Development of an additive-controlled, SmI2-mediated stereoselective sequence: Telescoped spirocyclisation, lactone reduction and Peterson elimination

  1. ,
  2. and
University of Manchester, School of Chemistry, Oxford Road, Manchester M13 9PL, United Kingdom
  1. Corresponding author email
Guest Editor: C. Stephenson
Beilstein J. Org. Chem. 2013, 9, 1443–1447.
Received 20 May 2013, Accepted 28 Jun 2013, Published 18 Jul 2013
Full Research Paper
cc by logo


Studies on SmI2-mediated spirocyclisation and lactone reduction culminate in a telescoped sequence in which additives are used to “switch on” individual steps mediated by the electron transfer reagent. The sequence involves the use of two activated SmI2 reagent systems and a silicon stereocontrol element that exerts complete diastereocontrol over the cyclisation and is removed during the final stage of the sequence by Peterson elimination. The approach allows functionalised cyclopentanols containing two vicinal quaternary stereocentres to be conveniently prepared from simple starting materials.


Samarium diiodide (SmI2) has become an essential tool for chemists since its introduction by Kagan [1,2], efficiently mediating a wide range of reductive transformations [3]. The reagent’s versatility and the high degree of control usually observed in SmI2-mediated reactions make it the first choice for an array of reductive electron transfer processes [4-13]. Cyclisations are one of the most notable classes of transformation induced by SmI2 and have been widely employed in natural-product syntheses [8-10]. Importantly, fine tuning of the reagent’s reduction potential through the use of additives allows complex, polyfunctionalised starting materials to be manipulated selectively [3-16].

Recently, we reported the use of a C–Si bond to control the stereochemical course of SmI2-mediated cyclisations. For example, complete diastereocontrol was achieved in the construction of cyclobutanols [13,17-22] and spirocyclopentanols (Scheme 1) [23-28]. The use of MeOH as an additive with SmI2 was key to the success of these cyclisations [24].


Scheme 1: SmI2-mediated cyclisations directed by a C–Si bond.

In the case of spirocyclopentanol products 2, further manipulation was hampered by their sensitivity to standard reductive conditions, and initially their reduction could only be achieved in two steps via the corresponding lactols [28]. An alternative solution for the manipulation of spirocyclopentanols 2 arose from our recent introduction of SmI2−H2O−amine [29-39] as a mild and efficient reagent system for the electron transfer reduction of carboxylic acid derivatives [40-42]. Pleasingly, SmI2−H2O−amine provided direct access to highly functionalised triols such as 3b from spirocyclopentanol 2b (Scheme 2) [42].


Scheme 2: Reduction of a spirocyclic lactone using SmI2−H2O−Et3N.

In this manuscript, we report studies on SmI2-mediated cyclisation and lactone reduction that culminate in a “telescoped” sequence, i.e., a sequence of steps carried out on a single reaction mixture by the sequential addition of various reagents. In the sequence, additives are used with SmI2 to “switch on” individual steps: spirocyclisation, lactone reduction and Peterson elimination allow rapid access to functionalised cyclopentanols, containing two vicinal quaternary stereocentres, from simple starting materials. The sequence involves the use of two activated SmI2 reagent systems, and a silicon stereocontrol element exerts complete diastereocontrol over the cyclisation and is removed during the final stage of the sequence.

Results and Discussion


We first set out to examine the scope of the reductive-aldol spirocyclisation [23-27] directed by a C–Si bond, by varying the nature and functionalisation of the side chain. The ratio of 2b/4b was optimized by adjusting the SmI2/MeOH ratio and the reaction time to minimise retro-aldol reaction and the formation of saturated ketolactone byproduct 4b (Table 1). Lowering the amount of SmI2 and MeOH used and shortening the reaction time resulted in improved selectivity for spirolactone 2b. We believe that spirolactones such as 2b undergo retro-aldol fragmentation (to give products such as 4b) upon prolonged exposure to Lewis acidic Sm(II)/(III)-species present in the reaction mixture.

Table 1: Optimisation of SmI2–mediated spirocyclisation conditions.

[Graphic 1]
Entry SmI2a (equiv) MeOH (equiv) SmI2/MeOH 2b/4bb
1 2.2 128 1:58 1.8:1
2 2.5 128 1:52 1.9:1
3 3 128 1:43 2.4:1
4 4 128 1:32 2.6:1
5 2.2 70 1:32 3.2:1
6 2.5 80 1:32 3.3:1
7 3 96 1:32 3.2:1
8c 2.5 80 1:32 4:1
9c 2.5 96 1:38 4:1

a0.1 M solution in THF. bFrom 1H NMR of crude product mixture. cReaction time 3–5 min.

Pleasingly, the process proved general, affording the desired spirocycles 2 in good yields and as single diastereoisomers with only small amounts of saturated ketolactone byproducts (cf. 4b) observed. No byproducts arising from reaction of the additional functional groups present were formed (Scheme 3). Of particular note, keto-lactone 1f bearing an ester-containing side chain gave the expected spirocycle 2f, albeit with low conversion (unoptimized). As expected, no products arising from the reduction of the ester were observed [40-42].


Scheme 3: Stereoselective spirocyclisation of functionalised keto-lactone substrates directed by a C–Si bond.

Telescoped spirocyclisation/lactone reduction

Although the reduction of the spirocycles 2 proceeds smoothly with SmI2−H2O−Et3N [40-42], we recognised the advantages of performing both SmI2-mediated steps in a telescoped fashion. The strongly coordinating H2O and amine additives used to activate SmI2 [29-42] in the second lactone reduction step suggested that this far more reducing system would tolerate the presence of samarium(III) salts and a less-activating additive (MeOH) from the first reduction step. Pleasingly, when subjected to the telescoped sequence, substrates 1 gave the desired triols 3 in comparable yields to those obtained from the stepwise process, without any need for further optimisation (Scheme 4).


Scheme 4: Telescoped stereoselective spirocyclisation/lactone reduction.

The process is carried out by transferring the reaction mixture after the first reduction stage (SmI2–MeOH) to a preformed solution of SmI2−H2O−Et3N. The telescoped procedure proved robust and was scaled up to 1.2 g (3.5 mmol) without any drop in yield.

Telescoped spirocyclisation/lactone reduction/Peterson elimination

With an efficient process combining spirocyclisation and lactone reduction in hand, we proposed that manipulation of the triol products by Peterson elimination [43,44] could be added to the telescoped sequence. Crucially, Peterson elimination of triols 3 would result in removal of the silicon stereocontrol element used to control the stereochemical course of C–C bond formation. In early studies, treatment of triol 3b with t-BuOK gave vinyl cyclopentanol 5b in moderate yield [45], but the reaction suffered from poor reproducibility. Following a screen of reaction conditions, moderate but consistent yields were obtained when eliminations were performed in an open vessel, using undried solvents.

When combined with the spirocyclisation and lactone reduction sequence, the Peterson elimination gave diols 5, with good overall yields comparable to those obtained for the stepwise process (Scheme 5).


Scheme 5: Telescoped stereoselective spirocyclisation/lactone reduction/Peterson elimination.

We are currently exploring the use of the telescoped route to cyclopentanols 5 in an asymmetric approach [46] to the antitumor natural product pseudolaric acid B [47].


In summary, we have developed a convenient, telescoped, three-step sequence to access functionalised cyclopentanols bearing two vicinal quaternary stereocentres from simple keto-lactone starting materials. The process involves the use of two activated SmI2 reagent systems and a silicon stereocontrol element that results in complete diastereocontrol and is removed in the final stage of the sequence. The procedure is scalable and the overall yields of the telescoped sequences compare well to the combined yields of the analogous stepwise processes. The use of additives to “switch on” individual steps in a particular sequence mediated by the same electron transfer reagent constitutes an exciting new opportunity for efficient synthesis.

Supporting Information

Supporting Information File 1: General experimental procedures and characterisation data.
Format: PDF Size: 560.0 KB Download


We thank the EPSRC (project studentship, B.S.), Astrazeneca (CASE award, K.D.C.), and the University of Manchester.


  1. Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim. 1977, 1, 5.
    Return to citation in text: [1]
  2. Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693. doi:10.1021/ja00528a029
    Return to citation in text: [1]
  3. Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic Synthesis using Samarium Diiodide: A Practical Guide; RSC Publishing: Cambridge, 2009.
    Return to citation in text: [1] [2]
  4. Kagan, H. B. Tetrahedron 2003, 59, 10351. doi:10.1016/j.tet.2003.09.101
    Return to citation in text: [1] [2]
  5. Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. doi:10.1021/cr950019y
    Return to citation in text: [1] [2]
  6. Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745. doi:10.1021/cr980326e
    Return to citation in text: [1] [2]
  7. Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727. doi:10.1039/A908189E
    Return to citation in text: [1] [2]
  8. Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371. doi:10.1021/cr030017a
    Return to citation in text: [1] [2] [3]
  9. Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140. doi:10.1002/anie.200902151
    Return to citation in text: [1] [2] [3]
  10. Szostak, M.; Procter, D. J. Angew. Chem., Int. Ed. 2011, 50, 7737. doi:10.1002/anie.201103128
    Return to citation in text: [1] [2] [3]
  11. Flowers, R. A., II. Synlett 2008, 1427. doi:10.1055/s-2008-1078414
    Return to citation in text: [1] [2]
  12. Beemelmanns, C.; Reissig, H.-U. Chem. Soc. Rev. 2011, 40, 2199. doi:10.1039/c0cs00116c
    Return to citation in text: [1] [2]
  13. Harb, H. Y.; Procter, D. J. Synlett 2012, 6. doi:10.1055/s-0031-1290093
    Return to citation in text: [1] [2] [3]
  14. Dahlén, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393. doi:10.1002/ejic.200400442
    Return to citation in text: [1]
  15. Sautier, B.; Procter, D. J. Chimia 2012, 66, 399. doi:10.2533/chimia.2012.399
    Return to citation in text: [1]
  16. Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem. Commun. 2012, 48, 330. doi:10.1039/c1cc14252f
    Return to citation in text: [1]
  17. Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron Lett. 1999, 40, 4913. doi:10.1016/S0040-4039(99)00910-7
    Return to citation in text: [1]
  18. Johnston, D.; McCusker, C. F.; Muir, K.; Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2000, 681. doi:10.1039/A909549G
    Return to citation in text: [1]
  19. Johnston, D.; Francon, N.; Edmonds, D. J.; Procter, D. J. Org. Lett. 2001, 3, 2001. doi:10.1021/ol015976a
    Return to citation in text: [1]
  20. Johnston, D.; Couché, E.; Edmonds, D. J.; Muir, K. W.; Procter, D. J. Org. Biomol. Chem. 2003, 1, 328. doi:10.1039/b209066j
    Return to citation in text: [1]
  21. Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org. Chem. 2003, 68, 3190. doi:10.1021/jo026827o
    Return to citation in text: [1]
  22. Baker, T. M.; Edmonds, D. J.; Hamilton, D.; O’Brien, C. J.; Procter, D. J. Angew. Chem., Int. Ed. 2008, 47, 5631. doi:10.1002/anie.200801900
    Return to citation in text: [1]
  23. Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345. doi:10.1021/ol0260472
    Return to citation in text: [1] [2]
  24. Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5, 4811. doi:10.1021/ol0358399
    Return to citation in text: [1] [2] [3]
  25. Sloan, L. A.; Baker, T. M.; Macdonald, S. J. F.; Procter, D. J. Synlett 2007, 3155. doi:10.1055/s-2007-1000821
    Return to citation in text: [1] [2]
  26. Guazzelli, G.; Duffy, L. A.; Procter, D. J. Org. Lett. 2008, 10, 4291. doi:10.1021/ol8017209
    Return to citation in text: [1] [2]
  27. Baker, T. M.; Sloan, L. A.; Choudhury, L. H.; Murai, M.; Procter, D. J. Tetrahedron: Asymmetry 2010, 21, 1246. doi:10.1016/j.tetasy.2010.03.047
    Return to citation in text: [1] [2]
  28. Harb, H. Y.; Collins, K. D.; Altur, J. V. G.; Bowker, S.; Campbell, L.; Procter, D. J. Org. Lett. 2010, 12, 5446. doi:10.1021/ol102278c
    Return to citation in text: [1] [2]
  29. Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron Lett. 1995, 36, 949. doi:10.1016/0040-4039(94)02398-U
    Return to citation in text: [1] [2]
  30. Dahlén, A.; Hilmersson, G. Tetrahedron Lett. 2002, 43, 7197. doi:10.1016/S0040-4039(02)01673-8
    Return to citation in text: [1] [2]
  31. Dahlén, A.; Hilmersson, G. Chem.–Eur. J. 2003, 9, 1123. doi:10.1002/chem.200390129
    Return to citation in text: [1] [2]
  32. Dahlén, A.; Sundgren, A.; Lahmann, M.; Oscarson, S.; Hilmersson, G. Org. Lett. 2003, 5, 4085. doi:10.1021/ol0354831
    Return to citation in text: [1] [2]
  33. Dahlén, A.; Hilmersson, G.; Knettle, B. W.; Flowers, R. A., II. J. Org. Chem. 2003, 68, 4870. doi:10.1021/jo034173t
    Return to citation in text: [1] [2]
  34. Davis, T. A.; Chopade, P. R.; Hilmersson, G.; Flowers, R. A., II. Org. Lett. 2005, 7, 119. doi:10.1021/ol047835p
    Return to citation in text: [1] [2]
  35. Dahlén, A.; Hilmersson, G. J. Am. Chem. Soc. 2005, 127, 8340. doi:10.1021/ja043323u
    Return to citation in text: [1] [2]
  36. Dahlén, A.; Nilsson, A.; Hilmersson, G. J. Org. Chem. 2006, 71, 1576. doi:10.1021/jo052268k
    Return to citation in text: [1] [2]
  37. Ankner, T.; Hilmersson, G. Tetrahedron 2009, 65, 10856. doi:10.1016/j.tet.2009.10.086
    Return to citation in text: [1] [2]
  38. Wettergren, J.; Ankner, T.; Hilmersson, G. Chem. Commun. 2010, 46, 7596. doi:10.1039/c0cc02009e
    Return to citation in text: [1] [2]
  39. Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503. doi:10.1021/ol802243d
    Return to citation in text: [1] [2]
  40. Szostak, M.; Spain, M.; Procter, D. J. Chem. Commun. 2011, 47, 10254. doi:10.1039/c1cc14014k
    Return to citation in text: [1] [2] [3] [4]
  41. Szostak, M.; Spain, M.; Procter, D. J. Org. Lett. 2012, 14, 840. doi:10.1021/ol203361k
    Return to citation in text: [1] [2] [3] [4]
  42. Szostak, M.; Collins, K. D.; Fazakerley, N. J.; Spain, M.; Procter, D. J. Org. Biomol. Chem. 2012, 10, 5820. doi:10.1039/c2ob00017b
    Return to citation in text: [1] [2] [3] [4] [5]
  43. Peterson, D. J. J. Org. Chem. 1968, 33, 780. doi:10.1021/jo01266a061
    Return to citation in text: [1]
  44. Ager, D. J. Synthesis 1984, 384. doi:10.1055/s-1984-30849
    Return to citation in text: [1]
  45. Performed by opening the vessel to air to quench the remaining SmI2 and adding t-BuOK portionwise to the reaction mixture until completion by TLC.
    Return to citation in text: [1]
  46. Pace, V.; Rae, J. P.; Harb, H. Y.; Procter, D. J. Chem. Commun. 2013, 49, 5150. doi:10.1039/c3cc42160k
    Return to citation in text: [1]
  47. Chiu, P.; Leung, L. T.; Ko, B. C. B. Nat. Prod. Rep. 2010, 27, 1066. doi:10.1039/b906520m
    Return to citation in text: [1]
Other Beilstein-Institut Open Science Activities