Synthesis and resolution of a novel chiral diamine ligand and application to asymmetric lithiation-substitution

Article abstract of DOI:10.1021/ol9903133

(equation presented) A short, efficient synthesis of chiral 1,5-diaza-cis-decalins (7) is presented. In the lithiation of N-Boc pyrrolidine, the ligands with the smallest most electron rich R groups (Me > Et > CH₂^tBu > CH₂CF₃ ≈ Bn) were most effective. In the asymmetric deprotonation/substitution of benzylic substrates, (R,R)-7 (R = Me, R′ = H) conferred modest selectivity. The ready availability of both enantiomers of the 1,5-diaza-cis-decalins and the ability to tune steric and electronic properties renders these compounds an attractive new class of diamine ligands.

Full text of DOI:10.1021/ol9903133

ORGANIC
LETTERS
2000
Vol. 2, No. 7
875-878
Synthesis and Resolution of a Novel
Chiral Diamine Ligand and Application
to Asymmetric Lithiation−Substitution
Xiaolin Li, Laurie B. Schenkel, and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104
marisa@a.chem.upenn.edu
Received October 4, 1999
ABSTRACT
A short, efficient synthesis of chiral 1,5-diaza-cis-decalins (7) is presented. In the lithiation of N-Boc pyrrolidine, the ligands with the smallest
most electron rich R groups (Me > Et > CH tBu > CH CF3 ≈ Bn) were most effective. In the asymmetric deprotonation/substitution of benzylic
2
2
substrates, (R,R)-7 (R ) Me, R′ ) H) conferred modest selectivity. The ready availability of both enantiomers of the 1,5-diaza-cis-decalins and
the ability to tune steric and electronic properties renders these compounds an attractive new class of diamine ligands.
Despite the host of applications of chiral diamine ligands in
asymmetric synthesis, few significantly different structures
have found general utility. The most widely used chiral
diamines (1-6) are outlined in Figure 1, and extensive
compounds, ligands of this type have not been employed in
asymmetric synthesis. On the basis of the well-defined chiral
cavity of 7, we believe diaza-cis-decalins could add signifi-
cantly to the utility of this group of compounds.
In this Letter, we outline the synthesis and application of
bis-tertiary amines 11 (Figure 3) based upon diaza-cis-decalin
skeleton 7. These compounds can be synthesized in a
straightforward manner in three-four steps (Figure 2). As
Figure 2.
Figure 1.
reviews on these compounds can be found.1,2 Compound 7
was identified as a potential lead from our efforts in the
computer-aided identification of novel ligand scaffolds.3
Interestingly, while diaza-cis-decalins (7, R ) H) are known
the first step, commercially available 3-aminopyridine (8)
is readily converted to known 1,5-naphthyridine (9) in 64%
yield via a Skraup reaction.4 The reduction of naphthyridine
9 to the saturated derivative was improved greatly over that
10.1021/ol9903133 CCC: $19.00 © 2000 American Chemical Society
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reported5 by employing rhodium/alumina as the hydrogena-
tion catalyst6 with acetic acid to yield a 90:10 mixture of
cis:trans isomers of 10 in 95% yield. The more crystalline
trans isomer could be readily removed by extraction or
recrystallization to yield (()-10 in a g95:5 cis:trans ratio.7
At this point, precipitation of the racemic diamine 10 with
0.5 equiv of (R,R)-tartaric acid and recrystallization from
water/ethanol gave a 37% yield (74% of the total possible
yield) of the (R,R)-10 (R,R)-tartrate salt in g98% ee free of
any residual trans isomer.8 The mother liquors from these
recrystallizations could be treated with the (S,S)-tartaric acid
to generate (S,S)-10 with similar selectivity.
The absolute configuration of the 1,5-diaza-cis-decalin
(+)-10, and subsequent derivatives, was determined by an
X-ray crystallographic analysis of the (R,R)-tartrate salt
(Figure 4). The structure definitively indicates that the (R,R)-
With the chiral diamine 10 in hand, a variety of substituted
derivatives were readily made (Figure 3). Dimethyl analogue
Figure 4. X-ray structure of (R,R)-tartaric acid (R,R)-10 complex
(hydrogens, except on heteroatoms or stereogenic centers, omitted
for clarity).
tartrate crystallized with (R,R)-10.8 Notably, the cis-decalin
component adopts the conformation expected under acidic
conditions (see below, Figure 5 11-in, R ) H), and only
Figure 3. N,N′-Dialkylation of diamine 10.
(R,R)-11a was produced by Eschweiler-Clarke reductive
amination. Other dialkylated derivatives, (R,R)-11b-f, were
produced by acylation with the corresponding acyl chloride
followed by reduction with LiAlH4.9 This protocol was
superior when compared to direct alkylation in that the amide
intermediates are oxidatively stable, easily purified, and can
be stored indefinitely.
(1) (a) Lucet, D.; LeGall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580-2627. (b) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997,
97, 3161-3195. (c) Mukaiyama, T.; Asami, M. Top. Curr. Chem. 1985,
127, 133-167.
(2) (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
2282-2316. (b) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552-560.
(3) Kozlowski, M. C.; Evans, C. A. Submitted for publication.
(4) Armarego, W. L. F. J. Chem. Soc. C 1967, 377-383.
Figure 5. Conformations of (-)-sparteine and 1,5-diaza-cis-
decalins.
(5) Decahydronaphthyridine has been produced in about 20% yield from
naphthyridine as a 2:1 cis:trans mixture in the presence of 1 equiv of
PtO2: Albert, A. J. Chem. Soc. 1960, 1790-3.
(6) Hoffmann et al. have independently shown that similar reaction
conditions result in similar improvement (see ref 12a).
(7) To 9 (8.15 g, 62.7 mmol) in absolute EtOH were added 5% Rh/
Al2O3 (0.817 g) and HOAc (70 mL). The mixture was hydrogenated at
1200 psi of H2 for 12 h. After filtration, the residue was washed with MeOH
and the filtrates were saturated with HCl. Removal of the solvent gave a
solid (10.5 g, 95%). Recrystallization from MeOH and H2O yielded pure
trans HCl salt. The mother liquor was concentrated and dissolved in H2O
which was made basic with NaOH, saturated with NaCl, and extracted with
Et2O. Drying the Et2O extracts with Na2SO4 and removal of the Et2O
afforded a 94:6 mixture of cis-10 and the trans isomer. Distillation (89-
90 °C, 3 mmHg) afforded pure 10 (4.2 g, 48%) as a waxy white solid. See
Supporting Information for analytical data.
(8) (R,R)-10 (R,R)-tartrate was prepared by dissolving racemic 10 (0.98
g, 7.0 mmol) in MeOH (5 mL) and then adding this solution slowly to a
MeOH (5 mL) solution of L-(+)-tartaric acid (525 mg, 3.5 mmol) at rt.
After the solution clarified, acetic acid (0.36 mL, 6.3 mmol) was added.
H2O (2 mL) was added, and the mixture was warmed. Upon standing at 0
°C overnight, the tartrate salt of 5 (887 mg, 44%) was isolated in 87% ee.
Recrystallization of a portion (550 mg) from EtOH/H2O caused enrichment
to g98% ee (458 mg, 83%). See Supporting Information for analytical data.
one carboxylic acid of the tartrate interacts with the diamine
from the concave face. Examination of the crystal packing
diagram reveals that the second carboxylate of the tartrate
interacts with a neighboring diamine from the convex face.
(9) For example, 11e was produced from 10 (75:25 cis:trans HCl salt,
1.92 g, 10.9 mmol) in CH2Cl2 (40 mL) at 0 °C by addition of Et3N (7.6
mL, 54.5 mmol), DMAP (221 mg, 1.8 mmol), and PhCOCl (4.2 mL, 36.0
mmol). After being stirred at rt overnight, the insoluble solid was filtered
off and the resultant oil was purified by silica chromotography (2:1 EtOAc:
hexanes) to afford the bisamide (2.45 g, 65%) as a white solid. The bisamide
(1.15 g, 3.3 mmol) was reduced with LiAlH4 (570 mg, 15.0 mmol) in
anhydrous THF (50 mL) by heating to reflux for 1 h and then stirring 12
h at room temperature. After the reaction was quenched with an aqueous
NaOH solution, the mixture was filtered and purified by silica chromotog-
raphy (95:5 CH2Cl2:MeOH) to afford 11e (0.98 g, 93%) as a waxy white
solid. See Supporting Information for analytical data.
876
Org. Lett., Vol. 2, No. 7, 2000

The potential application of bis-tertiary amines (11)
derived from 1,5-diaza-cis-decalin as sparteine alternates is
particularly interesting (Figure 5). Much effort has been
devoted to the development of efficient asymmetric synthetic
methods based upon chiral carbanions.2 Chiral carbanions
undergo a wide range of selective alkylation, carbonyl
addition, and most recently conjugate addition reactions.10
The key to the ready utility of this rich chemistry has been
in the generation of enantiomerically enriched lithium
carbanion pairs in which the carbanionic center carries chiral
information. Substitution of the lithium occurs stereospe-
cifically, often with retention of configuration. Chiral lithium
carbanions are typically generated by the action of an achiral
alkyllithium base (i.e., BuLi) in the presence of a chiral
ligand. Many chiral ligands have been utilized in this
chemistry with the natural alkaloid (-)-sparteine (6) enjoying
the most widespread utility. This methodology suffers in that
the (+)-enantiomer of sparteine is not readily available. A
host of diamine ligands have been screened in the hope of
solving this dilemma, but the utility of these replacements
tends to fall short of the parent.11
As is the case for sparteine, 1,5-diaza-cis-decalins are
conformationally mobile and interconvert between two stable
conformations by ring inversion (Figure 5). For sparteine,
the desired conformation for bidentate coordination of a
cation, 6-in, is actually slightly less stable than 6-out.2a
Nevertheless, the addition of lithium species appears to
perturb this equilibrium and complexes of the 6-in confor-
mation are generally regarded as responsible for the selec-
tivities observed in sparteine-mediated carbanion chemistry.
In the case of the 1,5-diaza-cis-decalins, the position of the
equilibrium between the desired conformation capable of
bidentate coordination, 11-in, and the other major conforma-
tion, 11-out, varies depending upon substituents (R), solvent,
and additive. In an elegant study, Hoffmann and co-workers12
have shown that when the R groups are small, 11-in is
favored and when the R groups are large, 11-out becomes
favored. Regardless, the two conformations are energetically
similar enough that the addition of acid or LiClO4 shifts the
equilibrium toward 11-in. Visual examination of 11-in
reveals an asymmetric environment upon coordination of a
tetrahedral ion such as lithium. With these considerations in
mind, derivatives of 11 were examined as reagents for
asymmetric lithiation.
Figure 6.
of a diamine. Not surprisingly, the more hindered versions
of 11 (larger R groups) were less reactive.11a The larger R
groups shield the lithium significantly, which may account
t
for the lower reactivity following the series Bn < BuCH2
< Et < Me. Interestingly the trifluoroethyl derivative 11c
proved to be completely unreactive. The strongly electron
withdrawing trifluoro groups undoubtedly create a less
electron rich ligand. Whether this ligand possesses a lower
affinity for the lithium species or its lesser donicity renders
the sec-butyl anion less nucleophilic remains to be delineated.
Examination of the resolved form of the optimal ligand (R,R)-
11a in this reaction led to a disappointingly low selectivity
(12% ee).
A second test substrate, 14,14 was surveyed with the 1,5-
diaza-cis-decalins 11a and 11e (Figure 7). Lithiation of 14
in the presence of the less hindered (R,R)-11a and treatment
with acetone yielded tertiary alcohol 15a in 39% ee which
was comparable to the 39% ee achieved by (-)-sparteine
except that the opposite configuration of 15a was produced.
Further studies with substrate 14 using allyl electrophiles
revealed that the degree of enantioselectivity imparted by
diamine 11a is remarkably independent of the electrophile
and the sense of enantioselection was again opposite that of
(-)-sparteine (Figure 7). As is the case for (-)-sparteine,
allyl halides appear to give reaction via an inversion pathway
and allyl tosylate via a retention pathway. Warming of
deprotonated 14 to -20 °C prior to treatment with the
electrophile caused only small changes in selectivity (entries
5 vs 6 and 7 vs 8). Most likely, a dynamic kinetic resolution
in which one diastereomeric anion is more reactive that the
other is operative. This result is analogous to that observed
by Beak for substrate 14 with (-)-sparteine.14 As such, it
appears that diamine 11a causes reaction pathways similar
to those observed with (-)-sparteine.
In initial studies, the s-BuLi complexes with 11 were tested
for reactivity in the deprotonation of N-Boc pyrrolidine 12
(Figure 6).13 This case is especially useful for assaying the
utility of ligands as almost no lithiation occurs in the absence
(10) (a) Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc.
1997, 119, 10537-8. (b) Curtis, M. D.; Beak, P. J. Org. Chem. 1999, 64,
2296-7.
(11) (a) Gallagher, D. J.; Wu, S.; Nikolic, N. A.; Beak, P. J. Org. Chem.
1995, 60, 8148-54. (b) Uemura, M.; Hayashi, Y.; Hayashi, Y. Tetrahe-
dron: Asymmetry 1994, 5, 1427-30. (c) Hoffmann, R. W.; Klute, W.; Dress,
R. K.; Wenzel, A. J. Chem. Soc., Perkin Trans. 2 1995, 1721-6.
(12) (a) Santos, A. G.; Klute, W.; Torode, J.; Bo¨hm, V. P. W.; Carbrita,
E.; Runsink, J.; Hoffmann, R. W. New. J. Chem. 1998, 993-7. (b)
Fleischhauer, J.; Raabe, G.; Santos, A. G.; Schiffer, J.; Wollmer, A. Z.
Naturforsch. A: Phys. Sci. 1998, 53, 896-902.
Examination of the structures of (-)-sparteine and decalin
derivative (R,R)-11a provides insight into the important
(13) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231-9,
(14) Thayumanavan, S.; Basu, A.; Beak, P. J. Am. Chem. Soc. 1997,
119, 8209-16.
Org. Lett., Vol. 2, No. 7, 2000
877

(-)-sparteine and (R,R)-11a in which the plane of the two
nitrogens and a bound lithium ion (not shown) are perpen-
dicular to the plane of the page. Comparison of the
stereochemically accessible quadrants reveals that these
ligands block enantiomeric quadrants, which is consistent
with the observation of enantiomeric products (see above)
This result signifies that, in principle, diamines based on 11
can allow access to enantiomeric forms not readily achieved
with (-)-sparteine.
Notably, the energy differences imparted by these chiral
ligands is very small. For example, an energy difference of
1.26 kcal/mol between reaction pathways would account for
the 92% ee observed with (-)-sparteine (Figure 7, entry 9)
and a difference of 0.40 kcal/mol would account for the 45%
ee observed with the decalin derivative (R,R)-11a (Figure
7, entry 5). As such, minor modifications may result in
substantial differences in selectivity.11 To this end, modified
derivatives of 7 (R′ ) alkyl, Figure 1) are being explored.
In conclusion, the preparation of a unique class of chiral
ligands, the 1,5-diaza-cis-decalin derivatives, has been
described. These compounds have been shown to be mod-
erately effective in asymmetric carbanion chemistry. Future
efforts will be directed toward modifying the steric and
electronic characteristics of this family of ligands which can
be readily accomplished by variation of the substituent
N-alkyl groups. Because of the well-defined and easily
modulated chiral environment of these 1,5-diaza-cis-decalins,
it is anticipated that this new class of diamine ligands will
find a number of applications in asymmetric synthesis.
Figure 7.
topological features relevant to the stereoselectivity in these
reactions. Figure 8 shows a view of lithium coordinated to
Acknowledgment. Financial support was provided by the
University of Pennsylvania, the National Science Foundation
(CHE-9730576), Merck, and DuPont. Acknowledgment is
made to the donors of the Petroleum Research Fund,
administered by the American Chemical Society, for partial
support of this research. The invaluable assistance of Dr.
Patrick Carroll in obtaining the X-ray structure of the tartrate
complex is gratefully acknowledged.
Supporting Information Available: Experimental details
and characterization of all new compounds is provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 8. View of the stereochemically accessible quadrants of
lithium-coordinated (-)-sparteine and (R,R)-11a. The lithium ion
(not shown) is located at the crosshair defining the accessible
quadrants.
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Org. Lett., Vol. 2, No. 7, 2000