anti selective dihydroxylation by the ketimine derivatives of the allylic amine in monosubstituted olefins

Article abstract of DOI:10.1016/S0040-4039(02)01654-4

Transformation of the allylic amine of monosubstituted olefins into the aryl ketimine derivatives resulted in consistent higher anti diastereofacial selectivity in the osmium-catalyzed dihydroxylation reactions, compared to the selectivities obtained from commonly used allylic amino derivatives such as N-acyl, N-Boc or N,N-dibenzyl. The anti selectivity ranged from 3:1 to 7:1 in dry THF and the best was observed with the 3,3′-difluorobenzophenone ketimine derivative. Application of the ketimine group is also reported with the substrates of biological importance.

Full text of DOI:10.1016/S0040-4039(02)01654-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7209–7212
anti Selective dihydroxylation by the ketimine derivatives of the
allylic amine in monosubstituted olefins
Joon Seok Oh, Doh Yeon Park, Bu Sop Song, Jae Gwang Bae, Seung Woong Yoon and
Young Gyu Kim*
School of Chemical Engineering, College of Engineering, Seoul National University, Seoul 151-744, South Korea
Received 12 July 2002; revised 5 August 2002; accepted 8 August 2002
Abstract—Transformation of the allylic amine of monosubstituted olefins into the aryl ketimine derivatives resulted in consistent
higher anti diastereofacial selectivity in the osmium-catalyzed dihydroxylation reactions, compared to the selectivities obtained
from commonly used allylic amino derivatives such as N-acyl, N-Boc or N,N-dibenzyl. The anti selectivity ranged from 3:1 to 7:1
in dry THF and the best was observed with the 3,3%-difluorobenzophenone ketimine derivative. Application of the ketimine group
is also reported with the substrates of biological importance. © 2002 Elsevier Science Ltd. All rights reserved.
There has been considerable interest in the synthesis of
optically active amino alcohols and amino acids
because of their wide occurrence in biologically active
molecules.1 They are also widely used as chiral interme-
diates, auxiliaries or ligands in asymmetric synthesis
(Fig. 1).
reported that the anti selectivity was observed in the
dihydroxylation of the cyclic allylic amino derivatives
under the less favorable environment for the hydrogen
bonding.3 The similar results have been obtained with
both cyclic and acyclic allylic alcohols.2 However, the
mixed results have been met with the acyclic allylic
amides or carbamates that have flexible conforma-
tion.2a,4 To the best of our knowledge, few systematic
studies on asymmetric induction by allylic amino sub-
stituents in the dihydroxylation of acyclic olefins have
been performed.3b,5
Both efficient and stereoselective construction of the
amino alcohol moiety could be achieved, in principle,
by controlled osmium-catalyzed dihydroxylation reac-
tions of chiral allylic amines. The amines can be readily
prepared from one of the chirality pools, a-amino acids.
Although the diastereoselective dihydroxylation of
allylic alcohols has been well established,2 there are
only a few reports on diastereoselection in the dihy-
droxylation reactions of allylic amines. We and others
We report herein a systematic study on the diastereo-
facial selectivity of monosubstituted olefins with allylic
amino aryl ketimine derivatives.6 For the monosubsti-
tuted olefins, the common protecting groups such as
N-acyl, N-alkoxycarbonyl or N,N-dibenzyl have
resulted in mostly the poor to reversed selectivities with
several exceptions.2a,4,5,7 They have also been challeng-
ing substrates in the stereoselective reactions of olefins
such as the Sharpless asymmetric dihydroxylation or
the Jacobsen asymmetric epoxidation owing to its lower
selectivities.8 We think it is the first time to employ the
aryl ketimine group to improve the diastereofacial
selectivity in the osmium-catalyzed dihydroxylation.9a
Electronic effects by the allylic amino group can also be
examined by simply changing the substituent on the
phenyl ring of the aryl ketimines. The electronic factor
of the allylic alcohol/alkoxy group is known to affect
the facial selectivity in the dihydroxylation reactions.2,10
They are also stable to the osmylation conditions, and
relatively easy to introduce and to remove.9b
Figure 1.
* Corresponding author. Tel.: +82-2-880-8347; fax: +82-2-885-6989;
e-mail: ygkim@plaza.snu.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01654-4

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J. S. Oh et al. / Tetrahedron Letters 43 (2002) 7209–7212
Table 2. Dihydroxylation reactions of the aryl ketimines
2–10
The required allylic amine, 1-phenyl-2-propenamine,
was obtained as its hydrochloride salt 1 from cin-
namaldehyde through the [3,3]-sigmatropic rearrange-
ment of the imidate intermediate (Scheme 1).11
Preparation of the various ketimine derivatives with
different substituents in electronic property could be
achieved effectively by condensation of 1 with commer-
cially available benzophenone derivatives in the pres-
ence of TiCl4 and TEA (Table 1).12 Excess use of 1 (2
equiv.) facilitated separation of the ketimine products
2–10 from the reaction mixture.
Olefin
Diacetate
Ratio anti:syn
Yield (%)
2
3
4
5
6
7
8
9
11
12
13
14
15
16
17
18
19
3.0:1a
3.1:1b
3.3:1a
3.8:1a
3.5:1b
5.2:1a
4.8:1a
4.4:1b
4.0:1b
82
70
83
70
90
69
94
89
75
Osmium-catalyzed dihydroxylation reactions of the
ketimine derivatives were then explored under the fol-
lowing standard conditions; 1 equiv. of the ketimine
derivative, 0.1 equiv. of OsO4, 2 equiv. of NMO in dry
THF. The results are shown in Table 2. Use of the dry
solvent13 was necessary for in-situ conversion of the
diols produced into the corresponding diacetates. Oth-
erwise, an undesired cyclization reaction by one of the
hydroxyl groups with the ketimine carbon into an
oxazolidine ring complicated the analysis of the
diastereomeric ratio of the diol products.14
10
a Analysis by GC: HP 5, 30 m×0.25 mm, I.D. 0.25 mm.
b Analysis by LC: Allsphere Silica 5m, 150×4.6 mm.
observed.5,7 Specifically, the opposite syn selectivity
(anti:syn=1:1.3) was found with the N-Boc derivative
of 1. Krysan and co-workers reported also the similar
syn selectivity (anti:syn=1:1.5) with the N-Boc mono-
substituted olefin in i-PrOH.5 Therefore, the consistent
anti selectivity obtained with the ketimine derivatives in
the present study should be important for the reliable
prediction of the stereochemical outcome in the dihy-
droxylation products of monosubstituted olefins.
In Table 2, the anti selectivity is evident with all of the
ketimine derivatives used, regardless of the electronic
property of the substituents. It is also apparent that the
electron-withdrawing substituents bring about a little
higher selectivity than the electron-donating sub-
stituents. However, the degree of increase does not
match the electron-withdrawing capabilities of the sub-
stituents. The best selectivity (5.2:1) obtained with 7 is
much higher than those with the N-trichloroacetyl,
N-benzoyl, N-Boc, or N,N-dibenzyl substituted allylic
amines, for which the poor to reversed selectivities were
Use of conventional aqueous THF (1:1) instead of dry
THF as a reaction solvent resulted in slightly lower
selectivity (4.4:1) but higher yield (82%) of the same
product, compared to those of diacetate 16. The effect
of solvents on the facial selectivity has been known5,15
Scheme 1. Preparation of the model substrate 1.
Table 1. Preparation of the aryl ketimine derivatives 2–10
Olefin
X
X%
Yield (%)
2
3
4
Me
OMe
H
H
H
H
Quant.
70
98
5
6
7
F
Cl
H
H
H
F
Quant.
Quant.
73
8
9
10
H
H
Cl
CF3
NO2
NO2
53
96
Quant.
Scheme 2. Determination of the relative stereochemistry of
the diastereomers in 20.

J. S. Oh et al. / Tetrahedron Letters 43 (2002) 7209–7212
7211
other products 11–19 was confirmed by comparison of
the same HCl salts of the crude amino diols as 21 on
and was tested in several dry solvents. The similar
selectivities of about 5.2:1, 5.0:1, and 5.4:1 for the anti
isomer were achieved in toluene, CH2Cl2, and acetone,
respectively. The ratio was lower in benzene (4.1:1) and
i-PrOH (3.7:1). The solvent polarity does not seem to
have a bearing on the selectivity.
1
the H NMR spectra.
Stereodirecting results by the ketimine derivative on
some monosubstituted olefins 24–26, prepared from the
corresponding amino acids,18 are shown in Table 3. The
higher anti selectivity is clearly maintained, compared
to the corresponding N-Boc derivatives. The inherent
selectivity of the N-Boc derivative of 25 for the anti diol
isomer was 1.5:1 regardless of the osmium reagents
used; i.e. cat. OsO4/NMO, AD-mix-a, or AD-mix-b.4b
The amino diol with the same stereochemistry as that
of 28 anti was required for the preparation of the
nitrogen analogue of Saquinavir, an HIV protease
inhibitor. The N-Boc derivatives of 24 and 26 showed
the reversed (anti:syn=1:2) and no (1:1) selectivities
(1H NMR), respectively. The relative stereochemistry of
the diastereomers in each product was also confirmed
as described above for 20. It is interesting to note the
selectivity increases as the alkyl group gets bigger. The
similar results by the alkyl groups have been known,
too.4a,19
Possibility of the kinetic resolution in the in situ acetyl-
ation of the diol products seems very low. The crude
amino diol HCl salt, obtained after direct hydrolysis of
the dihydroxylation product of 7, showed similar selec-
tivity (ca. 5:1) on the 1H NMR spectrum. Use of
stoichiometric amount of OsO4 to prevent the sec-
ondary catalytic osmylation cycle did not improve the
selectivity.5,16
For determination of the relative stereochemistry of the
product, a diastereomeric mixture was transformed into
the corresponding oxazolidinone derivatives (Scheme
2). It is well known that the coupling constant (J4,5) on
1
the H NMR spectrum of a cis isomer of oxazolidinone
rings is larger than that of a trans isomer.17 The starting
diastereomeric mixture 20 with a ratio of about 2.5:1
was produced from the dihydroxylation reaction of 4 in
i-PrOH without additional water.6
In Scheme 3, a selective synthesis for a derivative of
a-hydroxystatine,20 a stable transition-state isostere for
pseudopeptide templates, is shown using the ketimine
group. Lower selectivities for the anti diol product
(1.5:1 and 2.4:1) have been reported with the N-Boc
derivative of 30 in the literature.4a,20a
The mixture was separable with column chromatogra-
phy after conversion of 20 to the N-Cbz-O-TBS pro-
tected amino diol derivative 22 via amino diol HCl salt
21. The major and the minor isomers, 22 anti and 22
syn, were isolated in 67 and 28% yield, respectively.
Each isomer was then independently cyclized to give
the corresponding 1,3-oxazolidin-2-one, 23 cis and 23
trans, respectively. The low yield for 23 cis seems to
reflect the unfavorable cyclization of 22 anti giving the
cis isomer. Measurement of the coupling constants
(J4,5) reveals that the relative stereochemistry of the
major isomer of 22 is anti (J4,5 of 23 cis=8.1 Hz) and
that of the minor isomer is syn (J4,5 of 23 trans=5.9
Hz). The larger chemical shift of both protons at C-4
and C-5 of 23 cis (lH-4 4.98 and lH-5 4.86) than that of
23 trans (lH-4 4.86 and lH-5 4.36) is another indication
of their relative stereochemistry.17 The major isomer of
The sense and trend of the selectivity in the present
study could be explained by employing the transition
state models that are advanced for the diastereoselec-
tive dihydroxylation reactions of allylic alcohols and
ethers; i.e. Kishi, Houk, and Vedejs models.21 The
transition state model in Fig. 2 is a combination of the
Houk and Vedejs models. It represents a subtle inter-
play between the steric and electronic aspects. Accord-
Table 3. Dihydroxylation reactions of the aryl ketimines
with different alkyl side chains
Scheme 3. An application of the ketimine group to a conju-
gated disubstituted E-olefin.
R
Olefin
Diacetate
Ratioa anti:syn Yield (%)
Me
PhCH2 25
Ph
i-Pr
24
27
28
16
29
3.7:1
4.6:1
5.2:1
7.0:1
68
80
69
77
7
26
Figure 2. A proposed transition state model (P=aryl
ketimine).
a Analysis by GC: HP 5, 30 m×0.25 mm, I.D. 0.25 mm.

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J. S. Oh et al. / Tetrahedron Letters 43 (2002) 7209–7212
ing to the Houk model, a deactivating substituent
would take preferentially the ‘inside’ conformer in the
absence of strong steric interaction with a double bond.
As a result, the N-inside conformer will be predomi-
nant here with the electron-deficient aryl ketimines in
the monosubstituted olefins. However, the selectivity
depends on the size of the alkyl substituents as shown
in Table 3, which cannot be explained by the Houk
model only. The Vedejs model would be suitable for the
steric effect by the alkyl groups. The severe allylic
strain, A1,2 or A1,3, between the large alkyl side chain
and the substituents on the double bond22 would
strongly disfavor the N-outside conformer.
National Meeting, Chicago, IL, Aug. 26–30, 2001,
ORGN No. 286.
7. The selectivities with N-trichloroacetamide, N-benzoyl,
N-Boc, and N,N-dibenzyl derivatives for the dihydroxyl-
ation reactions of a monosubstituted olefin in aqueous
THF were about 1:1–1.3:1. See: Yoon, S. W. M.E. The-
sis, Seoul National University, Feb. 1997.
8. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547; (b) Jacobsen, E. N.;
Wu, M. H. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 2, pp. 649–677.
9. For use of the benzophenone ketimine derivatives in the
enantioselective dihydroxylation reactions of allylamine,
see: (a) Corey, E. J.; Guzman, P. A.; Noe, M. C. J. Am.
Chem. Soc. 1995, 117, 10805–10816. For the ketimines as
a protecting group, see: (b) Greene, T. W.; Wuts, P. G.
M. Protective Groups in Organic Synthesis, 3rd ed.; John
Wiley & Sons: New York, 1999; pp. 587–590.
10. (a) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N.
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13. Poli, G. Tetrahedron Lett. 1989, 30, 7385–7388.
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Acknowledgements
This work was supported in part by Pacific Corpora-
tion, Ministry of Health and Welfare (HMP-98-D-5-
0050), and the Brain Korea 21 Project.
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