Cycloaddition of chiral tert -butanesulfinimines with trimethylenemethane

Article abstract of DOI:10.1021/ol400720b

The cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane is found to give facile access to methylene-pyrrolidines with good yields and diastereoselectivities. The full scope of the cycloaddition is explored, and a range of transformations of the formed methylenepyrrolidines to give a range of functionalized chiral pyrrolidines is presented.

Full text of DOI:10.1021/ol400720b

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2030–2033
Cycloaddition of Chiral
tert-Butanesulfinimines with
Trimethylenemethane
George Procopiou,† William Lewis,† Gareth Harbottle,‡ and Robert A. Stockman*,†
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, U.K., and
Pfizer, Ramsgate Road, Sandwich, Kent, CT13 9NJ, U.K.
Robert.stockman@nottingham.ac.uk
Received March 18, 2013
ABSTRACT
The cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane is found to give facile access to methylene-pyrrolidines with
good yields and diastereoselectivities. The full scope of the cycloaddition is explored, and a range of transformations of the formed
methylenepyrrolidines to give a range of functionalized chiral pyrrolidines is presented.
Chiral amines are an important class of compounds for
both the synthesis of complex natural products and drug
discovery. In particular, the pyrrolidine substructure
occurs in a wide range of biologically important natural
products, such as preussin,1 lactacystin,2 and kainic acid.3
One of the most common and practical methods for the
synthesis of chiral amines is by reaction of a chiral sulfini-
mine with a nucleophile.4 Over the past two decades, led by
the seminal contributions of Davis5 andEllman,6 hundreds
of reports have been published on the transformations of
chiral p-tolyl and tert-butane sulfinimines.7 Despite this
large body of work, reports on the cycloaddition chemistry
of sulfinimines remain scarce, with just a few reports of the
use of p-tolyl sulfinimines,8 one report of polyfluorinated
sulfinimines,9 and a single example of the use of a tert-
butane sulfinimine in a cycloaddition reaction.10 Drawn by
the highly useful trimethylenemethane cycloaddition meth-
odology of Trost,11 and encouraged by two reports of such
a cycloaddition on aryl N-BOC imines12 and on N-tosyl
imines with a stabilized variant of the TMM reagent,13 we
decided to investigate the potential [3 þ 2] cycloaddition
of TMM with tert-butanesulfimines, which would yield
chemically interesting methylenepyrrolidines as products.
Initially, we decided to optimize conditions using the
benzaldehyde-derived tert-butanesulfinimine 1a. As our
† University of Nottingham.
‡ Pfizer.
(1) Schwartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.; Honeycutt,
S.; Garrity, G.; Fromtling, R. A. J. Antibiot. 1988, 41, 1774.
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Rev. 2009, 38, 1162. Morton, D.; Stockman, R. A. Tetrahedron 2006, 62,
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C.; Alonso, M.; Tortosa, M.; Flores, A.; Martı
I.; Andre, I.; Rodrı
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(10) Kawecki, R. Tetrahedron: Asymmetry 2006, 17, 1420.
(11) Yamago, S.; Nakamura, E. Org. React. 2002, 61, 1.
(12) Trost, B. M.; Silverman, S. M.; Stambuli, J. P. J. Am. Chem. Soc.
2007, 129, 12398.
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Chen, B.-C . Chem. Soc. Rev. 1998, 27, 13.
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r
10.1021/ol400720b
Published on Web 04/04/2013
2013 American Chemical Society

starting point, we decided to use conditions developed
by Harrity for a TMM [3 þ 3] cycloaddition to
tosylaziridines,14 which involved the use of palladium
acetate, triisopropyl phosphite, and butyl lithium. We were
encouraged by the successful outcome of this reaction,
gaining the pyrrolidine product 2a in 36% yield. With this
initial successful cycloaddition in hand, we looked into
optimizing the reaction conditions (Table 1). We found
that tetrakis(triphenylphosphine) palladium was an excel-
lent catalyst if freshly recrystallized prior to use. The
reaction was found to work in acetonitrile, methanol, or
dry THF as a solvent, with THF (freshly distilled from
sodium benzophenone ketal) giving the best diastereo-
selectivities and good yields. The concentration of the
reaction was found to be important, with 0.5 M being
found to be best. Similarly, we found reactions at room
temperature gave decent diastereoselectivities and much-
increased yields compared to reactions at lower tempera-
tures. It was found that the sulfinyl directing/protecting
group could be removed in quantitative yield by treatment
of 2 with 2 M HCl in ether.
The tert-butyl sulfinimine 2a gave far superior yields and
diastereoselectivities compared to the mesityl sulfinimine
2b, and thus we decided to investigate solely tert-butyl
sulfinimines for the rest of the study. It was found that,
once purified, the major diastereomer of 2a could be
crystallized, and we were able to gain an X-ray crystal
structure (Figure 1). From this, it can be seen that the
overall stereoinduction is derived from the dipoleꢀdipole
repulsion of the sulfinimine, which places the tert-butyl
group on the Re face, and thus the cycloaddition occurs
from the Si face as this is less sterically encumbered.
In general, yields were found to be decent to excellent for
a wide range of aryl, heteroaryl, and alkyl sulfinimines,
with aryl chlorides and bromides tolerated under the
reaction conditions, which will prove useful for leaving
functional groups suitable for further elaboration. The free
phenolic OH was found to hinder the yield and stereo-
selectivity in the formation of 2e. A similar erosion of yield
and dr was found in the formation of naphthalene-derived
2n, as this reaction required heating to reflux in order for
the reaction to take place.
With these successful results in hand, we decided to test
the tolerance and scope of the cycloaddition reaction, by
investigating the reaction of TMM with sulfinyl ketimines.
The results of these investigations are summarized in
Table 3.
Table 1. Screen of Reaction Conditions
catalyst
solvent
THF
temp
yield
36%
dr
Pd(OAc)2,
P(OiPr)3, BuLi
Pd2(dba)3
65 °C
2:1
THF
rt
0%
ꢀ
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
THF
rt
95%
25%
36%
99%
84%
0%
6:1
8:1
2:1
4:1
4:1
ꢀ
THF
ꢀ78 °C
THF
65 °C
rt
MeCN
MeOH
CH2Cl2
toluene
EtOAc
rt
rt
rt
0%
ꢀ
rt
0%
ꢀ
Figure 1. X-ray structure of major diastereomer of 2a.
Having found a reliable set of conditions for the cyclo-
addition, we set about determining the scope and limita-
tions. A wide range of sulfinimines were synthesized using
Ellman’s standard procedures. The result of the reactions
of a range of aldimines is shown in Table 2.
We decided initially to test the directing group ability
of both N-tert-butane and N-mesityl sulfinimines.15 Thus
both types of sulfinimine were made using benzaldehyde
as a precursor and subjected to the optimized conditions.
Ketimines are much more sterically hindered, and thus
we found the yields of cycloaddition were lower than in the
case of aldimine substrates. Similarly, diastereoselectivities
were found to be poorer for these substrates, although the
indanone-based spiro compound, 3e, was formed in a
respectable yield and diastereoselectivity for such a short
synthetic sequence to access this type of complex building
block.
Next, we decided to investigate the exploitation of the
methylene pyrrolidines for the formation of further func-
tionalized building blocks for synthesis, and in particular
as scaffolds for early stage drug discovery. To this end,
we investigated a number of transformations of the pure
diastereomer 2a, as shown in Scheme 1.
(14) Harrity, J. P. A; Provoost, O. Y.; Hazelwood, A. J. Beilstein J.
Org. Chem. 2007, 3, 8.
(15) Davis, F. A.; Ramachandar, T.; Wu, Y. J. Org. Chem. 2003, 68,
ꢀ
6894. Roe, C.; Moragas Sola, T.; Sasraku-Neequaye, L.; Hobbs, H.;
Churcher, I.; MacPherson, D.; Stockman, R. A. Chem. Commun. 2011,
47, 7491.
Org. Lett., Vol. 15, No. 8, 2013
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Table 2. Reaction of tert-Butanesulfinyl Aldimines with TMM
a Reaction carried out at reflux. b Dr determined from comparison of tert-butyl peaks in 1H NMR of crude reaction mixture after workup.
c Diastereomers were separable by column chromatography.
Initially we looked into the removal of the sulfinyl
group, which was found to be easily achieved by the use
of 2 M HCl in diethyl ether, to give NꢀH pyrrolidine 5
after basic workup. Hydrogenation of the alkene of 2a
was possible, and the use of platinum oxide was found
to give excellent yields of 6, and also to leave the sulfinyl
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Org. Lett., Vol. 15, No. 8, 2013

Table 3. Reaction of Sulfinyl Ketimines with TMM
Scheme 1. Exploratory Reactions Using 2a as a Building Block
cleavage of the exoalkene of 2a to give ketone 8 also
oxidized the silfinyl group to a BUS16 group. Alkene 2a
could be converted into γ-amino acid derivative 9 by cross-
metathesis using the HoveydaꢀGrubbs second generation
catalyst17 in dichloromethane in a microwave at 110 °C,
followed by hydrogenation.
In conclusion, we have demonstrated the first general
cycloadditions of chiral tert-butane sulfinimines. The pyr-
rolidine products are of great potential use as building
blocks for screening collections18 or for potential use in the
synthesis of natural products. Studies toward these ends
are ongoing in our laboratories and will be reported in due
course.
Acknowledgment. The authors thank EPSRC (RAS,
EP/H015078) and Pfizer (GP) for funding.
group intact. Hydroboration of 2a with 9-BBN, followed
by in situ oxidation, gave the hydroxymethyl compound
6 with a good degree of diastereoselectivity. Oxidative
Supporting Information Available. Experimental pro-
cedures, NMR, IR, ms data and NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62, 8604.
(17) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41,
9973. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(18) Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem. Int
Ed. 2012, 51, 1114.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
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