A stereoselective approach to 1,3-amino alcohols protected as cyclic carbamates: Kinetic vs. thermodynamic control

Article abstract of DOI:10.1002/ejoc.200700503

Direct enantiocontrolled access to 1,3-amino alcohols protected as cyclic carbamates is described. The approach is based on the addition of a silyl dienolate to aldehydes in the presence of 10 % of Carreira's catalyst (vinylogous Mukaiyama-aldol addition)

Full text of DOI:10.1002/ejoc.200700503

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700503
A Stereoselective Approach to 1,3-Amino Alcohols Protected as Cyclic
Carbamates: Kinetic vs. Thermodynamic Control
Garance Broustal,[a] Xavier Ariza,[b] Jean-Marc Campagne,*[c] Jordi Garcia,*[b]
Yohan Georges,[b] Angela Marinetti,[a] and Raphaël Robiette*[d]
Dedicated to Barry M. Trost on the occasion of his 65th birthday
Keywords: Palladium / Allylation / 1,5-Diols / Carbamates / Aldol reactions
Direct enantiocontrolled access to 1,3-amino alcohols pro-
tected as cyclic carbamates is described. The approach is
based on the addition of a silyl dienolate to aldehydes in the
presence of 10% of Carreira’s catalyst (vinylogous Mukai-
yama-aldol addition). The obtained δ-hydroxyesters were re-
duced to pent-2-ene-1,5-diols, which were converted into the
corresponding dicarbamates with tosyl isocyanate. Stereose-
lective cyclization of these dicarbamates proceeded with 1,3-
asymmetric induction under either thermodynamic or kinetic
control to afford enantioselectively six-membered-ring cyclic
carbamates. Calculations enabled us to rationalize the ob-
served stereoselectivity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Catalytic methods for the stereoselective formation of
new chiral centers are used extensively in organic synthe-
sis.[1] In some cases, the success of these approaches has
overcome the traditional use of chiral auxiliaries.[2] Never-
theless, transferring chirality by substrate control is proba-
bly still the most common way to create stereocenters. In
this context and as a part of a program directed at the syn-
thesis of polyols[3] and hydroxy amino acids,[4] we were in-
terested in the development of catalytic addition processes
that could generate an initial chiral center that, in turn,
could transfer its chirality to the neighboring atoms. Par-
ticularly, we focused our attention on the synthesis of 1,3-
amino alcohols and γ-hydroxy α-amino acid substructures.
Our idea for the generation of the first chiral center was
based on our experience in the catalytic and asymmetric
vinylogous Mukaiyama reactions (CAVM, Scheme 1).[5]
These types of additions have already proved to be very
effective in yielding highly enantioenriched 2-alkene-1,5-di-
ols via an α,β-unsaturated δ-lactone.[6]
Scheme 1. Catalytic asymmetric vinylogous Mukaiyama-aldol ad-
dition.
We expected these diols to react with tosyl isocyanate to
give the corresponding dicarbamates, which could be cy-
clized to 1,3-oxazinan-2-ones with 1,3-asymmetric induc-
tion (Scheme 2). Indeed, on the basis of related previous
work,[7] we anticipated that the stereochemistry of the final
product would be thermodynamically driven by equilibra-
tion through the π-allyl intermediate. If this was the case,
[a] Institut de Chimie des Substances Naturelles,
Avenue de la Terrasse, Bat. 27, 91198 Gif-Sur-Yvette, France
[b] Departament de Química Orgànica, Facultat de Química, Uni-
versitat de Barcelona,
C/Martí i Franquès 1–11, 08028 Barcelona, Spain
[c] Institut Charles Gerhardt Montpellier, UMR 5253, ENSCM,
8 Rue de l’Ecole Normale, 34296 Montpellier, France
[d] Unité de Chimie Organique et Médicinale, Université Catho-
lique de Louvain,
Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 2. Pd0 cyclization.
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J.-M. Campagne, J. Garcia, R. Robiette et al.
SHORT COMMUNICATION
the stereochemical outcome of the reaction could be de- Table 1. Conformational analysis of 1–4.[8]
duced from the relative stability of the two stereoisomers
(cis and trans).
Results and Discussion
Before embarking on the synthesis of these compounds,
our initial efforts were directed towards the determination
of the relative energy of the possible diastereoisomeric ox-
azinan-2-ones, and, hence, the prediction of the thermo-
dynamic stereoselectivity of the cyclization by computa-
tional means (DFT methods).[8] Calculations were carried
out on representative cyclized products 1–4 (Figure 1) hav-
ing an aryl or alkyl substituent at the 6-position and a
methyl group (anti) or a hydrogen atom at the 5-position.[9]
The chiral centers at the 5- and 6-positions were fixed and
the two epimers at C-4 were explored (named as cis and
trans indicating the C-4–C-6 relative configuration).
Entry R1
R2
Isomer
ΔE [kcal/
mol][a]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
iPr
iPr
iPr
iPr
H
H
Me
Me
H
H
Me
Me
cis-1
trans-1
cis-2
trans-2
cis-3
trans-3
cis-4
trans-4
2.2
4.2
3.2
6.6
2.7
2.8
1.8
4.2
[a] ΔE = E(equatorial) – E(axial)
.
the preference of the vinylic group to be in the pseudoaxial
position (vide supra), which is the case in the trans isomers
(and not in the cis ones).
Figure 1. Cyclic carbamates.
Table 2. Calculation of the trans/cis equilibrium.[8]
First, we examined the conformational equilibrium of
compounds 1–4 in either their cis or trans configuration
(Table 1). This study revealed that, in all cases, the substitu-
ent at the 6-position (Ph/iPr) prefers to be pseudoequato-
rial, especially for the trans isomers. A detailed analysis of
the structures (see Supporting Information) indicates that
the preference for this pseudoequatorial position can
mainly be accounted for by the presence of a 1,3-diaxial
interaction in the pseudoaxial conformer. A 1,3-diaxial de-
stabilizing interaction of R1 with the aromatic phenylsulfo-
nyl group is also possible.
Entry R1
R2
Product cis
trans
Predicted
[kcal/mol] [kcal/mol] trans/cis[a]
1
2
3
4
Ph
Ph
iPr
H
Me
H
1
2
3
4
1.4
0.7
0.9
0.1
0
0
0
0
91:9
76:24
80:20
54:46
iPr Me
Another important structural feature is the presence of a
stabilizing C–H···O hydrogen bond between one oxygen
atom of the sulfonyl group and the pseudo-axial vinylic
substituent (see Supporting Information) in the case of a
[a] Ratio predicted at room temp.
From the above calculations one can conclude that if
pseudoaxial positioning of this later. Additionally, in con- thermodynamically controlled the synthesis of the cyclic
formers having the vinylic substituent in a pseudoequatorial carbamates should be, in most cases, stereoselective, espe-
position a destabilizing gauche interaction is present. These cially for product 1. Therefore, the synthesis of 7 (related to
two interactions contribute to an additional relative stabili- 1) was first attempted (Scheme 3). α,β-Unsaturated lactone
zation of the conformers having the vinylic substituent in 5a was obtained by using a CAVM reaction in 70% yield
the pseudoaxial position (e.g. cis-pseudoaxial and trans- and 85%ee. Reduction of the lactone was then carried out
pseudoequatorial structures), which accounts for the larger in the presence of NaBH4/CeCl3, which led to 1,5-diol (Z)-
axial/equatorial discrimination in the case of the trans con- 6a. Treatment of the diol with an excess of tosyl isocyanate,
formers.
followed by a palladium-catalyzed Tsuji–Trost reaction,[10]
Having determined the lowest-energy conformer for each led to a clean conversion to the corresponding cyclic carb-
diastereoisomer, we investigated the trans/cis equilibrium amate in 62% yield and a 97:3 trans/cis ratio.[11] This result
(Table 2). Computed relative energies for the two diastereo- was in good agreement with the computed thermodynamic
isomers of the oxazinan-2-ones indicated a systematic selectivity (91:9 trans/cis ratio; Table 2) and thus supported
higher stability for the trans isomer (over the cis). This our hypothesis that the diastereoselectivity in the cycliza-
lower energy of the trans isomer can mainly be explained by tion was under thermodynamic control.
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An Approach to 1,3-Amino Alcohols Protected as Cyclic Carbamates
SHORT COMMUNICATION
Scheme 3. Synthesis of 7.
Scheme 5. (E)-Diols cyclization.
Encouraged by these positive preliminary results, the
syntheses of 8, 9 (possessing a chiral tertiary alcohol), and
10 were next investigated (Scheme 4). α,β-Unsaturated lac-
tones 5b–d were obtained in good yields and enantio-
selectivities from the corresponding aldehydes (or ketones)
and were next reduced to 1,5-diols (Z)-6b–d. Cyclizations
were carried out in the presence of Pd2(dba)3·CHCl3 to give
cyclic carbamates 8, 9, and 10 in 79, 96, and 72% yield,
respectively. Once again stereoselectivities were in good
agreement with calculations, resulting in a 80:20, Ͼ99:1,
and 63:37,[12] trans/cis ratio, respectively.[11]
As shown, cyclization of 1,5-diol (E)-6d gave a higher
trans/cis ratio than the corresponding (Z)-6d isomer (79:21
vs. 63:37), but closer to the predicted (by calculations)
thermodynamic selectivity (80:20). This result either indi-
cates that cyclization of (Z)-6d was mainly ruled by kinetic
control or that the 66 h reaction time was not sufficient to
reach thermodynamic equilibrium. Thus, we decided to
monitor the cyclization–isomerization process of (Z)-6d and
1
(E)-6d in [D8]THF by H NMR spectroscopy (Figure 2).
As shown, the (E) diol gave a high trans ratio immediately,
whereas the (Z) isomer initially gave the cis isomer, but it
then isomerized into the trans isomer very slowly (it took
145 h to reach the equilibrium and gave a 82:18 trans/cis
ratio). This experiment thus demonstrated that the kinetic
product in the cyclization of (Z) diols was the cis isomer
but that equilibration occurred under reaction conditions
leading to the more stable isomer; the trans cyclic carb-
amate. In the case of (E) diol cyclizations, the trans oxaz-
inan-2-ones appeared to be both the kinetic and thermo-
dynamic product.
Scheme 4. Synthesis of cyclic carbamates 8–10.
To obtain further evidence in support of the thermo-
dynamic control of the trans/cis ratio, the cyclization of ra-
cemic 1,5-diols (E)-6a and (E)-6d was next investigated. In-
deed, because an (E)- or (Z)-allylic system initially gener-
ates different π-allyl intermediates, which would lead to dif-
ferent carbamates, an influence of the stereochemistry of
the olefin on the kinetic selectivity should be expected.
Figure 2. Monitoring of the cyclization–isomerization process of
the (E)-6d and (Z)-6d isomers.
The above experiment suggested that, in certain cases,
Diols (E)-6a and (E)-6d were obtained in two steps by the control of the final relative stereochemistry could be
using a racemic TBAT-mediated vinylogous Mukaiyama re- achieved under kinetic conditions, leading to the cis isomer.
action followed by DIBAL-H reduction.[5d] The cyclization The requirements should be fast cyclization to the cis iso-
of the diols with the use of the TsNCO diprotection–Pd- mer and slow cis-to-trans isomerization. We anticipated that
cyclization sequence gave cyclic carbamates (rac)-7 and a good candidate would be a (Z)-1,5-diol with a large group
(rac)-10 in a Ͼ99:1 and 79:21 trans/cis ratio, respectively at C-6 and a methyl group at C-5, which would hinder the
(Scheme 5).
isomerization.
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J.-M. Campagne, J. Garcia, R. Robiette et al.
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Keeping this idea in mind, we prepared lactone 12 as a cleavage of the terminal double bond of 14, followed by the
single diastereoisomer by starting from enantiomerically esterification of the corresponding carboxylic acid, led to
pure TBDPS-protected Roche’s aldehyde 11 in 60% yield the protected γ-hydroxy-α-amino acid 15 in a (nonopti-
(Scheme 6). Reduction of the lactone to 1,5-diol 13, fol- mized) yield of 50%.
lowed by the protection–cyclization sequence led to cyclized
product 14 in 56% yield and a deserving 99:1 cis/trans ra-
tio.[11,13]
Conclusions
Cyclic carbamates 7–10 can be easily obtained by a three-
step process: (1) CAVM stereoselective addition of a silyl
dienolate to aldehydes (or ketones), (2) reduction of the ob-
tained lactone to a pent-2-ene-1,5-diol, and (3) dicarbamate
formation followed by an in situ Pd0-mediated cyclization.
These types of cyclizations seemed to be thermodynami-
cally controlled under the used cyclization conditions, lead-
ing selectively to the trans cyclic carbamates. Nevertheless,
it was possible to slow down the isomerization process that
leads to the thermodynamic stereoisomer in some sterically
crowded substrates such as carbamate 14 and, therefore, the
kinetic stereoisomer (cis) can be isolated.
Experimental Section
Scheme 6. Carbamate 14.
Typical Procedure for the Pd-Catalyzed Cyclization of 1,5-Diols: p-
The high cis selectivity (99:1) observed in the first place
Toluenesulfonyl isocyanate (92.4 μL, 0.61 mmol, 2.5 equiv.) was
in the case of 14 can thus be accounted for by: (1) a low
added to a solution of diol 6 (0.24 mmol, 1 equiv.) in anhydrous
thermodynamic discrimination between the two isomers
THF (1.2 mL) under an atmosphere of N2 at room temp. When
(see calculations: Table 2, Entry 4) and (2) a large decrease
in the rate of the equilibration reaction. This decrease in
rate may well be due to the increase in sterics in the proxim-
ity of the double bond; in the pseudoequatorial conformer
(the more stable one), the methyl indeed hinders one face
of the double bond, whereas the tosyl group hinders the
other one (see Figure 3 for the structure of 4, which is
closely related to 14).
the reaction was complete (TLC monitoring), the catalyst solution
was added by cannula. This catalyst solution was prepared by add-
ing (iPrO)3P (21.4 μL, 87.2 μmol, 0.36 equiv.) to (dba)3Pd2·CHCl3
(15 mg, 14.5 μmol) in anhydrous THF (1.2 mL) and stirring at
room temp. for 90 min. until a yellow color was obtained. The reac-
tion mixture was stirred at room temp. for 24 h. The solvent was
removed, and the residue was purified by flash column chromatog-
raphy (heptane/EtOAc) to give the corresponding cyclic carb-
amates.
Supporting Information (see footnote on the first page of this arti-
cle): Full computational details, optimized cartesian coordinates,
and corresponding energies for all species discussed in the text, and
characterizations for cyclized compounds 8, 9, 10, 14, and 15.
Acknowledgments
This work has been supported by the Ministerio de Ciencia y Tec-
nologia (BQU2003-01269, BCTQ2006-13249, and HF2004-0049),
the UCL (FSR), the FRS-FNRS (FRFC project no. 2.4502.05),
and the CNRS. R. R. is a Chargé de recherches FNRS. We thank
the Generalitat de Catalunya for a doctorate studentship to Y. G.
We thank the ICSN for a doctorate studentship to G. B.
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[3] a) Y. Georges, Y. Allenbach, X. Ariza, J.-M. Campagne, J. Gar-
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Figure 3. Lowest energy conformer of 4.
Finally, in a desire to explore the development of new
compounds with antidiabetic properties and structurally re-
lated to 4-hydroxyisoleucine,[14] we envisaged the conversion
of the protected amino alcohol 14 into the protected γ-hy-
droxy-α-amino acid 15 (Scheme 6). Thus, an oxidative
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An Approach to 1,3-Amino Alcohols Protected as Cyclic Carbamates
SHORT COMMUNICATION
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and the single-point calculations by using the Jaguar 6.5 pro-
gram package (Jaguar 6.5, Schrödinger, LLC, New York, NY,
2005). Relative energies correspond to electronic energies. See
Supporting Information for full computational details.
[9] The systematic positioning of the methyl at the 5-position and
the substituent at the 6-position in the trans relative configura-
tion was based on previous results showing that the Mukai-
yama-aldol addition occurs with high anti selectivity (see
ref.[5]).
[10] J. Tsuji, Palladium Reagents and Catalyst, Wiley & Sons, New
York, 2004, pp. 431–517.
[11] The cis/trans configurational assignments of the diastereoiso-
mers were achieved by 2D NOESY spectroscopic experiments.
[12] The reaction of 6d was quenched after 66 h at room temp.
[13] When compound 14 with a 99:1 cis/trans ratio was resubmitted
to equilibration conditions [Pd2(dba)3, (iPrO)3P in THF under
reflux], a 70:30 cis/trans mixture was recovered. A longer reac-
tion time generated significant amounts of decomposition
products.
[14] V. Rolland-Fulcrand, M. Rolland, M.-L. Roumestant, J. Marti-
nez, Eur. J. Org. Chem. 2004, 873–877 and references cited
therein.
Received: May 31, 2007
Published Online: July 19, 2007
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