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

Article abstract of DOI:10.3762/bjoc.9.163

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 activ

Full text of DOI:10.3762/bjoc.9.163

Development of an additive-controlled,
SmI2-mediated stereoselective sequence:
Telescoped spirocyclisation, lactone reduction
and Peterson elimination
Brice Sautier, Karl D. Collins and David J. Procter*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1443–1447.
University of Manchester, School of Chemistry, Oxford Road,
Manchester M13 9PL, United Kingdom
doi:10.3762/bjoc.9.163
Received: 20 May 2013
Accepted: 28 June 2013
Published: 18 July 2013
Email:
David J. Procter* - david.j.procter@manchester.ac.uk
*
Corresponding author
This article is part of the Thematic Series "Organic free radical chemistry".
Guest Editor: C. Stephenson
Keywords:
cyclisation; free radical; Peterson elimination; reduction; samarium;
telescoped process
© 2013 Sautier et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
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.
Introduction
Samarium diiodide (SmI2) has become an essential tool for complex, polyfunctionalised starting materials to be manipu-
chemists since its introduction by Kagan [1,2], efficiently medi- lated selectively [3-16].
ating a wide range of reductive transformations [3]. The
reagent’s versatility and the high degree of control usually Recently, we reported the use of a C–Si bond to control the
observed in SmI2-mediated reactions make it the first choice for stereochemical course of SmI2-mediated cyclisations. For
an array of reductive electron transfer processes [4-13]. Cyclisa- example, complete diastereocontrol was achieved in the
tions are one of the most notable classes of transformation construction of cyclobutanols [13,17-22] and spirocyclo-
induced by SmI2 and have been widely employed in natural- pentanols (Scheme 1) [23-28]. The use of MeOH
product syntheses [8-10]. Importantly, fine tuning of the as an additive with SmI2 was key to the success of these
reagent’s reduction potential through the use of additives allows cyclisations [24].
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Beilstein J. Org. Chem. 2013, 9, 1443–1447.
Scheme 1: SmI2-mediated cyclisations directed by a C–Si bond.
Results and Discussion
In the case of spirocyclopentanol products 2, further manipula-
tion was hampered by their sensitivity to standard reductive Spirocyclisation
conditions, and initially their reduction could only be achieved We first set out to examine the scope of the reductive-aldol
in two steps via the corresponding lactols [28]. An alternative spirocyclisation [23-27] directed by a C–Si bond, by varying the
solution for the manipulation of spirocyclopentanols 2 nature and functionalisation of the side chain. The ratio of
arose from our recent introduction of SmI2−H2O−amine [29-39] 2b/4b was optimized by adjusting the SmI2/MeOH ratio and the
as a mild and efficient reagent system for the electron reaction time to minimise retro-aldol reaction and the forma-
transfer reduction of carboxylic acid derivatives [40-42]. Pleas- tion of saturated ketolactone byproduct 4b (Table 1). Lowering
ingly, SmI2−H2O−amine provided direct access to highly the amount of SmI2 and MeOH used and shortening the reac-
functionalised triols such as 3b from spirocyclopentanol 2b tion time resulted in improved selectivity for spirolactone 2b.
(
Scheme 2) [42].
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.
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 particu-
lar note, keto-lactone 1f bearing an ester-containing side chain
gave the expected spirocycle 2f, albeit with low conversion
Scheme 2: Reduction of a spirocyclic lactone using SmI2−H2O−Et3N.
In this manuscript, we report studies on SmI2-mediated cyclisa- (unoptimized). As expected, no products arising from the reduc-
tion and lactone reduction that culminate in a “telescoped” tion of the ester were observed [40-42].
sequence, i.e., a sequence of steps carried out on a single reac-
tion mixture by the sequential addition of various reagents. In Telescoped spirocyclisation/lactone reduction
the sequence, additives are used with SmI2 to “switch on” indi- Although the reduction of the spirocycles 2 proceeds smoothly
vidual steps: spirocyclisation, lactone reduction and Peterson with SmI2−H2O−Et3N [40-42], we recognised the advantages
elimination allow rapid access to functionalised cyclopentanols, of performing both SmI2-mediated steps in a telescoped
containing two vicinal quaternary stereocentres, from simple fashion. The strongly coordinating H2O and amine additives
starting materials. The sequence involves the use of two activ- used to activate SmI2 [29-42] in the second lactone reduction
ated SmI2 reagent systems, and a silicon stereocontrol element step suggested that this far more reducing system would tolerate
exerts complete diastereocontrol over the cyclisation and is the presence of samarium(III) salts and a less-activating addi-
removed during the final stage of the sequence.
tive (MeOH) from the first reduction step. Pleasingly, when
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Beilstein J. Org. Chem. 2013, 9, 1443–1447.
Table 1: Optimisation of SmI2–mediated spirocyclisation conditions.
Entry
SmI2a (equiv)
MeOH (equiv)
SmI2/MeOH
2b/4bb
1
2
3
4
5
6
7
2.2
2.5
3
128
128
128
128
70
1:58
1:52
1:43
1:32
1:32
1:32
1:32
1:32
1:38
1.8:1
1.9:1
2.4:1
2.6:1
3.2:1
3.3:1
3.2:1
4:1
4
2.2
2.5
3
80
96
8c
c
2.5
2.5
80
9
96
4:1
a0.1 M solution in THF. bFrom 1H NMR of crude product mixture. cReaction time 3–5 min.
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 reduc-
tion/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 3: Stereoselective spirocyclisation of functionalised keto-
lactone substrates directed by a C–Si bond.
subjected to the telescoped sequence, substrates 1 gave the
desired triols 3 in comparable yields to those obtained from the We are currently exploring the use of the telescoped route to
stepwise process, without any need for further optimisation cyclopentanols 5 in an asymmetric approach [46] to the anti-
(
Scheme 4).
tumor natural product pseudolaric acid B [47].
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Beilstein J. Org. Chem. 2013, 9, 1443–1447.
Scheme 4: Telescoped stereoselective spirocyclisation/lactone reduction.
Scheme 5: Telescoped stereoselective spirocyclisation/lactone reduction/Peterson elimination.
Conclusion
Acknowledgements
In summary, we have developed a convenient, telescoped, We thank the EPSRC (project studentship, B.S.), Astrazeneca
three-step sequence to access functionalised cyclopentanols (CASE award, K.D.C.), and the University of Manchester.
bearing two vicinal quaternary stereocentres from simple keto-
lactone starting materials. The process involves the use of two References
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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 consti-
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