A common approach to pyrrolizidine and indolizidine alkaloids; formal synthesis of ()-isoretronecanol, ()-trachelanthamidine and an approach to the synthesis of ()-5-epitashiromine and ()-tashiromine Kotha Kapu Sridhar Reddy a , Batchu Venkateswara Rao a,⇑ , Sagi Satyanarayana Raju b a Organic Division III, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India b Organic Division I (HPLC), Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India article info Article history: Received 15 February 2011 Accepted 18 March 2011 Available online 4 May 2011 abstract A common and short stereoselective route is described for the formal synthesis of pyrrolizidine alkaloids, ()-isoretronecanol and ()-trachelanthamidine. An approach to the synthesis of indolizidine alkaloids ()-5-epitashiromine and ()-tashiromine utilizing ring closing metathesis is also described starting from commercially available and inexpensive L-proline. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction The pyrrolizidine 1 and indolizidine 2 alkaloids are important classes of biologically active natural products and have attracted considerable attention in organic synthesis. Over the past five dec- ades, many studies aimed at the isolation and stereocontrolled syntheses of these alkaloids have been carried out. Several pyrroli- zine imides display amnesia-reversal activity. 3 It should be noted that pyrrolizidine N-oxide and indolizidine N-oxide have antineo- plastic activity and are in clinical trials. 4 Indolizidine alkaloids iso- lated from plant sources and animal sources (frog’s skin) have shown important biological properties. 5 Therefore, these alkaloids are popular targets and several efficient methods for the construc- tion of the azabicyclo [3.3.0] and azabicyclo [4.3.0] skeletons have been developed. Over the past few years, our laboratory has demonstrated the merit and potency of ring-closing metathesis in the construction of carbocycles, azasugars and oxygenated heterocycles from com- mercially available starting materials. 6 Herein we report a ring- closing metathesis protocol for the construction of pyrrolizidine and indolizidine skeletons in the form of formal synthesis of ()- isoretronecanol 7 1,()-trachelanthamidine 8 2, and an approach to the synthesis of ()-5-epitashiromine 9 3 and ()-thashiro- mine 10 4 from a common intermediate (Fig. 1). 2. Results and discussion It was envisaged that pyrrolizidine amides 5 and 6 and indolizi- dine amides 8 and 9 could be generated from intermediates 7 and 10 by using ring-closing metathesis followed by stereoselective hydrogenation. Intermediates 7 and 10 can be obtained from 11, which in the turn can be prepared from Boc protected prolinol es- ter 12 (Scheme 1) Our synthetic strategy (Scheme 2) started from the N-Boc proline ester 12. The reduction of the ester functionality in 12 with LAH afforded alcohol 13, which was converted to olefin 14 by performing a Swern oxidation followed by a one carbon Wittig homologation. 11 Dihydroxylation of the olefin functionality gave a diastereomeric mixture of diol 15. Regioselective benzylation of diol 15 with dibu- tyltinoxide in toluene followed by the addition of benzyl bromide in the presence of catalytic TBAI gave compound 16 in 88% yield. The secondary alcohol was oxidized to ketone 17 using TEMPO, after which the keto group was subsequently converted to olefin com- pound 18 by a one carbon Wittig homologation. 12 Deprotection of Boc with TFA/DCM (1:1) followed by neutralization of the resultant TFA salt with Et 3 N gave compound 11. N N N N H H H OH OH H OH OH (-)-isoretronecanol 1 (-)-trachelanthamidine 2 (-)-5-epitashiromine 3 (-)-tashiromine 4 Figure 1. 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.03.009 ⇑ Corresponding author. Tel./fax: +91 40 27193003. E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao). Tetrahedron: Asymmetry 22 (2011) 662–668 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy