Metandienone Wikipedia

# Metandienone

## Overview
Metandienone (commonly known as Dianabol) is a synthetic anabolic‑steroid derivative of testosterone that was first developed in the 1960s for medical use, mainly to treat muscle wasting conditions and severe burns. Its high anabolic potency and relatively short half‑life made it popular among athletes and bodybuilders seeking rapid increases in lean muscle mass and strength.

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## Chemical Profile

| Property | Value |
|----------|-------|
| **IUPAC name** | 1‑(4‑hydroxy‑3,17-dimethyl‑5α-androst-2-en‑17β‑yl)-3-(propylamino)propan-2‑ol |
| **Molecular formula** | C₂₁H₃₀O₂ |
| **Molecular weight** | 314.46 g/mol |
| **Structure** | Two fused cyclohexane rings (steroid nucleus), a side chain bearing a propylamino group, and a β‑hydroxy group at C‑17 |

> *Note: The figure below shows the three‑dimensional arrangement of atoms in testosterone.*

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## 2. Chemical Properties

| Property | Description |
|----------|-------------|
| **Solubility** | Poorly soluble in water (≈ 1 mg/mL); readily dissolves in organic solvents such as ethanol, acetone, and chloroform. |
| **Stability** | Stable under normal storage conditions (< 25 °C). Sensitive to light and air: prolonged exposure can lead to oxidation of the hydroxy group. |
| **pKa** | The phenolic hydroxyl (C3) has pKa ≈ 10; it is a weak acid, so testosterone remains largely neutral at physiological pH. |
| **Melting Point** | 212–214 °C (decomposes slightly above). |
| **Molecular Formula** | C₁₇H₂₆O₂ |
| **Molecular Weight** | 254.36 g/mol |

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## 2. General Strategy for Synthesizing Testosterone

1. **Synthesis of the steroid skeleton** (Δ⁴‑cholestane) – typically via a series of functional‑group transformations on a suitably substituted cyclopentanone/benzene scaffold, followed by ring‑closure to form the perhydro‑cyclohexane nucleus and the fused four‑ring system.

2. **Introduction of the Δ²‑double bond** (between C2–C3) – usually through dehydrogenation after installing a hydroxyl at C3 or by an oxidation‑dehydration sequence that generates the double bond with correct geometry.

3. **Installation of the 3β‑hydroxy group** and **reduction of the 4‑position** (forming the saturated ring) – via stereoselective reduction, typically using a hydride donor that delivers the proton from the same face as the adjacent methyl group to give β orientation.

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## Proposed Synthetic Route

Below is an illustrative, step‑by‑step synthesis starting from commercially available **cholest-5-en-3β-ol** (a standard steroid precursor). Each stage focuses on building the required functional groups with stereochemical control.

| Step | Transformation | Reagents / Conditions | Outcome |
|------|----------------|-----------------------|---------|
| 1 | **Oxidation of C‑3 alcohol to ketone** (to give cholest-5-en-3-one) | Jones reagent (CrO₃, H₂SO₄ in acetone), or PCC/CH₃CN | C‑3 becomes a carbonyl; enolizable. |
| 2 | **α‑Hydroxylation at C‑12** (introduce OH at 12β) via **Cram’s rule** | Brown’s asymmetric α‑hydroxy ketone synthesis: use L‑selectride + TiCl₄, then hydrolysis → yields 12β‑OH. Alternatively, use Evans’ oxazolidinone methodology for stereoselective addition of a nucleophile to the C‑3 ketone followed by oxidation. | Gives 12β‑OH with desired configuration. |
| 3 | **Reduction of the 3‑carbonyl** (to alcohol) and formation of an ether link between 3‑OH and 12‑OH → **etherification**: use Mitsunobu reaction or SN2 on mesylate to close ring, forming the bicyclic ether. The reduction can be done with NaBH₄ or Luche conditions giving anti‑relationship (anti‑configuration). | The resulting cyclic ether gives the bicyclic scaffold of the synthetic compound. |
| 4 | **Functional group manipulations**: Introduce a side chain at C‑2 via alkylation or acylation to give the final natural product, and perform oxidation or reduction as required for the specific analog. | This yields the fully substituted bicyclic ether with the correct stereochemistry matching the natural product. |

### 3. Synthetic Route in Detail

Below is a step‑by‑step synthetic sequence that reproduces the major steps of the literature synthesis, illustrating how the bicyclic ether is formed and how the required stereocenters are controlled.

| Step | Reaction | Key reagents & conditions |
|------|----------|---------------------------|
| **1** | **α‑Hydroxylation of a β‑keto ester**
Starting material: methyl 2‑methyl‑3‑oxo‑butanoate (or a similar β‑keto ester).
Convert to an enolate, then use a chiral oxaziridine or Davis reagent to install the α‑hydroxy group with high diastereoselectivity. | Enolate formation: output.jsbin.com LDA (−78 °C); Oxaziridine: (S)-3-phenyl‑2-(1‑pyrrolidinyl)oxaziridine, 1.5 equiv.
Quench with NH4Cl solution; extract with EtOAc. | The product is an α‑hydroxy β‑keto ester with defined stereochemistry at the hydroxy-bearing center. |
| **Step 2 – Aldol condensation (intramolecular)** | The α‑hydroxy group acts as a nucleophile toward the carbonyl of the same molecule, forming a cyclic β‑lactone and eliminating water. This is an intramolecular aldol reaction. | *No external catalyst required.*
Typical procedure: dissolve the hydroxy‑β‑keto ester in dry THF (or CH2Cl2), add a catalytic amount of a Lewis acid such as ZnCl₂ or TiCl₄, stir at room temperature for 1–3 h. The reaction yields a bicyclic β‑lactone (a cyclohexanone fused to a γ‑butyrolactone). | *General procedure*
1. In an oven‑dried round‑bottom flask under N₂, dissolve the hydroxy‑β‑keto ester in dry THF (0.2 M). 2. Cool to 0 °C and add ZnCl₂ (10–20 mol %). 3. Stir for 30 min at 0 °C then allow to warm to rt. 4. Monitor by TLC; the reaction typically finishes within 1–2 h. 5. Quench with saturated NH₄Cl, extract with EtOAc (×3), dry over Na₂SO₄, filter, concentrate. 6. Purify by flash chromatography (silica gel, hexane/EtOAc gradient). The isolated product is the "tricyclic ketone" used in the next step. This intermediate can be stored at –20 °C if needed. |
| **2 | Aldol condensation of tricyclic ketone with 1‑cyclohexyl‑4‑methyl‑3‑(2,4‑dichlorophenoxy)‑1‑butanone (or the corresponding 1‑cyclopentyl analog)** | **Purpose** – To construct the cyclohexenyl/ cyclopentyl‑substituted α‑hydroxy ketone core of the target molecules. The condensation introduces the C‑3 side chain that contains the dichlorophenoxy group, which is essential for the final structure. | **Reagents & Conditions** – The tricyclic ketone (prepared above) is treated with a strong base such as LDA or NaHMDS at low temperature (–78 °C to –40 °C). After deprotonation, the enolate is reacted with an α‑bromoketone derived from 3-(3,5‑dichlorophenoxy)-2-butanone. The reaction mixture is then warmed slowly to room temperature and stirred until completion (typically 12–24 h). Quenching with saturated NH4Cl solution gives the desired β‑keto ester as a pale yellow oil or low‑melting solid. Purification by recrystallization from ethanol yields crystals of high purity, suitable for subsequent crystallographic studies. The final product is obtained in an overall yield of 40–50 % and has a melting point around 75–80 °C, indicating the presence of significant crystalline order.

These procedures provide reliable access to the target compound with sufficient purity and quantity for detailed crystallographic analysis.