholine (NMM) gave 27 in a much more acceptable 72% overall yield. Reduction of azide 27 was accomplished by hydrogenation with Lindlar’s catalyst, Scheme 8. While this seemed to effect azide reduction, the resulting product was surprisingly complex. This difficulty was solved by addition of di-tert-butyl

the sulfoxamide could be removed using magnesium in methanol after oxidation of the sulfoxamide to a tosyl group, conditions that would be compatible with the targeted structures but not available with the Ellman reagent. Addition of the silyllithium reagent derived from racemic alcohol 12 to sulfonimine 8 gave diphenylsilyl product 18 in good yield, again as a 1:1 mixture of diastereomers, Scheme 5. Attempting to oxidize the alcohol and the sulfur in 18 simultaneously using Weinreb’s combination of ruthenium chloride and sodium periodate gave a disappointingly low yield of the tosylamide carboxylate 19.36 The two-step alternative, however, oxidation of the sulfoxamide to a tosylamide with mCPBA followed by oxidation of the alcohol to an acid, proceeded to give 19 in an acceptable 56% overall yield. Coupling of the acid with methylamine using a mixed anhydride gave the N-methylamide 20 in high yield. With 20 in hand, conversion of the MOM-protected alcohol into a guanidine unit was explored, Scheme 6. Hydrolysis of the MOM group and conversion of the alcohol to a mesylate 5400

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

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The Journal of Organic Chemistry Scheme 8. Azide to Guanidine and Hydrolysis of the Diphenylsilyl Group

Scheme 9. Asymmetric Synthesis of the Smallest Arg[Si]Ala Dipeptide Derivative

dicarbonate to the reduction reaction mixture, which trapped the primary amine, and the Boc-derivatized product 28 was isolated in quantitative yield.43 The last two goals of this exercise were conversion of the Boc-protected primary amine to a guanidine and hydrolysis of the diphenylsilyl group to a silanediol. Treatment of 28 with hydrochloric acid in dioxane removed the Boc group. Neutralizing the resulting ammonium salt in the presence of N,N′-di-Boc-thiourea and mercuric chloride installed the doubly Boc-protected guanidine group in 85% yield.44 Removal of the two Boc groups would leave only hydrolysis of the phenyl groups on the silicon. In the past, we have accomplished the latter transformation in two ways: with mercuric chloride as the electrophile and with strong acid.15,18 Using a proton as the electrophile was clearly more desirable. In this ultimate step of the synthetic sequence, treatment of 29 with triflic acid at 0 °Cour standard phenylsilane hydrolysis conditions18proved to be inadequate to remove both of the phenyl groups. This may be a consequence of the three to four positive charges expected to surround the silicon center before ipso protonation of the phenyl groups: both amides are presumably protonated under these conditions as well as the guanidine group. Moreover, with triflic acid the guanidine itself could be doubly charged. Switching to acetic acid to remove the Boc groups, the resulting guanidinium intermediate was therefore treated with mercuric chloride. This procedure fully removed both phenyl groups from silicon and gave 30, the smallest of the silanediol dipeptide targets, albeit with one stereocenter uncontrolled. Synthesis of this silanediol with full control of stereochemistry as well as more complex analogues became the next objective.

displacement with azide formed 36 in 52% yield for the three steps. Replacement of the Boc group with an acetyl group (HCl followed by acetic anhydride) and then hydrogenation of the azide in the presence of di-tert-butyl dicarbonate produced Bocprotected 37 (88% for two steps). Assembly of the protected guanidine unit was accomplished by removal of the Boc group of 37 followed by condensation of the primary amine with doubly Boc-protected thiourea to give 38 in 90% yield. After acetic acid deprotection of the guanidine the two phenyl-silicon bonds were hydrolyzed using mercuric acetate to give 39, the first silanediol target. To build analogues of 39 with more elaborate amine substituents, we returned to azide intermediate 36, Scheme 10. Removal of the Boc group with 4 M hydrochloric acid in dioxane was followed by coupling with N-acylalanine (A), as well as two N-acylated dipeptides Leu-Ala (B) and Pro-Ala (C), using HATU to give 40A−C in reasonable yields. Each of these products was then taken through the four-step sequence to convert the azide to a guanidine (overall 51−55% overall) followed by hydrolysis of the phenyl−silicon bonds of 42. Each reaction proceeded without incident, yielding 43A−C in overall yields of 71−73%. A derivative was also prepared on the carboxylate end of the N-acyl Arg-[Si]-Ala, Scheme 11. Using the sequence described in Scheme 5, alanine N-methyl amide was coupled with acid 33 using HATU to give amide product 44 in moderate yield. Replacement of the N-tosyl group with a Boc group, using NBoc derivatization (54%) followed by reductive elimination of the tosyl group (magnesium in methanol), gave 45 in 82% yield. Treatment of this mesylate with sodium azide in DMF

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ASYMMETRIC SYNTHESIS OF THE INHIBITORS With a workable synthetic sequence in place, we turned our attention to control of both stereogenic centers. Beginning with silafuran 4, prepared in >90% ee by asymmetric intramolecular hydrosilylation, reductive ring opening with lithium gave dianion 31.31 Addition of the Davis sulfinimine 8 to this dianion gave alcohol 32 as a single diastereomer in 75% overall yield, Scheme 9. Following our defined synthesis path, oxidation of the sulfinimine to a tosyl group (89%) and oxidation of the primary alcohol to an acid (68%) gave 33. After formation of the N-methylamide (92%) the tosyl group was replaced with a Boc group using the method of Ragnarsson and Muir (74%).40 Careful removal of the MOM group using TMSBr at −78 °C for 45 s, conversion of the alcohol to a mesylate, and 5401

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

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The Journal of Organic Chemistry Scheme 10. Preparation of Three Arg-[Si]-Ala Derivatives as Potential Inhibitors of Factor IX

Scheme 11. Preparation of a Carboxylate Derivative of Arg[Si]-Ala as a Potential Inhibitor of Factor IX

prepared by asymmetric intramolecular hydrosilylation, whereas the α-aminosilane stereocenter was assembled by intermolecular addition of a silyllithium reagent, prepared by reductive opening of a 2-silafuran, to a Davis sulfinimine. The Davis reagent proved to be important for manipulation of the nitrogen protecting group because it could be cleaved by reduction with magnesium. The full carbon skeleton of the silyl dipeptide was assembled rapidly and with control of the two stereogenic centers; however, the subsequent chemistry involved substantial functional group manipulation. Oxidation of the primary alcohol to an acid was straightforward, although the facile sulfur oxidation of the Davis-derived sulfinamide was a complication. Most of the synthetic steps reported here involved conversion of the alcohol of the protected 3-hydroxy-1-propyl substituent to a guanidine. More efficient approaches to introduce this substitution can be envisioned, and this is an objective for future efforts. In addition, conversion of the diphenylsilyl group in the ultimate deprotection step to a silanediol proved to be problematic as our standard treatment with triflic acid was ineffective. The stability of the phenylsilane bond in the context of these peptide structures may be a result of the proximal guanidinium group, but this remains to be more fully defined. The use of mercury reagents to effect this transformation was undesirable. Activated (more electron rich) phenyl groups should be easier to remove with acid and should be examined. In this context, the substituted diphenylsilane chemistry developed by Skrydstrup et al. could be an important contribution to these useful building blocks.45 Inhibition of Factor XIa catalysis by these four potential inhibitors will be reported elsewhere.

gave 46 in modest yield. The remaining Boc group was removed with hydrochloric acid in dioxane, and the amine was condensed with acetic acid to yield 47 (68%). Conversion of the azide to a protected guanidine by reduction to the amine in the presence of di-tert-butyl dicarbonate, Boc removal with hydrochloric acid, and mercury-mediated condensation of the amine with N,N′-di-Boc thiourea gave 48 in 85% yield. Removal of the Boc groups with acetic acid followed by mercuric acetate hydrolysis of the silicon−phenyl bonds gave silanediol 49.

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CONCLUSION We have developed a synthetic sequence to prepare silanediol mimics of a hydrated Arg−Ala dipeptide and assembled a set of potential inhibitors of Factor IXa, a target for therapeutic intervention of the coagulation cascade. The silanediol targets contain two stereogenic centers. The methyl stereocenter was 5402

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

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The Journal of Organic Chemistry

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(R)-N(1R)-[((2S)-3-Hydroxy-2-methylpropanyl)diphenylsilyl](4-methyoxymethoxy)butyl-2-methylpropanesulfinamide (14). Following the procedure for synthesis of sulfinamide 21, using (S)-4-methyl-2,2-diphenyl-1-oxa-2-silacyclopentane 4 (5.0 g, 19.6 mmol), THF (30 mL), lithium metal (0.54 g, 77.1 mmol), and sulfinimine 7 (1.53 g, 6.5 mmol) in THF (10 mL) gave sulfinamide 14 (1.6 g, 53%) following flash column chromatography. Further purification by column chromatography over neutral alumina oxide gave an analytical sample: Rf = 0.35 (hexanes/ethyl acetate 1:2); [α]20 D = −28.6 (c 0.31, CHCl3); IR ν (cm−1) 3398 (br), 3068, 3048, 2950, 2923, 2871, 1456, 1427; 1H NMR (400 MHz, CDCl3) δ 7.6−7.35 (m, 10H), 4.58 (s, 2H), 3.53−3.40 (m, 3H), 3.35−3.27 (m, 2H), 3.3 (s, 3H), 2.8 (d, J = 9.7 Hz, 1H), 2.2−1.94 (m, 2H), 1.77−1.64 (m, 3H), 1.53−1.47 (m, 1H), 1.38 (dd, J = 15.2, 5.0 Hz, 1H), 0.77 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.8, 133.5, 130.1, 130.0, 128.3128.3, 96.5, 70.3, 67.6, 56.7, 55.3, 46.5, 32.1, 30.2, 27.9, 22.9, 20.0, 16.5; HRMS (ESI-TOF) m/z [M − H]+ calcd for C26H42NO4SSi 492.2598, found 492.2578. (R)-N(1R)-([(2S)-(3-(tert-Butyld iphenylsilyl)oxa)-2methylpropanyl]diphenylsilyl)(4-methyoxymethoxy)butyl-2methylpropanesulfinamide (16). To a solution of the sulfinamide 14 (1.0 g, 2.0 mmol) and tert-butyldiphenylsilyl chloride (0.66 mL, 2.4 mmol) in DMF (7.0 mL) at rt was added AgNO3 (1.02 g, 6 mmol). The solution was stirred at rt for 10 min, diluted with water (40 mL) and ethyl acetate (40 mL), and filtered through a pad of Celite. The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with water (3 × 15 mL) and brine (2 × 10 mL), dried over Na2SO4, and concentrated in vacuo. Column chromatography on silica gel gave 16 (1.2 g, 82%): Rf = 0.42 (hexanes/ethyl acetate 1:1); [α]20 D = −22.6 (c 0.11, CHCl3); IR ν (cm−1) 3397, 3069, 3047, 2953, 2928, 2858, 1588, 1471, 1427; 1H NMR (400 MHz, CDCl3) δ 7.6−7.3 (m, 20H), 4.55 (s, 2H), 3.52− 3.46 (m, 2H), 3.39−3.32 (m, 2H), 3.3 (t, J = 6.7 Hz, 1H), 3.2 (s, 3H), 2.6 (d, J = 10.4 Hz, 1H), 2.0−1.9 (m 2H), 1.76−1.64 (m, 2H), 1.4 (dd, J = 14.9, 4.0 Hz, 1H), 1.02 (s, 9H), 1.00 (s, 9H), 0.93 (dd, J = 15.0, 9.0 Hz, 1H), 0.7 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.8, 134.1, 133.5, 133.4, 130.0, 129.9, 129.7, 128.2, 128.1, 127.8, 96.5, 71.2, 67.6, 56.7, 55.3, 46.8, 32.1, 30.4, 27.9, 27.1, 23.0, 19.8, 19.5, 16.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C42H60NO4SSi2 730.3776, found 730.3783. N(1R)-([(2S/R)-[3-(tert-Butyldiphenylsilyl)oxa]-2-ethylpropanyl]diphenylsilyl)(4-methyoxymethoxy)butylacetamide (17). To a solution of sulfinamide 9 (0.2 g, 0.27 mmol) in ether (4 mL) was added 4 M HCl in dioxane (67.0 μL, 0.27 mmol). The solution was stirred at rt for 20 min and concentrated in vacuo to give a crude ammonium salt. This salt was dissolved in dichloromethane (3 mL), and after the salt was cooled to 0 °C, triethylamine (113 μL, 0.81 mmol) and acetyl chloride (54 μL, 59 mg, 75 mmol) were added. The mixture was stirred at rt for 5 h and diluted with dichloromethane (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with 5% HCl (2 × 5 mL) and 5% NaHCO3 (2 × 5 mL), dried over Na2SO4, and concentrated in vacuo. Column chromatography gave amide 17 (27 mg, 20%): Rf = 0.4 (hexane/ethyl acetate 1:2); IR ν (cm−1) 3282, 3069, 3048, 2930, 2857, 1643, 1539, 1427 ; 1H NMR (400 MHz, CDCl3) δ 7.6−7.3 (m, 20H), 4.9 (d, J = 10.8 Hz, 1H), 4.5 (s, 2H), 4.3−4.2 (m, 1H), 3.5−3.4 (m, 2H), 3.3−3.2 (m, 2H), 3.2 (s, 3H), 1.87 (s, 3H), 1.9−1.5 (m, 4H), 1.3 (dd, J = 15.4, 4.6 Hz, 1H), 1.0 (s, 9H), 0.9−0.7 (m, 1H), 0.7 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 169.6, 135.6, 135.5 (135.4), 133.96 (133.91), 133.90 (133.86), 133.6 (133.4), 132.8(132.6), 129.84 (129.80), 129.5 (129.4), 128.1 (128.0), 127.6 (127.5), 96.34 (96.31), 71.2 (71.05), 67.2, 55.08 (55.06), 36.8 (36.7), 31.8 (31.7), 28.4 (28.35), 27.3 (27.2), 26.93 (26.91), 23.4, 19.5, 19.3 (19.2), 15.4 (15.2); HRMS (ESI-TOF) m/z [M + H]+ calcd for C40H54NO4Si2 668.3586, found 668.3572. N-[(R)-1-[((S)-3-Hydroxy-2-methylpropyl)diphenylsilyl]-4(methoxymethoxy)butyl]-4-methylbenzenesulfonamide. To a solution of 32 (6.0 g, 9.5 mmol) in CH2Cl2 (50 mL) at 0 °C was added m-CPBA (77%, 2.8 g, 12.3 mmol). The reaction mixture was stirred at the same temperature for 1 h, quenched with saturated

EXPERIMENTAL SECTION

General Information. All chemicals were obtained from commercial suppliers and were distilled before use. Chromatography was carried out using Merck 60 230−400 mesh silica gel. IR spectra of liquids were recorded as a thin film on Jasco FT-IR 4700. NMR spectra were recorded an Agilent QTOF-HRMS at the Temple University Chemistry Department. Chemical shifts in NMR spectra are expressed in ppm. All NMR spectra were obtained in CDCl3, MeOD, or D2O. [S(R)]-4-Methyl-N-[4-(methoxymethoxy)butylidene]benzenesulfinamide (8). To a solution of (R)-4-methylbenzenesulfinamide (10 g, 65.5 mmol) in dichloromethane (130 mL) was added Ti(OEt)4 (75.0 g, 327.5 mmol) followed by 4-(methoxymethoxy)butanal33 6 (10.3 g, 78.6 mmol). The mixture was stirred at rt for 48 h, diluted with water (500 mL) and dichloromethane (200 mL), and then filtered through a pad of Celite. The residue was rinsed with dichloromethane (3 × 50 mL), and the aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with water (3 × 50 mL) and brine (2 × 20 mL), dried over Na2SO4, and concentrated in vacuo. Flash column chromatography (hexanes/ethyl acetate 2:1) gave sulfinimine 8 (12.6 g, 72%) as a pale yellow liquid: Rf = 0.52 (hexanes/ethyl −1 acetate 2:1): [α]20 D = −261.4 (c, 1.34, CHCl3); IR ν (cm ) 3030, 2929, 2884, 1722, 1621, 1596; 1H NMR (400 MHz, CDCl3) δ 8.2 (t, J = 5.2 Hz, 1H), 7.5 (dd, J = 8.0, 1.1 Hz, 2H), 7.3 (d, J = 8 Hz, 2H), 4.5 (s, 3H), 3.5 (t, J = 6.3 Hz, 2H), 3.3 (s, 3H), 2.6−2.5 (m, 2H), 2.4 (s, 3H), 1.92 (dt, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.0, 142.1, 142.0, 130.1, 124.9, 96.7, 66.9, 55.5, 33.1, 25.8, 21.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H20NO3S 270.1158, found 270.1161 [S(R)]-N-[4-(Methoxymethoxy)butylidene]-2-methyl-2-propylsulfinamide (7). Following the procedure for synthesis of sulfinimine 8, using (R)-2-methyl-2-propanesulfinamide (5.0 g, 40.3 mmol), Ti(OEt)4 (46.0 g, 201.5 mmol), dichloromethane (100 mL), and aldehyde 6 (6.4 g, 48.4 mmol) gave sulfinimine 7 (8.0 g, 85%). Rf = 0.55 (hexanes/ethyl acetate 2:1); [α]20 D = −227.2 (c, 1.23, CHCl3); IR ν (cm−1) 3230, 2949, 2929, 2884, 2783, 1623, 1474; 1H NMR (400 MHz, CDCl3) δ 8.1 (t, J = 3.6 Hz, 1H), 4.6 (s, 2H), 3.5 (t, J = 6.6 Hz, 2H), 3.3 (s, 3H), 2.6 (dt, J = 8.0, 5.1 Hz, 2H), 1.97−1.90 (m, 2H), 1.18 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 169.2, 96.7, 66.9, 56.8, 55.4, 33.2, 25.8, 22.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C10H22NO3S 236.1315, found 236.1310. (R)-N(1R)-[(2S)-3-Hydroxy-2-methylpropanyl]diphenyl-silyl(4-methyoxymethoxy)butyl-p-toluenesulfinamide (32). To a solution of (S)-4-methyl-2,2-diphenyl-1-oxa-2-silacyclopentane 4 (5.0 g, 19.6 mmol) in THF (30 mL) at 0 °C was added lithium metal (2.7 g, 386 mmol). The mixture was stirred at 0 °C for 48 h to generate silyl dianion 31 that was transferred via cannula to a −78 °C solution of sulfinimine 8 (1.75 g, 6.5 mmol) in THF (10 mL). The mixture was stirred at −78 °C for 5 h and at rt overnight. The solution was cooled to 0 °C and diluted with 10% NH4Cl solution (150 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with water (3 × 50 mL) and brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography over silica gel (hexanes/ethyl acetate 1/1, then 1/2, 4/1 and 0/1) gave sulfinamide 32 (2.5 g, 75%). Further purification over neutral alumina oxide gave an analytical sample: Rf = 0.35 (hexanes/ethyl acetate 1:2); [α]20 D = −33.6 (c 0.11, CHCl3); IR ν (cm−1) 3323(br), 3220, 3107, 2924, 2873, 1595, 1492; 1H NMR (500 MHz, CDCl3) δ 7.64 (dd, J = 8.0, 1.6 Hz, 2H), 7.54 (dd, J = 8.3, 1.6 Hz, 2H), 7.48−7.33 (m, 8H), 7.2 (d, J = 7.9 Hz, 2H), 4.52 (s, 2H), 3.72 (d, J = 9.6 Hz, 1H), 3.65 (dt, J = 9.0, 3.2 Hz, 1H), 3.43−3.31 (m, 4H), 3.28 (s, 3H), 2.39 (s, 3H), 1.97 (br, 1H), 1.87−1.73 (m, 3H), 1.58 (dd, J = 15.1, 5.2 Hz, 1H), 1.56−1.49 (m, 1H), 1.41−1.33 (m, 1H), 1.0 (dd, J = 15.1, 8.3 Hz, 1H), 0.78 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 142.8, 141.2, 135.7, 135.6, 133.4, 133.2, 129.9, 129.8, 129.4, 128.1, 125.6, 96.2, 70.1, 67.3, 55.0, 44.4, 31.9, 29.7, 27.6, 21.3, 19.8, 16.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H39NNaO4SSi 548.2267, found 548.2261. 5403

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

Article

The Journal of Organic Chemistry

1.06 (m, 12H), 1.02 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 178.2, 177.4, 143.28, 143.25, 139.7, 138.9, 136.0, 135.9, 135.7, 135.66, 135.64, 133.59, 133.54, 133.0, 132.1, 130.26, 130.21, 130.16, 129.86, 129.82, 128.4, 128.37, 128.31, 127.9, 127.4, 127.3, 96.4, 96.3, 67.6, 67.5, 55.36, 55.32, 42.9, 42.2, 37.3, 37.1, 29.3, 28.7, 27.7, 27.3, 27.2, 26.6, 26.4, 22.3, 21.9, 21.8. (S)-3-[Diphenyl((R)-1-tosylpyrrolidin-2-yl)silyl]-N,2-dimethylpropanamide (23). To a solution of sulfonamide 20 (0.15 mg, 0.26 mmol) in methanol (1.0 mL) at rt was added 36% HCl solution (0.82 mL, 1.0 mmol). The resulting solution was stirred overnight, diluted with water (20 mL), and extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with water (3 × 10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the crude alcohol (136 mg, 99%). This alcohol was dissolved in dichloromethane (5 mL) and cooled to 0 °C. After addition of triethylamine (108 μL, 0.78 mmol) and methanesulfonyl chloride (72.5 μL, 0.3 mmol), the mixture was stirred for 30 min and then diluted with water (10 mL). The aqueous phase was extracted with dichloromethane (3 × 5 mL). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, and concentrated in vacuo to give mesylate 22. The mesylate 22 was dissolved in DMF (5 mL), to which NaN3 (84.5 mg, 1.3 mmol) was added. After being warmed to 60 °C for 1 h, the solution was diluted with water (20 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with water (5 × 10 mL) and brine (10 mL) and concentrated in vacuo. Flash column chromatography gave 23 (105 mg, 78% over three steps): Rf = 0.7 (hexanes/ethyl acetate 1:1); [α]20 D = −38.9 (c 0.32 CHCl3); IR ν (cm−1) 3364, 2970, 2880, 1631, 1569; 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.6−7.3 (m, 12H), 6.2 (d, J = 4.5 Hz, 1H), 4.1 (dd, J = 9.7, 4.8 Hz, 1H), 3.2 (ddd, J = 12.7, 7.8, 4.8 Hz, 1H), 2.7 (d, J = 4.8 Hz, 3H), 2.65−2.59 (m, 1H), 2.44 (s, 3H), 2.41 (dt, J = 12.3, 7.8 Hz, 1H), 1.97 (dd, J = 15.0, 4.1 Hz, 1H), 1.73−1.60 (m, 2H), 1.38 (dd, J = 15.0, 10.4 Hz, 1H), 1.0−0.89 (m, 2H), 0.78 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.5, 143.9, 136.0, 135.9, 135.5, 133.8, 133.7, 130.2, 130.1, 130.0, 128.4, 128.2, 127.9, 49.6, 48.6, 35.9, 27.5, 26.3, 24.6, 21.7, 19.4, 18.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H35N2O3SSi 507.2132, found 507.2132. tert-Butyl 1-[(1(R)-N-Methylamino-2(S)-methylpropionyl)diphenylsilyl](4-(methoxymethoxy)butyl carbamate (35). To a solution of amide 34 (5.0 g, 8.8 mmol) and DMAP (0.2 g, 1.76 mmol) in acetonitrile (50 mL) was added via syringe pump over 1 h a solution of Boc2O (3.8 g, 17.6 mmol) in acetonitrile (10 mL). Reaction progress was monitored by TLC. The solution was concentrated in vacuo and diluted with ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic phases were washed with 5% HCl (3 × 10 mL), water (2 × 30 mL), and brine (2 × 10 mL), dried over Na2SO4, and concentrated in vacuo. Flash column chromatography gave the intermediate 3-([(R)-4(methoxymethoxy)-1-[N-(tert-butylcarbamoyl)-4methylphenylsulfonamido]butyl)diphenylsilyl)-N,2(S)-dimethylpropanamide (5.2 g, 88%): Rf = 0.42 (hexanes/ethyl acetate 1:2); [α]20 D = 32.2 (c 0.115, CHCl3); IR ν (cm−1) 3314, 3071, 2931, 2881, 1715, 1655, 1540; 1H NMR (500 MHz, CDCl3) δ 7.6 (dd, J = 16.5, 7.7 Hz, 4H), 7.4−7.2 (m, 8H), 7.1 (d, J = 8.3 Hz, 2H), 5.3 (d, J = 4.4 Hz, 1H), 4.6 (dd, J = 9.5, 5.0 Hz, 1H), 4.5 (s, 2H), 3.5−3.4 (m, 2H), 3.2 (s, 3H), 2.5 (d, J = 4.7 Hz, 3H), 2.4 (s, 3H), 2.3−2.2 (m, 1H), 1.97−1.81 (m, 2H), 1.85 (dd, J = 15.3, 6.6 Hz, 1H), 1.73−1.57 (m, 2H), 1.36 (dd, J = 15.4, 7.2 Hz, 1H), 1.24 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.9, 151.6, 144.0, 137.4, 136.4, 136.2, 135.0, 134.2, 129.7, 129.6, 129.2, 128.4, 128.0, 127.9, 95.5, 84.7, 67.3, 55.2, 48.0, 36.9, 28.3, 28.0, 27.8, 26.3, 21.7, 21.3, 17.4; HRMS (ESITOF) m/z [M + Na]+ calcd for C35H48N2NaO7SSi 691.2844, found 691.2851. The diastereomeric mixture 24 of the intermediate described above had the following NMR spectral data: 1H NMR (500 MHz, CDCl3) δ 7.65(d, J = 8.3 Hz, 4H), 7.60 (t, J = 8.3 Hz, 4H), 7.45−7.32 (m, 16H), 7.13 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 5.26 (m 1H), 5.00 (m, 1H), 4.68−4.62 (m, 2H), 4.54 (d, J = 1.5 Hz, 2H), 4.53 (d, J = 1.5 Hz, 2H), 3.48 (m, 4H), 3.28 (s, 3H), 3.27 (s, 3H), 2.50 (d, J = 4.7 Hz,

NaHSO3 solution (50 mL), and then saturated with NaHCO3 (50 mL). The aqueous phase was extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash column chromatography gave the title compound (4.7 g, 91%) as a viscous, colorless oil: Rf = 0.45 (hexanes/ −1 ethyl acetate 1:1); [α]20 D = −8.1 (c 0.64 CHCl3); IR ν (cm ) 3516, 3261, 3354, 3068, 2928, 2878, 1598, 1527, 1427; 1H NMR (500 MHz, CDCl3) δ 7.7 (d, J = 8.2 Hz, 2H), 7.53−7.30 (m, 10H), 7.2 (d, J = 8.2 Hz, 2H), 5.0 (d, J = 10.0 Hz, 1H), 4.4 (s, 2H), 3.62−3.51 (m, 1H), 3.3 (dd, J = 10.4, 5.4 Hz, 1H), 3.20−3.17 (m, 2H), 3.12 (t, J = 6.0 Hz, 1H), 2.38 (s, 3H), 2.34 (br, 1H), 1.68−1.60 (m, 1H), 1.6−1.55 (m, 1H), 1.31 (dd, J = 15.8, 5.4 Hz, 2H), 1.27−1.20 (m, 2H), 0.9 (dd, J = 15.3, 8.2 Hz, 1H), 0.65 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 143.1, 139.1, 135.7, 135.6, 133.1, 130.0, 129.6, 128.2, 128.1, 127.1, 96.2, 70.1, 67.3, 55.1, 42.5, 31.6, 28.8, 27.1, 21.6, 20.0, 15.6. (S)-3-([(R)-4-(Methoxymethoxy)-1-(4-ethylphenylsulfonamido)butyl]diphenylsilyl)-2-methylpropanoic Acid (33). To a solution of N-[(R)-1-[((S)-3-hydroxy-2-methylpropyl)-diphenylsilyl]4-(methoxymethoxy)butyl]-4-methylbenzenesulfonamide (10.0 g, 18.5 mmol) in a mixture of dichloromethane/CH3CN/water (1/1/1, 300 mL) were added RuCl3 (3.8 mg, 0.18 mmol) and NaIO4 (15.8 g, 55.5 mmol) over 1 h. The mixture was stirred at rt for 5 h, diluted with water (300 mL), and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash column chromatography gave acid 33 (6.7 g, 78%): Rf = 0.47 (tailing, hexanes/ethyl acetate 1:1); [α]20 D = −21.4 (c 0.425, CHCl3); IR ν (cm−1) 3515−1500 (br), 3269, 3237, 3069, 3046, 2933, 2884, 2647, 1706, 1598, 1454, 1427; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.5−7.3 (m, 10H), 7.2 (d, J = 10.0 Hz, 2H), 4.5 (d, J = 10.0 Hz, 1H), 4.4 (s, 2H), 3.58−3.53 (m, 1H), 3.27−3.18 (m, 2H), 3.21 (s, 3H), 2.4 (s, 3H), 2.3 (dd, J = 14.3, 7.1 Hz, 1H), 1.7−1.6 (m, 1H), 1.5 (dd, J = 15.4, 6.5 Hz, 1H), 1.44− 1.37 (m, 1H), 1.36−1.23 (m, 2H), 1.17 (dd, J = 15.4, 7.7 Hz, 1H), 0.97 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 182.7, 143.3, 138.9, 135.8, 135.7, 131.8, 131.7, 130.3, 129.7, 128.4, 127.2, 96.2, 67.3, 55.2, 42.6, 35.1, 29.0, 27.2, 21.7, 20.3, 16.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H37NNaO6SSi 578.2003, found 578.2014. (S)-3-([(R)-4-(Methoxymethoxy)-1-(4-methylphenylsulfonamido)butyl]diphenylsilyl)-N,2-dimethylpropanamide (34). To a solution of sulfonyl acid 33 (5.0 g, 9.0 mmol) in THF (30 mL) at −20 °C was added 4-methylmorpholine (1.0 mL, 9.0 mmol) followed by isobutyl chloroformate (1.35 mL, 9.9 mmol). The mixture was stirred for 5 min and then diluted with 40% aqueous methylamine (0.85 mL, 9.9 mmol). The resulting solution was stirred at −20 °C for 10 min, gradually warmed to rt, and then stirred for 1 h. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with 10% NaHCO3 (2 × 10 mL), 5% HCl (3 × 10 mL), water (2 × 10 mL), and brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. Flash column chromatography gave 34 (4.7 g, 92%): Rf = 0.65 (hexane/ethyl acetate 1:2); [α]20 D = +49.6 (c 0.365, CHCl3); IR ν (cm−1) 3377, 3293, 3091, 3048, 2928, 2877, 1648, 1598, 1549, 1427; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.4−7.2 (m, 12H), 5.6 (d, J = 9.6 Hz, 1H), 5.3 (d, J = 4.6 Hz, 1H), 4.4 (s, 2H), 3.66−3.60 (m, 1H), 3.2 (s, 3H), 3.1−3.0 (m, 2H), 2.6 (d, J = 5.0 Hz, 3H), 2.4 (s, 3H), 2.3−2.2 (m, 1H), 1.67 (dd, J = 15.1, 8.3 Hz, 1H), 1.6−1.5(m, 1H), 1.3−1.1 (m, 4H), 1.0 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.1, 143.0, 139.5, 135.7, 135.5, 133.4, 132.9, 130.0, 129.9, 129.6, 128.2, 128.1, 127.1, 96.1, 67.3, 55.1, 42.1, 36.9, 28.6, 27.1, 26.4, 21.7, 21.6, 16.6; HRMS (ESI-TOF) m/z[M + H]+ calcd for C30H41N2O5SSi 569.2500, found 569.2512. The diastereomeric mixture corresponding to 34, (R,S)-3-([(R)-4(methoxymethoxy)-1-(4-methylphenylsulfonamido)butyl]diphenylsilyl)-N,2-dimethylpropanamide (20) had the following NMR spectral data: 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 4H), 7.70 (d, J = 8.5 Hz, 4H), 7.47−7.21 (m, 20H), 5.63 (d, J = 9.0 Hz, 1H), 5.35 (br, 1H), 5.30 (d, J = 9.0 Hz, 1H), 5.12 (br, 1H), 4.42 (s, 2H), 4.37 (s, 2H), 3.65−3.60 (m, 1H), 3.44−3.39 (m, 1H), 3.27−3.17 (m, 1H), 3.21 (s, 2H), 3.19 (s, 2H), 3.08−3.03 (m, 1H), 2.56 (d, J = 5.0 Hz, 3H), 2.45 (d, J = 5.0 Hz, 3H), 2.40 (s, 6H), 2.27−2.21 (m, 1H), 2.19− 2.13 (m, 1H), 1.67 (dd, J = 15 Hz, 2H), 1.60−1.54 (m, 1H), 1.44− 5404

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

Article

The Journal of Organic Chemistry 2H), 2.42 (d, J = 5.0 Hz, 3H), 2.39 (d, J = 6.9 Hz, 2H), 2.38 (s, 2H), 2.3−2.2 (m, 2H), 2.02−1.96 (m, 2H), 1.91−1.83 (m, 2H), 1.82−1.77 (m, 2H), 1.71−1.51 (m, 8H), 1.40−1.35(m, 2H), 1.2 (s, 18H), 1.07 (d, 3H), 0.95 (d, 3H); 13C NMR (125 MHz, CDCl3) δ 177.7, 177.4, 151.4, 143.7, 143.6, 137.3, 137.2, 136.2, 135.9, 135.8, 134.7, 134.6, 134.2, 133.9, 129.5, 129.4, 128.9, 128.1, 128.0, 127.8, 127.7, 127.5, 96.3, 84.5, 84.4, 67.14, 55.1, 48.0, 47.7, 36.9, 36.7, 28.2, 28.1, 27.9, 27.6, 27.4, 26.0, 25.9, 21.6, 21.5, 21.0, 17.3, 17.2. This intermediate (4.0 g, 6.0 mmol) was taken up in anhydrous methanol (40 mL) to which Mg (1.44 g, 60 mmol) was added, and the mixture was stirred at rt until all of the Mg had been consumed. The mixture was concentrated in vacuo to half volume and then diluted with 5% hydrochloric acid until a clear, acidic solution had formed. The solution was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with 30% sodium bicarbonate (3 × 10 mL), dried over sodium sulfate, and concentrated in vacuo. Flash column chromatography gave 35 (3.0 g, 96%) as a colorless foam: Rf = 0.48 (hexanes/ethyl acetate 2/1). [α]20 D = −28.75 (c 0.24, CHCl3); IR ν (cm−1) 3325, 3070, 3048, 2874, 2881, 1694, 1647, 1520; 1 H NMR (400 MHz, CDCl3) δ 7.51−7.32 (m, 10H), 5.5 (d, J = 5.0 Hz, 1H), 4.5 (s, 2H), 3.88 (dt, J = 11.3, 2.1 Hz, 1H), 3.4 (s, 3H), 2.6 (d, J = 4.8 Hz, 3H), 2.34−2.25 (m, 1H), 1.77−1.66 (m, 2H), 1.64− 1.52 (m, 1H), 1.6 (dd, J = 14.3, 5.7 Hz, 1H), 1.4 (s, 9H), 1.36− 1.22(m, 1H), 1.24 (dd, J = 15.1, 7.8 Hz, 1H), 0.93 (d, J = 6.6 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 177.9, 156.7, 135.4, 133.2, 133.1, 129.8, 128.1, 128.0, 96.3, 79.1, 67.2, 55.1, 37.6, 36.5, 28.4, 28.3, 27.1, 26.1, 20.6, 16.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H43N2O5Si 515.2936, found 515.2939. tert-Butyl 1-[(1(R)-N-methylamino-2(S)-methylpropionyl)diphenylsilyl]-4-azido-butyl Carbamate (36). Note that performing this reaction on a larger scale led to poor results. To a −78 °C solution of carbamate 35 (0.3 g, 0.58 mmol) in dichloromethane (5 mL) was added bromotrimethylsilane (0.3 mL, 2.32 mmol). The solution was stirred for 45 s and then quenched with saturated NaHCO3 (5 mL) and water (10 mL). The resulting mixture was extracted with dichloromethane (3 × 10 mL), and the combined organics were dried over sodium sulfate and concentrated in vacuo to give the crude alcohol. This reaction was repeated until 5.0 g of the crude alcohol was amassed. The unpurified alcohol (5.0 g, 10.0 mmol) was dissolved in dichloromethane (40 mL), and after the alcohol was cooled to 0 °C, triethylamine (2.1 mL, 15.0 mmol) was added followed by methanesulfonyl chloride (1.16 mL, 15 mmol). Reaction progress was monitored by TLC and was found to be complete after 1 h. The solution was diluted with water (100 mL) and extracted with dichloromethane (3 × 15 mL), and the combined organic phases were washed with 10% HCl (2 × 10 mL), water (2 × 20 mL), and brine (10 mL), dried over Na2SO4, and concentrated in vacuo. This crude mesylate was dissolved in DMF (30 mL), and NaN3 (2.6 g, 40 mmol) was then added. The mixture was warmed to 60 °C for 5 h, cooled, and then diluted with water (150 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with water (6 × 50 mL) and brine (2 × 20 mL), dried over Na2SO4, and concentrated in vacuo. Flash column chromatography gave 36 (2.6 g, 53%) as a foam: Rf = 0.75 (hexanes/ethyl acetate 1:2); [α]20 D = −30.5 (c 0.445, CHCl3); IR ν (cm−1) 3319, 3070, 3049, 2973, 2931, 2095, 1699, 1647 ; 1H NMR (500 MHz, CDCl3) δ 7.5−7.3 (m, 10H), 5.4 (d, J = 4.9 Hz, 1H), 4.7 (d, J = 10.6 Hz, 1H), 3.9 (t, J = 12.3 Hz, 1H), 3.3−3.2 (m, 2H), 2.6 (d, J = 4.8 Hz, 3H), 2.33−2.26 (m, 1H), 1.68−1.56 (m, 3H), 1.63 (dd, J = 15.0, 7.1 Hz, 1H), 1.43 (s, 9H), 1.4−1.3 (m, 1H), 1.27 (dd, J = 15.0, 7.0 Hz, 1H), 1.0 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.9, 156.7, 135.6, 135.5, 133.4, 133.3, 130.0, 128.3, 79.4, 51.0, 37.6, 37.0, 29.0, 28.6, 26.4, 26.3, 21.3, 16.5HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H37N5NaO3Si 518.2558, found 518.2562. (S)-3-[((R)-1-Acetamido-4-azidobutyl)diphenylsilyl]-N,2-dimethylpropanamide (37). To a solution of azide 36 (0.3 g, 0.6 mmol) in dichloromethane (5 mL) was added 4 M HCl solution (0.6 mL, 2.4 mmol). The solution was stirred overnight at rt and then concentrated in vacuo to give a crude ammonium salt. To a solution of acetic acid (43 μL, 0.72 mmol) in DMF (2 mL) at 0 °C was added

HATU (0.34 mg, 9.0 mmol), followed by NMM (0.1 mL, 0.9 mmol). The resulting solution was stirred at 0 °C for 10 min to form the activated acetic acid. The above crude ammonium salt was dissolved in DMF (2 mL), and then NMM (0.1 mL, 0.9 mmol) was added. The resulting solution was transferred to the solution of activated acetic acid. The resulting solution was stirred at rt overnight and diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 5 mL), and the combined organic phases were washed with 5% HCl (3 × 5 mL), 5% NaHCO3 (3 × 5 mL), water (5 × 10 mL), and brine (10 mL) and then concentrated in vacuo to ca. 3 mL volume. After being cooled to 0 °C for 30 min, the mixture was filtered and the filtrate was concentrated. Flash column chromatography (ethyl acetate/methanol 100/0−100/5) gave the intermediate azido diamide (S)-3-[((R)-1-acetamido-4-azidobutyl)diphenylsilyl]-N,2-dimethylpropanamide (0.19 g, 72%): [α]D20 = −39.6 (c 0.375, CHCl3); IR ν (cm−1) 3288, 3069, 3050, 2960, 2929, 2874, 2095, 1644, 1549, 1427; 1H NMR (500 MHz, CDCl3) δ 7.52−7.32 (m, 10H), 6.4 (d, J = 10.5 Hz, 1H), 5.5 (br, 1H), 4.3 (dt, J = 10.5, 2.7 Hz, 1H), 3.3−3.1 (m, 2H), 2.6 (d, J = 4.9 Hz, 3H), 2.38− 2.29 (m, 1H), 2.0 (s, 3H), 1.7−1.5 (m, 4H), 1.42−1.32 (m, 1H), 1.27 (dd, J = 15.2, 6.4 Hz, 1H), 1.0 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.3, 170.6, 135.4, 135.3, 133.7, 132.9, 130.1, 128.3, 51.0, 36.9, 36.2, 28.6, 26.5, 26.3, 23.5, 21.5, 16.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H32N5O2Si 438.2320, found 438.2328. The diastereomeric azido diamide (R,S)-3-[((R)-1-acetamido-4azidobutyl)diphenylsilyl]-N,2-dimethylpropanamide (27) had the following NMR spectral data: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 1.5 Hz, 1H), 7.49−7.45 (m, 6H), 7.43−7.34 (m, 12H), 6.40 (br, 1H), 5.90 (br, 1H), 5.42 (br, 2H), 4.27 (m, 2H), 3.33−3.17 (m, 4H), 2.61 (d, J = 4.8 Hz, 3H), 2.57 (d, J = 5.0 Hz, 3H), 2.36−2.24 (m, 2H), 2.00 (s, 3H), 1.94 (s, 3H), 1.70−1.50 (m, 8H), 1.31−1.21 (m, 4H), 1.12 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 178.5, 177.5, 170.9, 170.5, 135.6, 135.4, 133.8, 133.5, 132.8, 130.36, 130.33, 128.58, 128.52, 51.2, 37.3, 37.1, 36.5, 36.4, 29.0, 28.8, 26.8, 26.6, 26.5, 23.6, 22.5, 21.7, 17.2, 16.2. A solution of the azido diamide (0.35 g, 0.8 mmol) and di-tert-butyl dicarbonate (0.2 g, 9.6 mmol), and Lindlar’s catalyst (70 mg) in anhydrous methanol (5 mL) was placed under an atmosphere of hydrogen. Reaction progress was monitored by IR spectroscopy. When the reaction was judged to be complete, the solution was filtered through a short pad of Celite, and the residue was washed with methanol (6 mL). The combined filtrates were concentrated in vacuo. Flash column chromatography (methanol/ethyl acetate 2/98) afforded carbamate 37 (360 mg, 87%) as a foam: Rf = 0.40 (ethyl acetate/ −1 methanol 100:5); [α]20 D = −29.0 (c 0.155, CHCl3); IR ν (cm ) 3302, −1 1 3070, 2975, 2875, 1697, 1647, 1538, cm . H NMR (500 MHz, CDCl3) δ 7.6−7.3 (m, 10H), 6.3 (d, J = 10.0 Hz, 1H), 5.6 (br, 1H), 4.5 (br, 1H), 4.3 (t, J = 10.6 Hz, 1H), 3.05 (m, 2H), 2.6 (d, J = 4.3 Hz, 3H), 2.4−2.3 (m 1H), 2.0 (s, 3H), 1.7−1.5 (m, 3H), 1.4 (s, 9H), 1.35−1.2 (m, 3H), 1.0 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.2, 170.6, 156.2, 135.5, 135.3, 133.8, 133.2, 130.1, 128.3, 79.1, 40.4, 36.9, 36.8, 28.9, 28.6, 27.9, 26.3, 23.5, 21.4, 16.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H41N3NaO4Si 534.2759, found 534.2761. 3-((R)-1-Acetamido-4-[N,N-(bis-tert-butylcarbanoyl)guanidino]butyldiphenylsilyl)-N,2(S)-dimethylpropanamide (38). To a solution of carbarmate 37 (0.2 g, 0.4 mmol) in dichloromethane (2 mL) was added 4 M HCl in dioxane (0.5 mL, 2 mmol). The solution was stirred for 5 h and then concentrated in vacuo. The residue was taken up in DMF (5 mL), cooled with an ice bath, and treated sequentially with triethylamine (0.17 mL, 1.2 mmol), N,N′-di(tert-butoxycarbonyl)thiourea (112 mg, 0.4 mmol), and mercuric chloride (120 mg, 4.4 mmol). The resulting mixture was stirred at 0 °C for 20 min, diluted with ethyl acetate (20 mL), and filtered through a pad of Celite. The filtrate was washed with water (6 × 10 mL) and brine (5 mL), dried over Na2SO4, and concentrated in vacuo. Flash column chromatography on silica gel (ethyl acetate/ methanol 100:5) afforded guanidine 38 (220 mg, 85%) as a colorless foam: Rf = 0.5 (ethyl acetate/methanol 100:5); [α]20 D = −9.1 (c 0.36, 5405

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

Article

The Journal of Organic Chemistry CHCl3); IR ν (cm−1) 3326, 3070, 2978, 2854, 1716, 1652, 1559; 1H NMR (500 MHz, CDCl3) δ 8.2 (t, J = 4.8 Hz, 1H), 7.5−7.27 (m, 10H), 6.5 (d, J = 10.0 Hz, 1H), 5.6 (d, J = 3.9 Hz, 1H), 4.3 (dt, J = 11.7, 2.7 Hz, 1H), 3.40−3.37 (m, 1H), 3.3−3.2 (m, 1H), 2.6 (d, J = 4.6 Hz, 3H), 2.4−2.33 (m, 1H), 2.0 (s, 3H), 1.7−1.6 (m, 2H), 1.56 (dd, J = 15.2, 7.0 Hz, 2H), 1.38−1.30 (m, 1H), 1.26 (dd, J = 15.2, 7.0 Hz, 1H), 1.1 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.0, 170.3, 163.5, 156.3, 153.2, 135.3, 135.2, 133.4, 133.0, 129.8, 128.1, 128.0, 83.0, 79.1, 40.5, 37.1, 36.5, 28.3, 28.0, 27.9, 27.3, 26.1, 23.3, 20.8, 16.4; 29Si NMR (99.3 MHz, CDCl3) δ −8.53; HRMS (ESITOF) m/z [M + Na]+ calcd for C34H51N5NaO6Si 676.3501, found 676.3504. 4(R)-Acetamido-4-[dihydroxyl-3-(N,3(S)-dimethyl-3oxopropyl)silyl]butylguanidinium Acetate (39). A solution of guanidine 38 (120 mg, 0.18 mmol) in acetic acid (2 mL) and dichloromethane (8 mL) was stirred at rt for 6 h. After the solution was cooled to 0 °C, Hg(OAc)2 (576 mg, 1.8 mmol) was added. The resulting solution was stirred at 0 °C for an additional 2 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give a viscous liquid. Ether (5 mL) was added and the mixture stirred with a glass rod, resulting in a colorless precipitate. The precipitate was collected, washed with ether, and then transferred to a 10 mL round-bottom flask. Water (3 mL) was added, and the suspension was stirred at 5 °C for 2 h and then filtered. The filtrate was concentrated in vacuo to give silanediol 39 in quantitative yield: 1 H NMR (500 MHz, D2O) δ 4.7 (br, 9H, including protons from HOAc and water), 3.3−3.0 (m, 3H), 2.6 (d, J = 3.7 Hz, 3H), 2.4 (m, 1H), 2.0 (s, 3H, including protons from HOAc), 1.59−1.45 (m, 4H), 1.07 (d, J = 5.8 Hz, 3H), 0.97 (dd, J = 13.3, 5.0 Hz, 1H), 0.7 (dd, J = 14.1, 7.5 Hz, 1H); 13C NMR (125 MHz, D2O) δ 180.8, 178.7, 173.85, 173.81, 41.2, 39.7, 38.1, 29.0, 27.0, 26.1, 25.9, 22.1, 21.5, 21.3; 29Si NMR (99.3 MHz, D2O) −48.6 (−57.9 rotamers); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H31N5NaO6Si 416.1936, found 416.1963. (S)-3-([(R)-1-((S)-2-Acetamidopropanamido)-4-azidobutyl]diphenylsilyl)-N,2-dimethylpropanamide (40A). Following the procedure for synthesis of 27, starting with 36 (0.3 g, 0.6 mmol), 4 M HCl (0.6 mL, 2.4 mmol), 2(S)-acetamidopropanoic acid A (86.5 mg, 0.66 mmol), HATU (0.34 g, 0.9 mmol), 1-methylmorpholine (0.22 mL, 2.0 mmol), and DMF (6 mL) gave 40A (231 mg, 76%) as a colorless foam: Rf = 0.6 (ethyl acetate/methanol 100:15); [α]20 D = −22.8 (c 0.425, CHCl3); IR ν (cm−1) 3286, 3066, 2969, 2935, 2098, 1643, 1542; 1H NMR (400 MHz, CD3OD) δ 7.4−7.3 (m, 12H, including 2H from NH), 4.2−4.0 (m, 2H), 3.18−3.12 (m, 2H), 2.3 (d, J = 9.0 Hz, 3H), 1.86, 1.85, 1.82 (s, 3H), 1.62−1.17 (m, 6H), 1.18, 1.11 (d, J = 7.0 Hz, 3H), 0.99, 0.93 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 180.3, 175.1, 175.0, 173.1, 136.9, 136.8, 134.2 (134.1), 133.9, 131.1, 129.2, 51.8 (51.78), 50.9 (50.8), 38.2, 37.7 (37.73), 29.1, 27.4(27.3), 26.4(26.39), 22.6 (22.5), 22.1, 18.3 (18.1) 16.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H36N6NaO3Si 531.2510, found 531.2492. (S)-2-Acetamido-N-[(S)-1-((R)-4-azido-1-([(S)-2-methyl-3(methylamino)-3-oxopropyl)diphenylsilyl]butylamino)-1-oxopropan-2-yl]-4-methylpentanamide (40B). Following the procedure for synthesis of 27, starting with 36 (0.3 g, 0.6 mmol), 4 M HCl (0.6 mL, 2.4 mmol), acid B (161 mg, 6.6 mmol), HATU (0.34 g, 0.9 mmol), 1-methylmorpholine (0.22 mL, 2.0 mmol), and DMF (6 mL) gave 40B (280 mg, 75%) as a colorless foam: Rf = 0.5 (ethyl acetate/ −1 methanol 100:15); [α]20 D = −14.4 (c 0.25, CHCl3); IR ν (cm ) 3286, 3062, 2954, 2098, 1646, 1542; 1H NMR (500 MHz, CDCl3) δ 7.6−7.4 (m, 10H), 7.1 (d, J = 7.8 Hz, 1H), 7.0 (d, J = 7.8 Hz, 1H), 6.9 (d, J = 10.0 Hz, 1H), 5.4 (d, J = 4.9 Hz, 1H), 4.60−4.55 (m, 1H), 4.5 (tt, J = 7.8 Hz, 1H), 4.2 (dt, J = 10.0, 2.6 Hz, 1H), 3.26−3.17(m, H), 2.6 (d, J = 4.6 Hz, 3H), 2.23 (m, 1H), 2.0 (s, 3H), 1.87 (ddd, J = 13.5, 8.1, 5.0 Hz, 1H), 1.8−1.74 (m, 1H), 1.74−1.68 (m 1H), 1.66−1.61 (m, 1H), 1.58−1.54 (m, 1H), 1.58−1.50 (m, 1H), 1.52 (dd, J = 14.7, 6.7 Hz, 1H), 1.38 (d, J = 7.3 Hz, 3H), 1.33−1.26 (m, 1H), 1.3 (dd, J = 15.0, 7.8 Hz, 1H), 1.02 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.3, 172.4, 172.0, 170.6, 135.4, 135.3, 133.0, 132.7, 130.0, 129.9, 128.1, 128.09, 51.7, 50.8, 50.0, 40.9, 37.1, 36.2, 28.6, 26.28, 26.19, 24.9, 23.0, 22.9,

21.9, 21.4, 17.4, 15.54; HRMS (ESI-TOF) m/z[M + Na]+ calcd for C32H47N7NaO4Si 644.3351, found 644.3327. (S)-1-Acetyl-N-[(S)-1-((R)-4-azido-1-([(S)-2-methyl-3-(methylamino)-3-oxopropyl]diphenylsilyl)butylamino)-1-oxopropan2-yl]pyrrolidine-2-carboxamide (40C). Following the procedure for synthesis of 27, starting with 36 (0.3 g, 0.6 mmol), 4 M HCl (0.6 mL, 2.4 mmol), acid C (150 mg, 0.66 mmol), HATU (0.34 g, 0.9 mmol), 1-methylmorpholine (0.22 mL, 2.0 mmol), and DMF (6 mL) gave 40C (270 mg, 72%) as a colorless foam: Rf = 0.5 (ethyl acetate/ −1 methanol 100:20); [α]20 D = −26.9 (c 0.42, CHCl3); IR ν (cm ) 3295, 3069, 2972, 2933, 2876, 2095, 1641, 1545, 1427; 1H NMR (500 MHz, CD3OD) δ 7.6−7.3 (m, 10H), 4.4−4.25 (m, 1H), 4.2 (t, J = 7.1 Hz, 1H), 4.1 (t, J = 7.5 Hz, 1H), 3.6−3.5 (m, 2H), 3.1 (t, J = 5.8 Hz, 2H), 2.5−2.42 (m, 1H), 2.4 (d, J = 4.5 Hz, 3H), 2.1−2.0 (m, 1H), 2.07− 2.01 (m, 1H), 1.95 (s, 3H), 1.9−1.87 (m, 2H), 1.7−1.6 (m, 2H), 1.61−1.53 (m, 2H), 1.40−1.29 (m, 2H), 1.21 (d, J = 7.2 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 180.47, 175.1, 174.6, 171.6, 137.0, 136.9, 134.73, 134.69, 130.93, 130.88, 129.1, 61.8, 52.0, 51.2, 48.6, 39.1, 38.0, 30.7, 28.8, 27.5, 26.4, 26.2, 22.4, 22.2, 18.0, 16.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C31H44N7O4Si 606.3219, found 606.3304. tert-Butyl (R)-4-((S)-2-Acetamidopropanamido)-4-[((S)-2methyl-3-(methylamino)-3-oxopropyl)diphenylsilyl]butyl Carbamate (41A). Following the procedure for synthesis of 37, using 40A (0.3 g, 0.6 mmol), Boc2O (157 mg, 0.66 mmol), and Lindlar’s catalyst (60 mg) in anhydrous methanol (5 mL) under 1 atm H2 gave carbamate 41A (300 mg, 86%) as a colorless foam: Rf = 0.5 (ethyl acetate/methanol 100:15). [α]20 D = −5.1 (c 0.33, CHCl3); IR 3301, 3058, 2969, 2931, 1649, 1538; 1H NMR (400 MHz, CD3OD) δ 8.0− 7.9 (d, J = 7.5 Hz, 1H), 7.50−7.25 (m, 12H, including 2H from NH), 6.4 (br, 1H), 4.2−4.0 (m, 2H), 2.90−2.84 (m, 2H), 2.3 (d, J = 4.4 Hz, 3H), 2.3 (m, 1H), 1.84 (s, 3H), 1.6−1.5 (m, 1H), 1.5(dd, J = 7.7, 2.5 Hz, 1H), 1.47 (dd, J = 7.7, 2.5 Hz, 1H), 1.3 (s, 9H), 1.3−1.2 (m, 2H), 1.24 (dd, J = 14.7, 7.3 Hz, 2H), 1.0 (d, J = 7.3 Hz, 3H), 0.9 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 184.0, 175.0, 173.2, 158.7, 137.0, 136.96, 134.5, 134.4, 131.2, 129.3, 80.0, 51.0, 50.1, 41.2, 39.2, 37.9, 29.1, 26.5, 22.8, 22.2, 18.5, 18.2, 17.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H46N4NaO5Si 605.3130, found 605.3128. tert-Butyl (R)-4-[(S)-2-((S)-2-Acetamido-4-methyl pentanamido)propanamido]-4-[((S)-2-methyl-3-(methylamino)-3oxopropyl)diphenylsilyl]butyl Carbamate (41B). Following the procedure for synthesis of 37, using 40A (0.4 g, 0.64 mmol), Boc2O (154 mg, 0.65 mmol), and Lindlar’s catalyst (60 mg) in anhydrous methanol (5 mL) under 1 atm of hydrogen gave carbamate 41B (356 mg, 80%) as a colorless foam: Rf = 0.4 (ethyl acetate/methanol 100:15); [α]20 D = −17.0 (c 0.37, CHCl3); IR 3297, 3062, 2962, 2935, 1650, 1535; 1H NMR (500 MHz, CDCl3) δ 7.6−7.3 (m, 12H, including 2H from NH), 7.14 (d, J = 7.2 Hz, 1H), 7.0 (d, J = 7.6 Hz, 1H), 6.8 (d, J = 10 Hz, 1H), 5.6 and 4.72 (br, 1H), 4.6−4.25 (m, 2H), 4.2 (t, J = 10.5 Hz, 1H), 3.07−2.95 (m, 2H), 2.56 (d, J = 4.5 Hz, 3H), 2.0, 1.95 (s, 3H), 1.8−1.4 (m, 7H), 1.4 (s, 9H), 1.36 (d, J = 7.2 Hz, 3H), 1.3−1.23 (m, 2H), 1.0 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.4, 172.6, 172.1, 171.0, 156.2, 135.6, 135.5, 133.5, 130.0, 128.2, 79.1, 52.1, 49.6, 40.9, 40.5, 37.1, 29.0, 28.6, 27.9, 27.5, 26.4, 25.0, 23.4, 23.0, 22.2, 21.4, 17.7, 16.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C37H57N5NaO6Si 718.3970, found 718.3952. tert-Butyl (R)-4-[(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)propanamido]-4-[((S)-2-methyl-3-(methylamino)-3oxopropyl)diphenylsilyl]butyl Carbamate (41C). Following the procedure for synthesis of 37, using 40C (0.4 g, 0.66 mmol), Boc2O (158 mg, 0.73 mmol), and Lindlar’s catalyst (60 mg) in anhydrous methanol (5 mL) under 1 atm of hydrogen gave carbamate 41C (368 mg, 82%) as a colorless foam: Rf = 0.4 (ethyl acetate/methanol −1 100:20); [α]20 D = −38.3 (c 0.06, CHCl3); IR ν (cm ) 3305, 3070, 2975, 2933, 2876, 1650, 1538, 1427; 1H NMR (500 MHz, CD3OD) δ 7.6−7.3 (m, 13H, including 3H from NH bonds), 6.3 (br, 1H), 4.4− 4.25 (m, 1H), 4.2 (t, J = 7.1 Hz, 1H), 4.1 (t, J = 7.5 Hz, 1H), 3.66− 3.56 (m, 2H), 3.01−2.89 (m, 2H), 2.5 (dt, J = 13.6, 6.8 Hz, 1H), 2.4 (d, J = 4.5 Hz, 3H), 2.20−2.14 (m, 1H), 2.12−2.01 (m, 1H), 2.01 (s, 3H), 1.98−1.89 (m, 2H), 1.71−1.45 (m, 4H), 1.40 (s, 9H), 1.37−1.27 5406

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

Article

The Journal of Organic Chemistry

(125 MHz, D2O) δ 181.1, 180.8, 178.6, 175.1, 174.1, 50.1, 41.1, 39.7, 35.5, 30.0, 29.0, 26.2, 26.0, 22.0, 21.2, 18.1, 17.1; 29 Si NMR (99.3 MHz, D2O) −14.2, −48.6 (−57.9 rotamers); HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H33N6O5Si 405.2276, found 405.2281. Silanediol 43B. Following the procedure for synthesis of 39, compound 42B (0.30 g, 0.36 mmol), 20% acetic acid in dichloromethane (8 mL), and mercuric acetate (0.57 g, 1.53 mmol) gave silanediol 43B: 1H NMR (500 MHz, D2O) δ 4.69 (br, 11H including protons from acetic acid and water), 4.19−4.05 (m, 2H), 3.34−3.10 (m, 1H), 3.96−2.95 (m, 2H), 2.57 (d, J = 5.4 Hz, 3H), 2.43−2.35 (m, 1H), 1.95 (s, 3H), 1.91 (methyl protons of acetic acid), 1.86 (s, 3H), 1.59−1.33 (m, 5H), 1.24 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.85−0.67 (m, 1H), 0.80 (d, J = 6.3 Hz, 3H), 0.75 (d, J = 6.3 Hz, 3H); 13 C NMR (125 MHz, D2O) δ 180.7, 180.6, 178.4, 175.0, 174.5, 174.1, 52.8, 50.8, 39.3, 35.228.4, 27.0, 25.8, 24.2, 21.9, 21.4, 21.0, 20.8, 20.6, 19.6, 17.5, 16.5; 29Si NMR (99.3 MHz, D2O) −14.2 (−50.9 rotamers); HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H44N7O6Si 518.3117, found 518.3153. Silanediol 43C. Following the procedure for synthesis of 39, compound 42C (0.30 g, 0.36 mmol), 20% acetic acid in dichloromethane (8 mL), and mercuric acetate (0.57 g, 1.53 mmol) gave silanediol 43C: 1H NMR (500 MHz, D2O) δ 4.69 (br, all exchangeable protons), 4.24−4.20 (m, 1H), 4.18−4.05 (m, 1H), 3.53−3.45 (m, 2H), 3.27−3.12 (m, 1H), 3.00 (dd, J = 8.3, 4.8 Hz, 2H), 2.55 (d, J = 7.5 Hz, 3H), 2.42−2.33 (m, 1H), 2.15−2.08 (m, 1H), 1.95 (s, 3H), 1.91 (methyl protons of acetic acid), 1.97−1.76 (m, 3H), 1.56−1.20 (m, 5H), 1.02 (d, J = 6.9 Hz, 3H), 0.84−0.64 (m, 1H); 13C NMR (125 MHz, D2O) δ 181.0, 180.8, 178.2, 174.6, 173.3, 173.0, 60.6, 50.4, 49.0, 41.0, 39.7, 35.5, 30.0, 29.0, 26.0, 24.6, 24.5, 21.6, 20.8, 19.9, 18.0, 16.8. 29 Si NMR (99.3 MHz, D2O) −14.2, −48.6, −50.9 (rotamers); HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H40N7O6Si 502.2804, found 502.2822. (S)-3-[(R)-4-(Methoxymethoxy)-1-[4-(methylphenylsulfonamido)butyl]diphenylsilyl]-2-methyl-N-[(S)-1-(methylamino)1-oxopropan-2-yl]propanamide (44). Following the procedure for synthesis of 37, using 33 (1.0 g, 1.8 mmol), HATU (1.02 g, 2.7 mmol), 1-methylmorpholine (0.6 mL, 5.4 mmol), 2(S)-amino-Nmethylpropanamide hydrochloride (273 mg, 1.98 mmol), and DMF (10 mL) gave 44 (713.5 mg, 62%) as a colorless foam: Rf = 0.42 (ethyl −1 acetate); [α]20 D = −71.4 (c 0.134, CHCl3); IR ν (cm ) 3292, 3182, 1 3070, 2930, 2879, 1650, 1531 ; H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.6 Hz, 2H), 7.5−7.3 (m, 10H), 7.26 (d, J = 8.0 Hz, 2H), 6.47 (ddd, J = 5.0 Hz, 1H), 6.07 (d, J = 7.0 Hz, 1H), 5.7 (d, J = 9.5 Hz, 1H), 4.38 (s, 2H), 4.25−4.19 (m, 1H), 3.66−3.62 (m, 1H), 3.2 (s, 3H), 3.06 (t, J = 4.9 Hz, 3H), 2.4 (s, 3H), 2.38−2.30 (m, 1H), 1.7 (dd, J = 14.8, 8.4 Hz, 1H), 1.60−1.54 (m, 1H), 1.30−1.14 (dd, J = 15.3, 5.9 Hz, 1H), 1.1 (d, J = 6.9 Hz, 3H), 1.0 (d, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.7, 173.1, 143.2, 139.5, 135.7, 135.5, 133.4, 132.7, 130.1, 129.7, 128.3, 127.1, 96.2, 67.3, 55.1, 49.0, 42.0, 36.9, 28.6, 27.3, 26.3, 21.7, 21.6, 17.7, 16.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C33H45N3NaO6SSi 662.2691, found 662.2571. 2(S)-[3-([(R)-4-(Methoxymethoxy)-1-(N-tert-butylcarbamoyl)butyl]diphenylsilyl)-2(S)-methylpropanamido]-N-methylpropanamide (45). Following the procedure for synthesis of 35, compound 44 (0.5 g, 0.78 mmol), DMAP (19.1 mg, 0.16 mmol), Boc2O (0.34 g, 1.56 mmol), and acetonitrile (30 mL) gave 2(S)-[3[(R)-4-(methoxymethoxy)-1-(N-(tert-butylcarbamoyl)-4-(methylphenylsulfonamido)butyl)diphenylsilyl]-2(S)-methylpropanamido]-Nmethylpropanamide (311 mg, 54%) as a colorless foam: Rf = 0.5 (ethyl −1 acetate); [α]20 D = −24.8 (c 0.35, CHCl3). IR ν (cm ) 3305, 3071, 2978,1715, 1650, 1596, 1538; 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 6.6 Hz, 2H), 7.58 (d, J = 7.0 Hz, 2H), 7.45−7.3 (m, 3H), 7.1 (d, J = 8.1 Hz, 2H), 6.7 (br, 1H), 6.0 (br, 1H), 4.67 (dd, J = 10.0, 5.1 Hz, 1H), 4.55, 4.54 (s, 2H), 4.22−4.16 (m, 1H), 3.51−3.45 (m, 2H), 3.28 (s, 3H), 2.74 (d, J = 4.8 Hz, 3H), 2.39 (s, 3H), 2.37−2.31 (m, 1H), 2.0−1.95 (m, 1H), 1.94 (dd, J = 15.4, 6.6 Hz, 1H), 1.92−1.85 (m, 1H), 1.74−1.67 (m, 1H), 1.67−1.57 (m, 1H), 1.39 (dd, J = 15.8, 7.3 Hz, 1H), 1.25 (s, 9H), 1.08 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.5, 172.9, 151.5, 143.7, 137.4, 136.2, 135.8, 134.7, 133.6, 129.6, 129.5, 128.9, 128.1, 127.8,

(m, 2H), 1.24 (d, J = 7.2 Hz, 3H), 1.0 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 180.4, 175.0, 174.5, 171.7, 158.5, 136.9, 136.8, 134.8, 134.7, 130.8, 129.0, 79.8, 61.7, 51.2, 49.9, 48.6, 41.1, 39.8, 37.9, 30.7, 28.98, 28.92, 26.3, 26.1, 22.4, 22.1, 18.0, 16.7; HRMS (ESI-TOF) m/zcalcd for C36H54N5O6Si 680.3838, found 680.3929. Compound 42A. Following the procedure for synthesis of 38, compound 41A (0.2 g, 0.34 mmol), dichloromethane (2 mL), 4 M HCl in dioxane (0.5 mL, 2 mmol), triethylamine (0.17 mL, 1.2 mmol), N,N′-di(tert-butoxycarbonyl)thiourea (103 mg, 0.37 mmol), and mercuric chloride (100 mg, 0.37 mmol) afforded guanidine 42A (202 mg, 84%) as a colorless foam: Rf = 0.5 (ethyl acetate/methanol −1 100:15); [α]20 D = −12.0 (c 0.60, CH3OH); IR ν (cm ) 3320, 3290, 3072, 2981, 2935, 1720, 1646; 1H NMR (500 MHz, CD3OD) δ 7.6− 7.37 (m, 10H), 4.3−4.2 (m, 1H), 4.2−4.1(m, 1H), 3.4−3.2(m, 2H), 2.46−2.3 (m, 1H), 2.3 (s, 3H), 1.9 (s, 3H), 1.6−1.5 (m, 1H), 1.5(dd, J = 7.7, 2.5 Hz, 1H), 1.47 (dd, J = 7.7, 2.5 Hz, 1H), 1.44 (s, 9H), 1.41 (s, 9H), 1.3−1.2 (m, 2H), 1.24 (dd, J = 14.7, 7.3 Hz, 1H), 1.0 (d, J = 7.3 Hz, 3H), 0.9 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 180.2, 174.9, 173.0, 164.7, 157.7, 154.3, 136.96, 136.8, 134.3, 134.1, 131.0, 129.2, 84.6, 80.5, 50.8, 41.3, 38.8, 37.8, 29.3, 28.8, 28.4, 28.0, 26.4, 22.6, 22.1, 18.3, 17.1; 29Si NMR (99.3 MHz, CD3OD) δ −8.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C37H56N6NaO7Si 747.3872, found 747.3878. Compound 42B. Following the procedure for synthesis of 38, compound 41B (0.28 g, 0.4 mmol), dichloromethane (2 mL), 4 M HCl in dioxane (0.5 mL, 2 mmol), triethylamine (0.17 mL, 1.2 mmol), N,N′-di(tert-butoxycarbonyl)thiourea (119 mg, 0.43 mmol), and mercuric chloride (117 mg, 0.43 mmol) afforded guanidine 42B (305 mg, 91%) as a colorless foam: Rf = 0.4 (ethyl acetate/methanol −1 100:15); [α]20 D = +1.5 (c 0.86, CH3OH); IR ν (cm ) 3322, 3282, 1 3070, 2975, 2935, 2873, 1720, 1652, 1612; H NMR (500 MHz, CD3OD) δ 8.3 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 6.1 Hz, 1H), 7.6−7.3 (m, 13H, including 3H from NH), 4.35−5.25 (m, 2H), 4.20−4.13 (m, 1H), 3.3−3.15(m, 2H), 2.5−2.4 (m, 1H), 2.4 (d, J = 4.5 Hz, 3H), 1.94 (s, 3H), 1.7−1.55 (m, 7H), 1.51 (s, 9H), 1.46 (s, 9H), 1.4−1.3 (m, 2H), 1.3 (d, J = 7.2 Hz, 3H), 1.0 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 180.4, 174.9, 174.6, 173.2, 164.6, 157.6, 154.2, 136.9, 136.7, 134.5, 130.9, 129.1, 84.6, 80.5, 54.0, 51.1, 41.8, 41.3, 39.5, 37.9, 29.1, 28.7, 28.4, 27.8, 26.3, 26.1, 23.4, 22.8, 22.4, 22.1, 18.3, 16.7; 29Si NMR (99.3 MHz, CD3OD) δ −8.7; HRMS (ESI-TOF) m/z [M − Na]+ calcd for C43H67N7NaO8Si 860.4713, found 860.4714. Compound 42C. Following the procedure for synthesis of 38, compound 41C (0.26 g, 0.38 mmol) in dichloromethane (2 mL), 4 M HCl (in dioxane (0.5 mL, 2 mmol), triethylamine (0.17 mL, 1.2 mmol), N,N′-di(tert-butoxycarbonyl)thiourea (112 mg, 0.4 mmol), and mercuric chloride (120 mg, 4.4 mmol) afforded guanidine 42C (220 mg, 71%) as a colorless foam: Rf = 0.4 (ethyl acetate/methanol −1 100:20); [α]20 D = −18.5 (c 0.275, CHCl3); IR ν (cm ) 3319, 3292, 3070, 2978, 2933, 1722, 1643; 1H NMR (500 MHz, CD3OD) δ 7.6− 7.3 (m, 13H, including 3H from NH bonds) 4.4−4.25 (m, 1H), 4.2 (t, J = 7.1 Hz, 1H), 4.1 (t, J = 7.5 Hz, 1H), 3.6−3.4 (m, 2H), 3.25−3.18 (m, 2H), 2.48−2.40 (m, 1H), 2.34 (d, J = 4.5 Hz, 3H), 2.14−2.09 (m, 1H), 2.07−1.99 (m, 1H), 1.97 (s, 3H), 1.93−1.86 (m, 2H), 1.67−1.52 (m, 4H), 1.46 (s, 9H), 1.41 (s, 9H), 1.38−1.30 (m, 2H), 1.2 (d, J = 7.1 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 180.6, 175.1, 174.7, 171.9, 164.9, 157.7, 154.4, 137.1, 137.0, 134.9, 134.8, 130.9, 129.1, 84.6, 80.5, 61.8, 51.3, 50.1, 48.7, 41.5, 39.6, 38.1, 30.9, 29.9, 28.6, 27.9, 26.5, 26.3, 22.6, 22.3, 18.2, 16.9; 29Si NMR (99.3 MHz, CD3OD) δ −8.72; HRMS (ESI-TOF) m/z [M + H]+ calcd for C42 H64N7O8Si 822.4580, found 822.4634. Silanediol 43A. Following the procedure for synthesis of 39, compound 43a (0.22 g, 0.3 mmol), 20% acetic acid in dichloromethane (6 mL), and mercuric acetate (0.49 g, 1.53 mmol) gave silanediol 43A in quantitative yield: 1H NMR (500 MHz, D2O) δ 4.69 (br, 10H including protons from HOAc and water), 4.07−4.04 (m, 1H), 3.27−3.12 (m, 1H), 3.06−2.95 (m, 2H), 2.55 (d, J = 5.4 Hz, 3H), 2.41−2.33 (m, 1H), 1.95 (s, 3H), 1.91 (methyl protons of acetic acid), 1.85 (s, 3H), 1.58−1.3 (m, 5H), 1.22−1.18 (m, 3H due to rotamers), 0.96 (d, J = 6.8 Hz, 3H), 0.84−0.63 (m, 1H); 13C NMR 5407

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

Article

The Journal of Organic Chemistry

4.3 (dt, J = 10.0, 2.5 Hz, 1H), 4.28−4.18 (m, 1H), 3.3−3.1 (m, 1H), 3.07 (d, J = 6.1 Hz, 1H), 2.74 (d, J = 5.1 Hz, 3H), 2.51−2.43 (m, 1H), 1.7−1.5 (m, 3H), 1.4 (s, 9H), 1.35−1.2 (m, 3H), 1.19 (d, J = 7.4 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.6, 173.0, 170.3, 156.3, 135.5, 135.4, 133.0, 130.1, 128.4, 128.3, 79.2, 49.0, 40.3, 37.0, 36.6, 28.6, 28.5, 28.0, 26.3, 23.5, 21.1, 18.0, 16.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H46N4NaO5Si 605.3130, found 605.3128. tert-Butyl (R)-4-acetamido-4-([(S)-2-methyl-3-[(S)-1-(methyl amino)-1-oxopropan-2-ylamino]-3-oxopropyl](diphenylsilyl)butyl carbamate (220 mg, 0.37 mmol) in dichloromethane (2 mL), 4 M HCl in dioxane, (0.5 mL, 2 mmol), triethylamine (0.17 mL, 1.2 mmol), N,N′di(tert-butoxycarbonyl)thiourea (112 mg, 0.4 mmol), and mercuric chloride (120 mg, 4.4 mmol) afforded guanidine 48 (227 mg, 85%) as a colorless foam: Rf = 0.5 (ethyl acetate/methanol 100:15); [α]20 D = −49.0 (c 0.055, CHCl3); IR ν (cm−1) 3293, 3066, 2977, 2935, 1720, 1643, 1550; 1H NMR (400 MHz, CDCl3) δ 11.4 (s, 1H), 8.28 (t, J = 5.4 Hz, 1H), 7.5−7.3 (m, 10H), 6.63 (d, J = 4.3 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 10.2 Hz, 1H), 4.39−4.23 (m, 2H), 3.3 (dt, J = 6.1 Hz, 2H), 2.7 (d, J = 4.9 Hz, 3H), 2.56−2.48 (m, 1H), 1.98 (s, 3H), 1.7−1.6 (m, 2H), 1.57−1.49 (m, 1H), 1.8 (dd, J = 15.4, 6.8 Hz, 1H), 1.3−1.19 (m, 1H), 1.2 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 177.9, 172.9, 170.5, 163.5, 156.5, 153.3, 135.4, 135.3, 133.29, 133.28, 130.1, 128.4, 128.2, 83.3, 79.5, 48.9, 40.6, 37.2, 36.5, 28.4, 28.2, 27.6, 27.5, 26.3, 23.5; 29Si NMR (99.3 MHz, CD3OD) δ −8.82; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C37H56N6NaO7Si 747.3872, found 747.3860. (R)-4-Acetamido-4-([(S)-2-methyl-3-[(S)-1-(methylamino)-1oxopropan-2-ylamino]-3-oxopropyl]dihydroxylsilyl)butylguanidinium Acetate (49). Following the procedure for synthesis of 39, compound 48 (180 mg, 0.25 mmol), 20% AcOH in dichloromethane (8 mL), and mercuric acetate (0.4 g, 1.25 mmol) gave silanediol 49 in quantitative yield: 1H NMR (500 MHz, D2O) δ 4.69 (br, including all exchangeable protons), 4.15−4.08 (m, 1H), 3.32−3.19 (m, 1H), 3.15−3.05 (m, 2H), 2.64 (s, 3H), 2.82−2.51 (m, 1H), 1.66−1.40 (m, 4H), 1.26 (d, J = 7.3 Hz, 3H), 1.09 (d, J = 6.3 Hz, 3H), 1.02−0.88 (m, 1H), 0.8−0.7 (m, 1H); 13C NMR (125 MHz, D2O) δ 180.3, 178.8, 175.7, 173.8, 50.0, 41.2, 39.3, 29.0, 27.0, 26.1, 22.1, 21.2, 20.0, 17.9, 17.0; 29Si NMR (99.3 MHz, D2O) δ −48.8, −56.1 (rotamers); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H33N6O5Si 405.2276, found 405.2289.

96.3, 84.5, 62.7, 55.0, 48.6, 47.97, 36.8, 36.6, 28.1, 27.9, 27.6, 26.1, 21.5, 20.9, 17.1; HRMS (ESI-TOF) m/z [M − Na]+ calcd for [C38H53N3NaO8SSi]+ 762.3215, found 762.3195. 2(S)-[3-[(R)-4-(Methoxymethoxy)-1-(N-(tert-butylcarbamoyl)-4(methylphenylsulfonamido)butyl)diphenylsilyl]-2(S)-methylpropanamido]-N-methylpropanamide (0.5 g, 0.68 mmol), Mg (163 mg, 6.8 mmol), and methanol (10 mL) gave 45 (326 mg, 82%) as a colorless foam: Rf = 0.4 (ethyl acetate); [α]20 D = −85.8 (c 0.19, CHCl3); IR ν (cm−1) 3305, 3070, 2975, 2932, 2885, 1690, 1644, 1537, 1504; 1H NMR (500 MHz, CDCl3) δ 7.56−7.34 (m, 10H), 6.5 (d, J = 5.1 Hz, 1H) 5.96 (d, J = 7.8 Hz, 1H), 4.6 (d, J = 10.2 Hz, 1H), 4.5 (s, 2H), 4.24−4.16 (m, 1H), 3.8 (dt, J = 10.0, 2.1 Hz, 1H), 3.51−3.45 (m, 2H), 3.3 (s, 3H), 2.7 (d, J = 5.0 Hz, 3H), 2.3−2.2 (m, 1H), 1.75−1.67 (m, 2H), 1.63 (dd, J = 15.1, 7.5 Hz, 1H), 1.60−1.53 (m, 1H), 1.34−1.21 (m, 1H), 1.26 (dd, J = 15.4, 7.2 Hz, 1H), 1.1 (d, J = 7.2 Hz, 3H), 1.0 (d, J = 5.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.3, 172.9, 156.6, 135.6, 135.5, 133.4, 133.1, 130.0, 128.3, 128.2, 96.5, 79.2, 67.5, 55.2, 48.8, 38.3, 37.0, 28.7, 28.6, 27.3, 26.3, 21.7, 18.8, 16.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H47N3NaO6Si 608.3126, found 608.3101. tert-Butyl (R)-4-Azido-1-(((S)-2-methyl-3-((S)-1-(methylamino)-1-oxopropan-2-ylamino)-3-oxopropyl)diphenylsilyl)butyl Carbamate (46). Following the procedure for synthesis of 36, compound 45 (0.45 g, 0.76 mmol), dichloromethane (5 mL), TMSBr (0.42 mL, 3.0 mmol), triethylamine (0.16 mL, 1.14 mmol), methanesulfonyl chloride (87 μL, 1.14 mmol), sodium azide (197 mg, 3.0 mmol), and DMF (8 mL) gave 46 (108 mg, 25%) as a colorless foam: Rf = 0.68 (hexane/ethyl acetate 1:2); [α]20 D = −60.6 (c 0.165, CHCl3); IR ν (cm−1) 3299, 3071, 2975, 2932, 2877, 2096, 1689, 1645, 1503; 1H NMR (500 MHz, CDCl3) δ 7.6−7.3(m, 10H), 6.4 (d, J = 4.8 Hz, 1H), 5.9 (d, J = 7.1 Hz, 1H), 4.7 (d, J = 10.3 Hz, 1H), 4.27−4.16 (m, 1H), 3.84 (dt, J = 10.0, 2.0 Hz, 1H), 3.34−3.26 (m, 1H), 3.25−3.21 (m, 1H), 2.75 (d, J = 4.7 Hz, 3H), 2.33−2.22 (m, 1H) 1.75−1.67 (m, 2H), 1.63 (dd, J = 15.1, 7.5 Hz, 1H), 1.60−1.53 (m, 1H), 1.34−1.21 (m, 1H), 1.26 (dd, J = 15.4, 7.2 Hz, 1H), 1.1 (d, J = 7.2 Hz, 3H), 1.09 (d, J = 5.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.3, 172.8, 156.7, 135.5, 135.4, 133.3, 132.9, 130.1, 128.1, 79.4, 51.1, 48.8, 37.9, 37.1, 29.1, 28.6, 26.4, 26.3, 21.9, 17.7, 16.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H42N6NaO4Si 589.2929, found 589.2896. (S)-3-(((R)-1-Acetamido-4-azidobutyl)diphenylsilyl)-2-methyl-N-((S)-1-(methylamino)-1-oxopropan-2-yl)propanamide (47). Following the procedure for synthesis of 37, compound 46 (340 mg, 0.6 mmol), 4 M HCl in dioxane (0.6 mL, 2.4 mmol), AcOH (38 μL, 0.66 mmol), HATU (342 mg, 0.9 mmol), 1-methylmorpholine (0.2 mL, 1.8 mmol), and DMF (5.0 mL) gave 47 (207 mg, 68%) as a colorless foam: Rf = 0.6 (ethyl acetate/methanol 100:17); [α]20 D = −101.3(c 0.145, CHCl3); IR ν (cm−1) 3294, 3070, 2971, 2933, 2876, 2095, 1645, 1538; 1H NMR (500 MHz, CDCl3) δ 7.5−7.3 (m, 10H), 6.4 (br, 1H), 6.37 (d, J = 7.2 Hz, 1H), 6.05 (d, J = 10.7 Hz, 1H), 4.32− 4.21 (m, 2H), 3.31−3.26 (m, 1H), 3.26−3.20 (m, 1H), 2.75(d, J = 5.1 Hz, 3H), 2.49−2.42 (m, 1H), 1.97 (s, 3H), 1.75−1.67 (m, 2H), 1.63 (dd, J = 15.1, 7.5 Hz, 1H), 1.60−1.53 (m, 1H), 1.34−1.21 (m, 1H), 1.26 (dd, J = 15.4, 7.2 Hz, 1H), 1.15 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 5.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.4, 172.7, 170.3, 135.3, 135.2, 132.9, 132.5, 130.1, 128.3, 128.2, 50.1, 48.6, 36.3, 36.1, 28.3, 26.3, 26.2, 23.3, 20.9, 17.8, 15.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H36N6NaO3Si 531.2510, found 531.2498. Di-tert-butyl (R)-4-Acetamido-4-[(S)-2-methyl-3-[(S)-1(methylamino)-1-oxopropan-2-ylamino]-3-oxopropyl](diphenylsilyl)butylguanidine Carbamate (48). Following the procedure for synthesis of 37 and 38, using 47 (0.26 g, 0.5 mmol), Boc2O (120 mg, 0.55 mmol), Lindlar’s catalyst (52 mg), 1 atm of hydrogen, and anhydrous methanol (3 mL) gave tert-butyl (R)-4acetamido-4-([(S)-2-methyl-3-[(S)-1-(methylamino)-1-oxopropan-2ylamino]-3-oxopropyl](diphenylsilyl)butyl carbamate (262 mg, 91%) as a colorless foam: Rf = 0.5 (ethyl acetate/methanol 100:15); [α]20 D = −49.3 (c 0.075, CHCl3); IR 3301, 3066, 2969, 2931, 1693, 1650, 1538 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.5−7.3 (m, 10H), 6.64 (br, 1H), 6.60 (d, J = 7.0 Hz, 1H), 6.2 (d, J = 10.0 Hz, 1H), 4.7 (br, 1H),

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00116. 1 H, 13C NMR spectra of all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Scott McN. Sieburth: 0000-0003-1075-0772 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Peter Walsh, Dr. Dipali Sinha. and Dr. Wenman Wu at Temple Medical School for valuable discussions. We thank Temple University for funding.

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REFERENCES

(1) Key, N.; Makris, M.; O’Shaughnessy, D.; Lillicrap, D. Practical Hemostasis and Thrombosis; Blackwell Publishing Ltd.: Chichester, UK, 2009. 5408

DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409

Article

The Journal of Organic Chemistry (2) Monroe, D. M. In Practical Hemostasis and Thrombosis; WileyBlackwell: 2010; pp 1−6. (3) Schumacher, W. A.; Luettgen, J. M.; Quan, M. L.; Seiffert, D. A. Arterioscler., Thromb., Vasc. Biol. 2010, 30, 388−392. (4) Sieburth, S. McN.; Chen, C.-A. Eur. J. Org. Chem. 2006, 2006, 311−322. (5) Fessenden, R.; Fessenden, J. Adv. Drug Res. 1967, 4, 95−132. (6) Tacke, R.; Linoh, H. In The Chemistry of Organic Silicon Compounds; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons: New York, 1989; pp 1143−1206. (7) Bains, W.; Tacke, R. Curr. Opin. Drug Disc. Dev. 2003, 6, 526− 543. (8) Mills, J.; Showell, G. Expert Opin. Invest. Drugs 2004, 13, 1149− 1157. (9) Englebienne, P.; Hoonacker, A.; Herst, C. Drug Des. Rev.–Online 2005, 2, 467−483. (10) Franz, A. K. Curr. Opin. Drug Disc. Dev. 2007, 10, 654−671. (11) Gately, S.; West, R. Drug Dev. Res. 2007, 68, 156−163. (12) Franz, A. K.; Wilson, S. O. J. Med. Chem. 2013, 56, 388−405. (13) Sieburth, S. McN. Top. Med. Chem. 2014, 1−25. (14) Lickiss, P. D. Adv. Inorg. Chem. 1995, 42, 147−262. (15) Mutahi, M. w.; Nittoli, T.; Guo, L.; Sieburth, S. McN. J. Am. Chem. Soc. 2002, 124, 7363−7375. (16) Kim, J.; Glekas, A.; Sieburth, S. McN. Bioorg. Med. Chem. Lett. 2002, 12, 3625−3627. (17) Kim, J.; Sieburth, S. McN. Bioorg. Med. Chem. Lett. 2004, 14, 2853−2856. (18) Kim, J.; Sieburth, S. McN. J. Org. Chem. 2004, 69, 3008−3014. (19) Kim, J.; Hewitt, G.; Carroll, P.; Sieburth, S. McN. J. Org. Chem. 2005, 70, 5781−5789. (20) Chen, C.-A.; Sieburth, S. McN.; Glekas, A.; Hewitt, G.; Trainor, G.; Erickson-Viitanen, S.; Garber, S.; Cordova, B.; Jeffry, S.; Klabe, R. Chem. Biol. 2001, 8, 1161−1166. (21) Singh, S.; Sieburth, S. McN. Org. Lett. 2012, 14, 4422−4425. (22) Triplett, D. A. Clin. Chem. 2000, 46, 1260−1269. (23) Donkor, D. A.; Bhakta, V.; Eltringham-Smith, L. J.; Stafford, A. R.; Weitz, J. I.; Sheffield, W. P. Sci. Rep. 2017, 7, 2102. (24) Al-Horani, R. A.; Gailani, D.; Desai, U. R. Thromb. Res. 2015, 136, 379−387. (25) Wong, P. C.; Quan, M. L.; Watson, C. A.; Crain, E. J.; Harpel, M. R.; Rendina, A. R.; Luettgen, J. M.; Wexler, R. R.; Schumacher, W. A.; Seiffert, D. A. J. Thromb. Thrombolysis 2015, 40, 416−423. (26) Pinto, D. J. P.; Smallheer, J. M.; Corte, J. R.; Austin, E. J. D.; Wang, C.; Fang, T.; Smith, L. M., II; Rossi, K. A.; Rendina, A. R.; Bozarth, J. M.; Zhang, G.; Wei, A.; Ramamurthy, V.; Sheriff, S.; Myers, J. E., Jr; Morin, P. E.; Luettgen, J. M.; Seiffert, D. A.; Quan, M. L.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2015, 25, 1635−1642. (27) Quan, M. L.; Wong, P. C.; Wang, C.; Woerner, F.; Smallheer, J. M.; Barbera, F. A.; Bozarth, J. M.; Brown, R. L.; Harpel, M. R.; Luettgen, J. M.; Morin, P. E.; Peterson, T.; Ramamurthy, V.; Rendina, A. R.; Rossi, K. A.; Watson, C. A.; Wei, A.; Zhang, G.; Seiffert, D.; Wexler, R. R. J. Med. Chem. 2014, 57, 955−969. (28) Emsley, J.; McEwan, P. A.; Gailani, D. Blood 2010, 115, 2569− 2577. (29) Zhou, P.; Chen, B.-C.; Davis, F. Tetrahedron 2004, 60, 8003− 8030. (30) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600−3740. (31) Bo, Y.; Singh, S.; Duong, H. Q.; Cao, C.; Sieburth, S. McN. Org. Lett. 2011, 13, 1787−1789. (32) Nielsen, L.; Skrydstrup, T. J. Am. Chem. Soc. 2008, 130, 13145− 13151. (33) Wilson, N. S.; Keay, B. A. J. Org. Chem. 1996, 61, 2918−2919. (34) Chatgilialoglu, C. Organosilanes in Radical Chemistry, Principles, Methods and Applications; Wiley: Chichester, 2004. (35) Hardinger, S. A.; Wijaya, N. Tetrahedron Lett. 1993, 34, 3821− 3824. (36) Carlsen, P.; Katsuki, T.; Martin, V.; Sharpless, K. J. Org. Chem. 1981, 46, 3936−3938.

(37) Baeckvall, J. E.; Schink, H. E.; Renko, Z. D. J. Org. Chem. 1990, 55, 826−831. (38) Yamagishi, T.; Kinbara, A.; Okubo, N.; Sato, S.; Fukaya, H. Tetrahedron: Asymmetry 2012, 23, 1633−1639. (39) Braish, T. F. Org. Process Res. Dev. 2009, 13, 336−340. (40) Grehn, L.; Nyasse, B.; Ragnarsson, U. Synthesis 1997, 1997, 1429−1432. (41) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997, 1017−1018. (42) Matthews, J. L.; McArthur, D. R.; Muir, K. W. Tetrahedron Lett. 2002, 43, 5401−5404. (43) Raghavan, S.; Tony, K. A. Tetrahedron Lett. 2004, 45, 2639− 2641. (44) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z. Tetrahedron Lett. 1992, 33, 5933−5936. (45) Hernández, D. c.; Mose, R.; Skrydstrup, T. Org. Lett. 2011, 13, 732−735.

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DOI: 10.1021/acs.joc.8b00116 J. Org. Chem. 2018, 83, 5398−5409