Aminodiols via Stereocontrolled Oxidation of Methyleneaziridines

Abstract

A highly diastereoselective Ru-catalyzed oxidation/reduction sequence of bicyclic methyleneaziridines provides a facile route to complex 1-amino-2,3-diol motifs. The relative anti stereochemistry between the amine and the vicinal alcohol are proposed to result from 1,3-bischelation in the transition state by the C1 and C3 heteroatoms.

Aminodiols are ubiquitous in a host of bioactive molecules and natural products (Figure 1).¹ Popular approaches to these motifs often employ starting materials from the chiral pool or utilize the ring-opening of chiral epoxy alcohols with amine nucleophiles.^2,3 These strategies work well when the target aminodiol is relatively simple, but accessing more complex and densely substituted motifs can be difficult. While the dihydroxylation of chiral allylic amines addresses this challenge to some extent, high loadings of OsO₄ and variable dr are drawbacks.⁴

Figure 1.

Bioactive molecules containing NOO stereotriads.

Our group has developed new methods that introduce three new sp³ carbon–heteroatom bonds into an allene in a sterecontrolled manner. Rapid access to C–Nu/C–N/C–E stereotriads (motifs containing three contiguous chiral carbons, Ic, Scheme 1) from homoallenic sulfamates is enabled through the intermediacy of bicyclic methyleneaziridines Ia.⁵ This method offers diversity in the choices for the Nu and E groups of Ic but restricts the placement of nitrogen to the central carbon of the stereotriad. The utility of allene oxidation could be expanded if amine-containing stereotriads of other substitution patterns could be accessed. Herein, we report a highly diastereoselective formation of C–N/C–O/C–O (NOO) triads from simple homoallenic carbamates.

Scheme 1. Allene Functionalization Strategies.

The initial step of our strategy employs allene aziridination to a methyleneaziridine IIa (Scheme 1).⁶ The bicyclic nature of IIa was expected to promote dihydroxylation to a hemiaminal IIb in high dr. Unraveling of IIb to a 1,3-hydroxyaminated ketone IIc, followed by reduction, would yield either IId or IIe, depending on the nature of the reductant.

We initially attempted to use homoallenic sulfamates as substrates, but aziridine ring-opening prior to reaction of the exocyclic double bond was problematic. Treatment of homoallenic carbamate 1a (Table 1) with OsO₄ and NMO gave no reaction; however, a 1 mol % loading of RuCl₃ in the presence of NaIO₄ as the terminal oxidant (“flash dihydroxylation”) cleanly provided the desired ketone 2aE (IIc, Scheme 1 for general structure).⁷ The key to achieving excellent conversion and minimizing oxidative cleavage was to employ CeCl₃ as an additive.^7d,7g Under these conditions, the ketone 2aE was obtained as a single diastereomer, indicating excellent facial selectivity in the dihydroxylation. Immediate reduction of the ketone with NaBH₄ in MeOH yielded the 1-amino-2,3-diol 3aE in >20:1 dr (Table 1, entry 1).

Table 1. Stereocontrolled Transformation of gem-Dimethyl Bicyclic Methyleneaziridines to NOO Stereotriads.

^aCombined yield of E and Z.

^bdr of both the E and Z products.

^cThe E and Z methyleneaziridines were separated, and only E was used in the reaction.

^d100 mol % CeCl₃ and 3.0 equiv of NaIO₄ were employed in the oxidation, while Zn(BH₄)₂ in Et₂O at 0 °C was used in the reduction.

The scope of the reaction was investigated (Table 1).^5,6 In all cases, the 1-amino-2,3-diol was obtained in >20:1 dr, with both aryl (entries 1–3) and alkyl (entries 4–8) groups tolerated at C3 of the substrate. The presence of an EWG on the arene decreased the yield but did not impact the dr (Table 1, compare entry 3 to entries 1 and 2). The 1-amino-2,3-diols obtained from E methyleneaziridines contained the 1,2-anti:2,3-syn stereochemistry, as verified by X-ray crystallography of 3cE. The structures of 3aE and 3bE were assigned by analogy to 3cE (Supporting Information). The anti relationship between the C1 amine and the C2 alcohol was also observed when C3 was achiral (entries 4 and 5). When the two substituents at C3 of the allene were very similar, the mixtures of E and Z methyleneaziridines were difficult to separate (entries 6–8). However, the reaction could be carried out on the 70:30 E/Z mixtures and the resulting isomers separated to give the diastereomeric triads 3f–hE and 3f–hZ in excellent dr (E shown). Separating ketones 2gE and 2gZ and independently subjecting them to reduction clearly showed the dr of the reduction was >20:1. The relative stereochemistries of both 3gE and 3gZ were verified by X-ray crystallography as 1,2-anti:2,3-syn (Supporting Information) for 3gE and 1,2-anti:2,3-anti for 3gZ.

The 1,3-disubstituted methyleneaziridine 1i (entry 9) was challenging, as overoxidation to the diketone using Ru catalysis was problematic.⁷ Increasing the amount of CeCl₃ improved the selectivity for 2i, but at the cost of conversion. The use of a full equivalent of CeCl₃ and portionwise addition of 3.0 equiv of NaIO₄ gave a 66% yield of the desired product with minimal overoxidation.

To expand the reaction scope and shed light on the factors responsible for stereocontrol in the ketone reduction, methyleneaziridines lacking the gem-dimethyl group were explored (Table 2). These compounds were susceptible to ring-opening when the conditions described in Table 1 were employed. Substitution of AcOH or H₂SO₄ for CeCl₃ as the additive improved both the conversions and the yields in the dihydroxylation.

Table 2. Expanding the Scope of NOO Stereotriad Synthesis^*.

^*Conditions A: 1 mol % of RuCl₃, 50 mol % of AcOH, 1.5 equiv of NaIO₄, 2:1 MeCN/H₂O. Conditiosn B: 1 mol % of RuCl₃, 20 mol % of H₂SO₄, 1.5 equiv of NaO₄. 3:3:1 EtOAc/MeCN/H₂O.

^aYield of the product from the E isomer.

^bdr of the product from the E methyleneaziridine.

Oxidation of E-4a (Table 2, entry 1) gave the ketone 5a in 98% yield as a single diastereomer. Reduction of 5a with NaBH₄ in MeOH gave the 1,2-anti:2,3-syn stereoisomer 7a in 80% yield (verified by X-ray crystallography) and 5.7:1 dr, along with the minor isomer 8a. The dialkyl-substituted methyleneaziridines 4b and 4c were not easily separable, but the diastereomers could be resolved at either the ketone or the 1-amino-2,3-diol stage to give the products in dr of 7.1–8.3:1 (entries 2 and 3). Substrates with identical substituents at C3 (entries 4 and 5) exhibited a 1,2-anti relationship between the C1 amine and the C2 alcohol.

The unexpected stereochemical outcomes were initially puzzling. While Felkin–Anh and Cram chelation models are often invoked to explain stereochemical outcomes in the addition of nucleophiles to α-substituted carbonyls, control when a ketone is flanked by two different potential chelating groups is poorly understood.^8,9 We propose the −NH and the −OH of ketones of the general form 9 (Figure 2) participate in 1,3-bis-chelation to give a trans decalin-type intermediate 10. Reduction of the ketone from the top face should be favored to yield the 1,2-anti:2,3-syn relationship observed in the products. To determine how well this hypothesis fit our data, the reduction of ketones of several substitution patterns were examined more closely. In the case of 3fE and 3fZ, formed from the E and Z stereoisomers of 2f, an anti relationship between C1 and C2 was noted in both of the products (Table 1, entry 6 and Figure 2, A and B), ruling out stereocontrol of the reduction by C3. The observed results could be rationalized either by our proposed model or by assuming that the amine at C1 is responsible for controlling the reduction outcome. If C1 were solely responsible for stereocontrol of the reduction, the removal of a substituent from C3 of 2i (Table 1, entry 9 and Figure 2, C) would not be expected to influence the dr. However, we found that the dr of 3iE decreased to 2.2:1 using NaBH₄ in MeOH. Switching to a less polar solvent and a lower temperature increased the dr, while substitution of Zn(BH₄)₂ for NaBH₄ restored the dr to 7.9:1 with a 1,2-anti relationship as verified by X-ray crystallography. Chelation control through the C3 oxygen would be expected to yield the 1,2-syn:2,3-anti triad; thus, we propose that a tighter transition state exists in C when M = Zn (van der Waal radius of Zn²⁺ = 0.88 Å), as compared to M = Na (Na⁺ = 1.16 Å), leads to an increase in dr. In addition, the trans decalin transition state in C is disfavored by the need to place the alkyl group in the pseudoaxial position, a situation that is less favorable in the presence of a highly polar solvent and/or a large cation. Removal of the gem-dimethyl groups in 5a (Figure 2, D) lowered the dr, perhaps due to the lack of assistance from the Thorpe–Ingold effect in enforcing the trans decalin transition state.

Figure 2.

Possible α,α′-chelation models for stereocontrol.

In conclusion, rapid and diastereoselective conversion of homoallenic carbamates to 1-amino-2,3-diols has been achieved. Stereoselectivity in the reduction of the α,α′-substituted ketones depends on the specific substitution pattern of the substrate but often exhibits dr > 10:1. Coupled with our previous observations that the axial chirality of an allene can be transferred to point chirality, this protocol permits rapid access to densely functionalized, enantioenriched aminodiols.

Supporting Information Available

Experimental procedures and full characterizations are available for all new compounds. X-ray crystallographic data is available for compounds 3cE, 3gE, 3gZ, 7aE, and 3iE (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.

The authors declare no competing financial interest.

Funding Statement

National Institutes of Health, United States