Heterocyclic lithium amides as chiral ligands for an enantioselective hydroxyalkylation with n-BuLi

Article abstract of DOI:10.1021/jo8005396

(Chemical Equation Presented) Chiral heterocyclic structures based on 3-aminopyrrolidines (3APs), 3-aminotetrahydrothiophens (3ATTs), and 3-aminotetrahydrofurans (3ATFs) have been synthesized. The corresponding lithium amides have been evaluated as chiral ligands in the condensation of n-BuLi on o-tolualdehyde. The returned levels of induction were in the 46-80% ee range. The cheap and easily prepared 3ATFLi's turned out to be also the best ligands, giving access to the expected R or S alcohols in a same 80% level of induction at -78°C in THF. In all cases, the sense of induction depends on the absolute configuration of C⁸ on the 3-amino appendage. A general concept is proposed to rationalize the process of induction in the presence of organolithium species.

Full text of DOI:10.1021/jo8005396

Heterocyclic Lithium Amides as Chiral Ligands for an
Enantioselective Hydroxyalkylation with n-BuLi
Nicolas Duguet, Sylvain M. Petit, Philippe Marchand, Anne Harrison-Marchand, and
Jacques Maddaluno*
Laboratoire des Fonctions Azote´es & Oxyge´ne´es Complexes de l’IRCOF, UMR CNRS 6014 and FR CNRS
3038, UniVersite´ de Rouen and INSA de Rouen, 76821 Mont St Aignan Cedex, France
jmaddalu@crihan.fr
ReceiVed March 10, 2008
Chiral heterocyclic structures based on 3-aminopyrrolidines (3APs), 3-aminotetrahydrothiophens (3ATTs),
and 3-aminotetrahydrofurans (3ATFs) have been synthesized. The corresponding lithium amides have
been evaluated as chiral ligands in the condensation of n-BuLi on o-tolualdehyde. The returned levels of
induction were in the 46-80% ee range. The cheap and easily prepared 3ATFLi’s turned out to be
also the best ligands, giving access to the expected R or S alcohols in a same 80% level of induction at
-78 °C in THF. In all cases, the sense of induction depends on the absolute configuration of C8 on the
3-amino appendage. A general concept is proposed to rationalize the process of induction in the presence
of organolithium species.
Introduction
A nonracemic chiral environment can be introduced into org-
anometallic compounds in two general ways. The first one uses
classical complexing agents (Lewis bases) to coordinate the metallic
center (chiral ethers, tertiary amines, etc.).1 Alternatively, advantage
can be taken of dipole-dipole interactions between the reactant
and a chiral deprotonated entity such as an alcoholate or an amide.2
This second class of ligands is particularly efficient for organo-
lithium compounds: a tight noncovalent complex results from the
association of these polar entities and provides a highly reactive
mixed aggregate,3 which behaves as a good nucleophile toward
carbonyl compounds. However, reaching good enantioselectivities
in “classical” conditions (use of a single solvent, T g -78 °C)
with such systems still remains a challenge.
FIGURE 1. 3-Aminopyrrolidine lithium amides as chiral ligands for
organolithium reagents.
the addition of n-butyllithium onto o-tolualdehyde. The results
are presented here.
Previous studies evidenced that 3-aminopyrrolidine lithium
amides 1Li (Figure 1) can act as satisfying inductors for 1,2-
and 1,4-nucleophilic additions of organolithium reactants (76%
< ee < 80%).4
Results and Discussion
Synthesis of 3-Aminoheterocycles. The access to the new
3-aminoheterocycles was inspired from a strategy based on a
3-hydroxy heterocyclic intermediate.4c The case of the pyrro-
lidines has been considered first.
(a) Modification of the Lateral N-Chain of 1. A set of eight
new 3-aminopyrrolidines was prepared by varying the substitu-
tion of the lateral N-chain of 1. The synthesis relied on a
In an effort to improve the system (easier and cheaper syn-
thesis of the ligand, higher ee’s), four structural appendages on
1Li have been varied (Figure 2). The new set of 3-aminohet-
erocycle lithium amides has been evaluated as chiral ligands in
10.1021/jo8005396 CCC: $40.75
Published on Web 06/17/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5397–5409 5397

Duguet et al.
SCHEME 1. Synthesis of 3APs 15-20
TABLE 1. Yields Obtained for Syntheses of 3APs 15-20 Depicted
in Scheme 1
entries H2NCHR1R2 carbamate:% (from 2) 3AP:% (from carbamate)
1
2
3
4
5
6
7
8
3
9:58
15 (3S,8R):80
16a (3S,8R):87
16b (3S,8S):83
17 (3S,8R):81
18 (3S,8R):70
19 (3S,8R):71
20a (3S,8S):92
20b (3S,8R):82
4a
4b
5
6
7
8a
8b
10a:50
10b:51
11:49
12:44
13:50
14a:52
14b:64
FIGURE 2. Structural parameters modified on 1Li.
common intermediate (3R)-3-hydroxypyrrolidine 2 (Scheme 1),
accessible in 86% yield from commercial trans 4-hydroxy-L-
proline.4c A consecutive stereospecific nucleophilic substitution
of the triflate of 2 by various chiral amines (H2NCHR1R2, 3-8)
led to the protected 3-aminopyrrolidines 9-14. Reduction of
the Boc by LiAlH4 afforded the 3APs 15-20. Yields, step by
step, are summarized in Table 1, and the diastereomeric purities
of the final diamines (>92%) were checked by NMR or polar-
imetry.
Note that (R)-1-tert-butylethylamine 6 as well as diamines 7
and 8 are not commercially available. Amine 6 was obtained
from pinacolone following a route optimized by Moss and col-
leagues,5 while diamines 7, 8a, and 8b were synthesized from
(R)- or (S)-phenyloxirane according to the strategy reported by
O’Brien.6
(b) Modification of the pyrrolidinic N-chain of 1. Two new
triamines 28a (3S,8R) and 28b (3S,8S) were prepared following
two synthetic procedures based, as before, on trans 4-hydroxy-
L-proline. They vary by the order of introduction of the oxamoyl
group and the C3 amino appendage (Scheme 2).
In route 1, trans 4-hydroxy-L-proline was transformed into
intermediate 21 following the methodology described previ-
ously.4c The pyrrolidinic nitrogen was then deprotected by
trifluoroacetic acid (TFA), leading to diamines 22a (3S,8R) and
22b (3S,8S) in 84% and 93% yields, respectively. Each dia-
stereomer of 22 was then reacted with oxamoyl chloride 23,7
providing amido dicarbamates 24a (3S,8R) and 24b (3S,8S) in
(1) For nucleophilic additions on aldehydes, see: (a) Noyori, R.; Kitamura,
M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49–69. (b) Seebach, D.; Kalinowski,
H.-O.; Bastani, B.; Crass, G.; Daum, H.; Do¨rr, H.; DuPreez, N. P.; Ehrig, V.;
Langer, W.; Nu¨ssler, C.; Oei, H.-A.; Schmidt, M. HelV. Chim. Acta 1977, 60,
301–325. (c) Seebach, D.; Crass, G.; Wilka, E.-M.; Hilvert, D.; Brunner, E.
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(i) Jiang, B.; Feng, Y. Tetrahedron Lett. 2002, 43, 2975–2577. For nucleophilic
additions on imines, see: (j) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K.
Tetrahedron Lett. 1990, 31, 6681–6684. (k) Tomioka, K.; Inoue, I.; Shindo, M.;
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Vrancken, E.; Mangeney, P. Synlett 1998, 1165–1167. (x) Oguni, N; Miyagi,
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Hilmersson, G. Tetrahedron: Asymmetry 2003, 14, 439–447.
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J. Chem. Soc., Perkin Trans. 2 1999, 219, 2197–2201.
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Duhamel, P. J. Org. Chem. 1998, 63, 8266–8275. (b) Corruble, A.; Valnot, J.-
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5398 J. Org. Chem. Vol. 73, No. 14, 2008

EnantioselectiVe Hydroxyalkylation with Chiral Lithium Amides
SCHEME 2. Synthesis of 3AP 28a and 28b
SCHEME 3. Synthesis of 3APs 37; Both 36 and 37 Obtained as a 1:1 Mixture of Diastereomers
74% and 88% yields, respectively. Intermediates 24 could also
be attained following route 2, which introduces the oxamoyl
moiety immediately after the decarboxylation of the proline.
The amino alcohol 25, obtained in 75% yield, was reacted with
23, affording the hydroxy dicarbamate 26 in 62% yield. The
R-methylbenzylamino part was introduced next, reproducing the
SN2 sequence reported before. Following this second way, amido
dicarbamates 24a (3S,8R) and 24b (3S,8S) were recovered in
70% and 69% yields from 27. The final step to attain triamines
28a and 28b consisted in the complete reduction of 24 by
LiAlH4 (85% for 28a, 77% for 28b). Overall, route 1 is twice
as efficient as route 2 (40% vs 20% yield).
droxypyrrolidine 34 (Scheme 3), racemic equivalent of 2, is
not commercially available but could be prepared from cis-
1,4-dichlorobut-2-ene 29, transformed in three well-known
steps into 3-pyrroline 32 (Scheme 3). Note that this latter is
commercially available and inexpensive, but its purity rarely
exceeds 85%.
Pure 3-pyrroline 32 was thus prepared from cis-1,4-dichlo-
robut-2-ene 29 as described by Meyers,8 in an overall yield
comparable to that given in literature.8 An immediate protection
of the amino group of 32 into a carbamate (N-Boc) was next
carried out following Becker’s protocol9 and led to pyrroline
33 in 51% yield. A hydroboration10 run on 33 with the
borane-methyl sulfide complex in THF, followed by an
oxidation of the borane intermediate by a mixture of hydrogen
peroxide and sodium hydroxide, afforded racemic hydroxy
carbamate 34 in 60% yield. Sulfonate 35 was then synthesized
in 85% yield and reacted with an excess of R-methyl-
benzylamine to give amino carbamates 36a (8R) and 36b (8S)
(c) Modification of the C3 Configuration of 1. To evaluate
the respective contribution of the two stereogenic centers of 1
(C3 and C8) to the induction process, a synthesis of the analogue
racemic at C3 (37, Scheme 3) has been achieved. The 3-hy-
(5) Moss, N.; Gauthier, J.; Ferland, J.-M. Synlett 1995, 2, 142–144.
(6) (a) O’Brien, P.; Poumellec, P. Tetrahedron Lett. 1996, 37, 5619–5622.
(b) de Sousa, S. E.; O’Brien, P.; Poumellec, P. J. Chem. Soc., Perkin Trans.
1998, 1483–1492. (c) Curthbertson, E.; O’Brien, P.; Towers, T. D. Synthesis
2001, 693–695.
(8) Warmus, J. S.; Dilley, G. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 270–
271.
(9) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139–2145.
(10) Brown, H. C.; Prasad, J. V. N. V.; Zee, S.-H. J. Org. Chem. 1985, 50,
1582–1589.
(7) Vakemans, J.; Pollers-Wieers, C.; Hoornaet, G. Heterocycl. Chem. 1983,
20, 919–923.
J. Org. Chem. Vol. 73, No. 14, 2008 5399

Duguet et al.
SCHEME 4. Synthesis of 3ATTs 41
in the same 86% yield. A final reduction by LiAlH4 led to
diamines 37a and 37b in 76% and 81% yields, respectively.
Thus, eight steps are necessary to reach 37 in 8% overall yield.
(d) Modification of the Intracyclic Heteroatom of 1.
Amines 41 (tetrahydrothiophen, 3ATT, Scheme 4) and 44
(tetrahydrofuran, 3ATF, Scheme 5) are direct analogues of the
3AP 37, the difference being the nature of the heterocycle.
Amines 41a and 41b have been prepared following a three-
step synthetic scheme (Scheme 4) from commercially available
tetrahydrothiophenone 38. Reduction of this later by LiAlH4
led to the 3-hydroxytetrahydrothiophen 39 in 80% yield, next
transformed into mesylate 40 in 70% yield. Substitution of the
sulfonyloxy group by the (R)- or (S)-R-methylbenzylamino
appendage afforded 3-aminothiophen 41a (7R) and 41b (7S) in
59% and 65% yields, respectively.
In conclusion for this preliminary part, a series of 16 new
chiral amines has been synthesized following a single general
synthetic scheme based on a 3-hydroxy five-membered ring
heterocycle key intermediate.
Inductions in the Presence of 3-Amino Heterocyclic Lithium
Amides. Amines 15-20, 28, 37, 41, and 44 (Figure 3) were
deprotonated in the presence of a slight excess of n-butyllithium
to afford the corresponding lithium amides. Those were
employed in the model hydroxyalkylation of o-tolualdehyde by
n-butyllithium. Experimental conditions optimized before for
reference 1Li were retained,11 which consisted of working at
-78 °C in THF with a 1.5:2.5:1.0 lithium amide/nBuLi/o-
tolualdehyde ratio. Yields and enantiomeric excesses are
gathered in Table 2.
Medium (46%) to satisfying (80%) induction levels were
returned in this series of experiments. In all cases, switching from
8R to 8S on the lithium amide stereochemistry led to an inversion
of the configuration of the resulting 1-o-tolylpentan-1-ol.
SCHEME 5. Synthesis of 3ATFs 44
We believe these results can be discussed within the frame
of the induction model built from previous results. In preceding
papers, we proposed that the induction observed in the test
reaction with 1Li was correlated to the formation in solution
of noncovalent aggregates between one 1Li and one molecule
of alkyllithium.4 The interaction of these complexes with the
electrophilic aldehyde was also studied by DFT (Figure 4).12
According to these results, the enantiodetermining step takes
place right after the aldehyde is docked on the Li2 of the
N-Li-C-Li quadrilateral. Thus, modifying the immediate
The oxygenated heterocyclic analogues 44 were synthesized
from commercially available 3-hydroxytetrahydrofuran 42 fol-
lowing a two-step synthetic scheme (Scheme 5). Reacting 42
with methane sulfonyl chloride led to mesylate 43 in 91% yield,
which was transformed in amine 44a (7R) and 44b (7S) in 76%
and 74% yields, respectively.
FIGURE 3. Set of the 16 new 3-amino heterocycles synthesized.
5400 J. Org. Chem. Vol. 73, No. 14, 2008

EnantioselectiVe Hydroxyalkylation with Chiral Lithium Amides
TABLE 2. Yields and ee’s Obtained for the Model
Hydroxyalkylation Reaction; Results Obtained with 1Li4c Are
Entries 1 and 2
aggregation state of complexes involving 20Li or 28Li, one can
assume that an extra N-Li coordination is likely to interfere
with the pseudoequatorial docking of the aldehyde (Figure 5
left).12 In the second case (amide 28Li, entries 11 and 12), the
additional nitrogen exerts no effect, a result that can be
understood if this extra nitrogen is inefficient or interacts only
with Li1 (Figure 5 right).
entries chiral lithium amide t (h) yielda (%) ee (%)b 45 configuration
Let us now recall that in the absence of a chiral appendage
at C8, the C3 center (S) exerts a medium to good control of the
induction in the same model reaction.4a,11 We thus decided to
examine the role played by the stereogenic center at C3 of 1Li.
The yields and inductions obtained with lithium amides 37aLi
(8R) and 37bLi (8S), racemic at C3, turned out to be similar
with the ones determined for 1Li (compare entries 13 and 1,
then 14 and 2). Thus, the stereogenic R-methylbenzylamino
group at C8 would take precedence over C3, which seem to lose
its influence. This phenomenon can be simply understood in
light of Figure 6, representing the exo topology of amide 1aLi
(3S,8R), which provides alcohol R, and the endo topology of
amide 1bLi (3S,8S), which provides alcohol S (left). If we now
consider the enantiomer of 1aLi (that is 3R,8S), it will
necessarily adopt the same exo topology (mirror image) and
thus will lead to the alcohol S this time. The same reasoning
applies to endo 1bLi. Therefore, the inversion of the C3
configuration and, subsequently, that of the topology of the
aggregate explains that the sense of the induction finally does
not change.
1
2
3
4
5
6
7
8
1aLi (3S,8R)
1bLi (3S,8S)
15Li (3S,8R)
16aLi (3S,8R)
16bLi (3S,8S)
17Li (3S,8R)
18Li (3S,8R)
19Li (3S,8R)
20aLi (3S,8S)
20bLi (3S,8R)
28aLi (3S,8R)
28bLi (3S,8S)
37aLi (3rac, 8R)
37bLi (3rac, 8S)
41aLi (3rac, 8R)
41bLi (3rac, 8S)
44aLi (3rac, 8R)
44bLi (3rac, 8S)
2
2
2
2
2
2
2
6
6
6
2
2
2
2
2
2
2
2
60
72
74
72
68
58
54
69
56
63
58
54
62
56
68
70
66
71
80
71
75
80
76
74
66
67
46
66
80
66
79
65
58
46
80
80
R
S
R
R
S
R
R
S
R
S
R
S
R
S
R
S
R
S
9
10
11
12
13
14
15
16
17
18
a Isolated yields obtained after purification by column chromatography
on silica gel. b Enantiomeric excesses determined by HPLC analysis on
a Chiralpak OD-H chiral column.
FIGURE 4. Model of the interaction between mixed aggregate 1aLi/
RLi and o-tolualdehyde.
surroundings of this substructure seemed a reasonable strategy
to increase the induction potential of 1Li.
One of the most direct ways of influencing the rotation process
was to alter the lateral stereogenic appendage (C8). However, the
results of entries 3-7 show that the replacement of the phenyl
group by a naphthyl (entries 3-5), cyclohexyl (entry 6), or tert-
butyl (entry 7) moiety is not beneficial.
Another straightforward modification consisted of changing
the coordination pattern around the lithiums, for instance by
adding a supplementary nitrogen either on the lateral N-chain
or on the pyrrolidinic N-chain. In the first case (amides
19Li-20Li, entries 8-10), the sense of induction is conserved
(the CIP rules impose a formal inversion of the C8 asymmetric
center in these cases), but the ee’s tend to drop (by 20%) while
the rate of reaction is significantly slowed down (reaction time
should be tripled to reach a similar chemical yield: 6 versus
2 h, entries 8-10). Albeit we do not have direct insights on the
FIGURE 6. Topology of the diastereomeric aggregates involving racemic
amide 1Li.
Because the access to the racemic 3-hydroxypyrrolidine 34
intermediate is impractical, the synthesis of racemic 37Li is
somewhat tedious, and using this amide does not constitute an
attractive alternative to 1Li. However, when it comes to the
synthesis of 3-amino tetrahydrothiophen and tetrahydrofuran,
this remark becomes useful: 41 and 44 can be readily prepared
from the cheap racemic alcohols 39 and 42, respectively
(Schemes 4 and 5). Thus, 41 and 44 were tested directly under
their (3rac,8R and 3rac,8S) configurations. The inductions were
medium for 41Li (entries 15 and 16), while similar to those
obtained with 1Li in the case of 44Li (entries 17 and 18). These
observations suggest that an intramolecular S-Li and O-Li
coordination could occur with the sulfurated and oxygenated
heterocycles, which would trigger a puckering comparable to
that observed with the 3-aminopyrrolidine derivatives. NMR
and theoretical investigations are currently under progress to
substantiate this hypothesis. Note that if Figure 6 suggests that
(11) Harrison-Marchand, A.; Valnot, J.-Y.; Corruble, A.; Duguet, N.; Oulyadi,
H.; Desjardins, S.; Fressigne´, C.; Maddaluno, J. Pure Appl. Chem. 2006, 78,
321–331.
FIGURE 5. Putative structure of complexes derived from triamines
20 and 28 (S ) solvent).
(12) Yuan, Y.; Desjardins, S.; Harrison-Marchand, A.; Oulyadi, H.; Fressigne´,
C.; Giessner-Prettre, C.; Maddaluno, J. Tetrahedron 2005, 31, 3325–3334.
J. Org. Chem. Vol. 73, No. 14, 2008 5401

Duguet et al.
FIGURE 7. Schematic view of the 3-amino heterocycle lithium amides
before aggregation.
FIGURE 8. Switch from the exo to the endo arrangements by
modulation of the N-Li coordination.
diastereomers at C3 should afford the same sense of induction,
it does not give any clue on the respective contributions of each
epimer (compare for instance entries 1 and 2 or entries 9 and
10 of Table 1). Therefore, a separate testing of the pure dia-
stereomers remains necessary to evaluate properly the induction
potential of these new ligands.
Toward an Empirical Model for the Mixed Aggregates
of 3-Amino Heterocycle Lithium Amides. If we assume that
the new chiral lithium amides we have prepared all form 1:1
mixed aggregates with n-butyllithium and adopt arrangements
similar to those evidenced before, the above results can be put
in a relatively general perspective.
FIGURE 9. Empirical model of mixed aggregates between organo-
lithium and 3-amino heterocycle lithium amides.
Let us first reason about the formation of the aggregates
themselves, and thus the origin of the selectivity in favor of
the endo or exo topology. Two hypotheses can be made:
1. The aggregation is under kinetic control. In this case, the
formation of the endo or the exo forms would depend directly
on the accessibility for RLi of the two faces of the lithium amide
(Figure 7). Indeed, the nitrogen of the amide is expected to be
planar,13 and the entire structure to be rigidified by a norbornyl-
type folding, comparable to that discussed above.4b If we now
assume that the lithium cation is solvated by at least one
molecule of THF, it seems reasonable that the lateral chiral chain
CHR1R2 adopts a conformation in which the proton lies more
or less in the C-N-Li plane. This places R1 and R2 on the
two sides of the amide average plane, thus orientating the
approach of the incoming RLi: the relative bulkiness of R1 and
R2 is expected to irreversibly control the formation of the exo
or the endo complex. This would explain why for 1Li, for
example, the exo topology is obtained for the 3S,8R (R1 ) Me,
R2 ) Ph) derivatives, and similarly, why the 3S,8S (R1 ) Ph,
R2 ) Me) compounds lead to the endo arrangement.
considered as the “reaction story”. This central layer is sur-
rounded on one side by a “shield story” (the coordinating
heterocycle) and on the other by a “selector story” (the chiral
amino appendage on C3). Note that the efficiency of the
shielding is secured by the strength of the Y-Li coordination.
Keeping in mind the Curtin-Hammett principle, it is reason-
able to assume that the aggregates are directly involved in the
global enantioselective process. For the reaction to proceed, the
aldehyde has to approach the complex and to dock on one of
the two lithiums.14 As pointed out before, only lithium Li2 seems
to be accessible.12 On the basis of the empirical model, this
cation should be preferentially approached along the less
hindered face of the quadrilateral to which it belongs and that
bears the chiral selector. This preliminary phase ends up with
the rotation of the aldehyde around the O-Li direction to expose
its π-face to the nucleophilic alkyl R. The sense of this rotation,
probably determined by the Ar/R1+R2 interactions, corresponds
to the enantiodetermining event. Thus, the final success of the
induction would rely on the ability for the chiral lateral
appendage to discriminate between the opposite rotations.
2. The aggregation is under thermodynamic control. One must
assume in this case that the various species are in rapid
equilibrium, and that the endo or exo arrangement would result
from the balance between the steric and electronic interactions,
imposed by the lateral chiral chain. Passing from the exo to the
endo topology can indeed be regarded as a simple swap of the
coordination of the intracyclic heteroatom Y from one to the
other lithium cation (Figure 8, view 2). In these conditions, the
Li that is not picked up by Y becomes the Li2, i.e., the future
site for the aldehyde condensation.
Let us now reason on the reactivity of the complexes.
Whatever the hypothesis retained for their formation, the two
types of mixed aggregates can be looked upon as the assembling
of three “independent” layers (Figure 9). Both exhibit a
N-Li-C-Li quadrilateral at the heart of the structure, to be
Conclusion
This paper presents a general synthetic pathway to synthesize
easily new chiral structures based on 3-aminopyrrolidines,
3-aminotetrahydrothiophens, and 3-aminotetrahydrofurans scaf-
folds. Their lithium amides have been evaluated as chiral ligands
in the condensation of n-butyllithium on o-tolualdehyde. The
1-o-tolylpentan-1-ol was isolated in good yields and ee’s up to
80% in favor of the R or S enantiomer, depending on the
absolute configuration of the lateral chiral amino appendage.
These attractive values were obtained using the very simple,
cheap and easy to prepare lithium amide 3-(R or S-R-methyl-
benzylamido)-tetrahydrofuran 44Li. This later now constitutes
our favorite chiral ligand for organolithium derivatives and
(13) Fressigne´, C.; Maddaluno, J.; Giessner-Prettre, C.; Silvi, B. J. Org. Chem.
2001, 66, 6476–6479.
(14) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley &
Sons: New York, 1994; Chapter V, pp 255-297.
5402 J. Org. Chem. Vol. 73, No. 14, 2008

EnantioselectiVe Hydroxyalkylation with Chiral Lithium Amides
269 (M+ - Ot-Bu, 51), 239 (M+ - CO2t-Bu, 3), 185 (M+ - C12H11,
2), 170 (C12H12N and C9H16NO2, 85), 155 (C12H11, 100), 141 (M+
- C10H7 - Ot-Bu, 10), 129 (M+ - C10H7, 21), 113 (M+ - C10H7
- CO2t-Bu, 7), 85 (M+ - C12H11 - CO2t-Bu, 10), 57 (t-Bu, 28).
N-(tert-Butoxycarbonyl)-3-(S)-(1-(S)-ꢀ-naphthylethyl)ami-
nopyrrolidine 10b. Carbamate 10b was obtained reacting N-(tert-
butoxycarbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00 mmol)
with (S)-(+)-1-(ꢀ-naphthyl)ethylamine 4b (1.28 g, 7.50 mmol), and
following the above general procedure for the SN2. Purification of
the residue by flash chromatography (EtOAc/cyclohexane 40:60)
gave 10b (0.87 g, 51%) as a pale yellow oil: 1H NMR δ 1.30-1.53
(13H, m), 1.53-1.79 (1H, m), 1.79-2.12 (1H, m), 2.85-3.28 (3H,
m), 3.29-3.69 (2H, m), 3.97 (1H, q, J ) 6.7), 7.38-7.54 (3H, m),
7.74 (1H, s), 7.77-7.92 (3H, m); 13C NMR (293 K, two rotamers
observed) δ 24.8 (CH3), 28.6 (3 × CH3), 32.0 and 32.7 (CH2),
44.1 and 44.4 (CH2), 51.4 and 52.0 (CH2), 54.6 and 55.5 (CH),
56.9 (CH), 79.0 and 79.1 (C), 124.7, 125.2, 125.4, 125.6, 126.1,
127.7, 128.4 (7 × CH), 132.9, 133.4 (2 × C), 142.7 and 142.9
(C), 154.6 (C); IR (neat) ν 3479 (NH), 3308, 3053, 2973, 2929,
2875, 2244, 1686 (CdO), 1600, 1506, 1477, 1452, 1408, 1365,
further works testing its inductive potential on a large set of
enantioselective reactions, as well as spectroscopic investigations
to characterize their respective complexes, are under way. The
modifications made on the ligands were correlated to previous
structural data concerning 3APLi/nBuLi mixed aggregates (the
1Li/nBuLi exo and endo complexes). This led us to propose a
three-layer model, organized around a N-Li-C-Li quadrilat-
eral, to schematize the complexes. The docking of the aldehyde
on the under-coordinated lithium of this “reaction story” would
occur along its only accessible face that also bears the C8 chiral
appendage. Thus, the role of this selector is to influence the
sense of rotation of the aldehyde just before the C-C bond
forming reaction reaches its transition state.
Experimental Section
General Procedure for Stereospecific SN2 Reaction in the
Presence of Chiral Primary Amines (via a Triflate). A solution
of N,N-di-isopropylethylamine (1.83 mL, 10.5 mmol, 2.1 equiv)
in CH2Cl2 (2 mL) was added to a cooled (-30 °C) solution of
N-(tert-butoxycarbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00
mmol, 1.0 equiv) in CH2Cl2 (10 mL). Trifluoromethanesulfonic
anhydride (0.88 mL, 5.25 mmol, 1.05 equiv) was added dropwise
over a 10-min period and the mixture was stirred at -30 °C for 45
min. A solution of chiral amine 3-8 (7.50 mmol, 1.5 equiv) in
CH2Cl2 (10 mL) was introduced over a 5-min period and the
reaction mixture was stirred at room temperature for 24 h. The
solution was washed with saturated NaHCO3 (2 × 20 mL) and
brine (20 mL). The organic layer was separated, dried (MgSO4),
and concentrated under reduced pressure.
1253, 1169, 1125; [R]20 -90.5 (c 0.50, CHCl3); EIMS (70 eV)
D
m/z 340 (M+, 19), 325 (M+ - Me, 2), 283 (M+ - t-Bu, 18), 269
(M+ - Ot-Bu, 40), 239 (M+ - CO2t-Bu, 3), 185 (M+ - C12H11,
2), 170 (C12H12N and C9H16NO2, 100), 155 (C12H11, 90), 141 (M+
- C10H7 - Ot-Bu, 10), 129 (M+ - C10H7, 27), 113 (M+ - C10H7
- CO2t-Bu, 10), 85 (M+ - C12H11 - CO2t-Bu, 16), 57 (t-Bu, 36).
N-(tert-Butoxycarbonyl)-3-(S)-(1-(R)-cyclohexylethyl)aminopy-
rrolidine 11. Carbamate 11 was obtained reacting N-(tert-butoxy-
carbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00 mmol) with (R)-
(-)-1-cyclohexylethylamine 5 (1.11 mL, 7.50 mmol), and following
the above general procedure for the SN2. Purification of the residue
by flash chromatography (EtOAc/cyclohexane 40:60) gave 11 (0.73
N-(tert-Butoxycarbonyl)-3-(S)-(1-(R)-r-naphthylethyl)-ami-
nopyrrolidine 9. Carbamate 9 was obtained reacting N-(tert-
butoxycarbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00 mmol)
with (R)-(+)-1-(R-naphthyl)ethylamine 3 (1.28 g, 7.50 mmol), and
following the above general procedure for the SN2. Purification of
the residue by flash chromatography (EtOAc/cyclohexane 40:60)
gave 9 (0.99 g, 58%) as a viscous orange oil: 1H NMR δ 1.43-1.44
(9H, m), 1.50 (3H, d, J ) 6.4), 1.58-1.80 (2H, m), 1.87-2.10
(1H, m), 2.94-3.29 (3H, m), 3.33-3.66 (2H, m), 4.73 (1H, q, J )
6.7), 7.37-7.58 (3H, m), 7.59-7.71 (1H, m), 7.75 (1H, d, J )
8.3), 7.87 (1H, d, J ) 8.4), 8.01-8.29 (1H, m); 13C NMR (293 K,
two rotamers observed) δ 23.9 and 24.3 (CH3), 28.6 (3 × CH3),
31.4 and 32.2 (CH2), 44.1 and 44.5 (CH2), 51.6 (CH), 52.2 (CH2),
54.7 and 55.6 (CH), 79.1 (C), 122.8 (CH), 123.0 and 123.1 (CH),
125.4 and 125.5 (CH), 125.7, 125.9, 127.4, 129.1 (4 × CH), 131.2
(C), 134.0 (C), 140.9 and 141.0 (C), 154.6 and 154.7 (C); IR (neat)
ν 3316 (NH), 2973, 2928, 2873, 1681 (CdO), 1595, 1510, 1477,
g, 49%) as an orange oil: 1
H NMR δ 0.82-1.02 (5H, m), 1.02-1.30
(5H, m), 1.41 (9H, s), 1.50-1.78 (6H, m), 1.87-2.12 (1H, m),
2.30-2.50 (1H, m), 2.86-3.03 (1H, m), 3.12-3.61 (4H, m);
13C
3), 26.5,
NMR (293 K, two rotamers observed) δ 17.3 and 17.4 (CH
26.6, 26.8, 28.2, 28.6 (5 × CH
2), 29.8 (3 × CH3), 32.2 and 33.0
(CH
2), 43.3 (CH), 44.1 and 44.5 (CH2), 51.7 and 52.1 (CH2), 54.4
and 55.2 (CH), 55.9 and 56.0 (CH), 79.1 (C), 154.7 and 154.8 (C);
IR (neat) ν 3315 (NH), 2971, 2924, 2851, 1693 (CdO), 1540, 1477,
1449, 1407, 1364, 1254, 1168, 1120; [R]20
D -22.5 (c 1.06, CHCl3);
EIMS (70 eV) m/z 296 (M+
, <1), 213 (M+ - C6H11, 19), 157
(M+
(M+
- C6H11 - t-Bu, 100), 139 (M+ - C6H11 - Ot-Bu, 16), 110
- C6H11Et, 22), 70 (40), 58 (95).
N-(tert-Butoxycarbonyl)-3-(S)-(2-(R)-(3,3-dimethylbutyl))ami-
nopyrrolidine 12. Carbamate 12 was obtained reacting N-(tert-
butoxycarbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00 mmol)
with 3,3-dimethyl-2-(R)-butylamine 6 (0.76 g, 7.50 mmol), and
following the above general procedure for the SN2. Purification of
the residue by column chromatography (EtOAc/cyclohexane 20:
1453, 1411, 1365, 1255, 1215, 1168, 1123; [R]20 +6.0 (c 1.43,
D
1
CHCl3).
80) gave 12 (0.60 g, 44%) as a pale yellow oil: H NMR δ 0.85
(9H, s), 0.99 (3H, d, J ) 6.8), 1.45 (9H, s), 1.54-1.72 (1H, m),
1.96-2.11 (1H, m), 2.12-2.29 (1H, m), 2.96-3.12 (1H, m),
3.20-3.58 (4H, m); 13C NMR (293 K, two rotamers observed) δ
15.2 and 15.4 (CH3), 26.3 (3 × CH3), 28.5 (3 × CH3), 32.6 and
33.3 (CH2), 34.2 and 34.3 (C), 44.2 and 44.6 (CH2), 51.4 and 51.8
(CH2), 54.9 and 55.9 (CH), 60.0 and 60.1 (CH), 78.9 (C), 154.7
and 154.8 (C); IR (neat) ν 3320 (NH), 2968, 2870, 1697 (CdO),
N-(tert-Butoxycarbonyl)-3-(S)-(1-(R)-ꢀ-naphthylethyl)ami-
nopyrrolidine 10a. Carbamate 10a was obtained reacting N-(tert-
butoxycarbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00 mmol)
with (R)-(+)-1-(ꢀ-naphthyl)ethylamine 4a (1.28 g, 7.50 mmol), and
following the above general procedure for the SN2. Purification of
the residue by flash chromatography (EtOAc/cyclohexane 40:60)
gave 10a (0.85 g, 50%) as a pale yellow oil: 1H NMR δ 1.28-1.53
(13H, m), 1.53-1.95 (1H, 2m), 1.96-2.12 (1H, m), 2.83-3.65 (5H,
3m), 4.02 (1H, q, J ) 6.5), 7.38-7.55 (3H, m), 7.73 (1H, s),
7.77-7.89 (3H, m); 13C NMR (293 K, two rotamers observed) δ
24.5 and 24.6 (CH3), 28.3 and 28.4 (3 × CH3), 30.9 and 31.6 (CH2),
43.9 and 44.3 (CH2), 51.8 and 52.1 (CH2), 54.4 and 55.3 (CH),
56.3 and 56.7 (CH), 78.8 (C), 124.5 (CH), 125.0 and 125.1 (CH),
125.4, 125.9, 127.5, 127.6, 128.2 (5 × CH), 132.8, 133.3, 142.7 (3
× C), 154.4 and 154.5 (C); IR (neat) ν 3447 (NH), 3053, 2973,
2875, 2360, 2244, 1685 (CdO), 1600, 1507, 1476, 1451, 1410,
1364, 1252, 1168, 1125; [R]20D +24.9 (c 0.41, CHCl3); EIMS (70
eV) m/z 340 (M+, 21), 325 (M+ - Me, 3), 283 (M+ - t-Bu, 19),
1478, 1454, 1404, 1364, 1253, 1169, 1120; [R]20 -47.0 (c 0.98,
D
CHCl3).
N-(tert-Butoxycarbonyl)-3-(S)-(1-(R)-phenyl-2-N’-pyrrolidi-
nylethyl)aminopyrrolidine 13. Carbamate 13 was obtained reacting
N-(tert-butoxycarbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00
mmol, 1.0 equiv) with (R)-1-phenyl-2-(pyrrolidin-1-yl)ethanamine
7 (1.42 g, 7.50 mmol, 1.5 equiv), and following the above general
procedure. Purification of the residue by column chromatography
(EtOAc/acetone 95:5) gave 13 (0.90 g, 50%) as a pale yellow oil:
1H NMR δ 1.20-1.50 (9H, m), 1.50-2.10 (6H, m), 2.15-2.42
(1H, m), 2.42-3.21 (9H, m), 3.22-3.53 (2H, m), 3.63-3.84 (1H,
J. Org. Chem. Vol. 73, No. 14, 2008 5403

Duguet et al.
m), 7.12-7.40 (5H, m); 13C NMR (293 K, two rotamers observed)
δ 23.7 (2 × CH2), 28.6 (3 × CH3), 32.2 and 32.8 (CH2), 44.1 and
44.4 (CH2), 51.1 and 51.5 (CH2), 53.9 and 54.0 (2 × CH2), 54.4
and 55.6 (CH), 60.2 and 60.4 (CH), 63.5 and 63.8 (CH2), 79.2 (C),
127.5, 128.5 (5 × CH), 142.6 and 142.9 (C), 154.8 (C); IR (neat)
ν 3293 (NH), 3063, 2974, 2876, 2802, 2246, 1682 (CdO), 1602,
N-Methyl-3-(S)-(1-(R)-r-naphthylethyl)aminopyrrolidine 15.
Reduction of N-(tert-butoxycarbonyl)-3-(S)-(1-(R)-R-naphthylethy-
l)aminopyrrolidine 9 (0.68 g, 2.00 mmol) following the above
general procedure gave 15 (0.41 g, 80%) as an orange oil: 1H NMR
δ 1.48 (3H, d, J ) 6.8), 1.64-1.77 (1H, m), 1.97-2.19 (1H, m),
2.19-2.48 (2H, m), 2.29 (3H, s), 2.48-2.74 (2H, m), 3.17-3.33
(1H, m), 4.68 (1H, q, J ) 6.8), 7.37-7.57 (3H, m), 7.67 (1H, d, J
) 6.8), 7.74 (1H, d, J ) 8.3), 7.81-7.93 (1H, m), 8.07-8.30 (1H,
m); 13C NMR δ 24.1 (CH3), 33.1 (CH2), 42.4 (CH3), 51.5 (CH),
55.5 (CH2), 55.6 (CH), 63.6 (CH2), 123.0, 123.3, 125.3 (3 × CH),
125.8 (2 × CH), 127.2, 129.1 (2 × CH), 131.4, 134.0, 141.3 (3 ×
C) (diastereomer 3R,8R, visible peaks 24.2, 33.5, 51.8, 55.3, 55.4,
122.9, 123.0); IR (neat) ν 3304 (NH), 3047, 2960, 2863, 2833,
1477, 1454, 1413, 1366, 1255, 1167, 1125; [R]20 -67.5 (c 0.54,
D
CHCl3); CIMS (200 eV, t-BuH) m/z 360 (MH+, 100), 323 (13),
302 (MH+ - t-Bu, 7), 286 (MH+ - Ot-Bu, 7), 275 (MH+
-
C5H10N, 15), 219 (MH+ - C5H10N - t-Bu, 12), 174 (C12H16N, 6),
154 (12), 84 (C5H10N, 39); HRMS (m/z) [MH+] C21H34N3O2
requires 360.2659, found 360.2659.
N-(tert-Butoxycarbonyl)-3-(S)-(1-(S)-phenyl-2-N’-piperidinyl-
ethyl)aminopyrrolidine 14a. Carbamate 14a was obtained using
N-(tert-butoxycarbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00
mmol, 1.0 equiv) with (S)-1-phenyl-2-(piperidin-1-yl)ethanamine
8a (1.53 g, 7.50 mmol, 1.5 equiv), and following the above general
procedure. Purification of the residue by column chromatography
(EtOAc/acetone 95:5) gave 14a (0.98 g, 52%) as a pale yellow
oil: 1H NMR δ 1.24-1.70 (17H, 2m), 1.71-2.09 (1H, m),
2.10-2.74 (6H, 3m), 2.80-3.65 (5H, 3m), 3.67-3.88 (1H, m),
7.03-7.42 (5H, m); 13C NMR (293 K, two rotamers observed) δ
24.5 (CH2), 26.2 (2 × CH2), 28.6 (3 × CH3), 30.9 and 31.6 (CH2),
44.2 and 44.5 (CH2), 51.9 and 52.5 (CH2), 54.4 and 54.6 (2 ×
CH2), 55.2 and 55.4 (CH), 57.9 and 58.2 (CH), 66.3 (CH2), 79.1
and 79.2 (C), 127.4, 127.5, 128.5 (5 × CH), 142.9 (C), 154.7 and
154.8 (C); IR (neat) ν 3291 (NH), 3062, 3010, 2976, 2937, 2805,
21
2775, 1594, 1509, 1477, 1447, 1393, 1367, 1232, 1174, 1136; [R]D
+38.4 (c 0.87, CHCl3); EIMS (70 eV) m/z 254 (M+, <1), 170
(C12H12N, 13), 155 (C12H11, 25), 141 (3), 127 (C10H7 and C7H15N2,
8), 113 (5), 96 (14), 83 (M+ - C12H12N, 28), 58 (100).
N-Methyl-3-(S)-(1-(R)-ꢀ-naphthylethyl)aminopyrrolidine 16a.
Reduction of N-(tert-butoxycarbonyl)-3-(S)-(1-(R)-ꢀ-naphthylethyl)-
aminopyrrolidine 10a (0.68 g, 2.00 mmol) following the above
general procedure gave 16a (0.44 g, 87%) as a pale yellow oil: 1H
NMR δ 1.42 (3H, d, J ) 6.4), 1.46-1.95 (2H, m), 1.95-2.14 (1H,
m), 2.14-2.43 (2H, m), 2.27 (3H, s), 2.43-2.52 (1H, m), 2.52-2.71
(1H, m), 3.08-3.26 (1H, m), 3.96 (1H, q, J ) 6.4), 7.35-7.60
(3H, m), 7.73 (1H, s), 7.74-7.90 (3H, m); 13C NMR δ 24.5 (CH3),
32.7 (CH2), 42.2 (CH3), 55.2 (CH2), 55.4 (CH), 56.3 (CH), 63.5
(CH2), 125.0, 125.3, 125.4, 125.9, 127.6, 127.7, 128.1 (7 × CH),
132.8, 133.4, 143.0 (3 × C) (diastereomer 3R,8R, visible peaks
24.6, 33.4, 42.3, 55.19, 55.22, 56.7, 62.4, 124.9, 125.3, 125.4, 125.9,
127.6, 127.7, 128.2, 132.8, 133.4, 142.9); IR (neat) ν 3307 (NH),
2399, 1681 (CdO), 1602, 1476, 1453, 1414, 1365; [R]20 +57.1
D
(c 0.64, CHCl3); HRMS (m/z) [MH+] C22H36N3O2 requires 374.2816,
found 374.2826.
3054, 2962, 2838, 2783, 2359, 2189, 1600, 1506, 1477, 1448; [R]20
D
N-(tert-Butoxycarbonyl)-3-(S)-(1-(R)-phenyl-2-N’-piperidinyl-
ethyl)aminopyrrolidine 14b. Carbamate 14b was obtained using
N-(tert-butoxycarbonyl)-3-(R)-hydroxypyrrolidine 2 (0.94 g, 5.00
mmol, 1.0 equiv) with (R)-1-phenyl-2-(piperidin-1-yl)ethanamine
8b (1.53 g, 7.50 mmol, 1.5 equiv), and following the above general
procedure. Purification of the residue by column chromatography
(EtOAc/acetone 95:5) gave 14b (1.20 g, 64%) as a pale yellow
oil: 1H NMR δ 1.00-1.68 (17H, 2m), 1.70-1.95 (1H, m),
1.96-2.60 (6H, 2m), 2.81-3.21 (3H, m), 3.22-3.52 (2H, 2m),
3.53-3.85 (1H, m), 6.99-7.42 (5H, m); 13C NMR (293 K, two
rotamers observed) δ 24.6 (CH2), 26.3 (2 × CH2), 28.6 (3 × CH3),
32.3 and 33.0 (CH2), 44.1 and 44.5 (CH2), 51.2 and 51.6 (CH2),
54.5 (2 × CH2), 55.8 (CH), 58.4 (CH), 66.4 (CH2), 79.2 (C), 127.4,
127.5, 127.6, 128.5 (5 × CH), 142.9 and 143.2 (C), 154.8 (C); IR
(neat) ν 3290 (NH), 3061, 2975, 2935, 2854, 2805, 2244, 1686
(CdO), 1602, 1477, 1453, 1408, 1365, 1255, 1166, 1138, 1117;
+58.4 (c 1.02, CHCl3); EIMS (70 eV) m/z 254 (M+, 22), 170
(C12H12N, 100), 155 (C12H11, 46), 127 (C10H7 and C7H15N2, 9), 99
(M+ - C12H11, 56), 85 (M+ - C12H12N, 38), 57 (71).
N-Methyl-3-(S)-(1-(S)-ꢀ-naphthylethyl)aminopyrrolidine 16b.
Reduction of N-(tert-butoxycarbonyl)-3-(S)-(1-(S)-ꢀ-naphthylethyl)-
aminopyrrolidine 10b (0.68 g, 2.00 mmol) following the above
general procedure gave 16b (0.42 g, 83%) as a pale yellow oil: 1H
NMR δ 1.41 (3H, d, J ) 6.8), 1.42-1.59 (1H, m), 1.60-1.93 (1H,
m), 1.95-2.12 (1H, m), 2.12-2.40 (1H, m), 2.32 (3H, s), 2.40-2.52
(1H, m), 2.52-2.72 (2H, m), 3.07-3.26 (1H, m), 3.94 (1H, q, J )
6.8), 7.35-7.58 (3H, m), 7.73 (1H, s), 7.76-7.92 (3H, m); 13C
NMR δ 24.6 (CH3), 33.4 (CH2), 42.3 (CH3), 55.1 (CH2), 55.2 (CH),
56.7 (CH), 62.4 (CH2), 124.9, 125.3, 125.4, 125.9, 127.6, 127.7,
128.2 (7 × CH), 132.8, 133.4, 142.9 (3 × C) (diastereomer 3R,8S,
visible peaks 24.5, 32.7, 42.2, 55.3, 55.4, 56.3, 63.5, 125.0, 125.3,
125.4, 125.9, 127.6, 127.7, 128.1, 132.8, 133.4, 143.0); IR (neat)
ν 3307 (NH), 3054, 2963, 2839, 2783, 2189, 1600, 1506, 1477,
1448; [R]20D -72.1 (c 1.16, CHCl3); EIMS (70 eV) m/z 254 (M+,
14), 170 (C12H12N, 100), 155 (C12H11, 35), 127 (C10H7 and C7H15N2,
10), 99 (M+ - C12H11, 65), 85 (M+ - C12H12N, 31), 57 (73).
N-Methyl-3-(S)-(1-(R)-cyclohexylethyl)aminopyrrolidine 17.
Reduction of N-(tert-butoxycarbonyl)-3-(S)-(1-(R)-cyclohexylethyl)-
aminopyrrolidine 11 (0.59 g, 2.00 mmol) following the above
general procedure gave 17 (0.34 g, 81%) as a yellow-orange oil:
1H NMR δ 0.77-1.37 (7H, m), 0.95 (3H, d, J ) 6.4), 1.42-1.57
(1H, m), 1.57-1.80 (5H, m), 2.00-2.23 (1H, m), 2.23-2.35 (1H,
m), 2.30 (3H, s), 2.35-2.48 (2H, m), 2.48-2.77 (2H, 2m),
3.26-3.47 (1H, m); 13C NMR δ 16.8 (CH3), 26.4, 26.6, 26.7, 27.9,
29.9 (5 × CH2), 33.5 (CH2), 42.3 (CH3), 43.2 (CH), 55.0 (CH),
55.3 (CH2), 55.9 (CH), 63.1 (CH2) (diastereomer 3R,8R, visible
peaks 16.9, 28.0, 29.8, 32.9, 43.0, 55.1, 55.6, 63.7); IR (neat) ν
3304 (NH), 2922, 2850, 2772, 1476, 1447, 1373, 1344, 1232, 1155;
[R]20 -74.2 (c 0.78, CHCl3); CIMS (200 eV, t-BuH) m/z 374
D
(MH+, 100), 360 (4), 318 (3), 275 (MH+ - C6H12N, 4), 219 (MH+
- t-Bu - C6H12N, 5), 188 (5), 154 (2), 98 (C6H12N, 35), 86
(C5H12N, 4); HRMS (m/z) [MH+] C22H36N3O2 requires 374.2816,
found 374.2826.
General Procedure for Reduction of the Boc Group. A sol-
ution of N-(tert-butoxycarbonyl)-3-(S)-aminopyrrolidine 9-14 (2.00
mmol, 1.0 equiv) in dry THF (60 mL) was added over a 30-min
period to a suspension of lithium aluminum hydride (LiAlH4, 0.42 g,
11.0 mmol, 5.5 equiv) in freshly distilled THF (20 mL), placed
under an argon atmosphere at 0 °C. The solution was stirred at
room temperature for 5 h then heated at 60 °C for 1 h. After cooling
at 0 °C, the excess of LiAlH4 was hydrolyzed by successive addition
of cold water (1.2 mL), 4 M aqueous sodium hydroxide (1.2 mL),
and cold water (1.6 mL). The white precipitate was filtered on celite
and washed with CH2Cl2 (20 mL). The filtrate was concentrated,
and the residue was dissolved in Et2O (20 mL). Aqueous hydro-
chloric acid (1 M, 20 mL) was added and the solution was stirred
at room temperature for 15 min. The acidic aqueous layer was
extracted and NaHCO3 was slowly added until pH 9. The medium
was then extracted with CH2Cl2 (3 × 20 mL). The organic layers
were combined, dried (MgSO4), and concentrated under reduced
pressure.
[R]20 -24.0 (c 0.80, CHCl3); EIMS (70 eV) m/z 210 (M+, 6),
D
166 (5), 127 (M+ - C6H11, 56), 126 (C8H16N, 46), 93 (23), 82
(60), 70 (22), 58 (100).
N-Methyl-3-(S)-(2-(R)-(3,3-dimethylbutyl))aminopyrroli-
dine 18. Reduction of N-(tert-butoxycarbonyl)-3-(S)-(2-(R)-(3,3-
dimethylbutyl))aminopyrrolidine 12 (0.54 g, 2.00 mmol) following
5404 J. Org. Chem. Vol. 73, No. 14, 2008

EnantioselectiVe Hydroxyalkylation with Chiral Lithium Amides
the above general procedure gave 18 (0.26 g, 70%) as a colorless
4.9), 2.64-2.88 (2H, m), 2.91-3.14 (2H, m), 3.72 (1H, q, J )
6.8), 7.08-7.40 (5H, m); IR (neat) ν 3271 (NH), 3027, 2964, 2868,
1492, 1451, 1265; EIMS (70 eV) m/z 191 (M+, <1), 160 (9), 146
(3), 132 (4), 120 (C8H10N, 42), 105 (PhEt, 100), 85 (M+ - PhEt,
26), 77 (C6H5, 31).
1
liquid: H NMR δ 0.84 (9H, s), 0.94 (3H, d, J ) 6.4), 1.35-1.55
(1H, m), 2.06-2.33 (3H, m), 2.30 (3H, s), 2.34-2.46 (1H, m),
2.50-2.62 (2H, m), 3.25-3.42 (1H, m); 13C NMR δ 15.0 (CH3),
26.5 (3 × CH3), 33.9 (CH2), 34.2 (C), 42.5 (CH3), 55.5 (CH2),
55.9 (CH), 60.6 (CH), 63.1 (CH2) (diastereomer 3R,8R, visible
peaks 32.7, 45.7, 56.2, 60.0, 64.1); IR (neat) ν 2956, 2867, 2833,
2772, 1478, 1446, 1391, 1372, 1362, 1232, 1126; [R]21D -64.0 (c
1.00, CHCl3); EIMS (70 eV) m/z 184 (M+, <1), 143 (2), 127 (M+
- tBu, 11), 93 (8), 82 (14), 70 (11), 58 (70), 44 (C2H6N, 100).
N-Methyl-3-(S)-(1-(R)-phenyl-2-N’-pyrrolidinylethyl)aminopy-
rrolidine 19. Reduction of N-(tert-butoxycarbonyl)-3-(S)-(1-(R)-
phenyl-2-N’-pyrrolidinylethyl)amino pyrrolidine 13 (0.72 g, 2.00
mmol) following the above general procedure gave 19 (0.39 g, 71%)
3-(S)-(1-(S)-Phenylethyl)aminopyrrolidine 22b. Deprotection
of the Boc group of N-(tert-butoxycarbonyl)-3-(S)-(1-(S)-phenyl-
ethyl)aminopyrrolidine 21b (1.45 g, 5.00 mmol) by TFA following
the above general procedure gave 22b (0.88 g, 93%) as a pale
1
orange oil: H NMR δ 1.22 (3H, d, J ) 6.8), 1.15-1.35 (1H, m),
1.65-2.23 (3H, 2m), 2.59-2.75 (2H, m), 2.78 (1H, dd, J ) 10.9,
5.6), 2.84-3.07 (2H, m), 3.65 (1H, q, J ) 6.8), 7.00-7.30 (5H,
m); 13C NMR δ 24.7 (CH3), 33.9 (CH2), 45.8 (CH2), 53.1 (CH2),
56.3 (CH), 56.7 (CH), 126.6, 127.0, 128.5 (5 × CH), 145.6 (C);
IR (neat) ν 3276 (NH), 3024, 2964, 2867, 1492, 1450; [R]20D -91.9
(c 0.98, CHCl3); EIMS (70 eV) m/z 191 (M+, <1), 160 (7), 146
(5), 132 (4), 120 (C8H10N, 34), 105 (PhEt, 100), 85 (M+ - PhEt,
25), 77 (C6H5, 32).
1
as a pale yellow oil: H NMR δ 1.30-1.53 (1H, m), 1.54-1.80
(4H, m), 1.83-2.04 (1H, m), 2.04-2.30 (2H, m), 2.24 (3H, s),
2.30-2.63 (8H, 2m), 2.75 (1H, t, J ) 10.5), 2.90-3.16 (1H, m),
3.65 (1H, dd, J ) 10.5, 3.4), 7.00-7.39 (5H, m); 13C NMR δ 23.7
(2 × CH2), 33.6 (CH2), 42.6 (CH3), 54.2 (2 × CH2), 55.2 (CH2),
55.3 (CH), 60.7 (CH), 62.4 (CH2), 64.1 (CH2), 127.3, 127.6, 128.4
(5 × CH), 143.1 (C); IR (neat) ν 3296 (NH), 3062, 2966, 2874,
N,N-Dimethyloxamoyl chloride 23. Oxalyl chloride (0.52 mL,
6.00 mmol, 3.0 equiv) was added dropwise to a suspension of
dimethylamine hydrochloride (0.16 g, 2.00 mmol, 1.0 equiv) in
CCl4 (80 mL) at 0 °C and the reaction mixture was stirred at 65
°C for 18 h (until the liberation of HCl had stopped). After cooling
to room temperature, the excess of oxalyl chloride and the solvent
were removed under reduce pressure and CCl4 (30 mL) was added
and evaporated. This operation was performed twice to give 23 as
a colorless oil. The crude product was used in the next step without
any purification. The N,N-dimethyloxamoyl chloride 23 can be
characterized after hydrolysis of the crude product by MeOH. The
residue was purified by column chromatography (EtOAc) to give
the corresponding amidoester (0.13 g, 50%) as a pale yellow oil:
1H NMR δ 2.98 (3H, s), 3.01 (3H, s), 3.86 (3H, s); 13C NMR (293
K, two rotamers observed) δ 34.2 and 34.3 (CH3), 37.2 and 37.3
(CH3), 52.6 and 52.7 (CH3), 161.4 and 161.5 (C), 163.3 and 163.4
(C); IR (neat) ν 3511, 3011, 2957, 1743 (CdO), 1665 (CdO), 1508,
1436, 1414, 1280, 1249; EIMS (70 eV) m/z 131 (M+, 19), 72 (M+
s CO2Me, 100).
2789, 1602, 1491, 1478, 1451, 1381, 1349, 1216, 1149, 1117; [R]22
-98.8 (c 0.82, CHCl3).
D
N-Methyl-3-(S)-(1-(S)-phenyl-2-N’-piperidinylethyl)aminopy-
rrolidine 20a. Reduction of N-(tert-butoxycarbonyl)-3-(S)-(1-(S)-
phenyl-2-N’-piperidinylethyl)aminopyrrolidine 14a (0.75 g, 2.00
mmol) following the above general procedure gave 20a (0.53 g,
92%) as a pale yellow oil: 1H NMR δ 1.20-1.63 (7H, m),
1.75-2.90 (14H, m), 2.94-3.13 (1H, m), 3.69 (1H, dd, J ) 11.3,
3.4), 7.03-7.45 (5H, m); 13C NMR δ 24.6 (CH2), 26.2 (2 × CH2),
32.9 (CH2), 42.5 (CH3), 54.7, 55.4 (3 × CH2), 55.8 (CH), 58.4
(CH), 63.7 (CH2), 66.5 (CH2), 127.2, 127.7, 128.3 (5 × CH), 143.2
(C); IR (neat) ν 3284 (NH), 3062, 3017, 2939, 2852, 2788, 1491,
1467, 1452; [R]20D +97.6 (c 1.09, CHCl3); EIMS (70 eV) m/z 287
(M+, <1), 189 (M+ - C6H12N, 29), 98 (C6H12N, 100), 82 (22).
N-Methyl-3-(S)-(1-(R)-phenyl-2-N’-piperidinylethyl)aminopy-
rrolidine 20b. Reduction of N-(tert-butoxycarbonyl)-3-(S)-(1-(R)-
phenyl-2-N’-piperidinylethyl)aminopyrrolidine 14b (0.75 g, 2.00
mmol) following the above general procedure gave 20b (0.47 g,
82%) as a pale yellow oil: 1H NMR δ 1.18-1.61 (7H, 2m),
1.79-2.01 (1H, m), 2.02-2.60 (14H, m), 2.89-3.15 (1H, m), 3.66
(1H, dd, J ) 10.9, 3.4), 6.93-7.37 (5H, m); 13C NMR δ 24.6 (CH2),
26.2 (2 × CH2), 33.7 (CH2), 42.6 (CH3), 54.8, 55.2 (3 × CH2),
55.5 (CH), 58.8 (CH), 62.7 (CH2), 66.7 (CH2), 127.2, 127.7, 128.4
(5 × CH), 143.2 (C); IR (neat) ν 3392 (NH), 3060, 3024, 2934,
2771, 1490, 1466, 1452; [R]D21: -107.4 (c 0.91, CHCl3); CIMS
General Procedure for Introduction of the Oxamoyl Group
(CO)2NMe2 on Diamines 22a and 22b. A solution of diamine 22a
or 22b (0.38 g, 2.00 mmol, 1.0 equiv) in CH2Cl2 (30 mL) was
added at 0 °C to a solution of 23 (0.27 g, 2.00 mmol, 1.0 equiv) in
CH2Cl2 (50 mL) and the mixture was stirred at room temperature
for 2 h. The precipitate formed was filtered through a celite pad
and the filtrate was concentrated under reduce pressure.
N-(N’,N’-Dimethyloxamoyl)-3-(S)-(1-(R)-phenylethyl)ami-
nopyrrolidine 24a. The amine 24a was prepared using 3-(S)-(1-
(R)-phenylethyl)aminopyrrolidine 22a (0.38 g, 2.00 mmol) and N,N-
dimethyloxamoyl chloride 23 (0.27 g, 2.00 mmol) following the
above general procedure. The residue was purified by column
chromatography (CH2Cl2/MeOH 95:5) to give 24a (0.43 g, 74%)
as a yellow oil: 1H NMR (293 K, two rotamers observed) δ
1.18-1.37 (1H, m), 1.25 (3H, d, J ) 6.4), 1.51-1.80 (1H, m),
1.90-2.12 (1H, m), 2.83 and 2.84 (3H, 2 × s), 2.88 and 2.90 (3H,
2 × s), 2.78-2.98 and 3.00-3.10 (1H, 2 × m), 3.10-3.24 (1H,
m), 3.24-3.42 and 3.42-3.68 (3H, 2 × m), 3.68-3.82 (1H, 2 ×
q, J ) 6.4), 7.09-7.32 (5H, m); 13C NMR (293 K, two rotamers
observed) δ 24.5 and 24.6 (CH3), 30.4 and 31.6 (CH2), 33.5 and
33.6 (CH3), 36.9 and 37.0 (CH3), 43.2 and 44.9 (CH2), 51.0 and
52.6 (CH2), 53.8 and 55.5 (CH), 56.2 and 56.6 (CH), 126.4 and
126.5, 127.1, 128.4 and 128.5 (5 × CH), 145.1 and 145.2 (C), 163.2
(C), 164.9 and 165.0 (C); IR (neat) ν 3491 (NHbonded), 3305 (NHfree),
3053, 3025, 2996, 2883, 1631 (2 × CdO), 1466, 1451, 1434, 1391,
1265, 1146; [R]20D +26.6 (c 0.61, CHCl3); EIMS (70 eV) m/z 289
(M+, <1), 274 (M+ - CH3, 7), 189 (M+ - (CO)2NMe2, 9), 120
(C8H10N, 100), 105 (PhEt, 86), 85 (M+ - PhEt - (CO)2NMe2,
16), 72 (CONMe2, 72).
(200 eV, t-BuH) m/z 288 (MH+, 100), 205 (10), 189 (MH+
-
C6H12N, 31), 166 (6), 154 (14), 132 (7), 98 (C6H12N, 39), 82 (23);
HRMS (m/z) [MH+] C18H30N3 requires 288.2440, found 288.2439.
General Procedure for Deprotection of the Boc Group of
21a and 21b. Trifluoroacetic acid (TFA, 3.06 mL, 40.0 mmol, 8
equiv) was added dropwise to a stirred solution of amine 21a or
21b (1.45 g, 5.00 mmol, 1.0 equiv) in CH2Cl2 (50 mL). The reaction
mixture was stirred at room temperature for 7 h and then the excess
of TFA and the solvent were removed in vacuo. CH2Cl2 (30 mL)
was added and evaporated. This operation was performed twice.
The residue was diluted in CH2Cl2 (30 mL) and 1 M aqueous
hydrochloric acid solution (30 mL) was added. The resulting
mixture was stirred at room temperature for 15 min. The acidic
aqueous layer was extracted and 4 M aqueous sodium hydroxide
solution was slowly added until pH 9. The medium was then
extracted with CH2Cl2 (3 × 30 mL). The organic layers were
combined, dried (MgSO4) and concentrated under reduced pressure.
3-(S)-(1-(R)-Phenylethyl)aminopyrrolidine 22a. Deprotection
of the Boc group of N-(tert-butoxy-carbonyl)-3-(S)-(1-(R)-phenyl-
ethyl)aminopyrrolidine 21a (1.45 g, 5.00 mmol) by TFA following
the above general procedure gave 22a (0.80 g, 84%) as a pale
N-(N’,N’-Dimethyloxamoyl)-3-(S)-(1-(S)-phenylethyl)aminopy-
rrolidine 24b. The amine 24b was prepared using 3-(S)-(1-(S)-
phenylethyl)aminopyrrolidine 22b (0.38 g, 2.00 mmol) and N,N-
1
orange oil: H NMR δ 1.27 (3H, d, J ) 6.8), 1.42-1.60 (1H, m),
1.76-1.95 (1H, m), 1.98-2.35 (2H, br), 2.48 (1H, dd, J ) 11.3,
J. Org. Chem. Vol. 73, No. 14, 2008 5405

Duguet et al.
dimethyloxamoyl chloride 23 (0.27 g, 2.00 mmol) following the
above general procedure. The residue was purified by column
chromatography (CH2Cl2/MeOH 95:5) to give 24b (0.51 g, 88%)
with saturated NaHCO3 (2 × 2 mL) and brine (2 mL). The organic
layer was separated, dried (MgSO4), and concentrated under reduced
pressure.
N-(N’,N’-Dimethyloxamoyl)-3-(S)-(1-(R)-phenylethyl)ami-
nopyrrolidine 24a. The amine 24a was prepared from N-(N’,N’-
dimethyloxamoyl)-3-(R)-hydroxypyrrolidine 26 (0.37 g, 2.00 mmol)
and (R)-R-methylbenzylamine (0.39 mL, 3.00 mmol) following the
above general procedure. Purification of the residue by column
chromatography (CH2Cl2/MeOH 95:5) gave 24a (0.20 g, 54%) as
a yellow oil.
N-(N’,N’-Dimethyloxamoyl)-3-(S)-(1-(S)-phenylethyl)aminopy-
rrolidine 24b. The amine 24b was prepared from N-(N’,N’-
dimethyloxamoyl)-3-(R)-hydroxypyrrolidine 26 (0.37 g, 2.00 mmol)
and (S)-R-methylbenzylamine (0.39 mL, 3.00 mmol) following the
above general procedure. Purification of the residue by column
chromatography (CH2Cl2/MeOH 95:5) gave 24b (0.19 g, 51%) as
a yellow oil.
1
as a yellow oil: H NMR (293 K, two rotamers observed) δ 1.23
and 1.25 (3H, d, J ) 6.4), 1.46-1.69 (1H, m), 1.70-2.13 (2H,
m), 2.87 and 2.90 (6H, 2s), 3.05-3.21 and 3.21-3.38 (3H, 2m),
3.39-3.61 (2H, m), 3.61-3.78 (1H, m), 7.04-7.33 (5H, m); 13C
NMR (293 K, two rotamers observed) δ 25.1 (CH3), 31.4 and 32.8
(CH2), 33.9 and 34.0 (CH3), 37.3 (CH3), 43.6 and 45.2 (CH2), 50.8
and 52.5 (CH2), 54.1 and 55.4 (CH), 56.8 and 56.9 (CH), 126.6
and 126.7, 126.8 and 127.4, 127.4 and 128.8 (5 × CH), 145.3 (C),
163.5 and 163.7 (C), 165.3 and 165.4 (C); IR (neat) ν 3450 (NH),
3052, 2966, 2885, 1636 (2 × CdO), 1466, 1451, 1435, 1393, 1265;
[R]20 -91.9 (c 0.57, CHCl3); EIMS (70 eV) m/z 289 (M+, 4),
D
274 (M+ s CH3, 22), 189 (M+ - (CO)2NMe2, 22), 120 (C8H10N,
100), 105 (PhEt, 86), 85 (M+ - PhEt - (CO)2NMe2, 16), 72
(CONMe2, 72).
N-(N’,N’-Dimethyloxamoyl)-3-(R)-hydroxypyrrolidine 26. A
solution of 3-(R)-hydroxypyrrolidine 25 (0.15 mL, 1.81 mmol, 1.0
equiv) in CH2Cl2 (5 mL) was added dropwise to a solution of 23
(0.25 g, 1.81 mmol, 1.0 equiv) in CH2Cl2 (55 mL) at 0 °C and the
mixture was stirred at room temperature for 1 h. The precipitate
formed was filtered through a celite pad and the filtrate was
concentrated under reduce pressure. The residue was purified by
column chromatography (CH2Cl2/MeOH 99:1 f 95:5) to give 26
(0.21 g, 62%) as a pale brown oil: 1H NMR δ 1.90-2.10 (2H, m),
2.94-2.96 (3H, m), 2.98-3.00 (3H, m), 3.30-3.80 (5H, m),
4.35-4.57 (1H, m); 13C NMR (293 K, two rotamers observed) δ
32.7 and 34.0 (CH2), 33.8 and 33.9 (CH3), 37.2 (CH3), 43.1 and
44.6 (CH2), 53.6 and 54.9 (CH2), 69.2 and 70.3 (CH), 163.6 and
163.7 (C), 165.3 (C); IR (neat) ν 3407 (OH), 3053, 2945, 2358,
General Procedure for Introduction of the (R)- or (S)-r-Me-
thylbenzylamine Group from 27 (via a Mesylate). A mixture of
N-(N’,N’-dimethyloxamoyl)-3-(R)-methylsulfonyloxypyrrolidine 27
(0.53 g, 2.00 mmol, 1.0 equiv) and (R)- or (S)-R-methylbenzylamine
(2.06 mL, 16.0 mmol, 8 equiv) was heated at 105-110 °C for 24 h.
After cooling to room temperature, EtOAc (10 mL) and 4 M
aqueous NaOH solution (5 mL) were added and the mixture was
stirred vigorously. The aqueous layer was extracted with EtOAc
(2 × 5 mL) and the organic layers were combined, washed with
water (10 mL), dried (MgSO4) and concentrated under reduced
pressure.
N-(N’,N’-Dimethyloxamoyl)-3-(S)-(1-(R)-phenylethyl)ami-
nopyrrolidine 24a. The amine 24a was thus prepared from
N-(N’,N’-dimethyloxamoyl)-3-(R)-methylsulfonyloxypyrrolidine 27
(0.53 g, 2.00 mmol) and (R)-R-methylbenzylamine (2.06 mL, 16.0
mmol) following the above general procedure. Purification of the
residue by column chromatography (CH2Cl2/MeOH 95:5) gave 24b
(0.42 g, 70%) as a yellow oil.
1635 (2 × CdO), 1521, 1471, 1437, 1394; [R]19 -32.4 (c 1.21,
D
CHCl3); EIMS (70 eV) m/z 186 (M+, 3), 168 (M+ - H2O, 5), 149
(7), 114 (M+ - CONMe2, 29), 86 (M+ - (CO)2NMe2, 67), 72
(CONMe2, 100).
N-(N’,N’-Dimethyloxamoyl)-3-(R)-methylsulfonyloxypyrroli-
dine 27. Pyridine (0.33 mL, 4.14 mmol), methanesulfonyl chloride
(0.33 mL, 4.27 mmol), and a catalytic amount of 4-dimethylami-
nopyridine (4-DMAP, 15 mg) were added to a solution of N-(N’,N’-
dimethyloxamoyl)-3-(R)-hydroxypyrrolidine 26 (0.51 g, 2.74 mmol)
in CH2Cl2 (10 mL) at 0 °C. After being stirred for 72 h at room
temperature, the solution was concentrated and EtOAc (10 mL)
was added to the residue. The insoluble salt was filtered through
celite and the remaining solution was concentrated. The residue
was purified by column chromatography (CH2Cl2/MeOH 96:4) to
N-(N’,N’-Dimethyloxamoyl)-3-(S)-(1-(S)-phenylethyl)aminopy-
rrolidine 24b. The amine 24b was thus prepared from N-(N’,N’-
dimethyloxamoyl)-3-(R)-methylsulfonyloxypyrrolidine 27 (0.53 g,
2.00 mmol) and (S)-R-methylbenzylamine (2.06 mL, 16.0 mmol)
following the above general procedure. Purification of the residue
by column chromatography (CH2Cl2/MeOH 95:5) gave 24b (0.40
g, 69%) as a yellow oil.
General Procedure for Reduction of the Diamido Group of
24. A solution of amine 24a or 24b (0.29 g, 1.00 mmol, 1.0 equiv)
in dry THF (30 mL) was added over 30 min to a suspension of
lithium aluminum hydride (LiAlH4, 0.38 g, 10.0 mmol, 10.0 equiv)
in freshly distilled THF (10 mL), placed under argon atmosphere
at 0 °C. The solution was stirred at room temperature for 5 h then
heated at 60 °C for 1 h. After cooling at 0 °C, the excess of LiAlH4
was hydrolyzed by successive addition of cold water (0.9 mL), 4
M aqueous sodium hydroxide (0.9 mL) and cold water (1.3 mL).
The white precipitate was filtered on celite and washed with CH2Cl2
(15 mL). The filtrate was concentrated and the residue was dissolved
in Et2O (15 mL). 1 M aqueous hydrochloric acid (15 mL) was added
and the solution was stirred at room temperature for 15 min. The
acidic aqueous layer was extracted and NaHCO3 was slowly added
until pH 9. The medium was then extracted with CH2Cl2 (3 × 15
mL). The organic layers were combined, dried (MgSO4) and
concentrated under reduced pressure.
N-(N’,N’-Dimethylaminoethyl)-3-(S)-(1-(R)-phenylethyl)ami-
nopyrrolidine 28a. Reduction of N-(N’,N’-dimethyloxamoyl)-3-
(S)-(1-(R)-phenylethyl)aminopyrrolidine 24a (0.29 g, 1.00 mmol)
by LiAlH4 (0.38 g, 10.0 mmol) following the above general
procedure gave 28a (0.222 g, 85%) as pale orange oil: 1H NMR δ
1.26 (3H, d, J ) 6.4), 1.45-1.59 (1H, m), 1.59-1.88 (1H, br),
1.89-2.05 (1H, m), 2.06-2.22 (1H, m), 2.14 (6H, s), 2.25-2.62
(7H, m), 2.97-3.16 (1H, m), 3.71 (1H, q, J ) 6.4), 7.06-7.33
(5H, m); 13C NMR δ 24.4 (CH3), 31.6 (CH2), 45.8 (CH3), 45.9
(CH3), 53.6 (CH2), 54.2 (CH2), 54.7 (CH), 56.3 (CH), 58.2 (CH2),
1
give 27 (0.54 g, 75%) as a pale yellow oil: H NMR (293 K, two
rotamers observed) δ 2.00-2.44 (2H, m), 2.92 and 2.93 (3H, 2 ×
s), 2.97 and 2.98 (3H, 2 × s), 2.99 and 3.00 (3H, 2 × s), 3.49-3.91
(4H, m), 5.19-5.33 (1H, m); 13C NMR (293 K, two rotamers
observed) δ 30.8 and 32.7 (CH2), 33.9 and 34.0 (CH3), 37.2 and
37.3 (CH3), 38.8 (CH3), 42.8 and 44.2 (CH2), 51.4 and 53.0 (CH2),
78.3 and 79.4 (CH), 163.1 and 163.2 (C), 164.5 (C); IR (neat) ν
3489, 3014, 2936, 1636 (2 × CdO), 1517, 1469, 1436, 1395, 1354
(RSO2OR), 1263, 1233, 1172 (RSO2OR), 1150, 1082, 1059; [R]20
D
-31.4 (c 1.02, CHCl3); EIMS (70 eV) m/z 264 (M+, 4), 192 (M+
- CONMe2, 15), 164 (M+ - (CO)2NMe2, 15), 114 (M+
-
CONMe2 - SO2Me, 4), 96 (CH3SO3H, 17), 72 (CONMe2, 100).
General Procedure for Introduction of the (R)- or (S)-r-Me-
thylbenzylamine Group from Pyrrolidinol 26 (via a Triflate).
A solution of N,N-di-isopropylethylamine (0.73 mL, 4.20 mmol,
2.1 equiv) in CH2Cl2 (1.0 mL) was added to a cooled (-30 °C)
solution of N-(N’,N’-dimethyloxamoyl)-3-(R)-hydroxypyrrolidine
26 (0.37 g, 2.00 mmol, 1.0 equiv) in CH2Cl2 (5.0 mL). Trifluo-
romethanesulfonic anhydride (0.35 mL, 2.10 mmol, 1.05 equiv)
was added dropwise under a 10-min period and the mixture was
stirred at -30 °C for 45 min. A solution of (R)- or (S)-R-
methylbenzylamine (0.39 mL, 3.00 mmol 1.5 equiv) in CH2Cl2 (5
mL) was introduced over a 5-min period and the reaction mixture
was stirred at room temperature for 24 h. The solution was washed
5406 J. Org. Chem. Vol. 73, No. 14, 2008

EnantioselectiVe Hydroxyalkylation with Chiral Lithium Amides
61.5 (CH2), 126.8, 127.1, 128.5 (5 × CH), 145.2 (C) (diastereomer
3R,8R visible peaks 24.5, 32.5, 53.4, 54.4, 54.5, 56.7, 60.8); IR
(neat) ν 3304 (NH), 3026, 2959, 2860, 2814, 1492, 1451, 1265;
The aqueous layer was extracted with EtOAc (2 × 5 mL) and the
organic layers were combined, washed with water (10 mL), dried
(MgSO4) and concentrated under reduced pressure.
[R]20 +26.1 (c 0.52, CHCl3); EIMS (70 eV) m/z 261 (M+, 3),
(3R,3S)-N-(tert-Butoxycarbonyl)-3-(1-(R)-phenylethyl)-ami-
nopyrrolidine 36a. Carbamate 36a was prepared reacting (()-N-
(tert-butoxycarbonyl)-3-methylsulfonyloxypyrrolidine 35 (0.53 g,
2.00 mmol) with (R)-R-methylbenzylamine (2.06 mL, 16.0 mmol),
and following the above general procedure. Purification of the
residue by column chromatography (EtOAc/cyclohexane 60:40)
gave 36a (0.50 g, 86%) as a pale orange oil: 1H NMR (1:1 mixture
of diastereomers) δ 1.20-1.30 (2 × 3H, d, J ) 6.8), 1.30-1.43 (2
× 9H, s), 1.43-1.70 (2 × 1H, m), 1.71-2.02 (2 × 2H, 2m),
2.74-2.82 (1H, m), 2.82-3.55 (4H + 5H, 2m), 3.65-3.83 (2 ×
1H, q, J ) 6.8), 7.08-7.36 (2 × 5H, m); 13C NMR (293 K, 1:1
mixture of diastereomers, two rotamers observed for each) δ 25.2
and 25.3 (CH3), 25.4 and 25.5 (CH3), 29.1 (3 × CH3), 29.2 (3 ×
CH3), 31.7 and 32.5 (CH2), 32.6 and 33.4 (CH2), 44.6 and 45.1
(CH2), 44.7 and 45.0 (CH2), 52.0 and 52.6 (CH2), 52.5 and 52.9
(CH2), 55.1 and 56.0 (CH), 55.2 and 56.0 (CH), 57.0 (CH), 57.3
(CH), 79.7 and 79.9 (C), 79.8 (C), 127.2, 127.8, 129.2 (2 × 5 ×
CH), 146.0 (2 × C), 155.2 (C), 155.3 (C); IR (neat) ν 3436 (NH),
3052, 3026, 2975, 2876, 1681 (CdO), 1492, 1477, 1451, 1408,
1365, 1265, 1169, 1120; [R]20D +58.8 (c 0.78, CHCl3); EIMS (70
eV) m/z 290 (M+, <1), 232 (M+ - t-Bu, 10), 219 (M+ - Ot-Bu,
28), 129 (M+ - t-Bu - PhEt, 40), 118 (72), 101 (CO2t-Bu, 100),
83 (M+ - CO2t-Bu - PhEt, 43), 57 (t-Bu, 96).
(3R,3S)-N-(tert-Butoxycarbonyl)-3-(1-(S)-phenylethyl)-ami-
nopyrrolidine 36b. Carbamate 36b was prepared reacting (()-N-
(tert-butoxycarbonyl)-3-methylsulfonyloxypyrrolidine 35 (0.53 g,
2.00 mmol) with (S)-R-methylbenzylamine (2.06 mL, 16.0 mmol),
and following the above general procedure. Purification of the
residue by column chromatography (EtOAc/cyclohexane 60:40)
gave 36b (0.50 g, 86%) as a pale orange oil: 1H NMR (1:1 mixture
of diastereomers) δ 1.20-1.30 (2 × 3H, d, J ) 6.8), 1.30-1.43 (2
× 9H, s), 1.43-1.70 (2 × 1H, m), 1.71-2.02 (2 × 2H, 2m),
2.74-2.82 (1H, m), 2.92-3.55 (4H + 5H, 2m), 3.69-3.81 (2 ×
1H, q, J ) 6.8), 7.08-7.36 (2 × 5H, m); 13C NMR (293 K, 1:1
mixture of diastereomers, two rotamers observed for each) δ 25.2
and 25.3 (CH3), 25.4 and 25.5 (CH3), 29.1 (3 × CH3), 29.2 (3 ×
CH3), 31.7 and 32.5 (CH2), 32.6 and 33.4 (CH2), 44.6 and 45.1
(CH2), 44.7 and 45.0 (CH2), 52.0 and 52.6 (CH2), 52.5 and 52.9
(CH2), 55.1 and 56.0 (CH), 55.2 and 56.0 (CH), 57.0 (CH), 57.3
(CH), 79.7 and 79.9 (C), 79.8 (C), 127.2, 127.8, 129.2 (2 × 5 ×
CH), 146.0 (2 × C), 155.2 (C), 155.3 (C); IR (neat) ν 3436 (NH),
3052, 3026, 2975, 2876, 1681 (CdO), 1492, 1477, 1451, 1408,
1365, 1265, 1169, 1120; [R]20D -59.0 (c 1.15, CHCl3); EIMS (70
eV) m/z 290 (M+, <1), 232 (M+ - t-Bu, 10), 219 (M+ - Ot-Bu,
28), 129 (M+ - t-Bu - PhEt, 40), 118 (72), 101 (CO2t-Bu, 100),
83 (M+ - CO2t-Bu s PhEt, 43), 57 (t-Bu, 96).
D
260 (M+ - H, 19), 203 (M+ - CH2NMe2, 24), 160 (M+ - C6H5
- NMe2, 38), 140 (M+ - C8H10N, 17), 120 (C8H10N, 8), 105
(Ph(CH)Me, 63), 101 (100), 58 (CH2NMe2, 67).
N-(N’,N’-Dimethylaminoethyl)-3-(S)-(1-(S)-phenylethyl)ami-
nopyrrolidine 28b. Reduction of N-(N’,N’-dimethyloxamoyl)-3-
(S)-(1-(S)-phenylethyl)aminopyrrolidine 24b (0.29 g, 1.00 mmol)
by LiAlH4 (0.38 g, 10.0 mmol) following the above general
1
procedure gave 28b (0.20 g, 77%) as a pale yellow oil: H NMR
δ 1.29 (3H, d, J ) 6.8), 1.35-1.50 (1H, m), 1.50-1.89 (1H, br),
1.89-2.06 (1H, m), 2.20 (6H, s), 2.28-2.66 (8H, m), 3.02-3.18
(1H, m), 3.73 (1H, q, J ) 6.8), 7.12-7.33 (5H, m); 13C NMR δ
24.6 (CH3), 32.7 (CH2), 46.1 (2 × CH3), 53.6 (CH2), 54.6 (CH),
54.8 (CH2), 56.7 (CH), 58.5 (CH2), 61.1 (CH2), 126.8, 127.1, 128.5
(5 × CH), 145.6 (C); IR (neat) ν 3373 (NH), 3052, 2964, 2817,
1451, 1264; [R]20D -81.9 (c 0.80, CHCl3); EIMS (70 eV) m/z 261
(M+, 1), 260 (M+ - H, 2), 203 (M+ - CH2NMe2, 23), 160 (M+
- C6H5 - NMe2, 8), 140 (M+ - C8H10N, 26), 120 (C8H10N, 5),
105 (Ph(CH)Me, 67), 58 (CH2NMe2, 100).
(()-N-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine 34. 10 BMS
(0.45 mL, 5 mmol, 1.0 equiv) was added to a solution of N-(tert-
butoxycarbonyl)-3-pyrroline 33 (2.5 g, 15 mmol, 3 equiv) in freshly
distilled THF (15 mL) at 0 °C. The resulting reaction mixture was
stirred at room temperature for 4 h then cooled to 0 °C to be
oxidized by using 3 M sodium hydroxide (5 mL) and 30% hydrogen
peroxide (5 mL). The reaction mixture was stirred at room
temperature for 12 h and the aqueous phase was saturated with
anhydrous potassium carbonate (8 g). The organic layer was
extracted, dried (MgSO4), filtered and concentrated to yield 34 (1.7
1
g, 60%) as a pale yellow oil: H NMR δ 1.37 (9H, s), 1.70-2.00
(2H, m), 3.03-3.51 (4H, m), 3.65-3.99 (1H, m), 4.15-4.43 (1H,
m); 13C NMR (293 K, two rotamers observed) δ 28.5 (3 × CH3),
33.4 and 33.9 (CH2), 43.6 and 44.0 (CH2), 54.0 and 54.2 (CH2),
69.8 and 70.6 (CH), 79.4 (C), 154.9 (C); IR (neat) ν 3410 (OH),
2975, 2932, 2890, 1673 (CdO), 1478, 1419, 1365, 1165, 1121;
EIMS (70 eV) m/z 187 (M+, 25), 114 (M+ - Ot-Bu, 100), 87 (M+
- CO2t-Bu, 47); HRMS (m/z) [M+] C9H17NO3 requires 187.1208,
found 187.1207.
(()-N-(tert-Butoxycarbonyl)-3-methylsulfonyloxypyrroli-
dine 35. Pyridine (0.13 mL, 1.59 mmol, 1.5 equiv), freshly distilled
methanesulfonylchloride (0.13 mL, 1.68 mmol, 1.6 equiv) and
4-dimethylaminopyridine (4-DMAP, 15 mg) were successively
added to a solution of (()-N-(tert-butoxycarbonyl)-3-hydroxypyr-
rolidine 34 (0.20 g, 1.07 mmol, 1.0 equiv) in dry dichloromethane
(4 mL). After stirring 70 h at room temperature, dichloromethane
and pyridine were evaporated and the residue was dissolved in
EtOAc (4 mL). The salts were filtered and the filtrate was con-
centrated under reduce pressure. The residue was purified by column
chromatography (EtOAc/cyclohexane 30:70) to give 35 (0.241 g,
General Procedure for Reduction of the Boc Group of 36. A
solution of 36a or 36b (3.00 mmol, 1.0 equiv) in dry THF (90
mL) was added over a 30-min period to a suspension of lithium
aluminum hydride (LiAlH4, 0.63 g, 16.5 mmol, 5.5 equiv) in freshly
distilled THF (30 mL), placed under an argon atmosphere at 0 °C.
The solution was stirred at room temperature for 5 h then heated
at 60 °C for 1 h. After cooling at 0 °C, the excess of LiAlH4 was
hydrolyzed by successive addition of cold water (1.8 mL), 4 M
aqueous sodium hydroxide (1.8 mL) and cold water (2.4 mL). The
white precipitate was filtered on celite and washed with CH2Cl2
(45 mL). The filtrate was concentrated and the residue was dissolved
in Et2O (30 mL). Aqueous hydrochloric acid (1M, 30 mL) was
added and the solution was stirred at room temperature for 15 min.
The acidic aqueous layer was extracted and NaHCO3 was slowly
added until pH 9. The medium was then extracted with CH2Cl2 (3
× 30 mL). The organic layers were combined, dried (MgSO4) and
concentrated under reduced pressure.
1
85%) as a pale yellow oil: H NMR δ 1.40 (9H, s), 1.93-2.33
(2H, m), 3.00 (3H, s), 3.29-3.72 (4H, m), 5.20 (1H, br); 13C NMR
(293 K, two rotamers observed) δ 28.4 (3 × CH3), 31.7 and 32.6
(CH2), 38.7 (CH3), 43.2 and 43.6 (CH2), 51.7 and 52.2 (CH2), 79.6
and 80.1 (CH), 79.8 (C), 154.1 and 154.2 (C); IR (neat) ν 3470,
2977, 2936, 2888, 1693 (CdO), 1478, 1410, 1357; CIMS (NH3)
m/z 266 (MH+, 7), 250 (MH+ - CH3, 3), 210 (MH+ - t-Bu, 100),
166 (MH+ - CO2t-Bu, 23), 114 (MH+ - SO2CH3 - Ot-Bu, 7),
86 (MH+ - SO2CH3 - CO2t-Bu, 2); HRMS (m/z) [MH+]
C10H20NO5S requires 266.1062, found 266.1063.
General Procedure for Introduction of the (R)- or (S)-r-Me-
thylbenzylamine Group on 35. A mixture of (()-N-(tert-butoxy-
carbonyl)-3-methylsulfonyloxypyrrolidine 35 (0.53 g, 2.00 mmol,
1.0 equiv) and (R)- or (S)-R-methylbenzylamine (2.06 mL, 16.0
mmol, 8.0 equiv) was heated at 105-110 °C for 24 h. After cooling
to room temperature, EtOAc (10 mL) and 4 M aqueous NaOH
solution (5 mL) were added and the mixture was stirred vigorously.
(3R,3S)-N-Methyl-3-(1-(R)-phenylethyl)-aminopyrrolidine 37a.
Reduction of (3R,3S)-N-(tert-butoxycarbonyl)-3-(1-(R)-phenylethyl)-
aminopyrrolidine 36a (0.87 g, 3.00 mmol) following the above
J. Org. Chem. Vol. 73, No. 14, 2008 5407

Duguet et al.
general procedure gave 37a (0.47 g, 76%) as a yellow oil: 1H NMR
(1:1 mixture of diastereomers) δ 1.20 (2 × 3H, d, J ) 6.8),
1.38-1.41 (1H, m), 1.41-1.56 (1H, m), 1.82-2.02 (2 × 1H, m),
2.04-2.55 (2 × 4H, m), 2.15 (3H, s), 2.18 (3H, m), 2.92-3.10 (2
× 1H, m), 3.55-3.72 (2 × 1H, q, J ) 6.8), 7.02-7.26 (2 × 5H,
m); 13C NMR (293 K, 1:1 mixture of diastereomers) δ 24.4 and
24.6 (2 × CH3), 32.7 and 33.4 (2 × CH2), 42.2 and 42.3 (2 ×
CH3), 55.1 and 55.3 (2 × CH), 55.2 and 55.4 (2 × CH2), 56.2 and
56.5 (2 × CH), 62.6 and 63.5 (2 × CH2), 126.7 (4 × CH), 126.9
(2 × CH), 128.4 (4 × CH), 145.5 and 145.6 (2 × C); IR (neat) ν
3060, 3023, 2960, 2936, 2862, 2833, 2773, 1602, 1491, 1477, 1449;
(3R,3S)-(1-(R)-Phenylethyl)tetrahydrothiophen 41a. The amine
41a was prepared using (()-3-methylsulfonyloxytetrahydrothiophen
40 (0.89 g, 4.88 mmol) and (R)-R-methylbenzylamine (5.1 mL,
39.2 mmol) and following the above general procedure. Purification
of the residue by column chromatography (EtOAc/cyclohexane 30:
70) gave 41a (0.60 g, 59%) as a yellow oil: 1H NMR (1:1 mixture
of diastereomers) δ 1.26-1.29 (2 × 3H, d, J ) 6.4), 1.45-1.55 (2
× 1H, br), 1.70-2.00 (2 × 2H, m), 2.46 (1H, dd, J ) 10.6, 5.7),
2.63 (1H, dd, J ) 10.6, 5.3), 2.68-2.87 (2 × 3H, m), 3.13-3.27
(2 × 1H, m), 3.78 (2 × 1H, q, J ) 6.4), 7.12-7.35 (2 × 5H, m);
13C NMR (1:1 mixture of diastereomers) δ 24.8 and 25.2 (2 ×
CH3), 28.5 and 28.6 (2 × CH2), 35.3 and 36.2 (2 × CH2), 36.8
and 37.3 (2 × CH2), 56.5 (2 × CH), 59.9 and 60.1 (2 × CH),
126.7 and 126.8 (4 × CH), 127.2 (2 × CH), 128.6 (4 × CH), 145.5
and 145.7 (2 × C); IR (neat) ν 3305 (NH), 3060, 3023, 2961, 1492,
[R]20 +71.1 (c 1.75, CHCl3).
D
(3R,3S)-N-Methyl-3-(1-(S)-phenylethyl)-aminopyrrolidine 37b.
Reduction of (3R,3S)-N-(tert-butoxycarbonyl)-3-(1-(S)-phenylethyl)-
aminopyrrolidine 36b (0.87 g, 3.00 mmol) following the above
general procedure gave 37b (0.50 g, 81%) as a yellow oil: 1H NMR
(1:1 mixture of diastereomers) δ 1.28 (2 × 3H, d, J ) 6.8),
1.35-1.76 (2 × 2H, m), 1.90-2.11 (2 × 1H, m), 2.12-2.49 (2 ×
3H, m), 2.19 (3H, s), 2.23 (3H, s), 2.49-2.62 (2 × 1H, m),
3.00-3.16 (2 × 1H, m), 3.62-3.80 (2 × 1H, q, J ) 6.8), 7.07-7.35
(2 × 5H, m); 13C NMR (293 K, 1:1 mixture of diastereomers) δ
24.4 and 24.6 (2 × CH3), 32.7 and 33.4 (2 × CH2), 42.2 and 42.3
(2 × CH3), 55.1 and 55.3 (2 × CH), 55.2 and 55.4 (2 × CH2),
56.2 and 56.5 (2 × CH), 62.5 and 63.5 (2 × CH2), 126.7 (4 ×
CH), 126.9 (2 × CH), 128.35 and 128.4 (4 × CH), 145.5 (2 × C);
IR (neat) ν 3060, 3023, 2960, 2936, 2862, 2833, 2773, 1602, 1491,
1450; [R]20 +70.0 (c 1.00, CHCl3); EIMS (70 eV) m/z 207 (M+,
D
11), 192 (M+ - CH3, 11), 179 (18), 160 (24), 146 (29), 120 (C8H10N,
48), 105 (Ph(CH)Me, 100), 87 (M+ - C8H10N, 16), 71 (9).
(3R,3S)-(1-(S)-Phenylethyl)tetrahydrothiophen 41b. The amine
41b was prepared using (()-3-methylsulfonyloxytetrahydrothiophen
40 (0.89 g, 4.88 mmol) and (S)-R-methylbenzylamine (5.1 mL, 39.2
mmol) and following the above general procedure. Purification of
the residue by column chromatography (EtOAc/cyclohexane 30:
70) gave 41b (0.66 g, 65%) as a yellow oil: 1H NMR (1:1 mixture
of diastereomers) δ 1.26 (3H, d, J ) 6.8), 1.27 (3H, d, J ) 6.8),
1.35-1.55 (2 × 1H, br), 1.55-2.00 (2 × 2H, m), 2.37-2.51 (1H,
dd, J ) 10.5, 5.6), 2.55-2.88 (7H, m), 3.04-3.32 (2 × 1H, m),
3.76 (1H, q, J ) 6.8), 3.78 (1H, q, J ) 6.8), 7.02-7.35 (2 × 5H,
m); 13C NMR (1:1 mixture of diastereomers) δ 24.8 and 25.2 (2 ×
CH3), 28.4 and 28.5 (2 × CH2), 35.2 and 36.2 (2 × CH2), 36.7
and 37.3 (2 × CH2), 56.4 (2 × CH), 59.9 and 60.0 (2 × CH),
126.6 and 126.7 (4 × CH), 127.1 (2 × CH), 128.6 (4 × CH), 145.5
and 145.7 (2 × C); IR (neat) ν 3305 (NH), 3060, 3023, 2959, 2926,
2853, 2359, 1601, 1492, 1450; [R]20D -69.8 (c 1.00, CHCl3); EIMS
(70 eV) m/z 207 (M+, 39), 130 (M+ - C6H5, 7), 120 (C8H10N,
54), 105 (Ph(CH)Me, 100), 83 (46), 70 (32).
1477, 1449, 1367, 1348, 1306, 1233, 1198, 1152, 1131; [R]20
-72.2 (c 1.21, CHCl3).
D
(()-3-Hydroxytetrahydrothiophen 39. A solution of tetrahy-
drothiophen-3-one 38 (0.42 mL, 4.9 mmol) in THF (25 mL) was
added dropwise to a suspension of lithium aluminum hydride
(LiAlH4, 0.93 g, 24.5 mmol) in THF (25 mL) at 0 °C under argon
atmosphere. After stirring 3 h at room temperature, the excess of
LiAlH4 was hydrolyzed by addition of cold water (1 mL) at 0 °C.
The white precipitate was filtered through a celite pad and washed
with CH2Cl2 (4 × 20 mL). The organic layers were combined, dried
(MgSO4) and concentrated under reduced pressure to give 39 (0.41
(()-3-Methylsulfonyloxytetrahydrofuran 43. Pyridine (1.28
mL, 15.9 mmol), methanesulfonylchloride (1.31 mL, 17.0 mmol)
and a catalytic amount of 4-dimethylaminopyridine (4-DMAP, 15
mg) were added to a solution of ( ()-3-hydroxytetrahydrofuran 42
(0.92 mL, 11.4 mmol) in CH2Cl2 (20 mL) at 0 °C. After being
stirred 3 h at 0 °C and 20 h at room temperature, the mixture was
concentrated and EtOAc (10 mL) was added to the residue. The
resulting salt was filtered through a celite pad and the filtrate was
concentrated under reduce pressure. The residue was purified by
column chromatography (EtOAc) to give 43 (1.72 g, 91%) as a
pale yellow oil: 1H NMR δ 2.15-2.21 (2H, m), 2.98 (3H, s),
3.77-3.97 (4H, m), 5.23-5.24 (1H, m); 13C NMR δ 33.4 (CH2),
38.6 (CH3), 66.8 (CH2), 73.0 (CH2), 80.8 (CH); IR (neat) ν 3022,
2939, 2875, 1439, 1416, 1350; EIMS (70 eV) m/z 167 (M+, 40),
149 (M+ - H2O, 100), 113 (14), 86 (M+ - CH3SO2, 47), 71 (M+
- CH3SO3, 28). Anal. Calcd for C5H10O4S: C 36.13, H 6.06, S
19.29. Found: C 35.96, H 6.14, S 19.02.
General Procedure for Introduction of the (R)- or (S)-r-Me-
thylbenzylamine Group on 43. A mixture of (()-3-methylsulfo-
nyloxytetrahydrofuran 43 (0.50 g, 3 mmol, 1.0 equiv) and (R)- or
(S)-R-methylbenzylamine (3.1 mL, 24.0 mmol, 8 equiv) was heated
at 105-110 °C for 24 h. After cooling to room temperature, EtOAc
(15 mL) and 4 M aqueous NaOH solution (7.5 mL) were added
and the mixture was stirred vigorously. The aqueous layer was
extracted with EtOAc (2 × 5 mL) and the organic layers were
combined, washed with water (10 mL), dried (MgSO4) and
concentrated under reduced pressure.
1
g, 80%) as an orange oil without any purification: H NMR δ
1.60-1.85 (1H, m), 1.85-2.12 (1H, m), 2.48-3.01 (4H, m),
3.22-3.82 (1H, br), 4.35-4.58 (1H, m); 13C NMR δ 28.1 (CH2),
37.8 (CH2), 39.2 (CH2), 74.1 (CH); IR (neat) ν 3473 (OH), 2932,
1425.
(()-3-Methylsulfonyloxytetrahydrothiophen 40. Pyridine (3.2
mL, 39.5 mmol), methanesulfonylchloride (2.3 mL, 29.6 mmol)
and a catalytic amount of 4-dimethylaminopyridine (4-DMAP, 15
mg) were added to a solution of (()-3-hydroxytetrahydrothiophen
39 (2.05 g, 19.7 mmol) in CH2Cl2 (60 mL) at 0 °C. After being
stirred 3 h at 0 °C and 20 h at room temperature, the mixture was
concentrated and EtOAc (30 mL) was added to the residue. The
resulting salt was filtered through a celite pad and the filtrate was
concentrated under reduce pressure. The residue was purified by
column chromatography (EtOAc/cyclohexane 30:70) to give 40
(2.52 g, 70%) as a pale yellow oil: 1H NMR δ 1.98-2.14 (1H, m),
2.39-2.53 (1H, m), 2.85-3.23 (4H, m), 3.04 (3H, s), 5.37-5.50
(1H, m); 13C NMR δ 28.3 (CH2), 37.0, 37.1 (2 × CH2), 38.9 (CH3),
83.0 (CH); IR (neat) ν 3546, 3024, 2938, 2868, 1428; EIMS (70
eV) m/z 182 (M+, 20), 149 (11), 102 (M+ - CH3SO2, 10), 86 (M+
- CH3SO3, 100), 85 (66), 79 (8). Anal. Calcd for C5H10O3S2: C
32.95, H 5.53, S 35.19. Found: C 33.04, H 5.86, S 35.37.
General Procedure for Introduction of the (R)- or (S)-r-Me-
thylbenzylamine Group on 40. A mixture of (()-3-methylsulfo-
nyloxytetrahydrothiophen 40 (0.89 g, 4.88 mmol, 1.0 equiv) and
(R)- or (S)-R-methylbenzylamine (5.1 mL, 39.2 mmol, 8 equiv)
was heated at 105-110 °C for 24 h. After cooling to room
temperature, EtOAc (15 mL) and 4 M aqueous NaOH solution (7.5
mL) were added and the mixture was stirred vigorously. The
aqueous layer was extracted with EtOAc (2 × 5 mL) and the
organic layers were combined, washed with water (10 mL), dried
(MgSO4) and concentrated under reduced pressure.
(3R,3S)-(1-(R)-Phenylethyl)tetrahydrofuran 44a. The amine
44a was prepared using (()-3-methylsulfonyloxytetrahydrofuran
43 (0.50 g, 3 mmol) and (R)-R-methylbenzylamine (3.1 mL, 24.0
mmol) and following the above general procedure. Purification of
the residue by column chromatography (CH2Cl2/MeOH 90:10) gave
1
44a (0.44 g, 76%) as a pale yellow oil: H NMR (1:1 mixture of
5408 J. Org. Chem. Vol. 73, No. 14, 2008

EnantioselectiVe Hydroxyalkylation with Chiral Lithium Amides
diastereomers) δ 1.29 (3H, d, J ) 6.4), 1.30 (3H, d, J ) 6.4),
1.34-1.50 (2 × 1H, br), 1.50-1.64 (1H, m), 1.54-1.78 (1H, m),
1.85-2.05 (2 × 1H, m), 3.11 -3.23 (2 × 1H, m), 3.29-3.39 (1H,
dd, J ) 9.0, 4.9), 3.55-3.79 (7H, m), 3.79-3.90 (2 × 1H, m),
7.13-7.37 (2 × 5H, m); 13C NMR (1:1 mixture of diastereomers)
δ 24.5 (2 × CH3), 32.7 and 33.5 (2 × CH2), 56.0 and 56.1 (2 ×
CH), 56.5 and 56.7 (2 × CH), 66.9 and 67.1 (2 × CH2), 72.9 and
73.7 (2 × CH2), 126.5 and 126.6 (4 × CH), 126.9 and 127.0 (2 ×
CH), 128.4 (4 × CH), 145.3 (2 × C); IR (neat) ν 3308 (NH), 3082,
the preformed solution of lithium amide (3APLi or 3ATFLi or
3ATTLi) and the resulting mixture was stirred for 30 min at -20
°C. Then, the mixture was cooled to -78 °C and aged 30 min at
this temperature. A solution of o-tolualdehyde (0.5 mmol) in THF
(2 mL) was added at -78 °C over a 5-min period and the mixture
was stirred at -78 °C for the indicated time. The medium was
quenched at -78 °C with 3 M aqueous HCl solution (3 mL) and
was extracted with Et2O (3 × 10 mL) after reaching room
temperature. The combined organic layers were washed with
saturated NaHCO3 (10 mL) and brine (10 mL), dried (MgSO4) and
concentrated under reduce pressure. The residue was purified by
column chromatography to give the corresponding alcohol.
The chiral ligand engaged in the reaction can be recovered:
NaHCO3 was added to the acidic aqueous layer followed by several
drops of 4 M aqueous NaOH solution and the amine was extracted
with Et2O (3 × 10 mL). The combined organic layers were washed
with brine (10 mL), dried (MgSO4) and concentrated under reduce
pressure.
3060, 3024, 2965, 2862, 1602, 1492, 1451; [R]20 +73.0 (c 1.43,
D
CHCl3); EIMS (70 eV) m/z 191 (M+, 8), 176 (M+ - CH3, 79),
160 (28), 146 (23), 132 (6), 120 (C8H10N, 9), 105 (Ph(CH)Me,
100), 91 (Ph(CH), 36), 77 (C6H5, 76).
(3R,3S)-(1-(S)-Phenylethyl)tetrahydrofuran 44b. The amine
44b was prepared using (()-3-methylsulfonyloxytetrahydrofuran
43 (0.50 g, 3 mmol) and (S)-R-methylbenzylamine (3.1 mL, 24.0
mmol) and following the above general procedure. Purification of
the residue by column chromatography (CH2Cl2/MeOH 90:10) gave
1
1-o-Tolylpentan-1-ol 45. Purification of the residue by column
chromatography (EtOAc/cyclohexane 30:70) gave 1-o-tolylpentan-
1-ol 45 as a colorless oil: 1H NMR δ 0.83 (3H, t, J ) 6.8),
1.10-1.50 (4H, m), 1.50-1.70 (2H, m), 1.74 (1H, s), 2.25 (3H,
s), 4.85 (1H, t, J ) 6.8), 6.95-7.20 (3H, m), 7.39 (1H, d, J )
7.2); 13C NMR δ 14.0 (CH3), 19.0 (CH3), 22.6 (CH2), 28.1 (CH2),
37.8 (CH2), 70.5 (CH), 125.1, 128.2, 128.9, 130.2 (4 × CH), 134.4,
44b (0.42 g, 74%) as a pale yellow oil: H NMR (1:1 mixture of
diastereomers) δ 1.27 (3H, d, J ) 6.4), 1.28 (3H, d, J ) 6.4),
1.18-1.42 (2 × 1H, br), 1.45-1.61 (1H, m), 1.61-1.75 (1H, m),
1.81-2.04 (2 × 1H, m), 3.07 -3.21 (2 × 1H, m), 3.26-3.36 (1H,
dd, J ) 8.7, 4.5), 3.52-3.76 (7H, m), 3.76-3.88 (2 × 1H, m),
7.10-7.35 (2 × 5H, m); 13C NMR (1:1 mixture of diastereomers)
δ 24.5 (2 × CH3), 32.7 and 33.5 (2 × CH2), 55.9 and 56.1 (2 ×
CH), 56.5 and 56.7 (2 × CH), 66.9 and 67.0 (2 × CH2), 72.9 and
73.6 (2 × CH2), 126.5 and 126.6 (4 × CH), 126.9 and 127.0 (2 ×
CH), 128.4 (4 × CH), 145.3 (2 × C); IR (neat) ν 3308 (NH), 3082,
3060, 3024, 2965, 2862, 1951, 1602, 1492, 1451; [R]20D -75.2 (c
1.00, CHCl3); EIMS (70 eV) m/z 191 (M+, 8), 176 (M+ - CH3,
79), 160 (28), 146 (23), 132 (6), 120 (C8H10N, 9), 105 (Ph(CH)Me,
100), 91 (Ph(CH), 36), 77 (C6H5, 76).
143.1 (2 × C); IR (neat) ν 3344 (OH), 2957, 2856, 1465; [R]20
D
+54.1 (c 0.37, CHCl3) for R-isomer, 81% e.e. and -50.1 (c 0.75,
CHCl3) for S-isomer, 76% e.e. (HPLC Daicel Chiralpak OD-H,
hexane/i-PrOH 99:1, 1.0 mL/min, 218 nm, S-isomer 19.5 min and
R-isomer 21.5 min); EIMS (70 eV) m/z 178 (M+, 11), 160 (M+
H2O, 3), 121 (M+ - C4H9, 100), 93 (31), 91 (C7H7, 14).
-
Acknowledgment. N.D. acknowledges the Ministe`re de la
General Procedure for Enantioselective Nucleophilic Alky-
lations of n-Butyllithium onto o-Tolualdehyde in the Presence
of Chiral 3APLi, 3ATFLi, or 3ATTLi. Under an argon atmo-
sphere, n-BuLi (0.75 mmol, 2.5 M solution in hexanes) was added
to a solution of 3AP or 3ATF or 3ATT (0.75 mmol) in THF (15
mL) at -20 °C. After stirring 20 min, a second aliquot of n-BuLi
(1.25 mmol, 2.5 M solution in hexanes) was added dropwise to
Recherche et de la Technologie for a Ph.D. grant.
Supporting Information Available: Copies of the 1H NMR
and 13C spectra for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO8005396
J. Org. Chem. Vol. 73, No. 14, 2008 5409