Epoxy-annulations by reactions of α-amido ketones with vinyl sulfonium salts. Reagent versus substrate control and kinetic resolution

Article abstract of DOI:10.1021/ol800318h

(Chemical Equation Presented) Diphenyl vinyl sulfonium salt and chiral amido-ketones undergo highly diastereoselective epoxy-annulation reactions in good yield. The use of a chiral vinyl sulfonium salt dominates the stereochemical outcome of the annulatio

Full text of DOI:10.1021/ol800318h

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1501-1504
Epoxy-Annulations by Reactions of
-Amido Ketones with Vinyl Sulfonium
Salts. Reagent versus Substrate Control
and Kinetic Resolution
r
Matthew G. Unthank,† Bahareh Tavassoli,‡ and Varinder K. Aggarwal*,†
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol, BS8 1TS United
Kingdom and GlaxoSmithKline, Old Powder Mills, Tonbridge, Kent, TN11 9AN United Kingdom
V.aggarwal@bristol.ac.uk
Received February 12, 2008
ABSTRACT
Diphenyl vinyl sulfonium salt and chiral amido-ketones undergo highly diastereoselective epoxy-annulation reactions in good yield. The use
of a chiral vinyl sulfonium salt dominates the stereochemical outcome of the annulation reaction (reagent control is greater than substrate
control), and this has allowed the kinetic resolution of racemic amido-ketones to be achieved.
The development of novel methods for the asymmetric
synthesis of functionalized heterocycles is of great interest
Scheme 1. Vinyl Sulfonium Salt Mediated Epoxy-Annulation
in synthesis as such motifs are ubiquitous in both natural
products and biologically active pharmaceutical agents. We
recently reported that diphenyl vinyl sulfonium salt 1 reacts
with R-, â-, and γ-amido aldehydes/ketones to give 5-, 6-,
and 7-membered nitrogen heterocycles containing epoxides
in high yield.1a Furthermore, through the use of the chiral
vinyl sulfonium salt 2, high enantioselectivity could also be
achieved (Scheme 1).1a,2
Reaction of Achiral R-, â-, and γ-Amido Aldehydes/Ketones
As chiral R-amido aldehydes and ketones are very readily
available from the corresponding amino acids, it occurred
to us that this novel annulation methodology could potentially
be applied to a stereocontrolled synthesis of epoxy pyrro-
lidines bearing additional substituents. Issues of substrate
versus reagent control would clearly affect the outcome of
the reaction, and these issues are the focus of the current
paper.
† University of Bristol.
‡ GlaxoSmithKline.
(1) (a) Unthank, M. G.; Hussain, N.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2006, 45, 7066. For other applications of diphenyl vinyl sulfonium
salts in the synthesis of heterocycles, see: (b) Wang, Y.; Zhang, W.;
Colandrea, V. J.; Jimenez, L. S. Tetrahedron 1999, 55, 10659 and references
therein. For other work describing the use of chiral vinyl sulfonium salts
in synthesis, see: (c) Kim, K.; Jimenez, L. S. Tetrahedron: Asymmetry
2001, 12, 999.
We began our studies by probing the extent of substrate
control in the epoxy annulation reaction using the achiral
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© 2008 American Chemical Society
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diphenyl vinyl sulfonium salt 1. We chose alanine as our
starting point because it bears the smallest possible substitu-
ent in the R position and would therefore show the minimum
level of substrate control attainable. A series of R-amido
ketones 3, 4, and 53 and the corresponding aldehyde 64 were
therefore prepared using established Weinreb or alcohol
oxidation methodology, respectively.5 This series of sub-
pyrrolidines (Table 1, method A). The ketone substrates all
performed well, giving high yields of annulated products 8,
9, and 10, but the amino aldehyde 6 was less effective,
presumably due to its inherent instability.6 There was a broad
correlation between the size of the carbonyl substituent and
the degree of selectivity observed: large substituents (Ph,
Table 1, entries 6 and 7) gave high syn selectivity (>50:1)
whereas small substituents (H, Table 1, entry 1) gave
essentially no selectivity (1.2:1). No epimerisation of the
stereogenic center adjacent to the ketone functionality was
detected in any of the cases.
Table 1. Reactions of Alanine-Derived Amido-Ketones with
Vinyl Sulfonium Salts 1 and 2a
The substrate-controlled selectivity observed can be ra-
tionalized by considering the two Felkin-Ahn7 transition
states that ultimately lead to the two possible epoxides. The
factors that control the outcome of the reaction include (i)
preferred approach of the ylide over the H substituent rather
than the Me group (favors TS11, Scheme 2) and (ii) steric
Scheme 2. Proposed Model for Substrate-Controlled
Annulation Reaction
hindrance between the Me group and the carbonyl substituent
R (favors TS11). The latter effect will increasingly favor
TS11 as the carbonyl substituent increases in size, suggesting
that this factor is primarily responsible for the selectivity
observed in Table 1.
These results show that very high diastereoselectivity can
be observed in the substrate-controlled epoxy annulation
process employing the readily available diphenyl vinyl
sulfonium salt 1. Furthermore, syn isomers are preferentially
a Reagents and conditions. Method A (optimal conditions for substrate-
controlled reactions): diphenyl vinyl sulfonium salt 1 (1.2 equiv), DBU (2
equiv), CH2Cl2 (0.09 M), 2-4 h, 0 °C. Method B (optimal conditions for
“matched” reactions): chiral vinyl sulfonium salt 2 (1.0 equiv), NaH (1.2
equiv), CH2Cl2 (0.015 M), 5-18 h, 0 °C. Method C (optimal conditions
for “mis-matched” reactions): chiral vinyl sulfonium salt 2 (1.0 equiv),
DBU (2 equiv), CH2Cl2 (0.015 M), 18 h, 0 °C-rt b Major isomer (syn) from
the substrate-controlled reactions (Method A) is shown.
(3) For the synthesis of N-tosyl alanine, see: (a) Sdira, S. B.; Felix, C.
P.; Giudicelli, M-B. A.; Seigle-Ferrand, P. F.; Perrin, M.; Lamartine, R. J.
J. Org. Chem. 2003, 68, 6632. For the synthesis of amino-ketones from
their respective Weinreb amides, see: (b) Chen, W. B.; Jin, G. Y.
Heteroatom Chem. 2003, 14, 603.
(4) For the synthesis of highly epimerisable amino aldehydes, see: Myers,
A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon,
S. Tetrahedron Lett. 2000, 41, 1359.
strates were then treated with DBU in the presence of the
vinyl sulfonium salt 1 and gave the corresponding epoxy
(5) See Supporting Information for full details.
(6) Reaction of the amino aldehyde (()-6 was only carried out on the
racemate. This example was done to establish the relationship between the
size of the carbonyl substituent and level of substrate control. As both yield
and diastereoselectivity were low with this substrate, further work on the
enantioenriched material was not conducted.
(2) For the synthesis of the chiral sulfide from which 2 is derived, see:
(a) Aggarwal, V. K.; Fang, G.; Kokotos, C. G.; Richardson, J.; Unthank,
M. G. Tetrahedron 2006, 62, 11297. (b) Aggarwal, V. K.; Alonso, E.; Hynd,
G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.; Studley, J. R. Angew.
Chem., Int. Ed. 2001, 40, 1430.
(7) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9, 2199.
1502
Org. Lett., Vol. 10, No. 7, 2008

formed, which are of course the more difficult isomers to
access because alkene epoxidation (e.g., with mCPBA) favors
the anti isomers.8
Scheme 4. Proposed Model for “Mis-Matched” Reaction of
(S)-Amido Methyl-Ketone (S)-3 with Chiral Vinyl Sulfonium
Salt 2 (Method C)
We then investigated the reactions of the enantiomerically
enriched amido ketones9 3, 4, and 5 with the chiral vinyl
sulfonium salt 2 to explore the balance between reagent and
substrate control. We had previously shown1a that high levels
of reagent control could be achieved in the reaction of the
achiral R-amido ketones with the chiral vinyl sulfonium salt
2 (92-97% e.e.). However, when both reagent and substrate
could exert control, we were interested to know which would
dominate. To address this, we reacted (R)- and (S)-amido
ketones 3, 4, and 5 with the (+)-vinyl sulfonium salt 2, and
the results are summarized in Table 1. The two enantiomers
of the amido ketone required slightly different conditions to
achieve acceptable yields (methods B and C).
In all cases where the substrate and reagent favored the
formation of the same product (matched case), a single (syn)
diastereomer was formed in good yield. In the mis-matched
cases, the anti diastereomer was obtained predominantly
showing that the reagent dominated the outcome of the
The amido ketones could potentially racemize during the
course of the reaction although this was not detected with
the alanine-derived substrates. Racemization would be much
more of a potential problem in the extreme case of phenyl
glycine-derived ketone 15, and so to explore the limit of our
annulation reaction, this substrate was prepared11 and tested.
Reaction with diphenyl vinyl sulfonium salt 1 under standard
conditions afforded the syn epoxide with the expected high
diastereoselectivity (due to the bulky phenyl ketone moiety)
but some degree of racemization. However, using NaH in
place of DBU (method A*, Table 2), no racemisation was
Scheme 3. Proposed Model for “Matched” Reaction of
(R)-Amido Methyl-Ketone (R)-3 with Chiral Vinyl Sulfonium
Salt 2 (Method B)
Table 2. Substrate-Controlled Epoxy-Annulation Reaction with
Vinyl Sulfonium Salt 1a
reaction. The matched and mis-matched stereochemical
outcomes of amido ketone 3 are illustrated in Schemes 3
and 4, respectively. The factors affecting substrate control
have already been outlined, and the factors influencing
reagent control follow from our established model10 in which
ylide conformer 13 is favored over conformer 14 (see
Scheme 4), and in both cases, addition of the ylide occurs
on the opposite face to the bicyclic camphor moiety.
(8) For examples of epoxidation of unsaturated chiral 5-membered
heterocycles to give anti-isomers see: (a) Quibbel, M.; Ben, A.; Flinn, N.;
Monk, T.; Ramjee, M.; Ray, P.; Wang, Y.; Watts, J. Bioorg. Med. Chem.
2005, 13, 609. (b) Wang, Y.; Ben, A.; Flinn, N.; Monk, T.; Ramjee, M.;
Watts, J.; Quebell, M. Bioorg. Med. Chem. Lett. 2002, 15, 1327. (c) Lazaro,
A.; Garcia, L.; Correia, C. R. D. Tetrahedron Lett. 2003, 44, 1553. (d)
Severino, E. A.; Correa, C. R. D. Org. Lett. 2000, 2, 3039. (e) Baldwin, J.
E.; Field, R. A.; Lawrence, C. C.; Lee, V.; Robinson, J. K.; Schofield, C.
J. Tetrahedron Lett. 1994, 35, 4649. (f) Wardrop, D. J.; Bowen, E. G. Chem.
Commun. 2005, 5106. (g) Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994,
35, 7099.
a Reagents and conditions. Method A (optimal alanine-derived substrate-
controlled reaction conditions): diphenyl vinyl sulfonium salt 1 (1.2 equiv),
DBU (2 equiv), CH2Cl2 (0.09 M), 2 h, 0 °C. Method A* (optimal substrate-
controlled reaction conditions for highly epimerisable substrates): diphenyl
vinyl sulfonium salt 1 (1.2 equiv), NaH (1.2 equiv), CH2Cl2 (0.09 M), 2 h,
0 °C.
(9) Only the higher yielding chiral ketone substrates were chosen to react
with the valuable chiral vinyl sulfonium salt 2. The amino-aldehyde 6 was
considered unsuitable for these reactions due to its lack of substrate-
controlled diastereosectivity with diphenyl vinyl sulfonium salt 1.
(10) (a) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.;
Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson, R. A.;
Studley, J. R.; Vasse, J. L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125,
10926. (b) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611.
(c) Aggarwal, V. K.; Richardson, J. Chem. Commun. 2003, 2644.
detected and the product was obtained with equally high
diastereoselectivity, thus demonstrating the potential of the
method with sensitive substrates.
We recognized that due to the strong preference for bulky
phenyl ketones to form syn epoxides, we would expect the
Org. Lett., Vol. 10, No. 7, 2008
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mismatched reaction between (S)-15 and (+)-vinyl sulfonium
salt 2 to be slow. We believed that we could exploit the
difference in rates of reaction between matched and mis-
matched cases through a kinetic resolution of (()-15 with
the (+)-isomer of 2. Experimentally, it was found that by
using 2.2 equiv of (()-amido-ketone 15, with respect to (+)-
chiral vinyl sulfonium salt 2 at 0 °C a 66% yield of the syn-
heterocycle, 16a was obtained in 90% e.e. after 5 h. By
reducing the reaction temperature from 0 to -20 °C, the
syn epoxide was obtained in similar yield but the enantio-
meric excess was increased to 94% (Scheme 5). Thus, an
not the first to probe “matched” versus “mis-matched”
reactions of chiral electrophiles with a chiral sulfonium
ylide,12 it does represent the first report of a chiral sulfonium
ylide-mediated kinetic resolution.
In summary, a highly (syn) diastereoselective epoxy-
annulation reaction has been developed using alanine-derived
amido-ketones and the achiral diphenyl vinyl sulfonium salt
1. The (syn) diastereoselectivity of the reaction can be either
increased or over-turned to favor the anti isomer through
the use of the chiral vinyl sulfonium salt 2 indicating that
the reagent dominates the stereochemical outcome of the
annulation reaction. The phenyl ketones 5 and 15, in
particular, resulted in a very high degree of substrate-
controlled diastereoselectivity in reactions with the diphenyl
vinyl sulfonium salt 1 (>50:1 syn:anti), which was further
exploited in a kinetic resolution of a (()-15 using the chiral
vinyl sulfonium salt 2. Because both enantiomers of both
the chiral vinyl sulfonium salt and the amido ketones are
available, either enantiomer of either diastereomer of the
epoxy pyrrolidines can be prepared using this annulation
methodology.
Scheme 5. Kinetic Resolution of (()-Amido-Ketone 15
Acknowledgment. We thank GlaxoSmithKline and the
EPSRC for support of this work. We thank Mr. Saowanit
Saithong and Dr. J.P.H. Charmant for X-ray analysis.
Supporting Information Available: Experimental pro-
cedures and characterisation data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL800318H
(11) For the tosylation of phenyl glycine, see (a) Gonza´lez-Cameno, A.
M.; Bad´ıa, D.; Dom´ınguez, E.; Urtiaga, M. K.; Arriortua, M. I.; Solans, X.
Tetrahedron 1994, 50, 10971. For the synthesis of Weinreb amides of phenyl
glycine, see (b) Myers, M. C.; Wang, J.; Iera, J. A.; Bang, J.; Hara, T.;
Saito, S.; Zambetti, G. P.; Appella, D. H. J. Am. Chem. Soc. 2005, 127,
6152. For the temperature-controlled treatment of the Weinreb amides with
PhMgBr, see (c) Chen, W. B.; Jin, G. Y.; Heteroatom Chem. 2003, 14,
603.
(12) For other examples of reactions of chiral sulfur ylides with chiral
aldehydes, see (a) Aggarwal, V. K.; Bi, J. Beilstein J. Org. Chem. 2005,
http://bjoc.beilstein-journals.org/content/1/1/4. (b) Bellenie, B. R.; Good-
man, J. M. Chem. Commun. 2004, 1076.
effective kinetic resolution of phenyl glycine-derived (()-
amido-ketone 15 has been achieved. It is most likely that
kinetic resolution occurs in the ylide + ketone step (see
Scheme 5), implying that amide addition to the vinyl
sulfonium salt is reversible. Although this investigation is
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Org. Lett., Vol. 10, No. 7, 2008