Memory of chirality in intramolecular conjugate addition of enolates: A novel access to nitrogen heterocycles with contiguous quaternary and tertiary stereocenters

Article abstract of DOI:10.1039/b416535g

Nitrogen heterocycles with contiguous quaternary and tertiary stereocenters have been prepared in high enantiomeric purity by intramolecular conjugate addition of enolates generated from α-amino acid derivatives via memory of chirality. The Royal Society

Full text of DOI:10.1039/b416535g

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C O M M U N I C A T I O N
Memory of chirality in intramolecular conjugate addition of
enolates: a novel access to nitrogen heterocycles with contiguous
quaternary and tertiary stereocenters
Takeo Kawabata,* Swapan Majumdar, Kazunori Tsubaki and Daiki Monguchi
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
E-mail: kawabata@scl.kyoto-u.ac.jp; Fax: +81 774 38 3197
Received 29th October 2004, Accepted 11th March 2005
First published as an Advance Article on the web 30th March 2005
Nitrogen heterocycles with contiguous quaternary and ter-
tiary stereocenters have been prepared in high enantiomeric
purity by intramolecular conjugate addition of enolates
generated from a-amino acid derivatives via memory of
chirality.
and C gave racemic products, respectively, under the similar
conditions to those in Scheme 1 because the enolates generated
from these derivatives cannot be axially chiral along the
C–N axis.
We report here a new method for the asymmetric construction
of highly substituted nitrogen heterocycles via the intramolecu-
lar conjugate addition of enolates generated from a-amino acid
derivatives according to the strategy in Scheme 2. To preserve
chirality during enolate formation and the subsequent C–C bond
formation, the choice of the protecting group on the nitrogen
of the a-amino acids is critical. According to our previous
results on the inter- and intra-molecular alkylation of a-amino
acid derivatives,2,4,5 where the Boc group is essential for the
generation of a chiral non-racemic enolate intermediate of high
enantiomeric purity, the N-Boc-a-amino acid derivative with a
Michael acceptor 1 was designed as a substrate for the present
purpose. Substrate 1 was readily prepared from a-amino acid
ethyl esters through N-alkylation with an x-bromo-1-alkene,
introduction of a Boc group to the nitrogen, ozonolysis of the
double bond, and a Wittig reaction.
The conditions for the intramolecular conjugate addition of
the enolate generated from 1a were examined (Table 1). Treat-
ment of 1a with potassium hexamethyldisilazide (KHMDS)
in THF at −78 ◦C for 30 min gave 2 as a sole detectable
diastereomer in 51% ee and in 65% yield (entry 1). The relatively
low ee of 2 was thought to be the result of the equilibrium
between the enolate and the Michael adduct; however, this
seems unlikely because shorter (5 min) and longer (60 min)
reaction times did not significantly alter the ee of 2: 50% ee after
5 min, 51% ee after 30 min, and 47% ee after 60 min (entries 1–3).
Use of a 4 : 1 mixture of toluene–THF as a solvent, which is the
best solvent for the intermolecular asymmetric alkylation,3g,4 is
not suitable for the present purpose in terms of the low ee of
the product (19% ee, entry 4). The reaction in DMF gave a 1 : 1
mixture of 2 (84% ee) and 3 (83% ee) in a combined yield of 68%
(entry 5). Use of a 1 : 1 mixture of DMF and THF gave the best
result. Treatment of 1a with KHMDS in DMF–THF (1 : 1) gave
a 4 : 1 mixture of 2 (91% ee) and 3 (94% ee) in a combined yield of
81% (entry 6).6 Use of lithium amide bases did not give any of the
cyclization products (entries 7 and 8). The relative and absolute
configurations of the major product 2 were determined to be
(2R,3S) by an X-ray crystallographic analysis of its derivative
4 which was prepared through selective deprotection of the N-
Boc group of 2 with 1 M HCl in ethyl acetate, N-benzoylation,
deprotection of the tert-butyl ester with 4 M HCl in ethyl acetate,
followed by condensation with (R)-1-(1-naphthyl)ethylamine
(Fig. 1).7 Thus, the intramolecular conjugate addition of 1a took
The stereoselective construction of chiral quaternary stereo-
centers is one of the most challenging tasks in synthetic
organic chemistry.1 We have developed a direct method for
the enantioselective construction of a,a-disubstituted a-amino
acids from a-amino acids via memory of chirality.2,3 Under
these conditions, a-methylation of N-tert-butoxycarbonyl(Boc)-
N-methoxymethyl(MOM)-a-amino acid derivatives takes place
in up to 93% ee without the aid of external chiral sources such as
chiral auxiliaries or chiral catalysts [Scheme 1 (1)].4 A chiral non-
racemic enolate A (R = CH2Ph, X = CH2OMe) with a chiral
C–N axis has been proposed as the crucial intermediate for this
novel asymmetric induction, whose racemization barrier is 16.0
kcal mol−1 and the corresponding half-life of racemization is 22 h
at −78 ◦C. We further developed a route for the straightforward
synthesis of cyclic amino acids with a quaternary stereocenter
from readily available a-amino acids via memory of chirality
[Scheme 1 (2)].5 An axially chiral enolate intermediate A [X =
(CH2)nBr] was also proposed to be a crucial intermediate.
Experimental evidence for the axially chiral enolate inter-
mediates A involves the observation that a-alkylation of B
Scheme 1
Scheme 2
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
T h i s j o u r n a l i s
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 0 9 – 1 6 1 1
1 6 0 9
©

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Table 1 Asymmetric intramolecular conjugate addition of 1a
Yield (%)b
Entry
Basea
Solvent
Temp/◦C, time/min
2 (% ee)c
3 (% ee)c
e
e
e
e
1
2
3
4
5
6
7
8
KHMDSd
KHMDSd
KHMDSd
KHMDSd
KHMDSd
KHMDSd
LHMDSf
LTMPh
THF
THF
THF
−78, 30
−78, 5
65 (51)
61 (50)
61 (47)
56 (19)
34 (84)
−78, 60
−78, 30
−60, 30
−78, 30
−78, 30
−78, 30
Toluene–THF (4 : 1)
DMF
DMF–THF (1 : 1)
DMF–THF (1 : 1)
DMF–THF (1 : 1)
34 (83)
65 (91)
16 (94)
e, g
e, g
e, i
e, i
a 1.1 Equiv. of base was used. b Isolated yield. c Ee was determined with the corresponding N-benzoyl derivative by HPLC analysis. d Potassium
hexamethyldisilazide. e Not detected. f Lithium hexamethyldisilazide. g Several unidentified products. h Lithium 2,2,6,6-tetramethylpiperidide.
i Recovery of starting material.
Fig. 1 X-Ray structure of 4.
place with a retention of configuration at C(2) and a relative
trans-stereochemistry between the two ester groups.
enantioselectivity simply by the base-treatment of the precursors
derived from a-amino acids. Seven-membered ring cyclization
from 1d proceeded to give 7 in 91% ee, albeit in only 19%
yield. Compounds 2, 3, and 5–7 are regarded as precursors for
conformationally constrained L-glutamate analogues.8
The present protocol was applied to the synthesis of a
multi-substituted tetrahydroisoquinoline derivative. A precur-
sor for cyclization, 8, was prepared in 66% overall yield by
coupling of an alanine ethyl ester and (E)-tert-butyl 3-(2-
bromomethylphenyl)acrylate followed by the introduction of a
Boc group. Treatment of 8 with KHMDS in THF–DMF (1 : 1)
Six-membered ring cyclization by intramolecular conjugate
addition took place with almost complete stereoselectivity
(Scheme 3). Treatment of 1b with KHMDS in DMF–THF
(1 : 1) at −78 ◦C for 30 min gave 5 (97% ee) as a single detectable
diastereomer in 66% yield. While the absolute configuration
of 5 has not yet been determined, the relative stereochemistry
was confirmed from the NOESY spectrum. Similarly, tyrosine
derivative 1c gave 6 in 98% ee and in 74% yield. In these
reactions, 2,2,3-trisubstituted piperidines were obtained in high
Scheme 3
1 6 1 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 0 9 – 1 6 1 1

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Scheme 4
◦
at −78 C for 30 min gave 9 in 95% ee and in 94% yield as a
single diastereomer (Scheme 4). Thus, a highly stereoselective
and concise route to 3,3,4-trisubstituted tetrahydroisoquinoline
has been developed.
4 T. Kawabata, H. Suzuki, Y. Nagae and K. Fuji, Angew. Chem., Int.
Ed., 2000, 39, 2155–2157.
5 T. Kawabata, S. Kawakami and S. Majumdar, J. Am. Chem. Soc.,
2003, 125, 13 012–13 013.
6 Typical procedure for the intramolecular conjugate addition of
enolates: a KHMDS solution in THF (0.56 M in THF, 0.98 mL,
0.55 mmol) was diluted with THF–DMF (1 : 1, 3.0 mL) and cooled
down to −78 ◦C. A solution of starting compound 1a (0.5 mmol)
in THF–DMF (1 : 1, 1.5 mL) was added to the KHMDS solution
over 5 min. After 30 min, the mixture was quenched by saturated
aqueous NH4Cl (5 mL) and extracted with ethyl acetate (3 ×
25 mL). The combined organic layer was washed with brine, dried
over Na2SO4, filtered, and evaporated in vacuo. The residue was
purified by preparative TLC (ethyl acetate–hexane 15 : 85) to 2 (65%,
91% ee) and 3 (16%, 94% ee). The ee values were determined by HPLC
analysis of the corresponding N-benzoyl derivatives: for the benzoate
In summary, pyrrolidine-, piperidine-, and tetrahydroiso-
quinoline-derivatives with contiguous quaternary and tertiary
stereocenters were prepared in high enantiomeric purity simply
by base-treatment of the acyclic precursor derived from a-
amino acids in the absence of external chiral sources. This
provides a straightforward route to multi-substituted nitrogen
heterocycles, which are potentially useful as pharmacophores
for drug discovery9 and also as possible intermediates for natural
product synthesis.10
of 2, Chiralpak AD, flow 1.75 mL min−1, 10% i-PrOH/hexane, tR
11.7 (2R,3S), 17.8 (2S,3R) min; for the benzoate of 3, Chiralpak
AD, flow 1.5 mL min−1, 6% i-PrOH/hexane, tR = 10.9 (2R,3R), 13.4
(2S,3S) min.
=
Acknowledgements
We thank the Japan Society of Promotion of Science (JSPS) for
financial support to S. M. (P02393).
7 Crystal data for 4: C35H36N2O4, M = 548.66, monoclini◦c, a =
˚
10.197(5), b = 16.139(8), c = 10.043(5) A, b = 114.160(6) , V =
3
1508.0(13) A , space group P21, Z = 2, D = 1.208 g cm−1, Mo-
˚
˚
Ka (k = 0.71070 A, T = 93 K), measured reflections = 10 224.
Notes and references
1 For recent reviews, see: E. J. Corey and A. Guzman-Perez, Angew
Chem., Int. Ed., 1998, 37, 388; J. Christoffers and A. Mann, Angew.
Chem., Int. Ed., 2001, 40, 4591.
Structure solution by SIR-97, refinement by full-matrix least-squares
using all reflections (SHELXL-97), R = 0.062 [|Fo | > 2r(Fo)], Rw
= 0.136 (all reflections), GOF = 1.10. CCDC reference number
253569. See http://www.rsc.org/suppdata/ob/b4/b416535g/ for
crystallographic data in CIF or other electronic format.
2 T. Kawabata and K. Fuji, Topics Stereochem., 2003, 23, 175–205.
3 For reactions related to memory of chirality, see: (a) B. Beagley, M. J.
Betts, R. G. Pritchard, A. Schofield, R. J. Stoodley and S. Vohra,
J. Chem. Soc., Chem. Commun., 1991, 924; (b) M. J. Betts, R. G.
Pritchard, A. Schofield, R. J. Stoodley and S. Vohra, J. Chem. Soc.,
Perkin Trans. 1, 1999, 1067; (c) G. Gerona-Navarro, M. A. Bonache,
R. Herranz, M. T. Garc´ıa-Lo´pez and R. Gonza´lez-Mun˜iz, J. Org.
Chem., 2001, 66, 3538; (d) M. A. Bonache, G. Gerona-Navarro, M.
Mart´ın-Mart´ınez, M. T. Garc´ıa-Lo´pez, P. Lo´pez, C. Cativiela and
R. Gonza´lez-Mun˜iz, Synlett, 2003, 1007; (e) P. R. Carlier, H. Zhao,
J. DeGuzman and P. C.-H. Lam, J. Am. Chem. Soc., 2003, 125,
11 482; (f) T. Kawabata, O. Ozturk, H. Suzuki and K. Fuji, Synthesis,
2003, 505; (g) T. Kawabata, S. Kawakami, S. Shimada and K. Fuji,
Tetrahedron, 2003, 59, 965.
8 K. Shimamoto, M. Ishida, H. Shiozaki and Y. Ohfune, J. Org. Chem.,
1991, 56, 4167; A. F. Parsons, Tetrahedron, 1996, 52, 4149.
9 G. T. Wang, Y. Chen, S. Wang, R. Gentles, T. Sowin, W. Kati, S.
Muchmore, V. Giranda, K. Stewart, H. Sham, D. Kempf and W. G.
Laver, J. Med. Chem., 2001, 44, 1192; D. A. DeGoey, H.-J. Chen, W. J.
Flosi, D. J. Grampovnik, C. M. Yeung, L. L. Klein and D. J. Kempf,
J. Org. Chem., 2002, 67, 5445; C. Chen, X. Li and S. L. Schreiber,
J. Am. Chem. Soc., 2003, 125, 10 174.
10 S. Hannesian, M. Bayrakdarian and X. Luo, J. Am. Chem. Soc.,
2002, 124, 4716; H. He, B. Shen and G. T. Carter, Tetrahedron Lett.,
2000, 41, 2067; B. Jiang and M. Xu, Angew. Chem., Int. Ed., 2004, 43,
2543; M. Ori, N. Toda, K. Takami, K. Tago and H. Kogen, Angew.
Chem., Int. Ed., 2003, 42, 2540.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 0 9 – 1 6 1 1
1 6 1 1