Asymmetric [2,3]-rearrangement of glycine-derived allyl ammonium ylids

Article abstract of DOI:10.1021/ja043768i

The first examples of highly enantioselective [2,3]-sigmatropic rearrangements of acyclic allylic ammonium ylids are reported. Thus, a range of N-{2′-[(N′-allyl-N′,N′-dialkyl)ammonium]}acetyl camphor sultams undergo rearrangement at 0 °C in DME solution with high diastereofacial control (up to 99:1 dr) to give allylglycines in generally high yield. The power of the method has been demonstrated in a rapid and efficient synthesis of (R)-allyl glycine. Copyright

Full text of DOI:10.1021/ja043768i

Published on Web 12/21/2004
Asymmetric [2,3]-Rearrangement of Glycine-Derived Allyl Ammonium Ylids
†
†
†
‡,§
‡
James A. Workman, Neil P. Garrido, Julien San c¸ on, Edward Roberts, Hans Peter Wessel, and
,
†
J. B. Sweeney*
School of Chemistry, UniVersity of Reading, Reading RG6 6AD, UK, and Hoffmann-La Roche, Ltd.,
DiscoVery Chemistry, 4070-Basel, Switzerland
Received October 13, 2004; E-mail: j.b.sweeney@rdg.ac.uk
Rearrangement processes are very effective tools for organic
synthesis because of the inherently high efficiency of the reactions;
furthermore, these transformations often proceed with high levels
of stereocontrol. Since their discovery in the late 1960s, the [2,3]-
rearrangement reactions of allylic ammonium salts have received
much attention:1 the original reports of Baldwin concerning
sulfonium ylids were extrapolated by Ollis et al., the process
revolving around the preparation of N-allyl-N,N-dialkylammonium
salts 1, which react at ambient temperatures to give homoallyamines
Scheme 1 . [2,3]-Rearrangement of Acyclic Allyl Ammonium Ylids:
Mediocre Stereoselectivity
Scheme 2 . [2,3]-Rearrangement of Allyldimethyl Ammonium
Sultam Ylid: A Highly Diastereoselective Reaction
2
, via the intermediacy of ylids 3 (Scheme 1). Where suitable
1
1
electron-stabilizing substituents (R ) are present (especially R )
2
acyl), the ylids may be isolated and characterized and have also
been prepared in situ by reaction of allylamines with diazo
3
compounds. Although these rearrangements frequently proceed in
good yield, the stereoselectivity of the reactions is often mediocre,
especially by modern standards.1a,4
In contrast, the rearrangement of cyclic ylids is well-known to
be a highly stereoselective process, and we have described the use
of N-methyltetrahydropyridine-derived ester-stabilized ylids (a
The reaction proved to be a general one, with the rearrangements
of salts 4b-g all proceeding smoothly at 0 °C. Once again, high
levels of diastereoselectivity were observed in the process, giving
a range of allyl glycine derivatives (Table 1) with excellent
diastereocontrol. Where terminal substitution of the allyl group was
present (Table 1, entries 5 and 8), syn:anti ratios were high: syn-
configured 3-substituted allyl glycines were obtained as virtually
the only observable products. These allyl glycines are not easily
accessible by other routes, and the stereoselectivity of the [2,3]-
rearrangement is vastly improved compared to achiral reactions
5
reaction previously described to be unfeasible ) to prepare a range
6
of cis-configured proline analogues. We have recently turned our
attention to the design and execution of stereoselective acyclic
ammonium ylid rearrangements, with a specific focus on obtaining
an enantioselective method. Given the potent biological properties
7
of allyl glycines, any such methodology that would allow a highly
stereoselective rearrangement of glycine-derived acyclic ammonium
1
ylids (2, R ) CO
2
R) would represent a significant advancement.
(vide supra).
We here report the preliminary results of our investigations into
the asymmetric rearrangements of chiral derivatives of N-allyl
glycine salts, which reveal that allyl glycine derivatives may indeed
be prepared via [2,3]-rearrangement, with excellent enantiocontrol.
Though a modern paradigm, the use of chiral catalysis in this
type of ammonium ylid rearrangement is restricted for a number
of reasons, the most important being the fact that the nitrogen atom
must be quaternized in these ylids, thereby precluding any ligation
from the nitrogen lone pair to a chiral catalyst. This limitation to
the development of chiral catalysis has recently been tackled by
the use of Lewis acid complexation to generate ammonium ylids
Several other features are also noteworthy. First, the reactions
are predictable in terms of asymmetric control: (2R)-configured
auxiliary delivers predominantly (2′S)-configured products, while
the use of the (2S)-auxiliary gives (2′R)-products. Second, allyl
migration is favored over benzyl migration (Stevens [1,2]-rear-
rangement, see entry 4). Finally, the yields of rearrangement only
suffered when the allyl subunit was R-branched (as with cyclohex-
-enyl salt 4h, Scheme 3). In the latter reaction, a complex mixture
of products was obtained, which complicated the stereochemical
assignments. Thus, all four possible diastereoisomers were observed
2
(
for the first time in these reactions) (anti:syn ) 14:86), but the
8
in situ, but the methodology is far from mature. For these reasons,
enantioselectivity of this rearrangement was virtually nonexistent.
Given that the yield of this rearrangements was also <50%, it may
be the case that the presence of asymmetry adjacent to the
ammonium group is now exerting an influence and that there is a
difference in the rate of rearrangement of the N-diastereoisomers
in this more sterically demanding process.
It seems that the juxtaposition of the asymmetric auxiliary and
the nucleophilic carbon atom is not absolutely necessary for
stereoselective reaction. Thus, an isomeric ylid (6) in which the
chiral auxiliary was attached to the allylic substituent (rather than
the glycine moiety) also underwent rearrangement in excellent yield
and with high stereoselectivity, to give â-ethenyl aspartate derivative
the use of a chiral auxiliary is indicated to be an appropriate
synthetic choice. We first chose to examine the reactions of N-allyl
glycine salts bearing a pendant Oppolzer camphorsultam auxiliary,
and we were gratified to observe that the [2,3]-rearrangement of
N′,N′,N′-allyldimethyl glycinoyl (2R)-sultam 4a proceeded in high
yield at 0 °C. Moreover, allyl glycine derivative 5a was obtained
with a high level of diastereoselectivity, in favor of the (2′S)-isomer9
(dr ) 49:1) (Scheme 2).
†
University of Reading.
‡
F. Hoffmann-La Roche, Ltd.
§
Present address: K e´ mia, Inc., 9390 Towne Centre Drive, San Diego, CA 92121.
1066
9
J. AM. CHEM. SOC. 2005, 127, 1066-1067
10.1021/ja043768i CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. [2,3]-Rearrangement of Allyldimethyl Ammonium Sultam
Ylids (4a-g): A Highly Stereoselective Reaction
Scheme 5 . Efficient Enantioselective Synthesis of (R)-Allyl Glycine
via Asymmetric [2,3]-Rearrangement
yield 5
entry
salt
R1
R2
R3
R4
(%)
anti:syn
2′R:2′S
of these amino acid derivatives, we believe that this protocol will
find widespread use in the synthesis of biologically significant
compounds.
1
2
3
4
5
7
8
4ab
H
H
H
H
Me
Me
H
Me
Me
allyl allyl
Bn
Me
Me
allyl
99
99
86
80
86
70
2:98a
c,d
e
4b
4c
4d
4e
4f
4g
H
H
H
H
97:3
c,d
97:3e
d
e
allyl
Me
Me
Me
>99:1
Acknowledgment. We thank EPSRC for provision of analytical
services (at the University of Swansea) and the University of
Reading and F. Hoffmann-LaRoche, Ltd., for financial support, and
we acknowledge the mentorship provided by Mr. G. Buchman and
Mr. K. Mathieson.
Note Added after ASAP Publication. Due to a production error,
the numbers in the first column of Table 1 were incorrect in the
version published ASAP on December 21, 2004. The table was
corrected for final print and Web publication, and the correct version
was posted on January 5, 2005.
d
96:4a
>99:1
d
a
Me Me
Me
97:3
d
f
>99:1 >99:1a
MeO2C
H
64
a
Absolute stereochemistry was assigned using X-ray crystallography.
b
c
d
RC ) (2R)-camphorsultam. Iodide salt used. RC ) (2S)-camphorsultam.
Stereochemistry assigned by analogy and/or chemical correlation. Trace
e
f
amount of [1,2]-product also observed.
Scheme 3 . [2,3]-Rearrangement of 2-Cycloxenyl Ylid 4h
Supporting Information Available: X-ray structures, experimental
procedures, and data for key compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(
1) For reviews of the area, see: (a) Mark o´ , I. E. Compr. Org. Synth. 1991,
, 913. (b) Nitrogen, Oxygen and Sulfur Ylide Chemistry; Clark, J. S.,
3
Scheme 4 . [2,3]-Rearrangement of 4-(Aminocrotonoyl)sultam Ylid
Ed.; Oxford University Press: Oxford; 2002. (c) Doyle, M. P.; McKervey,
M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley & Sons: New York, 1998.
2) For original reports of onium ylid rearrangements, see: Baldwin, J. E.;
Hackler, R. E.; Kelly, D. P. J. Am. Chem. Soc. 1968, 90, 4758. Blackburn,
G. M.; Ollis, W. D.; Smith, C.: Sutherland, I. O. J. Chem. Soc., Chem.
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5) Burns, B.; Coates, B.; Neeson, S.; Stevenson, P. J. Tetrahedron Lett. 1990,
6: A Highly Stereoselective Reaction
(
(
(
(
7
(Scheme 4; the absolute stereochemistry of 7 was determined by
3
1, 4351. Neeson, S. J.; Stevenson, P. J. Tetrahedron Lett. 1988, 29, 3993.
X-ray crystallography).
(6) Sweeney, J. B.; Tavassoli, A.; Carter, N. B.; Hayes, J. F. Tetrahedron
2
002, 58, 10113.
Finally, we have used this reaction to accomplish a new and
efficient asymmetric synthesis of (R)-allyl glycine. Thus, salt 4c
underwent rearrangement10 (Table 1, entry 3, dr ) 32:1), deallya-
(
7) For reports of syntheses and the significance of allyl glycines, see: Walsh
C. Tetrahedron 1982, 38, 871. Duthaler, R. O. Tetrahedron 1994, 50,
1
539. Bioulac, B.; Benazzouz, A.; Burbaud, P.; Gross, C. Neurosci. Lett.
1
997, 226, 21. Myers, A. G.; Gleason, J. L.; Yoon, T. Y. J. Am. Chem.
tion,11 and saponification, yielding (R)-(+)-allylglycine ([R]D
+
12
20
Soc. 1995, 117, 8488. Gurjar M. K.; Talukdar A. Synthesis 2002, 315
and references therein.
32;13 cf. lit. 37.2 and 33.514b) in high overall yield (Scheme
14a
(
8) For a recent report of a Lewis-acid-mediated rearrangement, see: Blid,
J.; Brandt, P.; Somfai, P. J. Org. Chem. 2004, 69, 3043.
9) Stereochemistry confirmed by X-ray analysis.
10) For a previous report of [2,3]-rearrangements of triallylammonium salts,
see: Arbore, A. P. A.; Cane-Honeysett, D. J.; Coldham, I.; Middleton,
M. L. Synlett 2000, 236.
5). This process represents an efficient synthesis of this important
(
nonproteinogenic amino acid and exemplifies the inherent utility
of these [2,3]-rearrangements.
(
In summary, we have reported the first asymmetric [2,3]-
sigmatropic rearrangements of simple allylic ammonium ylids. A
range of substituted compounds have been used to generate a
collection of structurally diverse, densely functionalized allyl glycine
derivatives in generally good yields and with high diastereo- and
enantioselectivity. We have exploited this methodology to execute
a highly efficient synthesis of (R)-allylglycine. Given the importance
(
(
(
11) Garro-Helion, F.; Merzouk, A.; Guib e´ , F. J. Org. Chem. 1993, 58, 6109.
12) Oppolzer, W.; Tamura, O.; Deerberg, J. HelV. Chim. Acta 1992, 75, 1965.
13) There is significant variation between the values reported for the specific
rotation of the antipodes of allylglycine: the N-Cbz-OMe derivative of
our material was shown to be g95% (R)-configured by HPLC.
14) (a) Myers, A. G.; Gleason, J. L. Org. Synth. 1999, 76, 57. (b) Broxterman,
Q. B.; Kaptein, B.; Kamphuis, J.; Schoemaker, H. E. J. Org. Chem. 1992,
(
57, 6286.
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