Access to Functionalized Steroid Side Chains via Modified Julia Olefination

Abstract

Various functionalized steroidal side chains were conveniently accessed by a modified Julia olefination strategy using a common sulfone donor and an appropriate α-branched aldehyde acceptor. For the coupling of these hindered classes of reaction partners (and in contrast to typically observed trends), the benzothiazolyl(BT)-sulfone anion gave superior outcomes compared to the phenyltetrazolyl(PT)-sulfone anion.

Steroids with oxidatively modified side chains comprise an important family of compounds, largely because of their biological properties (e.g., 1-4, Figure 1). Our interest in the preparation of analogs of sea lamprey pheromone components (e.g., 3^1d) drove a need for a flexible strategy in which a common intermediate could be used in a conjunctive fashion to attach an array of structurally diverse side chains (cf. Table 1). In this regard, we have studied the use of the modified Julia olefination² involving C22-sulfonyl steroids as the anionic donor partner, and our results are described here.

Figure 1.

Some of the related highly potent C24-functionalized steroids (11a-b, 2^1c, 3^1d, and 4^1e).

Table 1.

Alkenes 14 via the Modified Julia Olefination.

entry	aldehyde	R	yield (%)	E/Za
1			82	94:6
2			80	82:18
3			90	75:25
4			60	85:15
5			81	90:10
6			60	ca. 65:35 from 14e- (24S)

^aE/Z ratios determined by ¹H NMR analysis of product mixtures.

Previously, steroidal aldehydes 5 have been used as the electrophilic acceptor component in Horner-Wadsworth-Emmons (HWE, 6a),3a-e modified Julia (6b),^3f and Wittig (with stabilized ylides, 6c)^3g-m olefination reactions to forge the C22-C23 alkene in products 9. Alternatively, steroidal phosphonium ylide (7a) and phenylsulfonyl (7b) donors were coupled with aldehyde acceptors 8 via Wittig³ⁿ and classical Julia^3o olefination reactions, respectively (Scheme 1). In this study, we have established the modified Julia coupling with donors 7c, primarily with the benzothiazolyl (BT) sulfone [although we have also compared the use of the 1-phenyl-1H-tetrazol-5-yl (PT) sulfone] and a variety of acceptor aldehydes 8.

Scheme 1.

Overview of the Coupling Strategies to Construct Oxygenated Steroidal Side Chains.^a

a St = generic steroid nucleus; BT = benzothiazolyl; PT = 1-phenyl-1H-tetrazol-5-yl.

To test feasibility, both the PT and BT sulfones 13-PT and 13-BT, respectively, were prepared as outlined in Scheme 2 from i-stigmasteryl methyl ether (10, two steps, 74% yield from stigmasterol).⁴ Ozonolysis (and reductive workup with NaBH₄) of the disubstituted olefin smoothly provided the primary alcohol 11 [and (S)-2-ethyl-3-methylbutan-1-ol]. It is worth noting that a major problem associated with the ozonolysis of i-steroids, namely undesired oxidation of the methine C–H bond at the C6-ether,⁵ is avoided by using the unconventional solvent tetrahydrofuran as component of the reaction medium (THF/MeOH; 10:1). The resulting alcohol 11 was formed in high yield (86%), and butyrolactone was isolated as a byproduct, its amount increasing with increased reaction time. We believe that THF effectively buffers the ozonolysis reaction by acting as a sacrificial reductant and preventing over-oxidation of 10 and its derived products. The thioethers 12-PT and 12-BT were then prepared from 11 using the Mitsunobu protocol (PTSH, DIAD, PPh₃). Each was subsequently oxidized to the sulfone 13-PT or 13-BT (ammonium paramolybdate, H₂O₂).

Scheme 2.

Synthesis of the Key Sulfones 13-PT and 13-BT.

We first attempted olefination using the potassium anion of 13-PT and 13-BT. Preforming the anion (KHMDS, THF, −78 °C) and addition of propionaldehyde provided none of the expected olefination product, nor was the starting sulfone recovered. When a solution of KHDMS was added at −78 °C to a THF solution containing both the sulfone 13-BT and propionaldehyde, the desired propylidene coupling product was isolated in low yield with the cis isomer predominating.

We then turned our attention to the sodium anions derived from 13-PT and 13-BT by studying the relative stability of the sulfones upon metallation with NaHMDS in THF at −78 °C (Scheme 3). Each anion was quenched with saturated NH₄Cl solution 15 minutes after addition of base. The starting sulfones were reisolated by SiO₂ chromatography (MPLC) with 61 vs 96% recovery efficiency, respectively. This shows that the 13-BT anion was more stable than that of 13-PT.

Scheme 3.

Recovery/Stability of Sulfone Anions.^a

a Stoichiometric ratio of sulfone/NaHMDS was 1:1.2.

We next tested the relative efficiency of each of the donor sulfones 13 to effect olefination using butyraldehyde (8a) as a simple acceptor substrate and NaHMDS as the base (Scheme 4). The behavior mirrored that seen in the above stability studies; namely, the yield of alkene 14a was higher when the benzothiazolyl sulfone 13-BT was used.

Scheme 4.

Olefination of Sulfones 13-PT or 13-BT with 8a.^a

a Stoichiometric ratio of sulfone/8a/NaHMDS was 1:1:1.2.

Moreover (and as described elsewhere⁶), the use of HMPA as an additive improved the 14a-E:14a-Z product ratio.

We then studied the olefination reactions of a series of aldehydes 8 with 13-BT as the sulfone donor (Table 1). The aldehydes contain α-methyl or α-alkoxy branching. Aldehyde (S)-8b provided 14b both in high yield and with excellent E/Z-selectivity (entry 1). Use of the enantiomeric aldehyde (R)-8b gave the C24-epimer in 80% yield and with an E/Z-ratio of 82:18 (entry 2). Entries 3-5 demonstrate additional scope of the method. Aldehyde (S)-8e showed a high E/Z-selectivity. Use of the racemate rac-8e (2 equiv, entry 6) produced similar amounts of C24-epimers. While the E/Z-ratio of product 14e-(24R) was essentially the same as that observed in entry 5 (i.e., 90:10), the epimeric mixture of alkenes 14e-(24S) was formed with reduced selectivity for alkene geometry (i.e., 65:35). Thus, the degree of matching/mis-matching for the substrates in either of entries 1 vs. 2 or 5 vs. 6 is small.

In conclusion, this study demonstrates the utility of a modified Julia olefination strategy for providing easy access to steroidal products containing a variety of functionalized side chains. The steric demand of both α-branched coupling partners that participate in this transformation is noteworthy. Contrary to the general trend observed for modified Julia reaction using less hindered pairs of substrates, the olefination efficiency and alkene diastereoselectivity of the steroidal BT-sulfonyl donor was found here to be superior to the PT-sulfonyl version.⁷ This is likely a result of greater lability of the metallated PT-sulfone anion (Scheme 3). An ancillary observation of note is the use of THF as the bulk solvent to improve the ozonolysis of cyclopropyl-contianing substrate 10. This protocol may be useful for chemoselective transformation of other complex substrates bearing functionality senstitive to oxidation.