Directed Reduction of β-Amino Ketones to Syn or Anti 1,3-Amino Alcohol Derivatives

Article abstract of DOI:10.1021/ol026456y

(Equation Presented) The reduction of β-amino ketones with samarium(II) iodide has been investigated. Either the syn or anti 1,3-amino alcohols can be obtained as the major product due to a divergence in selectivity with different N-protecting groups.

Full text of DOI:10.1021/ol026456y

ORGANIC
LETTERS
2002
Vol. 4, No. 18
3131-3134
Directed Reduction of â-Amino Ketones
to Syn or Anti 1,3-Amino Alcohol
Derivatives
Gary E. Keck* and Anh P. Truong
Department of Chemistry, UniVersity of Utah, 315 South 1400 East RM 2020,
Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
Received July 2, 2002
ABSTRACT
The reduction of â-amino ketones with samarium(II) iodide has been investigated. Either the syn or anti 1,3-amino alcohols can be obtained
as the major product due to a divergence in selectivity with different N-protecting groups.
The development of methodology for the efficient generation
of relative stereochemistry in acyclic systems continues to
be a subject of major importance in synthetic organic chem-
istry. Recently, a protocol for the reduction of â-hydroxy
and certain â-alkoxy ketones with SmI2 was developed in
our laboratories. Anti 1,3-diols and certain anti 1,3-alkoxy
alcohols can be produced with high selectivity in this
electron-transfer reduction.1 The product-determining event
was suggested to be protonation of an intermediate samarium
carbanion in a favored conformation of a chelate formed by
complexation of a second samarium between the â-oxygen
and the carbonyl oxygen. The â-oxygen was also shown to
be responsible for a significant rate enhancement in these
reductions. We record herein the results of an investigation
of â-nitrogen substituents in such reductions. In this context,
it shou1d be noted that 1,3-amino alcohol fragments are of
interest due to their presence in several antibiotics and other
biologically active natural products.2 Thus, several reduction
methods for accessing such structures have previously been
developed.3 For example, Narasaka achieved good syn
diasteroselectivity in the LiAlH4-NaOMe reduction of
O-benzyl oximes derived from â-hydroxy ketones.4 Pilli and
co-workers have also developed a stereoselective route to
anti and syn N-aryl-â-amino alcohols via reduction with
Et3BHLi and Zn(BH4)2, respectively.5
The first set of â-amino ketones used in this study was
prepared by the sequence shown in Scheme 1. Allylation of
cyclohexylcarboxaldehyde with methallyl-tri-n-butylstannane
gave the corresponding homoallylic alcohol.6 Conversion to
the mesylate and displacement with sodium azide gave the
desired homoallylic azide 1 in 57% overall yield. Reduction
of azide 1 was accomplished with LiAlH4 in THF at 0 °C.
The resulting amine was then protected as either the
(3) Barluenga, J.; Aguilar, E.; Fustero, S.; Olano, B.; Viado, A. J. Org.
Chem. 1992, 57, 1219 and references therein.
(4) Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem. Soc. Jpn. 1986,
59, 525.
(5) (a) Pilli, R. A.; Russowsky, D.; Dias, L. C. Chem. Commun. 1987,
1053. (b) Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin
Trans. 1 1990, 1213.
(6) For an asymmetric version of this reaction, see: Keck, G. E.;
Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543.
(1) (a) Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J Org. Chem.
1999, 64, 2172. (b) Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.
(2) Nogradi, M. Stereoselective Synthesis; VCH: Wienheim, Germany,
1987; Chapters 3, 5, 6.
10.1021/ol026456y CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/03/2002

removal of the trifluoroacetate7 (K2CO3/MeOH/H2O) from
both the major (syn) and minor (anti) diastereomers of 3a
provided samples of the free amino alcohols.
Scheme 1. Preparation of N-Acyl â-Amino Ketones
These were then compared with the amino alcohols
obtained by removal of the protecting groups present in the
major diastereomers of 3b-d. In all cases, the major
diastereomer was 1,3-syn. The observed stereochemical
outcome is initially quite surprising given the anti selectivity
previously observed in reductions of both â-hydroxy and
â-alkoxy ketones under these conditions. A different class
trifluoroacetamide, acetamide, tert-butyl carbamate, or benzyl
carbamate using standard protocols. Subsequent ozonolysis
provided the corresponding N-protected amino ketones in
good yields (Scheme 1).
Each of these N-acyl-â-amino ketones (2a-d) was first
reduced with NaBH4 to afford a mixture containing roughly
equal amounts of the 1,3-syn and 1,3-anti diastereomers.
These mixtures were then used to develop an analytical
HPLC separation of the reduction products expected from
each substrate. Reductions with SmI2 were then investigated.
In a typical reaction, the ketone and 20 equiv of MeOH were
dissolved in THF and added to a freshly prepared solution
(0.1-0.5 M) of SmI2 in THF at 0 °C.
Figure 1. Structure of the major diastereomer of N-trifluoro-
acetamide 3a by X-ray analysis.
of protected â-amino ketones was also synthesized using the
methodology of Kobayashi.8 This reaction was applied
successfully to the synthesis of a number of N-aryl-â-amino
ketones (Scheme 2). Again, each of these substrates (4a-f)
The results of these experiments (Table 1) showed that
high yields and reasonable levels of stereoselectivity are
Scheme 2. Preparation of N-Aryl â-Amino Ketones
Table 1. Reduction of N-Acyl â-Amino Ketones Using
SmI2-MeOH
entry
P
time (h)
yield of 3 (%)
ratio (syn:anti)
1
2
3
4
TFA
Ac
Boc
Cbz
4.75
86
96
quant
84
90:10
89:11
81:19
84:16
was reduced with NaBH4 to secure mixtures containing
comparable amounts of the expected 1,3-syn and 1,3-anti
reduction products; these were then used to develop analytical
HPLC separations for each substrate as before.
6
4
7
Under our standard conditions, these N-aryl-â-amino
ketones were also reduced to the corresponding 1,3-amino
alcohols in excellent yield (90-99%). Stereochemical as-
signments for the products of these reactions were again
made unambiguously through use of the X-ray crystal
structure determination of 3a. This involved the removal of
obtained for the reduction of these protected â-amino
ketones. However, at this point the stereochemistry of the
products was not known.
The structure of the major diastereomer formed in these
reactions was unambiguously established by an X-ray crystal
structure determination of the major product obtained from
2a. This was followed by chemical correlation of that
material with the major products obtained from 2b-d. Thus,
(7) Boger, D. L.; Yohannes, D. J. Org. Chem. 1989, 54, 2498.
(8) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.; Wataya,
Y. J. Org. Chem. 1999, 64, 6833.
3132
Org. Lett., Vol. 4, No. 18, 2002

the o-MeOPh (catalytic amount of silver nitrate and am-
monium persulfate in aqueous CH3CN)9 or p-MeOPh (CAN
in aqueous CH3CN)10 groups from each of the reduction
products 5a-e.11 The resulting free â-amino alcohols were
then directly compared (13C NMR) to the free â-amino
alcohols that were obtained from the major (syn) and minor
(anti) diastereomers of 3a. It was found that a complete
reVersal of stereoselectiVity for the reduction occurs between
the two classes of substrates: whereas the N-acyl deriVatiVes
all reduced to afford the 1,3-syn diastereomer as the major
product, the N-aryl deriVatiVes all afforded the 1,3-anti
diastereomer as the major product.
Thus, these N-aryl â-amino ketones are reduced in the
same sense (1,3-anti diastereoselectivity) as the previously
studied â-hydroxy and â-alkoxy ketones. We suggest that
the overall mechanism is as previously proposed for those
cases. However, the present situation seems more complex
than with the oxygen series. Reductions of two N-alkyl-â-
amino ketones were examined in order to determine the
extent to which these reductions paralleled those of the
â-alkoxy ketones.
In contrast to the corresponding O-benzyl derivative, the
N-benzyl derivative was reduced but with a low level of
stereoselectivity (3.5:1). The N-methyl derivative also re-
duced, but, in contrast to previous observations in the oxygen
series, afforded a 1:1 mixture of diastereomers. Reductions
of such â-methoxy ketones in our previous study showed
very high levels of stereoselectivity; note eq 2. Although
the substituents differ in the cases shown (cyclohexyl vs
phenyl) in eqs 1 and 2, inspection of Table 2 shows that the
these reductions. In this context, reduction of substrate 4f,
which lacks any additional electron-releasing substituents on
the aryl ring other than nitrogen, leads to a somewhat lower
level of stereoselectivity than is observed with the methoxy-
substituted compounds. Moreover, since both the ortho and
para methoxy compounds are reduced with similarly high
levels of diastereoselectivity, a chelation motif involving the
nitrogen and the methoxy group itself cannot be involved
as a control element in determining the stereochemical
outcome.8,12 However, it does seem plausible based upon the
available data that complexation of the electron-rich aryl ring
by samarium may influence the stereochemical outcome of
the reduction in these cases.
At first glance, the syn stereochemistry observed in
reduction of the N-acyl derivatives would seem to preclude
a mechanism involving chelation as a control element;
however, these results are easily accommodated by such a
mechanism. Since samarium(II) is believed to be a hard
oxophilic Lewis acid,13 it is reasonable to expect that the
oxygen of the amidate, rather than the nitrogen, is involved
in initial coordination to samarium. The reduction could then
occur via the formation of an intermediate eight-membered
ring chelated structure as shown in Scheme 3. Initial
Table 2. Reduction of N-Aryl â-Amino Ketones
Scheme 3
entry
R
P
yield of 5 (%) ratio (anti:syn)
1
2
3
4
5
7
n-C3H7
C6H11
PhCHdCH o-MeOPh
n-C3H7
C6H11
o-MeOPh
o-MeOPh
95
100
90
95
98
97:3
97:3
97:3
94:6
>99:1
85:15
p-MeOPh
p-MeOPh
Ph
n-C3H7
96
level of asymmetric induction realized is relatively inde-
pendent of this substituent. Cases in which this substituent
was a phenyl group were not examined in the present study
due to the low stability of these materials toward â-elimina-
tion.
Thus N-substitution by an electron-rich aryl ring seems
to be required to realize high levels of stereoselectivity in
(9) Saito, S. S.; Hatanaka, K.; Yamamoto, H. Org. Lett. 2000, 2, 1891.
(10) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765.
(11) The stereochemistry of product 5f has not been unambiguously
established but is assumed on the basis of the results with the other N-aryl
1
compounds and the similarity of the H and 13C NMR data.
Org. Lett., Vol. 4, No. 18, 2002
3133

coordination of samarium to the oxygen of the amidate is
followed by a one-electron transfer to the carbonyl to give
III. A second equivalent of Sm(II) donates another electron
to the resulting radical leading to the samarium carbanion
IV. Finally, protonation of this anion then leads to the syn
amino alcohol V in the stereochemistry-determining step.
The syn stereochemical outcome predicted by this scheme
relies upon extrapolation of the known conformational
preferences in eight-membered carbocyclic rings14 to this case
involving samarium. The A value associated with the
substituent “R” in structure IV is known to be very large in
eight-membered ring carbocycles.
for the synthesis of 1,3-amino alcohols. High levels of
stereoselectivity and excellent yields are possible in the
reduction of N-aryl â-amino ketones, while a variety of
N-acyl derivatives are reduced in good yield and with
moderate levels of 1,3-syn stereoselectivity. One especially
attractive feature of the process is that by employing different
protecting groups, one can easily access both syn and anti
diastereomers of these â-amino alcohols.
Acknowledgment. Financial assistance provided by the
National Institutes of Health (Grant GM-28961) is gratefully
acknowledged.
In summary, the reduction of â-amino ketones using
samarium(II) iodide provides a versatile synthetic method
Supporting Information Available: Full experimental
details and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) For previous proposals of such a complexation mode in reactions
involving o-hydroxy anilines and derivatives, see: Ishitani, H.; Ueno, M.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180 and references therein.
(13) Molander, G. A. Org. React. 1994, 46, 211.
(14) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
OL026456Y
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