Modular amino alcohol ligands containing bulky alkyl groups as chiral controllers for Et2Zn addition to aldehydes: Illustration of a design principle

Article abstract of DOI:10.1021/jo034007l

A new family of enantiomerically pure (1S,2R)-1-alkyl-2-(dialkylamino)-3-(R-oxy)-1-propanols containing a very bulky alkyl substituent (tert-butyl or 1-adamantyl) on their hydrocarbon chains has been synthesized from the corresponding enantiopure epoxy alcohols, arising from the catalytic Sharpless epoxidation, by protection of the primary hydroxy group and subsequent regioselective ring opening of the epoxide by a secondary cyclic amine (C-2 attack). The performance of these amino alcohols as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehyde has been studied, with enantioselectivities of 92-96% being recorded. The best performing ligands, those with a bulky R-oxy group, also depict a convenient activity and selectivity profile in the addition of Et₂Zn to a representative family of aldehydes. An anomalous structure/enantioselectivity relationship of some ligands in the tert-butyl series has been studied using PM3 calculations, and conclusions have been drawn on the possible effects of including in modular designs structural fragments giving rise to a variety of rotameric transition states.

Full text of DOI:10.1021/jo034007l

Mod u la r Am in o Alcoh ol Liga n d s Con ta in in g Bu lk y Alk yl Gr ou p s
a s Ch ir a l Con tr oller s for Et2Zn Ad d ition to Ald eh yd es: Illu str a tion
of a Design P r in cip le
Ciril J imeno, Mireia Pasto´, Antoni Riera, and Miquel A. Perica`s*
Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB), Departament de Quı´mica Orga`nica/ Parc Cientı´fic
de Barcelona, Universitat de Barcelona, C/ J osep Samitier, 1-5, E08028 Barcelona, Spain
mapericas@pcb.ub.es
Received J anuary 3, 2003
A new family of enantiomerically pure (1S,2R)-1-alkyl-2-(dialkylamino)-3-(R-oxy)-1-propanols
containing a very bulky alkyl substituent (tert-butyl or 1-adamantyl) on their hydrocarbon chains
has been synthesized from the corresponding enantiopure epoxy alcohols, arising from the catalytic
Sharpless epoxidation, by protection of the primary hydroxy group and subsequent regioselective
ring opening of the epoxide by a secondary cyclic amine (C-2 attack). The performance of these
amino alcohols as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehyde
has been studied, with enantioselectivities of 92-96% being recorded. The best performing ligands,
those with a bulky R-oxy group, also depict a convenient activity and selectivity profile in the
addition of Et2Zn to a representative family of aldehydes. An anomalous structure/enantioselectivity
relationship of some ligands in the tert-butyl series has been studied using PM3 calculations, and
conclusions have been drawn on the possible effects of including in modular designs structural
fragments giving rise to a variety of rotameric transition states.
In tr od u ction
of these ligands is their modular construction and, thus,
the easy modification of their structures at any step of
the synthesis. This characteristic is important for the
fine-tuning of the catalytic activity and for a deeper
understanding of the structural effects in the addition
reaction outcome.
Addition of organometallic reagents to carbonyl com-
pounds is one of the most common and fundamental
reactions for the formation of carbon-carbon bonds.1 In
particular, the amino alcohol-catalyzed dialkylzinc ad-
dition to aldehydes has been extensively studied, allowing
the preparation of chiral secondary alcohols in high
enantiomeric purities.2 Furthermore, this reaction has
become a classical test when designing new ligands for
asymmetric catalysis.
Chiral â-amino alcohols are often prepared from the
corresponding R-amino acids or from other natural
products such as ephedrine. However, enantiomerically
pure amino alcohols of synthetic origin are becoming
increasingly important. In the past few years, we have
reported the synthesis of three new families of â-amino
alcohols through the regioselective and stereospecific ring
opening of epoxides arising from the Sharpless3 (1)4 and
J acobsen5 (2 and 3)6 epoxidations. The main advantage
In all these families of amino alcohols, aryl groups are
important structural elements: not only do they direct
the ring opening of the precursor epoxides but probably
their π-systems participate in important interactions in
the catalysis event.
Besides ligands where aromatic systems are important
structural elements (for instance, those derived from
ephedrine, taddol, and 1,1′-binaphthyl) an alternative,
rather successful approach to catalytic ligands has relied
on the use as stereodifferentiating elements of simple yet
bulky alkyl groups, like isopropyl (as in the case of valine)
or tert-butyl (as in the case of tert-leucine). In the absence
(1) (a) Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.;
J ohn Wiley & Sons: New York, 1994; pp 255-297. (b) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 46-49. (c) Soai,
K. Chem. Rev. 1992, 92, 833-856.
(2) For some leading references, see: (a) Pu, L.; Yu, H.-B. Chem.
Rev. 2001, 101, 757-824. (b) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; J ohn Wiley & Sons: New York, 1994; pp 255-297.
(3) For reviews, see: (a) Katsuki, T.; Mart´ın, V. S. Org. React. 1996,
48, 1. (b) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publisher: New York, 1993; pp 101-
158.
(5) J acobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH Publisher: New York, 1993; pp 159-202.
(4) (a) Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. J . Org.
Chem. 1997, 62, 4970-4982. (b) Vidal-Ferran, A.; Moyano, A.; Perica`s,
M. A.; Riera, A. Tetrahedron Lett. 1997, 38, 8773-8776. (c) Puigjaner,
C.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. J . Org. Chem.
1999, 64, 7902-7911.
(6) (a) Sola`, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Perica`s,
M. A.; Riera, A.; AÄ lvarez-Larena, A.; Piniella, J . F. J . Org. Chem. 1998,
63, 7078-7082. (b) Reddy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.;
Riera, A. J . Org. Chem. 1999, 64, 3969-3974. (c) Reddy, K. S.; Sola`,
L.; Moyano, A.; Perica`s, M. A.; Riera, A. Synthesis 2000, 165-176.
10.1021/jo034007l CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/18/2003
3130
J . Org. Chem. 2003, 68, 3130-3138

Modular Amino Alcohol Ligands
SCHEME 1
of π-systems, the action mode of these groups in directing
reactivity should be mostly,7 or even exclusively, of steric
nature.8
To see whether this approach could also be applied to
amino alcohol ligands arising from the ring opening of
synthetic epoxides, we decided to prepare epoxy alcohols
incorporating a bulky, tertiary group as a substituent of
the oxirane ring and submit them to the ring opening/
protection sequences already used for the preparation of
1. In this case, however, precedents due to Crotti9
indicate that the ring-opening process would take place
at the less hindered position, C2, leading to amino
alcohols of type 4.
SCHEME 2
We report here how amino alcohols 4 can be efficiently
prepared following the same strategies that were applied
to the synthesis of family 14 (ring opening plus selective
primary hydroxyl protection, or otherwise, initial hy-
droxyl protection followed by epoxide opening) by simply
changing the nature of the starting epoxide. The ligands
synthesized in this manner have been successfully opti-
mized and applied to the highly enantioselective dieth-
ylzinc addition to aldehydes, completing the study of the
catalytic activity of all four regioisomeric families of
â-amino alcohols (1-4).
carbaldehyde, respectively. This last aldehyde was ob-
tained in 72% overall yield, starting from commercial
1-(adamantyl)carboxylic acid, by reduction to the corre-
sponding alcohol with LiAlH410 and subsequent selective
oxidation using bleach in the presence of TEMPO.11 Both
aldehydes were subjected to the highly stereoselective
Wadsworth-Horner-Emmons olefination followed by
reduction with DIBALH (Scheme 1). In both cases, this
procedure is amenable to a multigram scale and takes
place with good overall yield.
Both allyl alcohols were epoxidized under catalytic
Sharpless conditions (Scheme 2), and the corresponding
epoxy alcohols (5a 12and 6a ) were isolated in 90 and 80%
yields, respectively. The enantiomeric excess of 5a was
96% according to the DSC (Differential Scanning Calo-
rimetry)13 of its trityl derivative (5d ), and the enantio-
meric excess of 6a was 94% determined by HPLC of its
acetyl derivative.14 Since epoxy alcohol 6a is a crystalline
solid, its ee could be raised to 98% after one recrystalli-
zation from hexanes.
For the selective protection of the primary hydroxyl
group (Scheme 3), epoxy alcohols 5a and 6a were
subjected to a variety of protection schemes that have
been summarized in Table 1.
For the regioselective and stereospecific ring opening
of epoxides with secondary amines, Crotti’s procedure,9
which involves the use of 5-10 M LiClO4 in acetonitrile,
was selected. Compounds 11a -e and 12a -c, where the
nitrogen atom in the dialkylamino residue is a part of a
Resu lts a n d Discu ssion
The starting epoxy alcohols were chosen taking into
account the results obtained by Crotti in the lithium
perchlorate-induced regioselective ring opening of ep-
oxides.9 Racemic O-benzyl epoxy alcohols usually react
at the C3 position under Crotti’s conditions, except when
very bulky substituents (i.e., tert-butyl) are bonded to that
carbon. In this case, harder reaction conditions are
needed and the ring opening takes place at the less
hindered position, C2.9c With these precedents in mind,
we chose 3-tert-butylepoxypropanol 5a and 3-(1-adaman-
tyl)epoxypropanol 6a , which looked suitable for our
purposes. (E)-3-tert-Butyl-2-propen-1-ol (9) and (E)-3-(1-
adamantyl)-2-propen-1-ol (10), the substrates for Sharp-
less epoxidation, were prepared starting from commer-
cially available pivalaldehyde and from 1-(adamantyl)-
(7) The importance of steric effects in the diarylhydroxymethyl group
present in many successful ligands has been stressed: Braun, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 519-522.
(8) For a recent example, see: Nugent, W. A. Org. Lett. 2002, 4,
2133.
(9) (a) Chini, M.; Crotti, P.; Macchia, F. J . Org. Chem. 1991, 56,
5939-5942. (b) Chini, M.; Crotti, P.; Flippin, L. A.; Macchia, F. J . Org.
Chem. 1991, 56, 7043-7048. (c) For the regioselective ring opening of
some racemic epoxyethers with different nucleophiles, see: Chini, M.;
Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.; Macchia, F.; Pineschi,
M. J . Org. Chem. 1993, 58, 1221-1227. (d) Calvani, F.; Crotti, P.;
Gardelli, C.; Pineschi, M. Tetrahedron 1994, 50, 12999-13022. (e)
Colombini, M.; Crotti, P.; Di Bussolo, V.; Favero, L.; Gardelli, C.;
Macchia, F.; Pineschi, M. Tetrahedron 1995, 51, 8089-8112. (f) Azzena,
F.; Calvani, F.; Crotti, P.; Gardelli, C.; Macchia, F.; Pineschi, M.
Tetrahedron 1995, 51, 10601-10626.
(10) Della, E. W.; Pigou, P. E. J . Am. Chem. Soc. 1984, 106, 1085-
1092.
(11) Anelli, P. L.; Biffi, C. B.; Montanari, F.; Quici, S. J . Org. Chem.
1987, 52, 2559.
(12) (a) Schweiter, M. J .; Sharpless, K. B. Tetrahedron Lett. 1985,
26, 2543-2546. (b) Konoike, T.; Hayashi, T.; Araki, Y. Tetrahedron:
Asymmetry 1994, 5, 1559-1566.
(13) Enantiomers, Racemates and Resolutions; J acques, J ., Collet,
A., Wilen, S. H., Eds.; J ohn Wiley & Sons: New York, 1981; pp 151-
159.
(14) Racemic epoxide was acetylated under standard conditions.
Conditions of its HPLC analysis: Chiralcel-OD column, 25 cm, eluent
) hexane/propan-2-ol (99:1); flow rate ) 0.3 mL/min; tR of enantiomers
) 25 and 28 min.
J . Org. Chem, Vol. 68, No. 8, 2003 3131

J imeno et al.
SCHEME 3
SCHEME 5
TABLE 1. P r otection of 5a a n d 6a w ith R 3X Rea gen ts
epoxy
alcohol
yield
(%)
reaction conditions
R3
epoxyether
SCHEME 6
5a
5a
5a
6a
6a
NaH, CH3I, DMF
Me
Bn
Tr
Me
Bn
5b
5c
5d
6b
6c
90
99
66
99
92
NaH, PhCH2Br, DMF
(Ph3C-pyr)BF4, CH3CN
NaH, CH3I, DMF
NaH, PhCH2Br, DMF
TABLE 2. Lith iu m P er ch lor a te-In d u ced Rin g Op en in g
of Ep oxid es w ith Secon d a r y Am in es
yield
(%)
SCHEME 7
epoxide
R
amine
product
5a
5b
5c
5d
5c
6a
6b
6c
H
piperidine
piperidine
piperidine
piperidine
pyrrolidine
piperidine
piperidine
piperidine
11a
11b
11c
11d
11e
12a
12b
12c
86
56
85
0a
99
98
77
70
Me
Bn
Tr
Bn
H
Me
Bn
TABLE 3. Scr een in g of Liga n d s in th e Ca ta lytic
En a n tioselective Ad d ition of Dieth ylzin c to
Ben za ld eh yd e
a
Recovery of 5d ) 95%.
conversiona
(%)
selectivityb
(%)
eec
(%)
SCHEME 4
entry
ligand
1
2
3
4
5
6
7
8
9
11a
11b
11c
11d
11e
11f
12a
12b
12c
12d
48
71
65
>99
30
>99
21
30
39
>99
95
>99
99
99
96
99
70
96
97
48 (S)
94 (S)
88 (S)
95 (S)
49 (S)
92 (S)
5 (S)
15 (S)
35 (S)
96 (S)
ring, were selected as targets bearing in mind the
excellent catalytic results provided by this type of amino
residue in ligand 1.4a,b The results of these reactions have
been summarized in Table 2. With trilylated epoxy
alcohol 5d , no reaction was detected at all, probably due
to its important hindrance at both oxirane carbons.
Methylated epoxy alcohol 5b reacted poorly with piperi-
dine, barely giving a 56% yield of the corresponding
â-amino alcohol 11b. Even though the reaction was
carried out in a sealed pressure tube, its high volatility
may have been crucial for the observed yield decrease.
To prepare â-amino alcohols with bulky protecting
hydroxy groups, a different strategy was envisaged.
Epoxy alcohols 5a and 6a were first submitted to the
regioselective ring opening by a secondary amine, and
the resulting amino diols 11a and 12a , respectively, were
then protected. For the introduction of the trityl group,
the best reaction conditions involved the use of 1.1 equiv
of N-(triphenylmethyl)pyridinium tetrafluororborate in
acetonitrile at room temperature (Scheme 5). The tert-
butyldimethylsilyl ether 11f was prepared in 82% yield
under standard conditions (Scheme 6).
10
98
a
Determined by integration of residual 13a in front of all new
b
products in the gas chromatogram of the reaction crude. Deter-
mined by integration of 14a (both enantiomers) in front of all new
products in the gas chromatogram of the reaction crude. c Deter-
mined by GC on a â-DEX 120 column.
0 °C for 5 h, using a 5% molar amount of ligand and 2
equiv of 1 M diethylzinc solution in hexanes (Scheme 7).
Results on the catalyst efficiency (conversion and selec-
tivity) and the enantiomeric excess of the resulting (S)-
1-phenylpropanol have been collected in Table 3. As we
had previously disclosed for the regioisomeric amino
alcohols 1,4 a bulky protecting group (R3) at the primary
hydroxyl is needed to achieve an efficient process. When
ligands containing a tert-butyl group (11a -f) were used,
an increase in the conversion as well as in the enanti-
oselectivity was observed when the size of the primary
hydroxyl protecting group was increased (entries 1-4 and
6 in Table 3). However, the O-benzylated ligand 11c
(15) For some recent work, see: (a) Kang, J .; Lee, J . W.; Kim, J . I.
J . Chem. Soc., Chem. Commun. 1994, 2009-2010. (b) Kang, J .; Kim,
D. S.; Kim, J . I. Synlett 1994, 842-844. (c) Qiu, J .; Guo, C.; Zhang, X.
J . Org. Chem. 1997, 62, 2665-2668. (d) Zhang, F. Y.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 3651-3655. (e) Huang, W. S.; Hu,
Q. S.; Pu, L. J . Org. Chem. 1998, 63, 1364-1365.
As an initial estimate of their performance, amino
alcohols 11 and 12 were tested as ligands in the enan-
tioselective addition of diethylzinc to benzaldeyde (13a )
in toluene solution.15 All experiments were performed at
3132 J . Org. Chem., Vol. 68, No. 8, 2003

Modular Amino Alcohol Ligands
TABLE 4. Ad d ition s of Dieth ylzin c to Sever a l Ald eh yd es Usin g 5 Mol % 11d or 12d
ligand 11d
ligand 12d
selectivityb
conversiona
(%)
selectivityb
(%)
eec
(%)
conversiona
(%)
eec
(%)
entry
starting aldehyde
benzaldehyde (13a )
p-tolualdehyde (13b)
m-tolualdehyde (13c)
o-tolualdehyde (13e)
1-naphthaldehyde (13f)
n-heptanal (13g)
(E)-R-methylcinnamaldehyde (13h )
(%)
1
2
3
4
5
6
7
>99
>99
99
99
99
98
96
95
94
96
92
>99
98
98
96
97
99
99
97
99
95
94
95
84
99
99
98
98
72
96
87
99
96
a
b
Determined by integration of residual 13 in front of all new products in the gas chromatogram of the reaction crude. Determined by
integration of 14 (both enantiomers) in front of all new products in the gas chromatogram of the reaction crude. c Determined by GC on
a â-DEX 120 column.
carbon supporting the hydroxyl group on the ligand.17 It
SCHEME 8
is also necessary to point out that the ligands used were
not completely enantiopure, since (2S,3S)-3-tert-butyl-2,3-
epoxypropanol (5a ) was a liquid of 96% enantiomeric
purity; all of its derived amino alcohols, 11a -f, were oils
as well, and none of them could be recrystallized to
increase their ee. Catalysts containing the 1-adamantyl
group, 12a -d , had 98% enantiomeric purities (the same
as the starting epoxy alcohol) since it was not possible
to recrystallize any of them. In this sense, and bearing
in mind that the bulky nature of the catalyst should
probably reduce the importance of the nonlinear effects18
operating in the studied reaction, enantioselectivities
recorded with the optimal ligands are within the limit of
the catalysts.
As already mentioned, modular design is important in
catalysis since it allows the separate optimization of
molecular fragments and, in successful cases, the ap-
plication of optimized molecular modules to new families
of ligands. In our work on the design of enantiopure,
stereodefined 3-aryl-1-alkoxy-3-amino-2-propanols as mul-
tipurpose ligands, we have repeatedly observed that both
enantioselectivity and catalytic activity increase with the
steric bulk of the 1-alkoxy module. This is the case for
the diethylzinc addition to aldehydes4 and imines,19 the
transfer hydrogenation of ketones,20 and the asymmetric
allylic alkylation21 (via the derived bis-oxazolines), and
in this way, the use of bulky alkoxy groups in these
ligands has become a design principle among us.
When we analyze the results obtained with ligands
12a -d , it is evident that the forementioned principle
fully applies: the highest catalytic activity and enantio-
selectivity are recorded with 12d . However, as indicated
above, this principle breaks for the family of ligands
11b-d , where either the most or the least bulky sub-
stituents (methyl in 11b and trityl in 11d ) lead to better
results than a substituent of intermediate bulk like
benzyloxy (in 11c). To justify this apparently odd behav-
ior, we decided to perform a theoretical study of the
showed a slightly odd result (entry 3) since the resulting
ee (88%) is lower than that obtained by the O-methylated
ligand 11b (entry 2), which offers the second highest ee
(94%) in this group of ligands, or the O-tritylated ligand
11d (entry 4, 95% ee), which is the optimal one. As in
the previously studied family of amino alcohols 1,4 the
ligand containing the pyrrolidinyl module (11e) did not
provide particularly good results (entry 5).
When ligands containing the 1-adamantyl group were
tested (entries 7-10), the previously mentioned effect of
the steric hindrance of R3 was even clearer; all three
studied parameters (conversion, selectivity, and ee) in-
crease with the size of the protecting group. Catalyst 12d
eventually afforded (S)-1-phenyl-1-propanol in excellent
yield and 96% ee, the highest detected among all of the
new compounds.
The best performing ligands resulting from this pre-
liminary screening, 11d and 12d , were subsequently
employed to induce enantioselective addition of dieth-
ylzinc to a representative family of aromatic aldehydes
(13b-f) (Scheme 8and Table 4). The enantiomeric purity
of the resulting (S)-alcohols (14b-f) was quite high in
most of the cases. As previously described,15c,e o-tolu-
aldehyde and 1-naphthaldehyde, the more congested
substrates, tend to experience dialkylzinc addition with
comparatively lower enantioselectivity than other aro-
matic substrates.16 The reaction of one aliphatic aldehyde
13g showed poor enantioselectivity. Finally, we tested
the addition to an R,â-unsaturated aldehyde, R-methyl-
cinnamaldehyde, and gratifyingly enough, for both ligands
the enantiomeric purity of the resulting alcohol was very
high.
(16) Interestingly, ligand families 2 and 3 are complementary in this
respect (see ref 6)
(17) See ref 1a, pp 265-266.
(18) Recent review: (a) Girard, C.; Kagan, H. B. Angew. Chem., Int.
Ed. 1998, 37, 2922. (b) Buono, F.; Walsh, P. J .; Blackmond, D. G. J .
Am. Chem. Soc. 2002, 124, 13653.
(19) J imeno, C.; Readdy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.;
Riera, A. Org. Lett. 2000, 2, 3157.
(20) Pasto´, M.; Riera, A.; Perica`s, M. A. Eur. J . Org. Chem. 2002,
2337-2341.
(21) Perica`s, M. A.; Puigjaner, C.; Riera, A.; Vidal-Ferran, A.; Go´mez,
M.; J ime´nez, F.; Muller, G.; Rocamora, M. Chem. Eur. J . 2002, 8, 18.
It is noteworthy that all these â-amino alcohols follow
Noyori’s empirical rule on the dependence of the sense
of enantioselectivity on the absolute configuration of the
J . Org. Chem, Vol. 68, No. 8, 2003 3133

J imeno et al.
TABLE 6. Rela tive En er gies (k ca l/m ol) w ith Resp ect to
th e Mor e Sta ble Con for m er of th e a n ti-(R) a n d a n ti-(S)
Tr a n sition Sta tes for Liga n d 11c
anti-(S)
anti-(R)
conformer 1 (tube)
conformer 2 (ball and wire)
conformer 3 (wire)
0
2.844
1.82
0
0.222
0.533
(anti-(S) for all of them) and the next lowest energy TS
(anti-(R) for 11b, anti-(R) for 11c, and syn-(R) for 11d ),
the better the observed enantioselectivity. Very interest-
ingly, the present calculations succeed in predicting that
both 11b and 11d are better ligands than 11c (R ) Bn).
In Figure 2 we present for ligands 11b-d the opti-
mized structures of the most stable diastereomeric
transition states (anti-(S)) in the addition process sepa-
rately and in superimposed form.24 A closer inspection
evidences an important geometric characteristic at the
level of the OR protecting group that could explain the
different energetic gaps that we have obtained for every
ligand. In this sense, despite the long distance between
the alkoxy group and the site where the bond-forming
process takes place (more than 8 Å), the OR protecting
group represents a structural element of the ligand
located in a stereoinducing region spatially congruent
with the site of chemistry.25
Ligand 11c shows a fundamental difference from
ligands 11b and 11d : whereas for the latter ligands no
isomerism arises from the rotation of the alkoxy group,
in the case of 11c, up to three accessible conformations
must be considered. Thus, in 11c the benzyl group may
rotate to avoid unfavorable steric interactions between
the phenyl and the tert-butyl group or the piperidinyl
ring, and it is the most stable conformation arising from
this process, which has to be considered (Figure 3). In so
doing, we found that the rotation of the benzyl group in
the anti-(S) TS structures gives rise to energy differences
of 0.53 kcal/mol, while in the anti-(R) TS structures, the
energetic differences between the most and the least
stable conformer are much more important and are up
to 2.84 kcal/mol (Table 6).
We have present in Scheme 9 the calculated energy
differences between transition states, which are respon-
sible for the enantioselectivity in reactions mediated by
11b and 11c. It is most interesting to observe that the
energy differences originated by the rotation of the benzyl
group can exert a dramatic influence on enantioselectiv-
ity. Thus, depending on rotamer transition state avail-
ability, the energy gap responsible for the enantioselec-
tivity could range from 6.92 to 10.30 kcal/mol in 11c
(compare with 8.11 kcal/mol in the case of 11b). There-
fore, even though the benzyl protecting group is bulkier
than methyl, ligand 11c is not so selective due to the
conformational flexibility of the benzyl group, which
provides a mechanism for energy relaxation and modu-
late the energies of the TSs.
F IGURE 1. Diastereomeric transition states for the dieth-
ylzinc addition to benzaldehyde mediated by ligands 11b-d .
TABLE 5. Rela tive En er gies (k ca l/m ol) of th e Most
Sta ble Con for m er s of th e Dia ster eom er ic Tr a n sition
Sta tes w ith Liga n d s 11b-d
R:Me, 11b
R:Bn, 11c
R:Tr, 11d
anti-(S)
anti-(R)
syn-(S)
syn-(R)
0
0
0
8.114
12.897
8.655
7.455
not found
8.059
13.462
13.222
11.461
geometries and relative energies of the diastereomeric
transition states involved in the diethylzinc addition to
benzaldehyde promoted by 11b-d .
The stereochemical outcome of the reaction could be
explained considering the relative energies of the four
diastereomeric transition states (anti-(S), syn-(S), anti-
(R), syn-(R)) despicted in Figure 1, which according to
the pioneering work of Noyori22 should be those deter-
mining the enantioselectivity of the reaction.
The geometries and relative energies of these four
species were calculated at the PM3 level23 (Table 5),
which in previous instances has been shown to provide
satisfactory results for the considered chemistry. In all
cases, conformational isomerism arising from both the
inversion of the piperidinyl ring and the rotation of the
transferred ethyl group was thoroughly investigated. This
leads to a maximum of six conformers for each diaster-
eomeric TS. In addition, rotation of the benzyl group was
also investigated in all TSs involving ligand 11c, leading
to a maximum of 18 conformational isomers for each basic
TS.
In so doing, we were pleased to find that the sense of
enantioselectivity induced by the three ligands 11b-d
was correctly predicted (anti-(S) is the most favorable TS
in all cases), and for every ligand the predicted gap
between the TSs for S and R attacks is in reasonable
agreement with the observed ee of the resulting alcohols.
In effect, comparing the TS energies makes it clear that
the bigger the energy gap between the most stable TS
Thus, the present theoretical study shows that confor-
mationally flexible ligands give rise to rotameric TSs that
(24) For a similar superimposition analysis of TSs in the fenchone-
based catalysts in dialkylzinc additions to benzaldehyde, see: Goldfuss,
B.; Steigelmann, M.; Rominger, F. Eur. J . Org. Chem. 2000, 1785-
1792.
(25) Lipkowitz, K. B.; D’Hue, C. A.; Sakamoto, T.; Stack, J . N. J .
Am. Chem. Soc. 2002, 124, 14255.
(22) Yamakawa, M.; Noyori, R. J . Am. Chem. Soc. 1995, 117, 6327-
6335.
(23) (a) Goldfuss, B.; Houk, K. N. J . Org. Chem. 1998, 63, 8998. (b)
Goldfuss, B.; Steigelmann, M.; Khan, S. I.; Houk, K. N. J . Org. Chem.
2000, 65, 77.
3134 J . Org. Chem., Vol. 68, No. 8, 2003

Modular Amino Alcohol Ligands
F IGURE 2. (a) anti-(S) TS for 11b. (b) anti-(S) TS for 11c. (c) anti-(S) TS for 11d . (d) Superposition of the anti-(S) TSs for
11b-d (hydrogen atoms have been omitted for clarity; N ) blue, O ) red, Zn ) green).
SCHEME 9. Rep r esen ta tion of th e Con for m er TS
En er gies
amines allows a variation of steric/electronic character-
istics that is key to the fine-tuning of catalytic properties.
Two optimized ligands, 11d and 12d , offer particular
potential, allowing us to perform the enantioselective
addition of Et2Zn to aromatic aldehydes with very high
ees.
On the other hand, the theoretical analysis of the
addition of diethylzinc to benzaldehyde mediated by
ligands 11b-d provides an excellent explanation for the
observed enantioselectivities and rules in favor of a
cautious use of conformationally flexible ligand fragments
that might diminish the energetic gap between the TSs
that determine the enantioselectivity of the catalytic
process. This observation represents an important warn-
ing that should be considered in the design of new and
more efficient ligands.
might decrease the energetic gap between the TS related
with the enantioselectivity of the processes for which they
have been designed.
Exp er im en ta l Section
Con clu sion s
Gen er a l Meth od s. Optical rotations were measured at
room temperature (23 °C) (concentration in g/100 mL). Melting
points were determined in open capillary tubes and are
uncorrected. Infrared spectra were recorded using NaCl film
or KBr pellet techniques. 1H NMR were recorded at 200 or
300 MHz (s ) singlet, d ) doublet, t ) triplet, m ) multiplet,
b ) broad). 13C NMR were recorded at 50.3 or 75.4 MHz.
Carbon multiplicities have been assigned by distortionless
In summary, the synthesis of chiral â-amino alcohols
containing a bulky alkyl substituent from enantiomeri-
cally enriched (2S,3S)-2,3-epoxy-3-alkylpropanols has led
to the development of a new family of ligands for the
enantioselective addition of diethylzinc to aldehydes. Our
synthetic strategy based on the protection of the primary
hydroxyl and the epoxide ring opening with secondary
J . Org. Chem, Vol. 68, No. 8, 2003 3135

J imeno et al.
18, 100), 226 (C13H20O2 + 18, 91); Anal. Calcd for C13H20O2:
C, 74.96; H, 9.68. Found: C, 74.37; H, 9.95.
(2S,3S)-3-ter t-Bu t yl-2-m et h oxym et h yloxir a n e, 5b . A
solution of 5a (2.0 g, 15.36 mmol) in DMF (16 mL) was added
via cannula to a suspension of sodium hydride (804 mg, ca.
18.43 mmol) in DMF (18 mL) at -20 °C, under N2. The mixture
was stirred at -20 °C for 20 min, and methyl iodide (1.2 mL,
19.97 mmol) was added via syiringe into the mixture. The
mixture was stirred for 3 h, allowing it to warm to room
temperature. MeOH (25 mL) and brine (40 mL) were added.
The aqueous solution was extracted with Et2O (3 × 60 mL).
The combined organic extracts were dried over Na2SO4 and
concentrated carefully in vacuo (water bath at 0 °C) due to
the high volatility of the product. The residual oil was
chromatographed on silica gel, eluting with pentane/ether
mixtures of increasing polarity. Compound 5b (1.0 g, 90%
yield) was isolated as an oil: [R]D -4.2 (c 2.64, CHCl3); 1H NMR
(200 MHz, CDCl3) δ 0.93 (s, 9H), 2.63 (d, J ) 3 Hz, 1H), 3.01
(m, 1H), 3.36 (dxd, J ) 11 Hz, J ′ ) 5 Hz, 1H), 3.40 (s, 3H),
3.65 (dxd, J ) 11 Hz, J ′ ) 3 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 25.7 (CH3), 30.5 (C), 53.7 (CH), 59.0 (CH3), 63.6 (CH),
72.9 (CH2); IR (film) 2950, 1440, 1350, 1205, 1110, 875 cm-1
MS (CI, NH3) m/z 162 (C8H16O2 + 18, 74), 91 (100).
;
+
(2S,3S)-2-Ben zyloxym eth yl-3-ter t-bu tyloxir a n e, 5c. The
same procedure described above for 5b was followed using the
following amounts of reagents: epoxy alcohol 5a (2.0 g, 15.36
mmol) in DMF (16 mL), NaH (804 mg, ca. 18.43 mmol) in DMF
(16 mL), and benzyl bromide (2.4 mL, 19.97 mmol). After one
workup identical to the one described for 5b and purification
by column chromatography eluting with hexane/ether (from
100/0 to 90/10), 5c was isolated in quantitative yield as a dense
1
oil: [R]D -4.3 (c 0.77, CHCl3); H NMR (200 MHz, CDCl3) δ
0.91 (s, 9H), 2.60 (d, J ) 2 Hz, 1H), 3.04 (m, 1H), 3.40 (dxd, J
) 11 Hz, J ′ ) 6 Hz, 1H), 3.70 (dxd, J ) 11 Hz, J ′ ) 3H, 1H),
4.54 (m, 2H), 7.31 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 25.6
(CH3), 30.4 (C), 53.8 (CH), 63.5 (CH), 70.6 (CH2), 72.9 (CH2),
127.4 (CH), 127.5 (CH), 128.1 (CH), 137.8 (C); IR (film) 3031,
2960, 2869, 1455, 1364, 1104, 737 cm-1; MS (CI, NH3) m/z 238
(C14H20O2 + 18, 100); HRMS (CI) calcd for C14H2002‚H+
+
221.1541, found 221.1522.
F IGURE 3. Superposition of the conformer TSs for 11c. A,
anti-(S); B, anti-(R) (hydrogen atoms have been omitted for
clarity; N ) blue, O ) red, and Zn ) green).
(2S ,3S )-3-t er t -Bu t yl-2-t r ip h e n ylm e t h oxym e t h yloxi-
r a n e, 5d . Epoxy alcohol 5a (265 mg, 2.03 mmol) and N-
triphenylmethylpyridinium tetrafluoroborate (1.5 g, 3.65 mmol)
in acetonitrile (5 mL) were stirred for 24 h at room tempera-
ture under N2. Et2O (15 mL) was added, and the precipitate
was filtered out. The solvent was removed in vacuo, and the
residual oil was purified by chromatography using hexane/
Et2O (from 100/0 to 90/10) to give 655 mg (87%) of 5d as a
solid. Recrystallization from hexane increased the product’s
ee from 96 to 99% (determined by DSC): mp 104-106 °C; [R]D
+6.4 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 0.92 (s, 9H),
2.60 (d, J ) 2 Hz, 1H), 3.02-3.27 (m, 3H), 7.22-7.49 (m, 15H);
13C NMR (50 MHz, CDCl3) δ 25.8 (CH3), 30.6 (C), 54.0 (CH),
64.2 (CH), 65.1 (CH2), 86.6 (C), 127.0 (CH), 127.8 (CH), 128.7
(CH), 143.9 (C); IR (KBr) 3070, 2960, 1451, 1364, 1214, 1070,
903, 791 cm-1; MS (CI, NH3) m/z 390 (C26H28O2+ + 18, 1), 243
(CPh3+, 100). Anal. Calcd for C26H28O2: C, 83.83; H, 7.58.
Found: C, 83.82; H, 7.71.
enhancement by polarization transfer (DEPT) experiments.
High-resolution mass spectra (CI) were measured by the
Unidade de Espectrometria de Masas, Universidade de San-
tiago de Compostela. Elemental analyses were performed by
the Servei de Microana`lisi del CSIC de Barcelona. Chromato-
graphic separations were carried out using Et3N-pretreated
(2.5% v/v) SiO2 (70-230 mesh), eluting (unless otherwise
stated) with hexanes-ethyl acetate mixtures of increasing
polarity.
(2S,3S)-3-(1-Ad a m a n tyl)-2,3-ep oxyp r op a n -1-ol, 6a . The
same procedure described above for the preparation of 5a was
followed, using the following amounts of reagents: allylic
alcohol 10 (1.7 g, 8.84 mmol), Ti(OiPr)4 (130 µL, 0.44 mmol),
L-(+)-DIPT (130 µL, 0.66 mmol), TBHP 5.4 M in isooctane (3.9
mL, 17.6 mmol), and 4 Å MS (0.56 g) in anhydrous CH2Cl2
(97 mL). A workup identical to the one described for 5a
followed by chromatography using hexane/EtOAc as the eluent
afforded 1.44 g (80% yield) of 6a . The enantiomeric purity of
the product was determined to be 94% (determined by HPLC
of its acetyl derivative; Chiralcel OD, 0.3 mL/min, hexane/i-
PrOH (99/1), λ ) 220 nm). After recrystallization from hexanes,
ee increased to 98% (determined by DSC): mp 52-53 °C, [R]D
(2S,3S)-3-(1-Ad a m a n tyl)-2-m eth oxym eth yloxir a n e, 6b.
The same procedure described above for 5b was followed using
the following amounts of reagents: epoxy alcohol 6a (200 mg,
0.960 mmol), NaH (54 mg, ca. 1.248 mmol), and MeI (97 µL,
1.560 mmol) in anhydrous DMF (2 mL). After the usual
workup and purification by flash chromatography, 6b was
obtained in quantitative yield: [R]D -15.3 (c 1.38, CH2Cl2); 1H
NMR (200 MHz, CDCl3) δ 1.54 (m, 6H), 1.70 (m, 6H), 1.98 (m,
3H), 2.48 (d, J ) 2 Hz, 1H), 3.10 (m, 1H), 3.34 (dxd, J ) 11
Hz, J ′ ) 6 Hz, 1H), 3.39 (s, 3H), 3.62 (dxd, J ) 11 Hz, J ′ ) 3
Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 27.9 (CH), 32.1 (C), 36.9
(CH2), 38.5 (CH2), 52.4 (CH), 59.0 (CH3), 64.0 (CH), 73.2 (CH2);
IR (film) 2906, 2850, 1453, 1198, 1121, 893 cm-1; MS (CI, NH3)
1
) -14.5 (c 1.02, CHCl3); H NMR (300 MHz, CDCl3) δ 1.53-
1.74 (m, 12H), 1.98 (m, 3H), 2.60 (d, J ) 2 Hz, 1H), 3.11 (m,
1H), 3.58 (m, 1H), 3.90 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
27.9 (CH), 32.1 (C), 36.9 (CH2), 36.9 (CH2), 38.6 (CH2), 54.1
(CH), 62.3 (CH2), 64.0 (CH); IR (KBr) 3502, 2904, 1453, 1343,
1077, 1026, 888 cm-1; MS (CI, NH3) m/z 227 (C13H20O2‚H+
+
m/z 240 (C14H22O2 + 18, 100), 223 (C14H22O2‚H+, 3).
+
3136 J . Org. Chem., Vol. 68, No. 8, 2003

Modular Amino Alcohol Ligands
(2S,3S)-3-(1-Adam an tyl)-2-ben zyloxym eth yloxir an e, 6c.
The same procedure described above for 5b was followed using
the following amounts of reagents: epoxy alcohol 6a (160 mg,
0.768 mmol), NaH (50 mg, ca. 0.998 mmol), and benzyl bromide
(165 µL, 1.152 mmol) in anhydrous DMF (2 mL). After the
usual workup and purification by column chromatography, 211
mg (92% yield) of 6c was isolated as an oil: [R]D -10.4 (c 1.47,
pyrrolidine (1.9 mL, 22.70 mmol) in dry acetonitrile (15 mL).
After 4 days at reflux, the reaction was quenched and treated
as described for 11a to give 11e in quantitative yield: [R]D
+5.0 (c 1.16, CHCl3); 1H NMR (200 MHz, CDCl3) δ 0.95 (s,
9H), 1.92 (m, 4H), 3.10 (m, 2H), 3.42 (m, 2H), 3.66 (s, 1H),
3.70-3.90 (m, 2H), 4.52 (s, 2H), 7.33 (m, 5H); 13C NMR (50
MHz, CDCl3) δ 23.1 (CH2), 26.2 (CH3), 35.2 (C), 45.5 (CH2),
47.3 (CH2), 51.4 (CH2), 64.2 (CH), 68.0 (CH2), 73.7 (CH2), 77.5
(CH), 127.9 (CH), 128.0 (CH), 128.4 (CH), 137.1 (C); IR (film)
3429, 2956, 1625, 1455, 1098 cm-1; MS (CI, NH3) m/z 292
(C18H29NO2‚H+, 100); HRMS (CI) calcd for C18H29NO2‚H+
292.2276, found 292.2280.
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 1.53 (m, 6H), 1.67 (m,
6H), 1.97 (m, 3H), 2.47 (d, J ) 2 Hz, 1H), 3.13 (m, 1H), 3.42
(dxd, J ) 13 Hz, J ′ ) 6 Hz, 1H), 3.70 (dxd, J ) 13 Hz, J ′ ) 3
Hz, 1H), 4.56 (m, 2H), 7.32 (m, 5H); 13C NMR (75 MHz, CDCl3)
δ 27.9 (CH), 32.1 (C), 36.8 (CH2), 38.5 (CH2), 52.5 (CH), 64.0
(CH), 70.9 (CH2), 73.0 (CH2), 127.5 (CH), 127.6 (CH), 128.2
(CH) 137.9 (C); IR (film) 3050, 2906, 2850, 1453, 1100, 893,
(1S,2R)-1-ter t-Bu tyl-2-p ip er id in o-3-tr ip h en ylm eth oxy-
1-p r op a n ol, 11d . The same procedure described above for 5d
was followed, using the following amounts of reagents: 11a
(520 mg, 2.41 mmol) and N-triphenylmethylpyridinium tet-
rafluoroborate (1.43 g, 3.48 mmol) in dry acetonitrile (10 mL).
After column chromatography, 635 mg (60% yield) of 11d was
obtained: [R]D -56.4 (c 1.96, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 0.73 (s, 9H), 1.32 (m, 2H), 1.45 (m, 4H), 2.05 (m, 2H),
2.34 (m, 4H), 3.48 (m, 1H), 3.63 (d, J ) 5 Hz, 1H), 7.10-7.60
(m, 15H); 13C NMR (75 MHz, CDCl3) δ 23.9 (CH2), 25.9 (CH2),
26.7 (CH3), 35.4 (C), 54.9 (CH2), 61.0 (CH2), 69.8 (CH), 84.2
(CH), 87.2 (C), 126.9 (CH), 127.5 (CH), 129.2 (CH), 144.9 (C);
735 cm-1; MS (CI, NH3) m/z 316 (C20H26O2 + 18, 100), 299
+
(C20H26O2‚H+, 7).
(1S,2R)-1-ter t-Bu tyl-2-p ip er id in o-1,3-p r op a n d iol, 11a .
Piperidine (7.6 mL, 76.8 mmol) was added via syringe into a
mixture of 5a (1.0 g, 7.68 mmol) and LiClO4 (12 g, 115.2 mmol)
in acetonitrile (20 mL) under N2. The resulting mixture was
heated at reflux. After 24 h, the solution was cooled to room
temperature, and water (40 mL) was added. The solution was
extracted with CH2Cl2 (3 × 30), and the combined organic
phases were dried (MgSO4) and concentrated in vacuo. The
residual crude was purified by column chromatography using
hexane/EtOAc as the eluent to give 1.42 g (86% yield) of 11a
as a dense oil: [R]D +18.0 (c 1.18, CHCl3); 1H NMR (200 MHz,
CDCl3) δ 0.98 (s, 9H), 1.57 (m, 6H), 2.51 (m, 6H), 3.44 (d, J )
5 Hz, 1H), 3.79 (m, 1H); 13C NMR (50 MHz, CDCl3) δ 24.1
(CH2), 26.0 (CH3), 26.7 (CH2), 34.2 (C), 54.7 (CH2), 61.0 (CH2),
66.3 (CH), 81.5 (CH); IR (film) 3408, 2939, 1443, 1391, 1279,
1119, 897 cm-1; MS (EI) m/z 128 (C5H10NC+HCH2OH, 29), 98
(C5H10NC+H2, 100); HRMS (CI) calcd for C12H25NO2‚H+
216.1963, found 216.1963.
(1S ,2R )-1-t er t -Bu t yl-3-m e t h oxy-2-p ip e r id in o-1-p r o-
p a n ol, 11b. The same procedure described above for 11a was
followed, except that the reaction was carried out in a selaed
tube, using the following amounts of reagents: epoxy ether
5b (700 mg, 4.85 mmol), LiClO4 (8.9 g, 83.2 mmol), and
piperidine (5.5 mL, 55.5 mmol) in acetonitrile (20 mL). After
5 days at reflux, the reaction was quenched and treated as
described for 11a to give 625 mg (56% yield) of 11b: [R]D -23.8
(c 1.10, CHCl3); 1H NMR (200 MHz, CDCl3) δ 0.94 (s, 9H), 1.49
(m, 6H), 2.45 (m, 2H), 2.65 (m, 3H), 3.33 (s, 3H), 3.47 (m, 1H),
3.64 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 24.7 (CH2), 26.2
(CH3), 26.5 (CH2), 35.4 (C), 50.8 (CH2), 58.8 (CH3), 64.4 (CH),
70.7 (CH2), 78.7 (CH); IR (film) 3487, 2933, 2805, 1457, 1364,
1106 cm-1; EM (EI) m/z 184 (tBuCHOHC+HNC5H10, 27), 142
(C5H10NC+HCH2OCH3, 100); HRMS (CI) calcd for C13H27NO2‚
H+ 230.2120, found 230.2107.
IR (film) 3460, 3090, 2939, 1490, 1450,1219, 1115, 1048 cm-1
;
MS (FAB+) m/z 458.3 (C31H39NO2‚H+, 14), 242.9 (C+Ph3, 100);
HRMS (CI) calcd for C31H39NO2‚H+ 458.3059, found 458.3052.
(1S,2R)-1-ter t-Bu tyl-3-ter t-bu tyld ip h en ylsilyloxy-2-p i-
p er id in o-1-p r op a n ol, 11f. A solution of 11a (500 mg, 2.32
mmol), tert-butyldiphenylsilyl chloride (700 mg, 2.55 mmol),
and imidazole (348 mg, 5.10 mmol) in anhydrous DMF (30 mL)
was heated at 65 °C for 24 h under N2. The reaction mixture
was cooled to room temperatue, and Et2O (20 mL) and brine
(20 mL) were added. The aqueous layer was extracted with
ether (2 × 20 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. The residual oil was
purified by flash chromatography, affording 860 mg (82% yield)
of 11f as a dense oil: [R]D -37.2 (c 4.00, CHCl3); 1H NMR (200
MHz, CDCl3) δ 0.85 (s, 9H), 1.03 (s, 9H), 1.28 (m, 2H), 1.40
(m, 4H), 2.13 (m, 2H), 2.28 (m, 2H), 2.41 (dxd, J ) 13 Hz, J ′
) 3 Hz, 1H), 2.62 (dxd, J ) 13 Hz, J ′ ) 7 Hz, 1H), 3.43 (d, J
) 5 Hz, 1H), 3.78 (m, 1H), 7.30-7.80 (m, 10H); 13C NMR (75
MHz, CDCl3) δ 19.3 (C), 23.9 (CH2), 25.8 (CH2), 26.6 (CH3),
27.0 (CH3), 34.9 (C), 55.0 (CH2), 63.8 (CH2), 69.7 (CH), 85.2
(CH), 127.4 (CH), 127.6 (CH), 129.5 (CH), 129.7 (CH), 133.5
(CH), 134.3 (C), 135.8 (CH), 135.9 (CH); IR (film) 3107, 3072,
2936, 1474, 1428, 1113 cm-1; MS (CI, NH3) m/z 455 (C28H43
-
NO2Si‚H+ + 1, 35), 454 (C28H43NO2Si‚H+, 100); HRMS (CI)
calcd for C28H43NO2Si‚H+ 454.3141, found 454.3140.
(1S ,2R )-1-(1-Ad a m a n t y l)-2-p ip e r id in o -1,3-p r o p a n -
d iol, 12a . The same procedure described above for 11a was
followed, using the following amounts of reagents: 6a (200
mg, 0.96 mmol), piperidine (1.1 mL, 10.4 mmol), and LiClO4
(1.7 g, 14.4 mmol) in dry acetonitrile (3 mL). After 24 h at
reflux, the reaction was quenched and treated as described
for 11a to give 278 mg (98% yield) of 12a as a dense oil: [R]D
+16.4 (c 0.98, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 1.45-
1.68 (m, 18H), 1.97 (m, 3H), 2.75 (m, 4H), 3.10 (b s, 2H), 3.29
(d, J ) 5 Hz, 1H), 3.37 (m, 1H), 3.50 (m, 1H), 3.93 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 23.5 (CH2), 25.2 (CH2), 28.3 (CH),
36.2 (C), 37.1 (CH2), 38.6 (CH2), 54.7 (CH2), 60.9 (CH2), 65.4
(CH), 82.2 (CH); IR (film) 3481, 2904, 2850, 1453, 1098, 623
cm-1; MS (EI) m/z 98 (C5H10NC+H2, 100); HRMS (CI) calcd
for C18H31NO2 - H2O 275.2249, found 275.2259.
(1S,2R)-1-(1-Adam an tyl)-3-m eth oxy-2-piper idin o-1-pr o-
p a n ol, 12b. The same procedure described above for 11a was
followed, using the following amounts of reagents: 6b (160
mg, 0.72 mmol), piperidine (1 mL, 10.1 mmol), and LiClO4 (770
mg, 7.20 mmol) in dry acetonitrile (4 mL). After 4 days at
reflux, the reaction was quenched and treated as described
for 11a to give 170 mg (77% yield) of 12b: [R]D -5.5 (c 1.40,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 1.40-1.68 (m, 18H), 1.98
(1S,2R)-3-Ben zyloxy-1-ter t-b u t yl-2-p ip er id in o-1-p r o-
p a n ol, 11c. The same procedure described above for 11a was
followed, using the following amounts of reagents: epoxy ether
5c (600 mg, 2.72 mmol), LiClO4 (4.3 g, 40.8 mmol), and
piperidine (2.7 mL, 27.2 mmol) in dry acetonitrile (10 mL).
After 4 days at reflux, the reaction was quenched and treated
as described for 11a to give 705 mg (85% yield) of 11c as a
dense oil: [R]D -15.4 (c 1.25, CHCl3); 1H NMR (200 MHz,
CDCl3) δ 0.94 (s, 9H), 1.48 (m, 6H), 2.42 (m, 2H), 2.68 (m, 2H),
2.86 (d, J ) 9 Hz, 1H), 3.45 (m, 1H), 3.73 (d, J ) 6 Hz, 2H),
4.51 (s, 2H), 7.33 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 24.8
(CH2), 26.2 (CH3), 26.7 (CH2), 35.5 (C), 50.8 (CH2), 64.5 (CH),
68.2 (CH2), 73.3 (CH2), 78.9 (CH), 127.5 (CH), 127.6 (CH), 128.3
(CH), 137.8 (C); IR (film) 3494, 2934, 1455, 1362, 1090, 1003,
735 cm-1; MS (EI) m/z 306 (C19H31NO2‚H+, 1), 218 (C5H10NC+-
HCH2OCH2Ph, 58), 184 (tBuCHOHC+HNC5H10
, 24), 91
(PhCH2+, 100); HRMS (CI) calcd for C19H31NO2‚H+ 306.2433,
found 306.2418.
(1S,2R)-3-Ben zyloxy-1-ter t-b u t yl-2-p yr r olid in o-1-p r o-
p a n ol, 11e. The same procedure described above for 11a was
followed, using the following amounts of reagents: epoxy ether
5c (500 mg, 2.27 mmol), LiClO4 (3.6 g, 34.05 mmol), and
J . Org. Chem, Vol. 68, No. 8, 2003 3137

J imeno et al.
(m, 3H), 2.40-2.80 (m, 6H), 3.22 (m, 1H), 3.33 (s, 3H), 3.60
(d, J ) 5 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 24.7 (CH2),
26.6 (CH2), 28.4 (CH), 37.2 (C), 37.3 (CH2), 38.1 (CH2), 50.7
(CH2), 58.8 (CH3), 62.9 (CH), 70.8 (CH2), 78.7 (CH); IR (film)
3477, 2904, 2848, 1451, 1345, 1306, 1106 cm-1; MS (EI) m/z
262 (C10H15CHOHC+HNC5H10, 25), 142 (C5H10NC+HCH2-
OCH3, 100); HRMS (CI) calcd for C19H33NO2‚H+ 308.2589,
found 308.2599.
reagents: 12a (360 mg, 1.23 mmol) and N-triphenylmethylpy-
ridinium tetrafluoroborate (1.0 g, 2.46 mmol) in dry acetonitrile
(10 mL). After purification by flash chromatography, 410 mg
(62% yield) of compound 12d was obtained: [R]D -27.2 (c 1.35,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.25-1.58 (m, 18H), 1.82
(m, 3H), 2.03 (m, 4H), 2.33 (d, J ) 5 Hz, 1H), 3.48 (m, 3H),
7.21-7.53 (m, 15H); 13C NMR (75 MHz, CDCl3) δ 23.9 (CH2),
25.9 (CH2), 28.4 (CH), 37.2 (CH2), 37.4 (C), 38.4 (CH2), 54.8
(CH2) 61.1 (CH2), 68.5 (CH), 84.5 (CH), 87.1 (C), 126.9 (CH),
127.4 (CH), 129.2 (CH), 144.9 (C); IR (film) 3200, 3058, 2902,
1490, 1266, 1048 cm-1; MS (CI, NH3) m/z 536 (M + 1, 41%),
535 (M+, 100%). HRMS (CI) calcd for C37H45NO2 535.3450,
found 535.3451.
(1S,2R)-1-(1-Ad a m a n t yl)-3-b en zyloxy-2-p ip er id in o-1-
p r op a n ol, 12c. The same procedure described above for 11a
was followed, using the following amounts of reagents: 6c (200
mg, 0.67 mmol), piperidine (1 mL, 10.1 mmol), and LiClO4 (710
mg, 6.70 mmol) in dry acetonitrile (4 mL). After 4 days at
reflux, the reaction was quenched and treated as described
for 11a to give 180 mg (70% yield) of 12c: [R]D -3.1 (c 0.69,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.40-1.62 (m, 18H), 1.72
(m, 3H), 2.50-2.70 (m, 5H), 2.82 (m, 1H), 3.27 (m, 1H), 3.70
(d, J ) 6 Hz, 1H), 4.51 (s, 2H), 7.33 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 24.7 (CH2), 26.6 (CH2), 28.3 (CH), 37.1 (C), 37.2
(CH2), 38.0 (CH2), 50.7 (CH2), 63.1 (CH), 68.2 (CH2), 73.2 (CH2),
78.8 (CH), 127.5 (CH), 137.9 (C); IR (film) 3489, 3050, 2906,
Ack n ow led gm en t. This research was supported by
DGI-MCYT (BQU2002-02459) and DURSI (2001SGR50).
C.J . thanks Generalitat de Catalunya for a predoctoral
fellowship.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 1-adamantylcarbaldehyde and
compounds 5a and 7-10 and for the enantioselective addition
of diethylzinc to aldehydes, as well as Cartesian coordinates
and energies of transition states 14-17. This material is
available free of charge via the Internet at http://pubs.acs.org.
2848, 1453, 1362, 1075 cm-1; MS (CI, NH3) m/z 384 (C25H37
-
NO2‚H+, 27), 383 (C25H37NO2+, 100); HRMS (CI) calcd for
C
25H37NO2‚H+ 384.2902, found 384.2901.
(1S ,2R )-1-(1-Ad a m a n t yl)-2-p ip e r id in o-3-t r ip h e n yl-
m eth oxy-1-p r op a n ol, 12d . The same procedure described
above for 5d was followed, using the following amounts of
J O034007L
3138 J . Org. Chem., Vol. 68, No. 8, 2003