Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 1,4-

Figure 1.2.1. Representative pharmaceuticals containing a diazepane-derived ring system.

Seeking to expand the accessible chemical space of chiral gem-disubstituted heterocycles with potential applications in medicinal chemistry, we identified 1,4- diazepanes as an underutilized substrate class. Diazepanes are common structural motifs found in a variety of pharmaceuticals (Figure 1.2.1), including the benzodiazepine anxiolytics,

⁸

the antipsychotic clozapine,

⁹

and the anti-insomnia drug suvorexant.

¹⁰

Notably, many of these compounds lack Csp

complexity. Suvorexant is a notable

N N O

Ar X

R¹ R

NH N

NMe

Cl N N

Me O N

O Cl

N N

Benzodiazepine Anxiolytics

Clozapine Suvorexant

exception as the only FDA-approved drug to date bearing a stereodefined chiral center in a diazepane ring.

The lack of stereochemically complex diazepanes in the drug landscape, especially those bearing all-carbon quaternary stereocenters, is likely due to a lack of asymmetric methods available for their synthesis, leading to a reliance on kinetic resolution, either of a quaternary building block or of the diazepane itself.

¹¹

The efficient and enantioselective incorporation of gem-disubstitution into diazepane heterocycles could enable the development of pharmaceutical agents with enhanced properties, due to the precedented benefits of increasing saturation in drug molecules.

^5,6

Furthermore, increasing substitution on the diazepane ring could potentially block metabolically labile sites, thus improving the pharmacokinetic profile of a drug candidate. Palladium-catalyzed decarboxylative asymmetric allylic alkylation represents a promising method for the synthesis of enantioenriched gem-disubstituted diazepane derivatives.

Starting from the commercially available N-Boc diazepanone 17, substrates were

readily accessible in a 3-step sequence analogous to that previously reported by our group

(Scheme 1.2.2).

^3e

N-Acylation of 17 with an acyl chloride, followed by C-acylation with

allyl cyanoformate, yielded allyl esters 18a–c. It is notable that this enolate acylation

proceeded smoothly despite the presence of a potential carbamate leaving group at the

amide β-position. Subsequent functionalization of 18a–c was conducted with a variety of

electrophiles, providing substrates 19a–l which bear diverse functional groups. The

divergence put in place by late-stage functionalization of dicarbonyls 18 could enable rapid

analoging in the context of medicinal chemistry.

Scheme 1.2.2. Synthetic route to diazepanone-derived allyl β-amidoesters 19a–l.

We began by examining conditions for the asymmetric allylic alkylation of diazepanone 19a (R

= Bn), utilizing Pd

(pmdba)

as a palladium source and (S)-(CF

)

-t- BuPHOX as a chiral ligand (Table 1.2.3). Polar solvents and toluene led to only modest ee of product 20a (entries 1−4). In prior research by our laboratory, 2:1 hexanes/toluene proved to be an effective solvent system for achieving high ee with a variety of lactam substrates.

^3e

Indeed, compound 20a was obtained in 87% ee under these conditions (entry 6). Finally, we were pleased to discover that an even more nonpolar solvent, methylcyclohexane,

¹²

further enhanced enantioselectivity, yielding 20a in 89% ee (entry 9). Despite its lack of polarity, methylcyclohexane affords homogeneous reaction mixtures.

While examining reaction conditions, we also discovered that use of the highly electron- deficient ligand (S)-Ty-PHOX

¹³

resulted in reduced ee (entry 8). This is in contrast with previous results indicating that more electron-deficient ligands often lead to higher enantioselectivity in related systems.

^3b–e

Using a more electron-rich ligand, (S)-t-BuPHOX, also sharply decreased the ee of the product (entry 11).

R¹N

NBoc O O

R² O HN

NBoc

O 1) n-BuLi, R¹Cl, THF, –78 °C

NC O

O Base THF, –78 °C

2) R¹N

NBoc

O O

O Enolate

Functionalization

17 18a–c

up to >99% yield

19a–l up to 95% yield

Table 1.2.3. Reaction optimization.

[a] Reaction optimization was performed on a 0.01-0.02 mmol scale.

[b] Values determined by chiral SFC analysis. [c] Average over 4 trials, values consistent within 1% ee.

We then applied the optimized reaction conditions to a variety of diazepanone substrates (Table 1.2.4). First, the effect of the electronics of the lactam protecting group on the reaction outcome was investigated. Switching from a benzoyl group (20b) to a more electron-poor p-CF

-benzoyl group (20c) had a minor effect on enantioselectivity.

Interestingly, the use of an electron-rich p-anisoyl (An) group delivered product 20d in an excellent 94% ee. It is worth noting that use of the p-anisoyl protecting group was not beneficial to enantioselectivity in all cases (20a/20e, 20f/20g) and was often on par with the unsubstituted benzoyl group. A variety of functional groups at the quaternary carbon

entry solvent ee^b (%)

BzN

NBoc OBnO

O Pd₂(pmdba)₃ (4 mol %) ligand (10 mol %)

BzN

NBoc OBn

19a 20a

solvent, 40 °C

ligand

1 THF (S)-(CF₃)₃-t-BuPHOX 20

2 1,4-dioxane (S)-(CF₃)₃-t-BuPHOX 38

3 MTBE (S)-(CF₃)₃-t-BuPHOX 70

4 PhCH3 (S)-(CF3)3-t-BuPHOX 66

5 2:1 hexanes/benzene (S)-(CF₃)₃-t-BuPHOX 84 6 2:1 hexanes/PhCH₃ (S)-(CF₃)₃-t-BuPHOX 87^c 7 cyclohexane (S)-(CF₃)₃-t-BuPHOX 88

8 cyclohexane (S)-Ty-PHOX 80

9 methylcyclohexane (S)-(CF₃)₃-t-BuPHOX 89^c 10 2:1 methylcyclohexane/PhCH₃ (S)-(CF₃)₃-t-BuPHOX 86

11 methylcyclohexane (S)-t-BuPHOX 50

Ph₂P

F₃C 2

F3C 2

(S)-t-BuPHOX (S)-(CF₃)₃-t-BuPHOX (S)-Ty-PHOX

N O

t-Bu

N O

t-Bu

N O

t-Bu

CF3 CF3

were tolerated, including groups bearing an alkenyl chloride (20h) and a tert-butyl carbamate (20l). This method also proved reliable for the formation of tertiary alkyl fluorides (20f, 20g). The low yield of propargyl lactam 20i and the necessity for elevated reaction temperatures are also noteworthy–allylic alkylation of other α-propargyl lactams studied by our group has proceeded smoothly.

^3e

It is possible that the geometry of the diazepanone substrate promotes coordination of the alkyne to palladium, hindering the desired reactivity. Additionally, this method allowed for the preparation of benzoyl lactam 20e on a 1 mmol scale, albeit in somewhat diminished yield and ee (see Table 1.2.4,

footnote c).

Table 1.2.4. 1,4-Diazepan-5-one substrate scope.

[a] Reactions were performed on a 0.1 mmol scale at a 0.014 M concentration. An = p-anisoyl. [b] Pd2(pmdba)3

was used instead of Pd2(dba)3. [c] 1 mmol scale: 82% yield, 83% ee. [d] Conducted at 50 °C for 17 h. [e]

Performed in 9:1 methylcyclohexane/PhCH3 to improve substrate solubility.

R¹N

NBoc

O O

R² O

R¹N

NBoc O R² Pd2(dba)3 (4 mol %)

L2 (10 mol %)

NBoc OMe

19a–l 20a–l

20b: R = Bz, 93% yield, 90% ee^b 20c: R = p-CF3-Bz, 90% yield, 92% ee

20d: R = An, 94% yield, 94% ee

NBoc O Bn

AnN

NBoc O

84% yield 90% ee

AnN

NBoc O

44% yield,^b,d 94% ee

AnN

NBoc O

96% yield, 95% ee

CO2Me

AnN

NBoc O

86% yield,^e 84% ee

BzN

NBoc O

76% yield, 93% ee BocHN

20h 20i 20j 20k 20l

20a: R = Bz, 93% yield, 90% ee^b

20e: R = An,

>99% yield, 89% ee^c methylcyclohexane, 40 °C, 2–24 h

NBoc

O F 20f: R = Bz, 84% yield, 90% ee^b

20g: R = An, 84% yield, 83% ee

Having demonstrated the functional group tolerance of this methodology, we performed a short synthesis of an enantioenriched quaternary stereocenter-containing analogue of suvorexant, an FDA-approved sedative used to treat insomnia (Scheme 1.2.5).

Diazepanone 20a was subjected to selective debenzoylation under basic conditions, followed by reduction with LiAlH

to yield diazepane 21 bearing a free secondary amine. Then, nucleophilic aromatic substitution of aryl bromide 22 with 21, followed by Boc deprotection with in situ generated HCl furnished secondary amine 23. A final coupling with the benzoyl chloride derived from carboxylic acid 24

¹⁴

in the same pot provided target compound 25, an analogue of suvorexant bearing an all-carbon quaternary stereocenter. The rapid synthesis of this drug analogue illustrates the ease with which gem-substituted diazepane units can be incorporated into pharmaceutically relevant molecules to produce new agents with potentially improved biological properties.

Scheme 1.2.5. Synthesis of a suvorexant analogue.

BzN

NBoc O Bn

1) LiOH·H₂O, i-PrOH

23 °C, 5 h HN

NBoc

Bn N

O Br Cl

K₂CO₃, MeCN, 23 °C, 24 h 2) AcCl, MeOH, 23 °C, 5 h

39% yield over 2 steps

N NH

N O

CO₂H

N N N

(COCl)₂, cat. DMF, CH₂Cl₂ 23 °C, 1 h 34% yield

N Bn N

N O

Me N N O N

20a 21

25 2) LiAlH₄, THF, 0 °C, 4 h

44% yield over 2 steps

1.3 PALLADIUM-CATALYZED DECARBOXYLATIVE ASYMMETRIC

Dalam dokumen synthesis of organic building blocks and synthetic (Halaman 37-43)