Asymmetric Wolff rearrangement reactions with α-alkylated-α-diazoketones: Stereoselective synthesis of α-substituted-β-amino acid derivatives

Article abstract of DOI:10.1021/ol006146k

matrix presented Photoinduced asymmetric Wolff rearrangement reactions were performed with α-amino-α′-melhyl-α′-diazoketones to afford α-methyl-β-amino acid esters with good stereoselectivity. Factors that may influence the stereochemistry were examined, including steric effects and temperature dependence, which had a great impact on the stereochemistry.

Full text of DOI:10.1021/ol006146k

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2177-2179
Asymmetric Wolff Rearrangement
Reactions with
r-Alkylated-r-diazoketones:
Stereoselective Synthesis of
r-Substituted-â-amino Acid Derivatives†
Hua Yang,* Katherine Foster, Corey R. J. Stephenson, William Brown, and
Edward Roberts
Department of Chemistry, AstraZeneca R&D Montreal, 7171 Frederick-Banting,
St. Laurent, Quebec, Canada H4S 1Z9
hua.yang@astrazeneca.com
Received June 1, 2000
ABSTRACT
Photoinduced asymmetric Wolff rearrangement reactions were performed with r-amino-r′-methyl-r′-diazoketones to afford r-methyl-â-amino
acid esters with good stereoselectivity. Factors that may influence the stereochemistry were examined, including steric effects and temperature
dependence, which had a great impact on the stereochemistry.
Wolff rearrangements are one of the most practical reactions
for one-carbon (methylene) extension methods in organic
Scheme 1
synthesis.1 R-Diazoketone 1 may undergo a Wolff rearrange-
ment to intermediate ketene 2 which may be trapped with a
nucleophile giving product 3, after CH2 insertion (Scheme
1).2 It is conceivable that R-alkylated-R-diazoketone 4 may
also undergo a Wolff rearrangement to prochiral ketene 5,
resulting in the chiral product 6.3 There are potentially
† This paper is dedicated to Professor Stephen Hanessian on the occasion
of his 65th birthday.
(1) For recent reviews on the Wolff rearrangement, see: (a) Meier, H.;
Zeller, K.-P. Angew. Chem., Int. Ed. Engl. 1975, 14, 32. (b) Baron, W. J.;
DeCamp, M. R.; Hendrick, M. E.; Jones, M., Jr.; Levin, R. H.; Sohn, M.
B. In Carbenes; Jones, M., Jr., Moss, R. A., Eds.; Robert E. Krieger
route to molecules with one carbon atom extended, incor-
Publishing Company: Malabar, 1983; Vol. 1, Chapter 1, pp 117-151. (c)
Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091.
numerous ways available to control the stereochemistry at
the R position.4 Therefore, the Wolff rearrangement reactions
with R-alkylated-R-diazoketones may provide an alternate
(2) Newman, M. S.; Arkell, A. J. Org. Chem. 1959, 24, 385.
(3) a) Lopez-Herrera, F. J.; Sarabia-Garcia, F. Tetrahedron Lett. 1993,
34, 3467. (b) Lopez-Herrera, F. J.; Sarabia-Garcia, F. Tetrahedron Lett.
1994, 35, 2929.
(4) a) Asymmetric Synthesis; Morrison, D. D., Ed.; Academic Press:
Orlando, FL, 1983-1986; Vols. 1-5. (b) Hanessian, S. Total Synthesis of
Natural Products: the Chiron Approach; Baldwin, J., Ed.; Pergamon
Press: New York, 1983.
10.1021/ol006146k CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

porating a new chiral center, introduced in a one-pot
synthesis. To test the concept, we prepared the R-alkylated-
R-diazoketones from R-amino acids and assumed that the
chiral center residing in the R-amino acid could influence
the stereochemistry of the newly established chiral center
of the Wolff rearrangement product. Herein we would like
to communicate our preliminary results of the asymmetric
Wolff rearrangement.
Table 1. Wolff Rearrangement with R-Diazoketones
R-Alkyl-R-diazoketones, precursors to the new Wolff
rearrangement reactions, were readily prepared from the
corresponding R-amino acids via the two-step sequence of
diazomethane coupling followed by anionic alkylation reac-
tions. Thus, the N-protected R-amino acids were treated with
i-BuOCOCl at -10 °C in THF followed by the addition of
diazomethane to afford the R-diazoketones,5 which were
subsequently deprotonated using a base and then trapped with
electrophiles at -78 °C in THF, in the presence of HMPA,
to give the R-alkyl-R-diazoketones (Scheme 2).
ratiob,c
yieldd
(%)
entry
R1
R2
R4
(anti/syn)
1
2
3
4
5
6
7
8
10
Me
i-Pr
Fmoc Me
Fmoc Me
1.5:1
6:1
5:1
37
33
43
25
48
49
45
77
38
1-naphthylmethyl Fmoc Me
Me
i-Pr
Bn
Boc
Boc
Boc
Boc
Me
Me
Me
Me
Me
6:1
>10:1
6:1e
6:1
Ph2CH
1-naphthylmethyl Boc
Me
6:1
1:1
Fmoc i-Pr
a All reactions run at -78 °C in a photochemical reaction apparatus
purchased from Aldrich, with nitrogen gas bubbling through the reaction
mixture. b Ratio determined by 1H NMR and/or HPLC analysis prior to
purification. c Stereochemistry determined by comparison with the com-
pound in entry 6. d Isolated yield. e Stereochemistry determined by X-ray
analysis of a single crystal and chemical correlations.6
Scheme 2
that the stereoselectivity of the Wolff rearrangement was
temperature-dependent. Better diastereoselectivity was ob-
tained with decreasing reaction temperature.6 The best ratios
were obtained when the reactions were run at -78 °C,
although the reaction yields were relatively low.
Photoinduced Wolff rearrangement of R-diazoketones most
likely proceeds via an excited singlet state.7 It has been
suggested that the migrating group be anti to the diazo
leaving group in order for the Wolff rearrangement to take
place efficiently.7,8 Decreasing the size of R3 would favor
the Wolff rearrangement reaction since the equilibrium would
move toward the isomer A, leading to the desired rearranged
products (Scheme 3). Thus, the Wolff rearrangement, in the
The Wolff rearrangement reactions were effected using
UV light at -78 °C in dichloromethane to give intermediate
ketenes which were then trapped with, for example, alcohols
to furnish the R-methyl-â-amino acid derivatives (Table 1).
The stereochemistry of the major diastereoisomer was
determined to be anti by a single-crystal X-ray crystal-
lographic analysis and chemical correlations.6
The steric size of the substituents in the Wolff rearrange-
ment precursor appears to have a great influence on the
stereochemistry of the reaction. The diastereomeric ratios
increased significantly from 2:1 to 6:1 with the size of R1
when the nitrogen atom was protected with Fmoc (entries
1-3, Table 1). Interestingly, when tert-butoxycarbonyl was
utilized as the nitrogen protecting group, in all the cases
studied so far, high diastereomeric ratios > 5:1 were
observed (entries 4-9, Table 1). This discrepancy in ste-
reoselection between Fmoc and Boc groups could be due to
the steric difference, that the tert-butyl group of the Boc is
bulkier than that of the Fmoc. When the bulkiness of the
trapping reagent was changed from MeOH to i-PrOH,
however, no improvement on the stereoselectivity was
observed (entry 10 Table 1). Further experiments indicated
Scheme 3
(5) Pizey, J. S. In Synthetic Reactions; Halsted: New York, 1974; Vol.
2, Chapter 4.
(6) For details, see the Supporting Information.
2178
Org. Lett., Vol. 2, No. 14, 2000

extreme case, where R3 ) H, gave better yields (54-87%).
An X-ray crystallographic analysis of a single crystal
structure of a diazoketone (R1 ) Bn, R2 ) Boc, and R3 )
H) clearly indicated that the migrating group is anti to the
diazo group, which should favor the Wolff rearrangement.
In contrast, when R3 ) Bn, a group which is sterically larger
than H and Me, the Wolff rearrangement reaction gave a
complex mixture at various temperatures, suggesting that the
predominant population is rotomer B, which is less inclined
toward the Wolff rearrangement reactions8 (Scheme 3). The
fact that a higher yield can be obtained at a higher
temperature6 implies the relative ease of rotation of the diazo
group around the C1-C2 bond at higher temperatures
(Scheme 3).7
The ketenes generated from the Wolff rearrangement
reactions are trapped with electrophiles to give the desired
products. It is at this stage that a new chiral center is created.
It is most likely that an intermediate ketene hemiacetal is
generated9 and then tautomerized to the final product
(Scheme 3). We tentatively assume that the most stable
conformation of the transition state of tautomerization is the
one resembling the lowest energy conformation of the final
product, as shown in Scheme 4.10,11 The proton may approach
the larger R1, R2, and R3, the higher the diastereomeric ratio
is. Furthermore, R4 points away from the R1 and R2 groups
and consequently imposes much less influence on the
prochiral center than R1 and R2 do. The model we have
proposed here is in harmony with the experimental results
obtained so far.
In summary, we have developed a novel method to extend
one carbon atom with concomitant introduction of one chiral
center using the Wolff rearrangement reaction. The new
chiral center is controlled by the chiral resident group in the
molecules. The stereochemistry of the reactions could also
potentially be controlled by chiral auxiliaries4a,12 and chiral
ligands.4a The results of these efforts will be reported in due
course. In short, the methodology described in this Letter is
complementary to existing methods13,14 and will find a variety
of applications in synthetic organic chemistry and medicinal
chemistry.
Acknowledgment. We thank Dr. D. Delorme and Profes-
sor S. Hanessian for helpful discussions, Dr. R. Schmidt for
HPLC analysis, Dr. M. Simard for X-ray crystallographic
analyses, and the Industrial NSERC Fellowships to K.F. and
C.S.
Supporting Information Available: Experimental pro-
cedures, characterization data, chemical correlations, X-ray
structures, and the temperature effects. This information is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 4
OL006146K
(10) Solution NMR studies and a single-crystal X-ray crystallography
analysis6 suggest that the most likely lowest energy conformation of the
anti product is the one as shown in Scheme 4.
(11) Molecular modeling studies of the ketene hemiacetal and the anti
and syn products suggest that the most likely transition state may be the
one resembling the lowest energy conformation of the final product, as
shown in Scheme 4, i.e., a later-transition state. The molecular modeling
studies were performed using a Sybyl software package, version 6.0, with
a SiliconGraphics workstation.
from one side of the ketene hemiacetal such that the strain
between R1 and R3, as well as between R2 and R3 could be
released to the maximum extent in the transient state. Hence,
(12) For trapping of ketenes generated from acid chlorides, with chiral
alcohols to control the stereochemistry, see: Larsen, R. D.; Corley, E. G.;
Davis, P.; Reider, P. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111,
7650.
(13) For recent reviews on synthesis of â-amino acids, see: (a) Cole,
D. Tetrahedron 1994, 50, 9517. (b) Enders, D.; Beltray, W.; Raabe, G.;
Runsink, J. Synthesis 1994, 1322.
(14) For a stereoselective synthesis of R-alkylated-â-amino acid deriva-
tives using anionic chemistry, see: Podlech, J.; Seebach, D. Liebigs Ann.
1995, 1217, and references therein. For a stereoselective synthesis of
R-alkylated-â-amino acid derivatives using free radical chemistry, see:
Hanessian, S.; Yang, H.; Schaum, R. J. Am. Chem. Soc. 1996, 118, 2507,
and references therein.
(7) Kaplan, F.; Meloy, G. K. J. Am. Chem. Soc. 1966, 88, 950.
(8) For discussion of the effects of conformation on Wolff rearrangement,
see: (a) Bartz, W.; Regitz, M. Chem. Ber. 1970, 103, 1463. (b) Kaplan, F.;
Mitchell, M. L. Tetrahedron Lett. 1979, 9, 759. (c) Tomioka, H.; Okuno,
H.; Izawa, Y. J. Org. Chem. 1980, 45, 5278. (d) Tomioka, H.; Kondo, M.;
Izawa, Y. J. Org. Chem. 1981, 46, 1090. (e) Toscano, J. P.; Platz, M. S.;
Nikolaev, V.; Popik, V. J. Am. Chem. Soc. 1994, 116, 8146. (f) Wang,
J.-L.; Toscano, J. P.; Platz, M. S.; Nikolaev, V.; Popik, V. J. Am. Chem.
Soc. 1995, 117, 5477. See also ref 3b.
(9) For some recent discussions about the regioselectivity of additions
to ketenes, see: (a) Sung, K.; Tidwell, T. T. J. Am. Chem. Soc. 1998, 120,
3043. (b) Allen, A. D.; Tidwell, T. J. Org. Chem. 1999, 64, 266.
Org. Lett., Vol. 2, No. 14, 2000
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