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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 November 16.
Published in final edited form as:
Tetrahedron Lett. 2009 November 16; 50(37): 5205–5207.
doi:  10.1016/j.tetlet.2009.06.125
PMCID: PMC2782829

Asymmetric synthesis of (2S,3R)-(-)-epi-CP-99,994 using sulfinimine-derived anti-2,3-diamino esters


A differentially protected C-3 N-sulfinyl, C-2 N,N-(diphenylmethylene) 2,3-diamino ester was employed in the synthesis of the amino piperidine (2S,3R)-(-)-epi-CP-99,994. Key steps in the synthesis included the chemoselective hydrolysis of the C-2 N,N-(diphenylmethylene) group and its reprotection as a dibenzylamino group

Optically active syn- and anti-2,3-diamino acids are an important class of non-protein amino acids. They are key components of natural products including peptide antibiotics, antifungal agents, as well as other medicinally valuable compounds.1 They are also useful precursors of chiral 1,2-diamines (vicinal diamines) which are found in a broad variety of natural products, are useful ligands for catalysis, and are building blocks for asymmetric syntheses.2 In 2004 we reported the enantioselective synthesis of syn-2,3-diamino esters via the addition of the enolate of ethyl (dibenzylamino) acetate (1) to sulfinimines (N-sulfinyl imines).3,4 For example, the lithium E-enolate of 1 was added to sulfinimine (S)-(+)-2 to give syn-2,3-diamino ester (+)-3 in 68% yield of the major diastereoisomer (Figure 1).4 In 2007 we disclosed that the Z-lithium enolate of N,N-(diphenylmethylene)glycine ethyl ester (4), in the presence of water, adds to (S)-(+)-2 to give the anti-2,3-diamino ester (-)-5 in high dr and in excellent yield.5 In the absence of water, an excess of this enolate afforded the syn-2,3-diamine esters.5 Our asymmetric synthesis of the novel tetracyclic marine antitumor agent (-)-agelastatin A (5)6 and the potent neurokinin substance P receptor antagonist (2S,3S)-(+)-CP-99,994 (6)7 relied on the fact that the two amino groups in the syn-2,3-diamino esters were differentially protected.8 A key step in these syntheses was the selective removal of the N-sulfinyl group. We describe here an efficient asymmetric synthesis of (2S,3R)-(-)-epi-CP99,994 (8) from anti-2,3-diamino ester (-)-5.9.

Figure 1
Applications of N-sulfinyl 2,3,-diamino esters

In considering the synthesis of (-)-8 from (-)-5 we envisioned a route similar to that used in the preparation of (+)-7, namely the construction of a diamino diene and using ring closing metathesis (RCM) to form the piperidine ring.7 However this requires selective hydrolysis of the N,N-(diphenylmethylene)amino group in (-)-5 without disturbing the N-sulfinylamino group. Initial attempts to accomplish this with TFA/MeOH or HCl/H2O under various reaction conditions failed, always resulting in removal of both protecting groups. Recently, Viso and co-workers reported that in the hydrolysis of N-sulfinylimidazolidines with H3PO4 the sulfinamide group was left intact.10 They attributed the remarkable chemoselectivity of this acid to the low nucleophilicity of the phosphate counterion.

Significantly, treatment of (-)-5 with 4 equiv of H3PO4 (85 wt % in H2O) in THF at 0 °C for 4 h produced an 86% isolated yield of the C-2 deprotected amine (SS,2S,3S)-(+)-9 (Scheme 1). While reaction of (+)-9 with benzyl bromide gave (+)-10 in excellent yield, attempts to add a second N-benzyl group resulted in complex mixtures of products. In an effort to prepare a diamine in which the C-3 amino group could be selectivity allylated, (+)-10 was hydrolyzed (TFA-MeOH) and urea (+)-11 was prepared in 83% yield using excess 1,1-carbonyldiimidazole/Et3N. Allylation with 8 equiv of allyl bromide/KHMDS afforded (-)-12 that on reduction with LAH gave alcohol (-)-13 all in good yields (Scheme 1). Next, (-)-13 was oxidized to the aldehyde with Dess-Martin periodinane (DMP). The aldehyde was treated with Na2S2O3, dried (Na2SO4) and added to a -78 °C THF solution of the Wittig reagent (Ph3PCH3Br/n-BuLi) to give the diamino diene (-)-14 in 48% isolated yield. Unfortunately, all attempts to hydrolyze the urea under acid (5 N HCl, 5 N H2SO4) or base (NaOH, Ba(OH)2) conditions failed, and starting material was recovered under all conditions.

Scheme 1
Synthesis of diamino diene (-)-14

For this reason we returned to (+)-10 in hopes of finding conditions for the chemoselective modification of one of the amino groups. Reasoning that the N-benzyl protected amine was a harder nucleophile than then N-sulfinyl amine, (+)-10 was treated with benzoyl chloride, a hard Lewis acid. Remarkably, (-)-15 was selectively formed in 70% yield (Scheme 2). Next, reduction of (-)-15 with 4.0 equiv of LAH at −78 °C to rt accomplished the reduction of both the amide and ester groups to give the N,N-dibenzylamino alcohol (+)-16 in 84% yield. Oxidation of the alcohol with DMP gave the aldehyde, which quickly decomposed on isolation. For this reason the crude aldehyde was treated with Na2S2O3, dried (Na2SO4), and immediately used in the next step. The Kocienski-modified Julia olefination11 using phenyltetrazole methyl sulfone (1.5 equiv) and KHMDS (3.6 equiv) at −20 °C gave (+)-17 in 70 % yield for the two steps (Scheme 3). The sulfinyl group was removed (TFA-MeOH), replaced with a Boc group and (+)-18 was allylated with excess allyl bromide/KHMDS at 0 °C to give the diamino diene (+)-19 in 74% yield. This highly-aminated diene smoothly underwent RCM with the Grubbs-Hoveyda catalyst 2012 to give the amino tetrahydropyridine (+)-21 in 94% isolated yield. 1,2,4,6-Tetrahydropyridines such as (+)-21 are useful chiral building blocks for the synthesis of natural products because of the many methods available for ring functionalization of the C-C double bond.13

Scheme 2
Synthesis of amino tetrahydropyridine (+)-21.
Scheme 3
Conversion to (-)-CP-99.994 (8)

The conversion of (+)-21 into the target (2S,3R)-(-)-epi-CP99,994 (8) followed the procedure that we used to prepare (+)-CP99,994 (7).7 The double bond in the key tetrahydropyridine intermediate (+)-21 was reduced (Pt-C, H2) to give (+)-22. Deprotection (Pd(OH)2-C, H2) of the dibenzyl amino group gave (+)-23 which was subjected to a one-pot reductive amination reaction with o-anisaldehyde/NaB(OAc)3H affording (+)-24 in 98% isolated yield (Scheme 3). Finally, removal of the N-Boc group (HCl-dioxane) gave (2S,3R)-(-)-epi-CP99,994 (8) in 80% yield as the hydrochloride salt.15

In summary, a new synthesis of (2S,3R)-(-)-epi-CP99,994 (8), the anti-analog of the potent neurokinin substance P receptor antagonist (2S,3S)-(+)-CP-99,994 (8) has been achieved. Highlights of this synthesis include the chemoselective hydrolysis of the N,N-(diphenylmethylene) protected C-2 amino group in (-)-5 to give N-sulfinyl diamino ester (-)-9 and the chemoselective N-benzoylation of the C-2 N-benzyl group in (+)-10 to give (-)-15.


This work was supported by grants from the National Institutes of General Medical Sciences (GM57878 and GM51982) and Boehringer Ingelheim Pharmaceuticals.


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