Scalable Synthesis of Cyclocitrinol

Abstract

A 10-step synthesis of the C25 steroid natural product cyclocitrinol from inexpensive, commercially available pregnenolone is reported. This synthesis features a biomimetic cascade rearrangement to efficiently construct the challenging bicyclo[4.4.1] A/B ring system, which enabled a gram-scale synthesis of the bicyclo[4.4.1] enone intermediate 18 in only nine steps. This work also provides experimental support for the biosynthetic origin of cyclocitrinol.

A biocatalytic hydroxylation-enabled unified approach to C19-hydroxylated steroids

“…Traditional chemical approaches for steroidal C19 hydroxylation require prefunctionalization at specific positions and multi-step chemical transformations (see Fig. 1) 7,8,14–18 ; necessitate harsh reaction conditions and suffer from low synthetic efficiency. To the best of our knowledge, only one example of biocatalytic direct C19 hydroxylation has been reported so far (from 1 to 2 ) 31 , but the synthesis suffered from very low efficiency (20% conversion).…”

“…The synthetic strategies developed so far include the Norrish-type II photoreaction and oxidative fragmentation method 7,8 for steroids containing a C11 carbonyl group, and the oxygen radical-induced remote C–H hydroxylation under Barton’s nitrite ester photocleavage 14,15 or Suάrez-type conditions (Fig. 1b) 16–18 . Despite the effectiveness in C19-hydroxylation, all of these methods required prefunctionalization at specific positions of steroids, and necessitated strict reaction conditions and multi-step chemical transformations, often leading to low synthetic efficiency.…”

Contemporary Synthetic Strategies towards Secosteroids, abeo-Steroids, and Related Triterpenes

“…Ding's synthesis 69 commenced from commercially available trans-nerolidol (Scheme 17) with a regioselective epoxidation followed by carbonate formation to give epoxysesquiterpene 132 in 53% yield over the two steps. Radicalmediated opening of the epoxide under titanium(III) catalysis triggered a 6-endo/7-endo-trig bicyclization to afford trans-fused [6,7]bicycle 133 in 75% yield. 70 Diastereoselective epoxidation with m-chloroperbenzoic acid to achieve the inversion of the C3 stereoconfiguration, Ley oxidation (TPAP, NMO), and Meerwein-Ponndorf-Verley reduction [Al(iOPr) 3 , iPrOH] were carried out and gave, after benzyl ether formation, epoxide 134 in 58% yield over the three steps.…”

“…In summary, Ding and co-workers were able to demonstrate the efficiency of titanium(III)-catalyzed radical reactions by employing this methodology for the diastereoselective construction of the [6,7]bicycle as well as the C10 and C14 quaternary stereocenters.…”

Empowering Synthesis of Complex Natural Products

“…Accordingly,s everal groups targeted these natural products for total synthesis;h owever,m any of these routes lacked brevity and scalability.G ui and co-workersb elievedt hat by targeting ab iomimetic pathway,t hey coulds ignificantly decrease the number of steps required to access cyclocitrinol (123), allowing forgreater scalability. [42] Gui's synthesis of cyclocitrinol (123)c ommencedw ith pregnenolone( 124)u ndergoing at wo-step ring contraction/hydroxylm igration to yield cyclopropane 125 on 8.40 gs cale (Scheme 10). The pendant methyl group was oxidized through an intramolecular tetrahydrofuran formed by Pb(OAc) 4 .T he intermediate tetrahydrofuran was openedb ye mploying BF 3 ·OEt 2 and the revealed free alcohol was phosphorylated to yield phosphate 126 on 10.6 gs cale.…”