A samarium(II)-mediated, stereoselective cyclization for the synthesis of azaspirocycles

Article abstract of DOI:10.1021/ol8017209

(Chemical Equation Presented) Unsaturated keto-lactams undergo sequential conjugate reduction-aldol cyclization on treatment with SmI₂ to give syn-spirocyclic pyrrolidinones and piperidinones containing vicinal, fully substituted stereocenters with complete diastereocontrol. The substituent on nitrogen and the lactam ring size have a marked impact on the efficiency of the spirocyclization.

Full text of DOI:10.1021/ol8017209

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4291-4294
A Samarium(II)-Mediated, Stereoselective
Cyclization for the Synthesis of
Azaspirocycles
Giuditta Guazzelli, Lorna A. Duffy, and David J. Procter*
School of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester, M13 9PL, U.K.
daVid.j.procter@manchester.ac.uk
Received July 28, 2008
ABSTRACT
Unsaturated keto-lactams undergo sequential conjugate reduction-aldol cyclization on treatment with SmI2 to give syn-spirocyclic pyrrolidinones
and piperidinones containing vicinal, fully substituted stereocenters with complete diastereocontrol. The substituent on nitrogen and the
lactam ring size have a marked impact on the efficiency of the spirocyclization.
Samarium(II) iodide (SmI2) is a one-electron reducing agent
that has found widespread use in organic synthesis.1 The reagent
has been used to mediate many processes ranging from
functional group interconversions to complex carbon-carbon
bond-forming sequences.1 Cyclization reactions are arguably
the most useful transformations mediated by SmI2, and these
have been used extensively in natural product synthesis.1f
We have previously studied the samarium(II)-mediated
cyclization reactions of γ,δ-unsaturated aldehydes2 and
ketones.3 Simple unsaturated ketones 1 undergo cyclization
upon treatment with SmI2 in THF with MeOH as cosolvent
to give spirocyclopentanol 2 (n ) 1) or methyl ester 3 (n )
2), formed from ring opening of the lactone ring by the
cosolvent, both as single diastereoisomers (Scheme 1). We
have recently used the spirocyclization process in an asym-
(1) For recent reviews on the use of samarium(II) iodide: (a) Molander,
G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321. (b) Kagan, H.; Namy,
J. L. In Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi,
S., Ed.; Springer: Berlin, 1999; p 155. (c) Steel, P. G. J. Chem. Soc., Perkin
Trans. 1 2001, 2727. (d) Kagan, H. B. Tetrahedron 2003, 59, 10351. (e)
Dahle´n, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393. (f) Edmonds,
D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104, 3371.
(2) (a) Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron Lett.
1999, 40, 4913. (b) Johnston, D.; McCusker, C. F.; Muir, K.; Procter, D. J.
J. Chem. Soc., Perkin Trans. 1 2000, 681. (c) Johnston, D.; Francon, N.;
Edmonds, D. J.; Procter, D. J. Org. Lett. 2001, 3, 2001. (d) Johnston, D.;
Couche´, E.; Edmonds, D. J.; Muir, K.; Procter, D. J. Org. Biomol. Chem.
2003, 328. (e) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org. Chem.
2003, 68, 3190.
Scheme 1
(3) (a) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345.
(b) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2003, 5, 4811.
(4) Sloan, L. A.; Baker, T. M.; Macdonald, S. J. F.; Procter, D. J. Synlett
2007, 3155.
10.1021/ol8017209 CCC: $40.75
Published on Web 09/04/2008
2008 American Chemical Society

metric approach to the functionalized cyclopentanol motif
found in the marine natural product, stolonidiol.4
Scheme 2
Preliminary studies aimed at extending the spirocyclization
to analogous unsaturated lactam substrates led to disappoint-
ing results, and spirocyclic products were obtained in low
yield (∼10%).3b In this Letter, we describe our work to
understand and optimize the stereoselective, conjugate
reduction-aldol cyclization of unsaturated keto-lactams. The
reaction provides convenient, stereocontrolled access to
functionalized azaspiro[4.4]nonane and azaspiro[4.5]decane
systems.
Spirocyclic pyrrolidines and piperidines are important
building blocks in medicinal chemistry and have been
prepared during studies in a variety of therapeutics areas.
For example, the motif can be found in compounds display-
ing antibacterial,5a antigastrin,5b and anticonvulsant5c activity
and in small molecule growth hormone secretagogues5d
(Figure 1). We proposed that the substituent on nitrogen in
Lactam phosphonates 6a-g were prepared from the
corresponding lactams6 using the procedures of Wiemer7 in
moderate to good yield.8 Deprotonation of the phosphonates
and treatment with ketoaldehydes 5a-d3b gave cyclization
substrates 4a-l in moderate to good yield and as a mixture
of E and Z isomers9 (Table 1).
Table 1. Preparation of Cyclization Substrates
n
R1
phosphonate
yield (mixture of E:Z)
1
1
1
1
1
2
2
2
2
2
2
2
Me
Me
Me
Me
i-Pr
Me
Me
Me
Et
6a
6b
6c
6d
6d
6e
6f
6g
6f
6f
4a R1 ) Me, R2 ) 4-C6H4OMe, 86%
4b R1 ) Me, R2 ) Ph, 63%
4c R1 ) Me, R2 ) 4-C6H4F, 63%
4d R1 ) Me, R2 ) 4-C6H4CF3, 69%
4e R1 ) i-Pr, R2 ) 4-C6H4CF3, 64%
4f R1 ) Me, R2 ) Bn, 54%
4g R1 ) Me, R2 ) 4-C6H4OMe, 76%
4h R1 ) Me, R2 ) 4-C6H4CF3, 55%
4i R1 ) Et, R2 ) 4-C6H4OMe, 59%
4j R1 ) i-Pr, R2 ) 4-C6H4OMe, 26%
4k R1 ) i-Pr, R2 ) 4-C6H4CF3, 56%
4l R1 ) c-Pr, R2 ) 4-C6H4OMe, 64%
Figure 1. Examples of biologically active spirocyclic pyrrolidines
and piperidines.
i-Pr
i-Pr
c-Pr
6g
6f
keto-lactam substrates 4 would have a significant effect on
the electronic properties of the double bond. This would in
turn effect the efficiency of the reaction by maintaining the
fine balance of reduction potentials needed for cyclization.
We began by synthesizing a range of unsaturated five- and
six-membered lactam substrates bearing different aryl sub-
stituents on the lactam nitrogen. Our synthetic approach to
keto-lactam substrates 4 involved the olefination of keto-
aldehydes 5 with cyclic phosphonates 6 (Scheme 2).
We next studied the reactions of five-membered lactam
substrates 4a-e with SmI2 in THF-MeOH at 0 °C. In all
cases, mixtures of spirocycles 7 and saturated lactams 8 were
obtained in moderate to good combined yields. As expected,
the presence of electron-withdrawing substituents on the
N-aryl substituent facilitated spirocyclization. For example,
the reaction of substrate 4d, bearing an N-4-C6H4CF3 group,
with SmI2, gave 7d in 54% yield (Table 2). The syn-
stereochemistry of 7d was confirmed by X-ray crystal-
(5) (a) Ma, Z.; Chu, D. T. W.; Cooper, C. S.; Li, Q.; Fung, A. K. L.;
Wang, S.; Shen, L. L.; Flamm, R. K.; Nilius, A. M.; Alder, J. D.; Meulbroek,
J. A.; Sun Or, Y. J. Med. Chem. 1999, 42, 4202. (b) Makovec, F.; Peris,
W.; Revel, L.; Giovanetti, R.; Mennuni, L.; Rovati, L. C. J. Med. Chem.
1992, 35, 28. (c) Obniska, J.; Kaminski, K.; Zagorska, A.; Dzierzawska-
Majewska, A.; Karolak-Wojciechowska, J. J. Fluorine Chem. 2006, 127,
417. (d) Yang, L.; Morriello, G.; Prendergast, K.; Cheng, K.; Jacks, T.;
Chan, W. W.-S.; Schleim, K. D.; Smith, R. G.; Patchett, A. A. Biorg. Med.
Chem. Lett. 1998, 8, 107.
(8) See Supporting Information for the synthesis of lactams and lactam
phosphonates.
(9) We have shown that the double-bond stereochemistry has no bearing
on the yield or stereochemical outcome of the reductive-aldol cyclization.
See ref 3b.
(10) See Supporting Information for CCDC numbers and X-ray crystal-
lographic data.
(11) 100 equiv of MeOH gave the best results for five-membered lactam
substrates, while 30 equiv was employed for six-membered lactams. For
the effect of the concentration of MeOH on carbonyl reduction with SmI2,
see: Chopade, P. R.; Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2004,
126, 44.
(6) N-Aryl lactams that were not commercially available were prepared
by the N-arylation of lactams according to the procedure of Buchwald:
Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421.
(7) (a) Jackson, J. A.; Hammond, G. B.; Wiemer, D. F. J. Org. Chem.
1989, 54, 4750. (b) Lee, K.; Jackson, J. A.; Wiemer, D. F. J. Org. Chem.
1993, 58, 5967. (c) Yu, J. S.; Weimer, D. F. J. Org. Chem. 2007, 72, 6263.
4292
Org. Lett., Vol. 10, No. 19, 2008

SmI2 (Table 2). Isopropyl ketone substrates 4j and 4k also
underwent efficient spirocyclization to give 9j and 9k,
respectively, as single, syn-diastereoisomers, thus illustrating
that the cyclization is insensitive to steric congestion around
the ketone carbonyl. The syn-stereochemistry of 9k was
confirmed by X-ray crystallography.10 The relatively low
yield observed in the spirocyclization of 4f bearing an N-Bn
group reaffirmed the requirement for an electron-withdrawing
group on nitrogen in six-membered lactam substrates (Fig-
ure 2).
A possible mechanism for the spirocyclization is shown
in Scheme 3.3b Reduction of the R,ꢀ-unsaturated carbonyl
generates a radical-anion that is protonated12 and reduced
further to give samarium enolate 10.13 A chelation-controlled
aldol cyclization then gives syn-spirocyclic products.14
Table 2. Cyclization of Five-Membered Lactams
substrates 4
products 7 and 8
4a R1 ) Me, R2 ) 4-C6H4OMe
4b R1 ) Me, R2 ) Ph
4c R1 ) Me, R2 ) 4-C6H4F
4d R1 ) Me, R2 ) 4-C6H4CF3
4e R1 ) i-Pr, R2 ) 4-C6H4CF3
7a 18%
7b 24%
7c 26%
7d 54%, X-ray
7e 31%
8a 20%
8b 27%
8c 58%
8d 29%
8e 69%
lography.10 Attempted cyclization of substrates bearing
toluenesulfonyl and Boc substituents resulted in loss of the
group from nitrogen.
Scheme 3
It is clear from these studies that an electron-withdrawing
group on the nitrogen of the five-membered lactam ring is
essential before significant spirocyclization is observed. We
have also found that these reactions are sensitive to the
amount of MeOH used in the reduction.11
The spirocyclization of six-membered lactams was found
to be far more efficient than that of the analogous five-
membered substrates (Figure 2). For example, substrate 4g
It is interesting to speculate as to why higher yields of
spirocyclic products are obtained in the reaction of six-
membered lactam substrates than for analogous five-
membered lactams. To investigate the efficiency of the
conjugate reduction stage of the process, unsaturated lactams
11 and 12, lacking the ketone carbonyl group, were combined
and reduced using a limiting amount of SmI2 in THF-MeOH
at 0 °C. Interestingly, the six-membered saturated lactam 13
was isolated in 90% yield, while the five-membered lactam
11 was recovered in 89% yield (Scheme 4).15 While these
Scheme 4
experiments indicate that the rate of conjugate reduction for
six-membered lactam substrates is greater than that for
analogous five-membered substrates, the use of excess SmI2
(12) Alternatively, reduction to a dianion intermediate may occur prior
to protonation and aldol reaction.
Figure 2. Cyclization of six-membered lactams.
(13) For a review on the chemistry of samarium enolates, see: Rudkin,
I. M.; Miller, L. C.; Procter, D. J. Organomet. Chem. 2008, 34, 19.
(14) We have reported that the use of t-BuOH as a cosolvent in the
cyclizations of lactone substrates, such as 1, results in a switch in reaction
course, and cyclobutanols are obtained diastereoselectively (see ref 3b).
For analogous lactam substrates, the use of t-BuOH as a cosolvent results
in mixtures of acyclic reduction products, spirocyclopentanols, and cy-
clobutanols.
bearing an N-4-C6H4OMe (PMP) group underwent diaste-
reoselective spirocyclization to give syn-spirocycle 9g in 79%
yield, while the analogous five-membered lactam substrate
4a gave only an 18% yield of spirocycle upon treatment with
Org. Lett., Vol. 10, No. 19, 2008
4293

gave smooth reduction of both 11 and 12. It is therefore likely
that the difference in reactivity observed for five- and six-
membered substrates arises during the aldol cyclization
step s samarium enolates 10 derived from five-membered
lactams undergo slower cyclization than analogous enolates
derived from six-membered lactams (Scheme 3). This may
be due to unfavorable steric interactions giving rise to a
higher energy transition state. The slower cyclization of
enolates 10, derived from five-membered lactams, leads to
competing protonation and the isolation of keto-lactams 8
(see Table 2).
cyclic piperidinones 17g and 17i, respectively, in excellent
isolated yields (Scheme 6).
Scheme 6
The spirocyclic lactam products are useful synthetic
building blocks. For example, spirocyclic piperidinone
products can be conveniently converted to the corresponding
piperidines. Protection of 9g and 9h and borane reduction
gave piperidines 15g and 15h in excellent overall yield.
Alternatively, direct borane reduction of spirocyclic piperi-
dinone 9g and 9j gives piperidines 16g and 16j, bearing a
free tertiary hydroxyl group, in high yield (Scheme 5).
Finally, the N-PMP group in products such as 9g and 9i
can be removed by anodic oxidation16 to give N-H spiro-
In summary, we have developed a SmI2-mediated,
reductive-aldol cyclization for the stereoselective synthesis
of azaspirocyclic systems. The process allows two vicinal,
fully substituted stereocenters to be constructed with com-
plete stereocontrol. The efficiency of the process depends
markedly on the substituent on the lactam nitrogen and also
on the ring size of the lactam substrate.
Acknowledgment. We thank the EC (Marie Curie EIF,
G. G.), EPSRC (project studentship, L. A. D.), and the
University of Manchester.
Scheme 5
Supporting Information Available: Full experimental
1
details, characterization data, and H and 13C NMR spectra
for all new compounds, X-ray crystal structures for 7d and
9k, and CCDC numbers. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL8017209
(15) For an example of the importance of ring size in SmI2 reductions,
see: Duffy, L. A.; Matsubara, H.; Procter, D. J. J. Am. Chem. Soc. 2008,
130, 1136.
(16) De Lamo Marin, S.; Martens, T.; Mioskowski, C.; Royer, J. J. Org.
Chem. 2005, 70, 10592. Attempts to remove the N-PMP group in 9g using
ceric(IV) ammonium nitrate gave low isolated yields (20-30%) of 17g.
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