Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to a new process for preparing substituted purine derivatives. More specifically, the process of the invention relates to the synthesis of 2,6,9-trisubstiruted purines which are useful in the treatment of proliferative disorders such as cancer, leukemia, psoriasis and the like.
• 2,6,9-Trisubstituted purine derivatives are known to have antiproliferative and other therapeutic properties by virtue of their ability to inhibit protein kinases, in particular, cyclin dependent kinases.
• CDK cyclin-dependent kinase
• CDKs The activity of CDKs is regulated post-translationally, by transitory associations with other proteins, and by alterations of their intracellular localisation. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin A/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cytotoxic and cytostatic drugs. While inhibition of cell cycle-related CDKs is clearly relevant in e.g. oncology applications, this may not be the case for the inhibition of RNA polymerase-regulating CDKs.
• CDK9/cyclin T function was recently linked to prevention of HIV replication and the discovery of new CDK biology thus continues to open up new therapeutic indications for CDK inhibitors (Sausville, E.A. Trends Molec. Med. 2002, 8,S32-S37).
• CDKs The function of CDKs is to phosphorylate and thus activate or deactivate certain proteins, including e.g. retinoblastoma proteins, lamins, histone Hl, and components of the mitotic spindle.
• the catalytic step mediated by CDKs involves a phospho-transfer reaction from ATP to the macromolecular enzyme substrate.
• Several groups of compounds (reviewed in e.g. Fischer, P.M. Curr. Opin. Drug Discovery Dev. 2001, 4, 623-634) have been found to possess anti-proliferative properties by virtue of CDK- specific ATP antagonism.
• WO 98/05335 discloses 2,6,9-trisubstituted purine derivatives that are selective inhibitors of cell cycle kinases.
• Such compounds are useful in the treatment of autoimmune disorders, e.g. rheumatoid arthritis, lupus, type I diabetes, multiple sclerosis, treating cancer, cardiovascular disease, such as restenosis, host v graft disease, gout, polycystic kidney disease and other proliferative diseases whose pathogenesis involves abnormal cell proliferation.
• WO 99/07705 (The Regents of the University of California) discloses purine analogues that inhibit inter alia protein kinases, G-proteins and polymerases. More specifically, WO 99/07705 relates to methods of using such purine analogues to treat cellular proliferative disorders and neurodegenerative diseases.
• WO 97/20842 also discloses purine derivatives displaying antiproliferative properties which are useful in treating cancer, psoriasis, and neurodegenerative disorders.
• WO 03/002565 (Cyclacel Limited) discloses similar such derivatives, whereas WO 04/016613 and WO 04/016612 (also in the name of Cyclacel Limited), disclose purine derivatives substituted in the 6-position by a pyridinylmethylamino group.
• WO 97/20842 describes the synthesis of roscovitine by preparing 6-benzylamino-2-chloropurine and subsequently converting to 6- benzylamino-2-chloro-9-isopropylpurine by treatment with isopropyl bromide/potassium carbonate in DMSO.
• 6-benzylamino-2-chloro-9- isopropylpurine is then treated with R(-)-2-amino-l-butanol to form 6-benzylamino-2- R-(l-ethyl-2-hydroxyethylamino)-9-isopropylpurine in racemic form.
• WO 04/016613 and WO 04/016612 disclose the synthesis of 2,6,9- trisubstituted purines in which the 6-substitutuent is a pyridinylmethylamino group.
• the present invention therefore seeks to provide an alternative synthetic route for preparing 2,6,9-trisubstituted purines. More preferably, the invention seeks to alleviate one or more of the problems associated with prior art synthetic routes, and in particular, seeks to provide a process which enables easier purification (i.e. cleaner reactions), and/or the use of reduced amounts of reagents, and/or improved yields.
• a first aspect of the invention relates to a process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof,
• R 3 , R 4 , R 7 and R 8 are each independently selected from H, alkyl, aryl and aralkyl, said alkyl, aryl and aralkyl groups each being optionally substituted with one or more R 12 groups, and wherein at least one of R 3 , R 4 , R 7 and R 8 is other than H;
• R 5 is OH, O-alkyl, H, alkyl, aryl or aralkyl, said alkyl, aryl and aralkyl groups each being optionally substituted with one or more R 12 groups;
• R 6 is NR 10 R 11 , wherein R 10 and R 11 are each independently H or hydrocarbyl;
• R 9 is hydrocarbyl; and each R 12 is independently selected from OR 13 , halo, alkyl, COOR 14 , CONR 15 R 16 ,
• X is halo and R is aryl, alkyl, cycloalkyl, aralkyl, heteroaryl or alkyl-heteroaryl; (ii) converting said compound of formula III to a compound of formula IV; and
• a second aspect of the invention relates to the use of a process as set forth above in the preparation of a 2,6,9-trisubstituted purine.
• a third aspect of the invention relates to the use of a process as set forth above in the preparation of a CDK inhibitor.
• the process of the present invention enables the synthesis of 2,6,9- trisubstituted purine derivatives in high yields.
• One particular advantage is that the inventive process allows for the use of reduced amounts of reagent in the amination step, i.e. in the introduction of the R 2 substituent. Overall, the reaction is cleaner, higher yielding, requires less amine and can be performed under milder conditions.
• the SR group introduced in the 6-position is subsequently activated by oxidation to form the corresponding SO 2 R derivative.
• the SO 2 R group is a labile leaving group that can readily be replaced by the desired R 6 group (NHR 8 ) in the final step of the process.
• hydrocarbyl refers to a group comprising at least carbon and hydrogen. If the hydrocarbyl group comprises more than one carbon then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain heteroatoms. Suitable heteroatoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen, oxygen, phosphorus and silicon. Where the hydrocarbyl group contains one or more heteroatoms, the group may be linked via a carbon atom or via a heteroatom to another group, i.e. the linker atom may be a carbon or a heteroatom.
• the hydrocarbyl group is an aryl, heteroaryl, alkyl, cycloalkyl, aralkyl, heterocycloalkyl, or alkenyl group. More preferably, the hydrocarbyl group is an aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or alkenyl group.
• the hydrocarbyl group may be optionally substituted by one or more R 12 groups, where each R 12 is independently selected from OR 13 , halo, alkyl, COOR 14 , CONR 15 R 16 , SO 2 NR 17 R 18 , NO 2 , CN, NR 19 R 20 SR 21 and CF 3 , where R 13"21 are each independently H, alkyl or aryl.
• alkyl includes both saturated straight chain and branched alkyl groups which may be substituted (mono- or poly-) or unsubstituted.
• the alkyl group is a Ci -20 alkyl group, more preferably a Ci -I5 , more preferably still a Ci -I2 alkyl group, more preferably still, a C 1-6 alkyl group, more preferably a C 1-3 alkyl group.
• Particularly preferred alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.
• Suitable substituents include, for example, one or more R 12 groups as defined above.
• the alkyl group is unsubstituted.
• alkenyl refers to a group containing one or more carbon- carbon double bonds, which may be branched or unbranched, substituted (mono- or poly-) or unsubstituted.
• the alkenyl group is a C 2-20 alkenyl group, more preferably a C 2-15 alkenyl group, more preferably still a C 2-12 alkenyl group, or preferably a C 2-6 alkenyl group, more preferably a C 2-3 alkenyl group.
• Suitable substituents include, for example, one or more R 12 groups as defined above.
• aryl refers to a C 6-I2 aromatic group which may be substituted (mono- or poly-) or unsubstituted. Typical examples include phenyl and naphthyl etc. Suitable substituents include, for example, one or more R 12 groups as defined above.
• heteroaryl refers to a C 2-I2 aromatic, substituted (mono- or poly-) or unsubstituted group, which comprises one or more heteroatoms.
• the heteroaryl group is a C 4-12 aromatic group comprising one or more heteroatoms selected from N, O and S.
• Suitable heteroaryl groups include pyrrole, pyrazole, pyrimidine, pyrazine, pyridine, quinoline, thiophene, 1,2,3-triazole, 1 ,2,4-triazole, thiazole, oxazole, iso-thiazole, iso-oxazole, imidazole, furan and the like.
• suitable substituents include, for example, one or more R 12 groups as defined above.
• cycloalkyl refers to a cyclic alkyl group which may be substituted (mono- or poly-) or unsubstituted.
• the cycloalkyl group is a C 3- 12 cycloalkyl group.
• Suitable substituents include, for example, one or more R 12 groups as defined above.
• aralkyl refers to a group having both aryl and alkyl functionalities.
• the term includes groups in which one of the hydrogen atoms of the alkyl group is replaced by an aryl group, e.g. a phenyl group optionally having one or more R 12 substituents, such as halo, alkyl, alkoxy, hydroxy, and the like.
• Preferred aralkyl groups include benzyl, phenethyl and the like.
• alkyl-heteroaryl refers to a group having both heteroaryl and alkyl functionalities.
• the term includes groups in which one of the hydrogen atoms of the alkyl group is replaced by a heteroaryl group, e.g. a pyridinyl group optionally having one or more R 12 substituents, such as halo, alkyl, alkoxy, hydroxy, and the like.
• Preferred alkyl-heteroaryl groups include CH 2 -pyridinyl and the like.
• one of R 3 and R 4 is alkyl, aryl or aralkyl, and the other is H.
• one of R 7 and R 8 is alkyl, aryl or aralkyl, and the other is H.
• one of R 3 and R 4 is alkyl, and the other is H.
• one of R 7 and R 8 is alkyl, and the other is H.
• one of R 3 and R 4 is methyl, ethyl or isopropyl, and the other is H.
• one of R 3 and R 4 is alkyl, and the other is H; and one of R 7 and R 8 is alkyl, and the other is H.
• one of R 3 and R 4 is H and the other is methyl, ethyl or iso-propyl; one of R 7 and R 8 is H, and the other is methyl, ethyl, iso-propyl or tert-butyl.
• R 5 is OH
• R 3 is ethyl
• R 4 is H
• R 5 is OH
• R 7 and R 8 are both H.
• R 9 is alkyl or cycloalkyl, each of which may be optionally substituted by one or more R 12 groups.
• R 9 is isopropyl or cyclopentyl.
• R 10 is H.
• R 11 is aryl, heteroaryl, aralkyl, alkyl-heteroaryl, alkyl, alkenyl or cycloalkyl, each of which may be optionally substituted with one or more R 12 groups.
• R 11 is aryl, aralkyl, heteroaryl or alkyl-heteroaryl, each of which may be optionally substituted with one or more R 12 groups.
• R 1 ' is phenyl, benzyl, pyridinyl or CH 2 -pyridinyl, each of which may be optionally substituted with one or more R 12 groups.
• each R 12 is independently selected from OH, alkoxy, halo, alkyl, COOH, COOMe, CONH 2 , SO 2 NH 2 , NO 2 , CN 5 NHMe 5 NH 2 , NMe and CF 3 .
• R 11 is selected from phenyl, benzyl, CH 2 -pyridin-2-yl, CH 2 - pyridin-3-yl and CH 2 -pyridin-4-yl, each of which may be optionally substituted by one or more halo, OH, OMe and/or NO 2 groups.
• the process of the present invention is suitable for preparing a wide range of substituted purine derivatives.
• the process is suitable for preparing substituted purines such as those described in WO 97/20842 (CNRS), and WO 03/002565, WO 04/016613 and WO 04/016612 (all in the name of Cyclacel Limited), the teachings of which are hereby incorporated by reference.
• the process of the invention is suitable for preparing compounds of formula I selected from the following:
• the process of the invention is suitable for preparing compounds of formula I selected from the following:
• roscovitine encompasses the resolved R and S enantiomers, mixtures thereof, and the racemate thereof.
• Roscovitine has been shown to be a potent inhibitor of cyclin dependent kinase enzymes, particularly CDK2.
• CDK inhibitors are understood to block passage of cells from the Gl /S and the G2/M phase of the cell cycle.
• the pure R-enantiomer of Roscovitine, "CYC202" (R-Roscovitine) has recently emerged as a potent inducer of apoptosis in a variety of tumour cells (McClue SJ, Blake D, Clarke R, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R- Roscovitine), Int J Cancer.
• Roscovitine has also been shown to be an inhibitor of retinoblastoma phosphorylation and therefore implicated as acting more potently on Rb positive tumors.
• roscovitine has therapeutic applications in the treatment of certain proliferative disorders that have to date been particularly difficult to treat, for example, multiple myeloma, B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (WO 2005/044275, WO 2005/002584 and WO 2005/044274, all in the name of Cyclacel Limited).
• the compound of formula I is the R enantiomer of roscovitine, namely 2-(l-R-hydroxymethylpropylamino)-6- benzylamino-9-isopropylpurine or "CYC202", the structure of which is shown below.
• the process of the invention comprises the steps of: (ia) converting said compound of formula II to a compound of formula Ha; and (ib) converting said compound of formula Ha to a compound of formula III
• step (ia) comprises treating said compound of formula II with R 9 -OH, where R 9 is as defined above.
• step (ia) comprises reacting said compound of formula II with R 9 -OH in the presence of PPh 3 and diisopropyl azodicarboxylate (DIAD).
• DIAD diisopropyl azodicarboxylate
• the solvent in step (ia) is THF.
• step (ib) of the process comprises reacting said compound of formula Ha with an amine of formula VII,
• step (ib) is carried out in the presence of a tertiary amine and an alcohol.
• step (ib) is carried out in the presence of "Pr 3 N and n-butanol.
• said compound of formula Ha, said amine of formula VIII, "Pr 3 N and n-butanol are heated at reflux temperature.
• Substituted amino alcohols VII (R 3 or R 4 ⁇ > H) can be synthesized from ⁇ -amino alcohols VIII (R 3 or R 4 ⁇ > H) as shown in Scheme 2 below. Many of the latter are available commercially; alternatively, they can be prepared readily by reduction of the corresponding ⁇ -amino acids.
• the initial reaction in the synthetic methodology adopted was trityl protection of the amino function to afford intermediate IX (R 3 or R 4 ⁇ > H; Evans, P. A., Holmes, A. B., and Russell, K. J. Chem. Soc, Perkin Trans. 1, 1994, 3397-3409).
• the amino alcohol of formula VII is 3- amino-pentan-2-ol, i.e. is an enantiomer selected from the following:
• D-threonine L-allo-threonine and D-allo-threonine are not commercially available as the analogous cbz protected methyl esters, cbz protection of threonine and subsequent methyl ester formation were required.
• Cbz protection of D-threonine 13 was carried out using sodium bicarbonate and benzyl chloroformate in aqueous THF giving the desired product 14 in quantitative yield.
• 1 HNMR spectroscopy confirmed the crude product was of sufficient purity to use in the next stage without purification. Reaction of compound 14 with TMSCI in methanol gave the methyl ester 15 in 79% yield. Again, 1 H NMR spectroscopy confirmed the crude product was of sufficient purity to use in the next stage without purification.
• (2S,3R)-3-Amino-pentan-2-ol 3 was synthesised from L-allo-threonine using the above methodology. The product was found to be >90% pure by 1 H NMR spectroscopy. Chiral HPLC analysis of the product after trityl protection gave a chiral purity of 93.7%. A total of 0.4 g of (2S,3R)-3-amino-pentan-2-ol 3 is available for use.
• step (ii) comprises treating said compound of formula III with potassium peroxymonosulfate, KHSO 5 , to form said compound of formula IV.
• step (ii) comprises treating said compound of formula III with 2KHSO 5 'KHSO 4 *K 2 SO 4 (Oxone®) to form said compound of formula IV.
• the active ingredient of Oxone® is potassium peroxymonosulfate, KHSO 5 (CAS-RN 10058-23-8), commonly known as potassium monopersulfate, which is present as a component of a triple salt with the formula 2KHSO S -KHSO 4 -K 2 SO 4 (potassium hydrogen peroxymonosulfate sulfate (5:3:2:2), CAS-RN 70693-62-8; commercially available from DuPont).
• KHSO 5 potassium peroxymonosulfate
• KHSO 5 CAS-RN 10058-23-8
• potassium monopersulfate potassium monopersulfate
• the oxidation potential of Oxone® is derived from its peracid chemistry; it is the first neutralization salt of peroxymonosulfuric acid H 2 SO 5 (also known as Caro's acid).
• step (ii) is carried out in a water/methanol solvent mixture.
• step (iii) comprises reacting said compound of formula IV with an amine of formula NHR 10 R 11 , where R 10 and R 11 are as defined above.
• step (iii) is carried out in an alcohol solvent. More preferably, the solvent is ethanol.
• said compound of formula IV, said amine of formula NHR 10 R 11 and the solvent are heated at reflux temperature.
• said compound of formula II is prepared by reacting a compound of formula V with a compound of formula RSH,
• Y is chloro and X is fluoro.
• said compound of formula V and said compound of formula RSH are reacted in the presence of a base. More preferably, the base is NEt 3 .
• said compound of formula V and said compound of formula RSH are reacted in an alcohol solvent. More preferably, the solvent is ethanol.
• R is aryl or aralkyl, more preferably, phenyl or benzyl. Even more preferably, R is benzyl.
• said compound of formula V is prepared from a compound of formula VI
• X is fluoro and Y is chloro
• said compound of formula V is prepared by treating 2-amino-6-chloropurine with HF/pyridine.
• the compounds prepared by the process of the invention can be in the form of salts or esters, in particular pharmaceutically and veterinarily acceptable salts or esters.
• compositions prepared by the process of the invention include suitable acid addition or base salts thereof.
• suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
• hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C !
• Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphon
• Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified.
• Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-tol
• Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide.
• Alcohols include alkanealcohols of 1-12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).
• the invention includes, where appropriate all enantiomers, diastereoisomers and tautomers of the compounds prepared by the process of the invention.
• the person skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics.
• the corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.
• Compounds prepared by the process of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
• Some of the compounds prepared by the process of the invention may exist as stereoisomers and/or geometric isomers, e.g. they may possess one or more asymmetric and/or geometric centres and so may exist in two or more stereoisomeric and/or geometric forms.
• the present invention contemplates the preparation of all the individual stereoisomers and geometric isomers of those inhibitor agents, and mixtures thereof.
• the terms used in the claims encompass these forms.
• the present invention also includes all suitable isotopic variations of the compounds prepared by the inventive process, or a pharmaceutically acceptable salts thereof.
• An isotopic variation of compound of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
• isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as H, H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
• isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies.
• Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
• the 3-aminopentan-2-ol intermediates were prepared by UFC from both the R- and S- amino acids (Scheme 12) as a mixture of stereoisomers at the C -2 position of the aminopentanols. Once incorporated into the purine nucleus, the two diastereomeric pairs were separated into chirally pure final products by Chiral Technologies by means of preparative HPLC.
• tert-butyl nitrite (90% w/w, 30ml, 0.228M) was added in 0.1ml portions over a period of Ih, with swirling to assist mixing. Foaming and an exotherm ensued.
• the internal temperature was maintained ⁇ 5 0 C by the rate of addition.
• the cooling bath was removed and the mixture was stirred Ih at room temperature. Some residual solid was present and the mixture was warmed to 22 0 C to obtain a homogeneous solution.
• the mixture was poured into ice-water (800ml) and neutralized with solid potassium hydrogen carbonate.
• the aqueous solution was extracted with ethyl acetate (3x600ml).
• Oxone (12.89g, 20.96mmol) was partially dissolved in water (40ml) and cooled to - 2 0 C.
• Compound 4a (4.49g, 11.65mmol) was dissolved in methanol (40ml) and added dropwise to the cooled aqueous solution over a period of 35 min. The mixture was stirred 5 min with cooling, then 2.5 h at room temperature. The mixture was concentrated to 2/3 its volume in vacuo and diluted with water (200ml). Extracted with ethyl acetate (3xl50ml). The combined organics were washed (brine), dried (MgSO 4 ), filtered and evaporated to a pale yellow solid. 4.09g (84%) obtained.
• Ci 9 H 27 N 7 O 369.46. MH + requires 370.47
• Trimethylsilyl chloride (10.7 mL) was added dropwise to a solution of cbz protected D-threonine 14 (10.7 g) in methanol (100 mL) at 0 to 5 0 C under nitrogen. The resulting solution was stirred at room temperature overnight after which time the solvent was removed in vacuo. The resulting residue was dissolved in DCM (200 mL), washed with water (2 x 200 mL), dried over MgSO 4 , filtered and stripped to give the desired product 15 as a white solid (8.9 g, 79%). 1 H NMR spectroscopy confirmed the identity of the product and showed it to be of sufficient purity for use in the next stage without purification.
• Hunig's base (17.6 mL) and TBDMSCI (10.7 g) were added to a solution of Z-(L)- threonine methyl ester 7 (6.0 g) in DMF (120 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature overnight.
• Water (300 mL) and ethyl acetate (300 mL) were added and the phases separated. The aqueous phase was extracted with ethyl acetate (2 x 200 mL) and the combined organic phase washed with water (200 mL), saturated aqueous sodium chloride (200 mL), dried over MgSO 4 , filtered and stripped to give a dark orange oil (16.6 g).
• DIBAL IM in toluene, 57.7 mL
• DIBAL IM in toluene, 57.7 mL
• the resulting solution was stirred at ⁇ -65°C for 1 hour. Tie showed the reaction was incomplete.
• DIBAL (1 M in toluene, 29.0 mL) was added dropwise to the reaction solution maintaining the temperature below -65 0 C.
• (2S,3S)-3-Amino-pentan-2-ol 2 (1.0 g) was dissolved in 2:1 water I dioxane (15 mL) at room temperature under nitrogen. A dual dropwise addition of benzoyl chloride (1.4 mL) and 5M aqueous NaOH (3.7 mL) was carried out maintaining the pH of the reaction solution at 8 to 9. The resulting solution was stirred at room temperature for 1 hour then stripped to dryness. The residue was dissolved in water (25 mL) and ethyl acetate (25 mL) and the phases separated.

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