Highly enantioselective synthesis of β-amino alcohols: A catalytic version

Article abstract of DOI:10.1021/jo071028x

(Chemical Equation Presented) Highly enantioselective rearrangement of β-amino alcohols was realized by using a catalytic amount of trifluoroacetic anhydride.

Full text of DOI:10.1021/jo071028x

Highly Enantioselective Synthesis of â-Amino Alcohols: A Catalytic
Version
Thomas-Xavier Me´tro, Domingo Gomez Pardo,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI-ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
domingo.gomez-pardo@espci.fr; janine.cossy@espci.fr
ReceiVed May 16, 2007
Highly enantioselective rearrangement of â-amino alcohols was realized by using a catalytic amount of
trifluoroacetic anhydride.
Introduction
sulfonates) has allowed the introduction of carbon,10-12
nitrogen,5a,c,11,12 oxygen,5a,13,14 phosphorus,5a,15 and sulfur5a,12,16
nucleophiles with anchimeric participation of the neighboring
nitrogen atom. As far as we know, these rearrangements always
need stoechiometric quantities of the reagents.
Recently, we have reported that prolinols of type A can be
rearranged stereoselectively to give optically active piperidin-
3-ols of type B via an aziridinium intermediate by using
(CF3CO)2O (1,5 equiv) and Et3N (3 equiv) followed by the addi-
tion of NaOH (8 equiv).17,18 When these conditions were applied
to linear optically active â-amino alcohols of type C, the latter
were rearranged to give â-amino alcohols of type D in a very
regio-, stereo-, and enantioselective process (Scheme 1).19
Amino alcohols are present in a large variety of naturally
occurring and pharmacologically active molecules,1 and the
relative stereochemistry of the hydroxy and amino groups is
highly important for the biological activity of these molecules.
Amino alcohols have also been used extensively in asymmetric
synthesis, both as chiral ligands and auxiliaries.2
Linear N,N-dialkyl-â-amino alcohols have been shown to
rearrange, via an aziridinium ion, into â-halogeno-amines on
treatment with SOCl2,3 SOBr2,4 MsCl,5 TsCl,5b CBr4/PPh3,6
Ph3PCl2,7 Ph3PBr2,7 DAST,8 or Deoxofluor.9 Transforming the
alcohol moiety into a good leaving group (such as halides or
(1) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576 and references
therein.
(2) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-
875.
(3) (a) Brode, W. R.; Hill, M. W. J. Am. Chem. Soc. 1947, 69, 724. (b)
Back, T. G.; Parvez, M.; Zhai, H. J. Org. Chem. 2003, 68, 9389-9393. (c)
Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2004, 45, 3725-3728.
(d) Sivaprakasam, M.; Couty, F.; Evano, G.; Srinivas, B.; Sridhar, R.; Rama
Rao, K. Synlett 2006, 5, 781-785.
(4) Nagle, A. S.; Salvatore, R. N.; Chong, B.-D.; Jung, K. W. Tetrahedron
Lett. 2000, 41, 3011-3014.
(10) Schultz, E. M.; Sprague, J. M. J. Am. Chem. Soc. 1948, 70, 48-
52.
(11) Gmeiner, P.; Junge, D.; Kaertner, A. J. Org. Chem. 1994, 59, 6766-
6776.
(12) Couturier, C.; Blanchet, J.; Schlama, T.; Zhu, J. Org. Lett. 2006, 8,
2183-2186.
(13) Bach, F. L.; Cohen, E. Chem. Commun. (London) 1968, 415-416.
(14) Okuda, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4585-4586.
(15) Dahlenburg, L.; Goetz, R. Eur. J. Inorg. Chem. 2004, 888-905.
(16) Jimeno, C.; Moyano, A.; Pericas, M. A.; Riera, A. Synlett 2001,
1155-1157.
(17) For comprehensive reviews, see: (a) Cossy, J.; Gomez Pardo, D.
Chemtracts 2002, 15, 579-605. (b) Cossy, J.; Gomez Pardo, D. Targets
Heterocycl. Syst. 2002, 6, 1-26.
(18) (a) Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur. J. Org. Chem.
1999, 1693-1699. (b) Brandi, A.; Cicchi, S.; Paschetta, V.; Gomez Pardo,
D.; Cossy, J. Tetrahedron Lett. 2002, 43, 9357-9359. (c) De´champs, I.;
Gomez Pardo, D.; Karoyan, P.; Cossy, J. Synlett 2005, 1170-1172. (d)
Mena, M.; Bonjoch, J.; Gomez Pardo, D.; Cossy, J. J. Org. Chem. 2006,
71, 5930-5935. (e) Roudeau, R.; Gomez Pardo, D.; Cossy, J. Tetrahedron
2006, 62, 2388-2394 and references therein. (f) De´champs, I.; Gomez
Pardo, D.; Cossy, J. ArkiVoc 2007, V, 38-45.
(5) (a) Dieter, R. K.; Deo, N.; Lagu, B.; Dieter, J. W. J. Org. Chem.
1992, 57, 1663-1671. (b) Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett.
2000, 2, 647-649. (c) Frizzle, M. J.; Caille, S.; Marshall, T. L.; McRae,
K.; Nadeau, K.; Guo, G.; Wu, S.; Martinelli, M. J.; Moniz, G. A. Org.
Proc. Res. DeV. 2007, 11, 215-222.
(6) Lehmann, T.; Hu¨bner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett.
2001, 11, 2863-2866.
(7) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama, K. J.
Org. Chem. 1999, 64, 7323-7329.
(8) Hook, D. F.; Gessier, F.; Noti, C.; Kast, P.; Seebach, D. ChemBio-
Chem 2004, 5, 691-706.
(9) Ye, C.; Shreeve, J. M. J. Fluorine Chem. 2004, 125, 1869-1872.
10.1021/jo071028x CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/21/2007
6556
J. Org. Chem. 2007, 72, 6556-6561

EnantioselectiVe Synthesis of â-Amino Alcohols
SCHEME 1. â-Amino Alcohol Rearrangement
SCHEME 3. Synthesis of Starting Amino Alcohols
SCHEME 2. Mechanism of Rearrangement
SCHEME 4. Rearrangement of Amino Alcohol 2a
The mechanism that we have postulated for this rearrange-
ment implies the formation of an aziridinium intermediate G,
which is formed from the ammonium trifluoroacetate E via the
aminoester F after treatment with Et3N (Scheme 2). As a
trifluoroacetate anion is liberated into the reaction media, this
anion can attack the more substituted carbon atom of the
aziridinium G, producing the aminoester H, which after
saponification leads to the rearranged â-amino alcohol D.
The synthesis of compounds 2d, 2e, and 2g-i was achieved
from the commercially available amino alcohols 1d, 1e, and
1g-i by bis N-benzylation using benzyl bromide (2.2 equiv) in
the presence of K2CO3 (3.0 equiv) and n-tetrabutylammonium
iodide (0.3 equiv) in refluxing acetonitrile.19 Compounds 2b,
2c, 2f, and prolinol 2j are commercially available and 2k was
prepared from trans-4-hydroxy-L-proline 1k (Scheme 3).18e
When compound 2a, in a THF solution, was treated under
the usual conditions, e.g., with 1.1 equiv of (CF3CO)2O for 15
min, then with Et3N (2.0 equiv) and heated at 100 °C under
microwave irradiation (MW) for 6 h, followed by addition of
NaOH (3.75 N), 3a was obtained in 61% yield and the starting
material was totally consumed (Scheme 4).
If the previously proposed mechanism intervened in the
rearrangement, a mixture of the two trifluoroacetates 2a′ and
2a′′ would be expected as a result of the two primary hydroxy
groups esterification of compound 2a with 1.1 equiv of (CF3-
CO)2O (Scheme 5). Upon heating, trifluoroacetate 2a′ will
rearrange into trifluoroacetate 3a′, whereas trifluoroacetate 2a′′
will form aziridinium 3a′′. Opening of this aziridinium 3a′′ by
a trifluoroacetate anion cannot lead directly to the rearranged
Results and Discussion
Here we report a catalytic version of this rearrangement by
using only 0.2 equiv of (CF3CO)2O followed by the addition
of NaOH (0.3 equiv). We have to point out that when using
(CF3CO)2O in catalytic quantities, Et3N is not necessary for
the rearrangement to proceed.
Amino diol 2a was prepared from the commercially available
amino alcohol 1a, which after reductive amination with ben-
zaldehyde led to the corresponding N-benzylamine 1a′ (PhCHO,
CH2Cl2, molecular sieves 4 Å, then NaBH4, 81% yield). After
treatment with methylbromoacetate (2.0 equiv) in the presence
of K2CO3 (3.0 equiv) in THF at room temperature for 48 h, the
crude material was directly engaged in the reduction with
LiAlH4 (1.3 equiv, THF, 2 h, rt) to furnish 2a (62% yield).
(19) Me´tro, T.-X.; Appenzeller, J.; Gomez Pardo, D.; Cossy, J. Org. Lett.
2006, 8, 3509-3512.
J. Org. Chem, Vol. 72, No. 17, 2007 6557

Me´tro et al.
SCHEME 5. Proposed Mechanism for Rearrangement of Amino Alcohol 2a
SCHEME 6. Rearrangement of Amino Alcohol 2b under
Catalytic Conditions
[(CF3CO)2O (0.2 equiv), THF, 180 °C, 2 h, MW then NaOH
(3.75 N; 0.3 equiv), rt, 1 h], the yields and the enantiomeric
excess for the rearranged â-amino alcohols were good to
excellent. We have to point out that for compounds 2e, 2h, 2i,
and 2k the rearrangement was performed at 100 °C for 18 h
(50 h for compound 2k) in order to prevent partial decomposi-
tion obtained at higher temperatures. In the case of the cyclic
compounds 2j and 2k, the 3-hydroxypiperidines 3j and 3k were
formed under the catalytic conditions in good to excellent yield
and good enantiomeric excess.
The (R) absolute configuration was established for compounds
3b,20 3c21 and 3f20 by comparison of the [R]D reported in the
literature. The (S) absolute configuration of 3h22 was determined
by comparison of the [R]D of the (S)-N,N-2-dibenzylamino-1-
phenylethanol synthesized from the commercially available (S)-
2-amino-1-phenylethanol by bis N-benzylation (BnBr, K2CO3,
CH3CN, reflux, 4 h), and the (S) absolute configuration of
compound 3g was established by application of the modified
Mosher method.23 The relative configuration of the two hydroxy
groups in diol 3i was determined by chemical correlation. The
racemic allylic alcohol (()-4 was treated by TBHP (1.5 equiv)
and VO(acac)2 (0.3 equiv) in CH2Cl2 during 18 h at room
temperature (Scheme 7), and a mixture of the two diastereoi-
somers (()-5 and (()-6 was isolated in 65% yield with a
diastereomeric ratio of 5/1.24 The two diastereoisomers (()-5
and (()-6 were then treated with dibenzylamine (3.0 equiv) in
acetonitrile at 100 °C during 10 h under microwave irradiation
and aminodiol (()-3i was synthesized in 64% yield. As this
aminoester 3a′ but only to the starting aminoester 2a′′. As the
starting amino alcohol 2a is totally consumed during the
reaction, it seems reasonable to have an equilibrium between
2a′ and 2a′′ due to an intramolecular transesterification. The
displacement of the equilibrium will be due to the formation of
the more stable amino ester 3a′, which will release the
rearranged amino alcohol 3a after saponification.
If an intermolecular transesterification can take place between
the rearranged aminoester and the starting amino alcohol, the
rearrangement could be induced by a catalytic amount of
(CF3CO)2O only. Thus, amino alcohol 2b was treated with
(CF3CO)2O (0.2 equiv) and Et3N (0.8 equiv) in THF at 180 °C
for 2 h under microwave irradiation. After addition of an
aqueous NaOH solution, 3b was isolated in 98% yield with an
enantiomeric excess of 99% (Scheme 6). It is worth noting that
the yield in 3b and its enantiomeric excess were very similar
to those obtained by using 3 equiv of (CF3CO)2O and 4 equiv
of Et3N (99% yield, 99% ee).19 Furthermore, by using catalytic
amounts of (CF3CO)2O the presence of Et3N in the reaction
media is not necessary, as the treatment of 2b with only 0.2
equiv of (CF3CO)2O (THF, 180 °C, 2 h, MW) followed by
saponification with NaOH led to 3b with similar yield and
enantiomeric excess (98%, 99% ee) (Scheme 6).
1
latter aminodiol had H and 13C NMR spectra identical with
those of the aminodiol obtained by rearrangement of compound
2i, the anti configuration of the two hydroxy groups in 3i has
been confirmed.
(20) Schwerdtfeger, J.; Kolczewski, S.; Weber, B.; Fro¨hlich, R.; Hoppe,
D. Synthesis 1999, 9, 1573-1592.
(21) Koppenhoefer, B.; Trettin, U.; Wa¨chtler, A. Synthesis 1994, 12,
1141-1142.
(22) Shibata, T.; Takahashi, T.; Konishi, T.; Soai, K. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2458-2460.
The reaction is general, and the results are reported in
Table 1. For comparison, the results obtained under stoechio-
metric conditions have been indicated in brackets.19 When
compounds 2b-k were submitted to the catalytic conditions
(23) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Tetrahedron: Asymmetry 2001,
12, 2915-2925.
(24) Dittmer, D. C.; Zhang, Y.; Discordia, R. P. J. Org. Chem. 1994,
59, 1004-1010.
6558 J. Org. Chem., Vol. 72, No. 17, 2007

EnantioselectiVe Synthesis of â-Amino Alcohols
TABLE 1. Rearrangement under Catalytic versus Stoechiometric Conditions
a Catalytic conditions. b Stoechiometric conditions. c CF3(CO)2O (3.0 equiv), Et3N (4.0 equiv), reflux, 37 h. d CF3(CO)2O (1.1 equiv), Et3N (2.0 equiv).
The formation of 3b from 2b under catalytic conditions
without any Et3N can be explained by the formation of a
catalytic amount of the ammonium trifluoroacetate ester 7b,
which can be deprotonated by any amines of type Bn2NR
present in the reaction media (R being either -CH(CH3)CH2-
OH, -CH(CH3)CH2OCOCF3, -CH2CH(CH3)OH, or -CH2CH-
J. Org. Chem, Vol. 72, No. 17, 2007 6559

Me´tro et al.
SCHEME 7. Synthesis of (()-3i
catalytic amount of 10b will be saponified by NaOH to furnish
the rearranged â-amino alcohol 3b. Because of the high
enantiomeric excess observed in the rearrangement, it is un-
likely that the reaction proceeds via a planar carbocation
intermediate.
Conclusion
We have shown that, when treated with a catalytic amount
of (CF3CO)2O, linear N,N-dialkyl â-amino alcohols of type C
and N-alkylated substituted prolinols of type A can be rearranged
into â-amino alcohols of type D and 3-hydroxypiperidines of
type B, respectively, with high yield and excellent enantiomeric
excess. Further studies using the rearranged â-amino alcohols
in the synthesis of pharmacologically active products are
currently under investigation.
Experimental Section
SCHEME 8. Supposed Mechanism for Rearrangement of
General Method A. To a solution of the N,N-dibenzylamino
alcohols 2a-k (1 mmol, 1.0 equiv) in THF (2 mL) cooled at 0 °C
was added dropwise trifluoroacetic anhydride (212 µL, 1.5 mmol,
1.5 equiv). After 20 min of stirring at room temperature, Et3N (212
µL, 2 mmol, 2.0 equiv) was added. The reaction mixture was then
heated at 100 °C during 2 h under microwave irradiation. After addi-
tion of an aqueous 3.75 M NaOH solution (2 mL), the mixture was
stirred at room temperature for 2 h, extracted with EtOAc, dried
over MgSO4, filtered, and concentrated in vacuo. Purification of
the residue by flash chromatography (silica gel, n-pentane/AcOEt)
afforded the corresponding N,N-dibenzylamino alcohols 3a-k.
General Method B. To a solution of the N,N-dibenzylamino al-
cohols 2b-k (1 mmol, 1.0 equiv) in THF (1.5 mL) at room tempera-
ture was added trifluoroacetic anhydride (28 µL, 0.2 mmol, 0.2
equiv). The reaction mixture was then heated at 180 °C during 2 h
under microwave irradiation or at 100 °C in a sealed tube placed
in an oil bath until the reaction was finished. After addition of an
aqueous 3.75 M NaOH solution (10 µL, 0.3 equiv), the mixture was
stirred at room temperature for 2 h, extracted with EtOAc, dried
over MgSO4, filtered, and concentrated in vacuo. Purification of
the residue by flash chromatography (silica gel, n-pentane/AcOEt)
afforded the corresponding N,N-dibenzylamino alcohols 3b-k.
(R)-1-[Benzyl-(2-hydroxyethyl)-amino]-3-phenylpropan-2-
ol (3a). CH2Cl2/MeOH 90/10; 61% yield [Method A with (CF3-
CO)2O (1.1 equiv), Et3N (2.0 equiv), THF, 100 °C, 6 h, MW];
yellow oil; C18H23NO2; MW ) 285.38 g mol-1; [R]20D ) -59.9 (c
1.0, CHCl3); IR (neat) 3500-3100, 3026, 3000-2500, 1601, 1494,
1452, 1027, 736, 697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31-
7.14 (10H), 3.88 (m, 1H), 3.76 (d, J ) 13.6 Hz, 1H), 3.63-3.50
(3H), 2.94 (bs, 2H), 2.78-2.48 (6H); 13C NMR (100 MHz, CDCl3)
δ 138.5 (s), 138.3 (s), 129.3 (d), 129.0 (d), 128.5 (d), 128.4 (d),
127.3 (d), 126.4 (d), 69.5 (d), 60.1 (t), 59.8 (t), 59.6 (t), 56.3 (t),
41.5 (t); HRMS (ESI) calcd for C18H24NO2 (M + H+) 286.1801,
found 286.1804.
â-Amino Alcohol 2b under Catalytic Conditions
(CH3)OCOCF3) (Scheme 8). An SN2 intramolecular substitution
by the N,N-dialkylamine functionnality of 8b can form the
aziridinium 9b, liberating a trifluoroacetate anion in the reaction
media. The latter anion could attack the more substituted carbon
atom of the aziridinium 9b, producing the amino ester 10b
according to a SN2 substitution. An intermolecular transesteri-
fication between the amino alcohol 2b and the amino ester 10b
can take place to form the â-amino alcohol 3b and the amino
ester 8b, which will be again transformed into the aziridinium
9b. By analogy with the work of Gmeiner,11 we assume that
compounds 8b and 10b are in equilibrium. Moreover, because
the species 2b, 3b, 8b, and 10b engaged in the transesterifi-
cation are also in equilibrium, we believe both the rearranged
amino alcohol 3b and the aminoester 10b are the thermo-
dynamic products. At the end of the reaction the resulting
(R)-1-N,N-Dibenzylaminopropan-2-ol (3b).20 Petroleum ether/
AcOEt 95/5; 99% yield (method A), 98% yield (method B); yellow
oil; C17H21NO; MW ) 255.35 g mol-1; [R]20 ) -92.2 (c 1,
D
CHCl3) [lit.20 [R]20D ) +99.4 (c 2, CHCl3) for S isomer]; IR (neat)
3433, 3027, 2967, 2931, 2801, 1494, 1452, 1372, 1248, 1056, 736,
697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.23 (10H), 3.89-
3.80 (3H), 3.40 (d, J ) 13.5 Hz, 2H), 3.24 (bs, 1H), 2.41 (d, J )
6.6 Hz, 2H), 1.05 (d, J ) 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 138.6 (s), 129.1 (d), 128.5 (d), 127.3 (d), 63.2 (d), 61.4 (t), 58.5
(t), 19.9 (q); MS-EI m/z (%) 255 (M+•, 1), 210 (83), 91 (100); 99%
ee (SFC, Daicel chiralcel OD-H, 100 bar of CO2, 5% MeOH, 8
mL/min, λ ) 220 nm, tR (major) ) 1.5 min, tR (minor) )
1.7 min).
(R)-1-(N,N-Dibenzylamino)-3-methyl-2-butanol (3c).21 Hexane/
AcOEt 90/10); 88% yield (method A), 93% yield (method B);
6560 J. Org. Chem., Vol. 72, No. 17, 2007

EnantioselectiVe Synthesis of â-Amino Alcohols
yellow oil; C19H25NO; MW ) 283.41 g mol-1; [R]20D ) -26.6 (c
0.5, MeOH) [lit.21 [R]20D ) +24.5 (c 1, MeOH) for S isomer]; IR
(neat) 3448, 3028, 2957, 2930, 2872, 2803, 1576, 1495, 1452, 1368,
309 (1), 252 (1), 210 (81), 181 (5), 107 (12), 91 (100); 99% ee
(SFC, Daicel chiralcel OD-H, 100 bar of CO2, 20% MeOH, 8 mL/
min, λ ) 220 nm, tR (major) ) 1.46 min, tR (minor) ) 1.94 min).
(S) isomer was determined by application of the modified Mosher
method;23 HRMS (CI+, CH4) calcd for C24H28NO2 (M + H+)
362.2120, found 362.2123.
1
1246, 1069, 967, 872, 746, 735, 697 cm-1; H NMR (400 MHz,
CDCl3) δ 7.35-7.23 (10H), 3.88 (d, J ) 13.4 Hz, 2H), 3.52 (bs,
1H), 3.43 (ddd, J ) 10.8, 6.4, 4.4 Hz, 1H), 3.36 (d, J ) 13.4 Hz,
2H), 2.46 (m, 2H), 1.51 (m, 1H), 0.90 (d, J ) 6.6 Hz, 3H), 0.82
(d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.4 (s),
129.1 (d), 128.4 (d), 127.3 (d), 71.5 (d), 58.3 (t), 57.1 (t), 32.3 (d)
18.4 (q), 18.3 (q); MS-EI m/z (%) 283 (M+•, 0.4), 240 (3), 210
(100), 181 (8), 118 (3), 91 (99); 99% ee (SFC, Daicel chiralcel
OD-H, 100 bar of CO2, 5% MeOH, 8 mL/min, λ ) 220 nm, tR
(major) ) 1.2 min, tR (minor) ) 1.4 min).
(S)-2-N,N-Dibenzylamino-1-phenylethanol (3h).22 Hexane/
AcOEt 95/5); 93% yield (method A), 78% yield (method B);
colorless oil; C22H23NO; MW ) 317.42 g mol-1; [R]20D ) +138.2
(c 0.95, CHCl3); IR (neat) 3427, 3027, 2834, 1494, 1452, 1026,
1
746, 696 cm-1; H NMR (400 MHz, CDCl3) δ 7.37-7.21 (15H),
4.71 (t, J ) 6.9 Hz, 1H), 3.92 (d, J ) 13.4 Hz, 2H), 3.79 (bs, 1H),
3.48 (d, J ) 13.4 Hz, 2H), 2.64 (d, J ) 6.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 142.1 (s), 138.3 (s), 129.1 (d), 128.5 (d),
128.3 (d), 127.4 (d), 127.3 (d), 125.9 (d), 69.6 (d), 61.9 (t), 58.4
(t); MS-EI m/z (%) 299 (M+• - H2O, 7), 210 (44), 106 (41), 91
(100), 77 (30); 99% ee (SFC, Daicel chiralcel OD-H, 100 bar of
CO2, 20% MeOH, 8 mL/min, λ ) 220 nm, tR (minor) ) 1.5 min,
tR (major) ) 2.1 min).
(R)-1-(N,N-Dibenzylamino)-4-methylpentan-2-ol (3d). Hexane/
AcOEt 95/5); 82% yield (method A), 89% yield (method B);
colorless oil; C20H27NO; MW ) 297.43 g mol-1; [R]20 ) -59.8
D
(c 1, CHCl3); IR (neat) 3400-3200, 3028, 2951, 2802, 1494, 1453,
1367, 1293, 1121, 1071, 1028, 975, 914, 882, 839, 735, 697 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (10H), 3.85 (d, J ) 13.4
Hz, 2H), 3.74 (m, 1H), 3.68 (d, J ) 13.4 Hz, 2H), 3.27 (bs, 1H),
2.45-2.37 (2H), 1.77 (m, 1H), 1.27 (ddd, J ) 13.9, 8.6, 5.6 Hz,
1H), 1.03 (ddd, J ) 13.5, 8.6, 4.0 Hz, 1H), 0.89 (d, J ) 5.2 Hz, 3H),
0.87 (d, J ) 5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.6
(s), 129.1 (d), 128.5 (d), 127.3 (d), 65.0 (d), 60.4 (t), 58.6 (t), 43.9
(t), 24.7 (d), 23.5 (q), 22.3 (q); MS-EI m/z (%) 297 (M+•, 0.2), 210
(100), 181 (7), 118 (4), 91 (79). Anal. Calcd for C20H27NO: C,
80.76; H, 9.15; N, 4.71. Found: C, 80.64; H, 8.88; N, 4.65.
(R)-1-N,N-Dibenzylamino-3,3-dimethylbutan-2-ol (3e).19 Hex-
ane/AcOEt 80/20); 99% yield (method A), 74% yield (method B);
yellow oil; C20H27NO; MW ) 297.43 g mol-1; [R]20D ) -85.4 (c
0.5, CHCl3); IR (neat) 3440, 3027, 2954, 1574, 1450, 1365, 1241,
(1R,2S)-3-(N,N)-Dibenzylamino-1-phenyl-1,2-propanediol (3i).19
CH2Cl2/MeOH 99/1); 66% yield (method A), 83% yield (method
B); yellow oil; C23H25NO2; MW ) 347.45 g mol-1; [R]20D ) -84.0
(c 0.3, CHCl3); IR (neat) 3387, 3028, 2839, 1494, 1452, 1064, 1027,
1
733, 697 cm-1; H NMR (400 MHz, CDCl3) δ 7.35-7.23 (15H),
4.62 (d, J ) 5.6 Hz, 1H), 3.82-3.75 (2H), 3.61 (d, J ) 13.2 Hz,
2H), 3.56 (d, J ) 13.2 Hz, 2H), 2.73 (dd, J ) 12.8 Hz, J ) 8.0
Hz, 1H), 2.46 (dd, J ) 12.9 Hz, J ) 5.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 140.1 (s), 137.9 (s), 129.3 (d), 128.6 (d), 128.4
(d), 127.7 (d), 127.5 (d), 126.4 (d), 76.3 (d), 70.1 (d), 58.9 (t),
53.7 (t); 99% ee (SFC, Daicel chiralcel OD-H, 100 bar of CO2,
20% MeOH, 5 mL/min, λ ) 220 nm, tR (major) ) 2.7 min, tR
(minor) ) 3.4 min); HRMS (CI+, CH4) calcd for C23H26NO2 (M
+ H+) 348.1964, found 348.1966.
1
1086, 973, 747, 730, 697 cm-1; H NMR (400 MHz, CDCl3) δ
7.37-7.23 (10H), 3.90 (d, J ) 13.4 Hz, 2H), 3.40 (dd, J ) 10.6,
3.3 Hz, 1H), 3.35 (d, J ) 13.4 Hz, 2H), 2.46 (m, 2H), 0.80 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 138.3 (s), 129.2 (d), 128.3
(d), 127.3 (d), 73.5 (d), 58.2 (t), 54.2 (t), 33.5 (s), 25.7 (q); MS-EI
m/z (%) 297 (M+•, 0.3), 282 (1), 240 (5), 210 (100), 181 (8), 91
(94); 99% ee (SFC, Daicel chiralcel OD-H, 100 bar of CO2, 2%
MeOH, 2 mL/min, λ ) 220 nm, tR (major) ) 9.6 min, tR (minor)
) 10.1 min); HRMS (CI+, CH4) calcd for C20H28NO (M + H+)
298.2171, found 298.2174.
(R)-1-Benzylpiperidin-3-ol (3j).18a n-Pentane/AcOEt 50/50; 63%
yield (method A), 87% yield (method B); yellow oil; C12H17NO;
MW ) 191.27 g mol-1; [R]20D ) -12.8 (c 1.0, MeOH); IR (neat)
3322, 2935, 2858, 2795, 1494, 1453, 1368, 1347, 1296, 1153, 1100,
1
1059, 1025, 972, 737, 798 cm-1; H NMR (400 MHz, CDCl3) δ
7.34-7.21 (5H), 3.80 (dddd, J ) 4.3, 4.3, 4.3, 4.3 Hz, 1H), 3.50
(s, 2H), 2.66-2.38 (4H), 2.26 (m, 1H), 1.78 (m, 1H), 1.65-1.46
(3H); 13C NMR (100 MHz, CDCl3) δ 138.2 (s), 129.1 (d), 128.3
(d), 127.1 (d), 66.3 (d), 63.0 (t), 60.3 (t), 53.5 (t), 31.8 (t), 21.7 (t);
MS-EI m/z (%): 191 (M+•, 31), 190 (18), 146 (10), 134 (22), 114
(18), 100 (36), 92 (11), 91 (100), 65 (11).
(R)-1-N,N-Dibenzylamino-3-phenylpropan-2-ol (3f).20 Hexane/
AcOEt 98/2; 97% yield (method A), 87% yield (method B);
colorless oil; C23H25NO; MW ) 331.45 g mol-1; [R]20 ) -87.4
D
(c 0.5, CHCl3) [lit.20 [R]20 ) +26.1 (c 1, CHCl3) 50% ee for S
(3R,5R)-1-Benzyl-5-(tert-butyldimethylsilanyloxy)-piperidin-
D
3-ol (3k).18e CH2Cl2/MeOH 95/5; 82% yield (method A), 61% yield
isomer]; IR (neat) 3438, 3026, 2803, 1494, 1453, 1370, 1246, 1072,
(method B); yellow oil; C18H31NO2Si; MW ) 321.53 g mol-1
;
1
1028, 735, 696 cm-1; H NMR (400 MHz, CDCl3) δ 7.33-7.15
[R]20 ) +24.6 (c 0.5, EtOH) [lit.18e [R]20 ) +25.3 (c 1.75,
D
D
(15H), 3.93 (m, 1H), 3.80 (d, J ) 13.4 Hz, 2H), 3.39 (d, J ) 13.5
Hz, 2H), 3.28 (bs, 1H), 2.72 (dd, J ) 13.6, 7.2 Hz, 1H), 2.58 (dd,
J ) 13.6, 5.7 Hz, 1H), 2.47 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 138.5 (s), 138.4 (s), 129.2 (d), 129.1 (d), 128.4 (d), 128.3 (d),
127.3 (d), 126.2 (d), 68.3 (d), 59.2 (t), 58.4 (t), 41.2 (t); MS-EI
m/z (%) 331 (M+•, 0.5), 328 (5), 210 (75), 181 (5), 120 (5), 106
(5), 91 (100); 99% ee (SFC, Daicel chiralcel OD-H, 100 bar of
CO2, 10% MeOH, 8 mL/min, λ ) 220 nm, tR (major) ) 2.0 min,
tR (minor) ) 2.3 min). (R) isomer was determined by application
of the modified Mosher method.23
EtOH)]; IR (neat) 3450, 1460, 1250, 1150, 1090, 840, 775, 740,
1
700 cm-1; H NMR (400 MHz, CDCl3) δ 7.37-7.24 (5H), 4.05
(h, J ) 4.8 Hz, 1H), 3.96 (m, 1H), 3.63 (d, J ) 13.2 Hz, 1H), 3.53
(d, J ) 13.2 Hz, 1H), 2.90 (m, 1H), 2.75 (m, 1H), 2.50 (bs, 1H),
2.19 (dd, J ) 11.4, 1.8 Hz, 1H), 2.09 (m, 1H), 1.97 (dd, J ) 10.1,
10.1 Hz, 1H), 1.38 (ddd, J ) 13.0, 10.3, 2.6 Hz, 1H), 0.88 (s, 9H),
0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 137.8
(s), 128.9 (d), 128.3 (d), 127.2 (d), 66.0 (d), 65.3 (d), 62.3 (t), 61.2
(t), 58.6 (t), 40.9 (t), 25.8 (q), 18.1 (s), -4.7 (q), -4.8 (q); MS-EI
m/z (%) 321 (M+•, 5), 264 (39), 246 (7), 134 (23), 120 (10), 101
(10), 91 (100), 73 (11).
(S)-1-N,N-Dibenzylamino-3-O-benzyl-2,3-propanediol (3g).19
Hexane/AcOEt 95/5; 76% yield (method A), 96% yield (method
B); yellow oil; C24H27NO2; MW ) 361.48 g mol-1; [R]20D ) -37.1
(c 0.7, CHCl3); IR (neat) 3429, 3027, 2854, 1494, 1452, 1365, 1250,
1100, 1027, 735, 696 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38-
7.22 (15H), 4.49 (s, 2H), 3.93 (m, 1H), 3.75 (d, J ) 13.5 Hz, 2H),
3.49 (d, J ) 13.5 Hz, 2H), 3.45 (dd, J ) 9.9 Hz, J ) 4.2 Hz, 1H),
3.38 (dd, J ) 9.9 Hz, J ) 5.9 Hz, 1H), 3.14 (bs, 1H), 2.59 (dd, J
) 12.8 Hz, J ) 8.6 Hz, 1H), 2.54 (dd, J ) 12.8 Hz, J ) 4.7 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 138.7 (s), 138.2 (s), 129.1
(d), 128.5 (d), 128.4 (d), 127.7 (d), 127.6 (d), 127.2 (d), 73.4 (t),
72.6 (t), 67.2 (d), 58.6 (t), 56.3 (t); MS-EI m/z (%) 361 (M+•, 0.1),
Acknowledgment. Sanofi-Aventis is greatly acknowledged
for financial support (grant to T.-X.M.)
Supporting Information Available: Experimental procedures
and characterization of the products 1a′, 2a, 2d, 2e, 2g, 2h, 2i, and
the corresponding mandelic esters 11a, 11b, 12a, and 12b from
amino alcohols 3f and 3g. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO071028X
J. Org. Chem, Vol. 72, No. 17, 2007 6561