Asymmetric Synthesis of Cα-Substituted Prolines through Curtin–Hammett-Controlled Diastereoselective N-Alkylation

Article abstract of DOI:10.1002/chem.201804965

Asymmetric synthesis of α-substituted proline derivatives has been accomplished by an efficient chirality-transfer method. High diastereoselectivity of the N-alkylation of the proline ester (C→N chirality transfer) was achieved when a 2,3-disubstituted be

Full text of DOI:10.1002/chem.201804965

A Journal of
Accepted Article
Title: Asymmetric Synthesis of Cα-Substituted Prolines via Curtin–
Hammett Controlled Diastereoselective N-Alkylation
Authors: Hyunkyung Cho, Hongjun Jeon, Jae Eui Shin, Seokwoo Lee,
Soojun Park, and Sanghee Kim
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To be cited as: Chem. Eur. J. 10.1002/chem.201804965
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Asymmetric Synthesis of Cα-Substituted Prolines via Curtin–
Hammett Controlled Diastereoselective N-Alkylation
Hyunkyung Cho, Hongjun Jeon, Jae Eui Shin, Seokwoo Lee, Soojun Park and Sanghee Kim*
Abstract: Asymmetric synthesis of α-substituted proline derivatives
has been accomplished by an efficient chirality transfer method. High
diastereoselectivity of the N-alkylation of the proline ester (C→N
chirality transfer) was achieved when a 2,3-disubstituted benzyl group
substitution, two types of methodologies have been developed:
self-reproduction of chirality[7] and C→N→C chirality transfer.[8]
The self-reproduction of chirality is a renowned methodology
developed by Seebach in which the carbon-centered chirality
transfers to the adjacent carbon, and the stereochemical
information of the newly generated stereocenter is transmitted
back to the original carbon stereocenter (Scheme 1a). Another
methodology, C→N→C chirality transfer, involves the
transmission of the carbon chirality through the nitrogen atom for
the installation of the substituted Cα-stereocenter (Scheme 1b–d).
Although the latter has great potential as an alternative and
complementary method to the former, it has not yet gained much
attention. Current limitations of this nitrogen-mediated chirality
transfer include the difficulty associated with the selective
generation of a chiral nitrogen center with the stereochemical
information from a carbon center.
was used as the N-substituent. DFT calculations provided
a
mechanistic rationale for the high degree of stereoselectivity. The
generated N-chirality of the quaternary ammonium salt was
transferred back to the α-carbon via stereoselective [2,3]-Stevens
rearrangement (N→C chirality transfer) to give α-substituted proline
ester.
Cα-substituted proline derivatives have been recognized as very
attractive substances due to their wide range of applicability in
chemistry and biology.[1] For example, they modulate the
conformational properties of the cyclic amino acid proline, and
thus, they are useful in the study of biologically relevant peptide
conformations[2] as well as in drug discovery science.[3] They are
also useful in the development of new organocatalysts for
asymmetric synthesis.[4] Moreover, they can be used as
intermediates in the synthesis of more complex structures
including natural products such as those depicted in Figure 1.[5]
A pioneer work on the synthesis of Cα-substituted prolines via
C→N→C chirality transfer is that of West and Glaeske (Scheme
1b).[8b] They achieved the asymmetric synthesis of proline ester F
from N-benzyl-proline ester D via the quaternary ammonium salt
E having chirality at the nitrogen atom. The main shortcoming of
this C→N→C chirality transfer is the low level of C→N chirality
transfer. The diastereoselectivity during the quaternization was
approximately 4:1, and thus, the diastereomerically pure
ammonium salt E was obtained by several recrystallizations. This
low diastereoselectivity was also observed by Coldham et al.[8c] in
the N-quaternization of the same proline substrate with allyl
bromide.
Figure 1. Examples of natural products containing the α-substituted proline
scaffold.
A number of strategies for the asymmetric synthesis of Cα-
substituted proline derivatives have been devised.[6] One
prevalent and effective strategy is the enantioselective α-
substitution of proline itself without the aid of external chiral
sources. To allow the conservation of chirality during the α-
[*]
H. Cho, Dr. H. Jeon, J. E. Shin, Dr. S. Lee, S. Park, Prof. Dr. S. Kim*
College of Pharmacy
Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul 08826 (Korea)
E-mail: pennkim@snu.ac.kr
Supporting information for this article is given via a link at the end of
the document
Scheme 1. Asymmetric synthesis of Cα-substituted proline derivatives.
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As an effort towards attaining a high degree of chirality
transfer from a carbon to a nitrogen in the synthesis of Cα-
substituted prolines via C→N→C chirality transfer, an N-fused
bicyclic system has been utilized.[8e,g,h] Somfai used the Lewis
acid BBr3 for the in situ formation of the rigid bicyclic complex H
from proline amide G (Scheme 1c).[8g] The subsequent [2,3]-
Stevens rearrangement provides the product with a high
enantiomeric ratio (e.r.). Our group recently reported
imidazolidinone J as a proline bicyclic system which imparts
complete diastereoselectivity in the N-quaternization (Scheme
1d).[8h] The obtained diastereomeric purity was completely
transferred to the enantiomeric purity of product L via a
diastereoselective [2,3]-rearrangement. While these bicyclic
systems delivered highly enantioenriched Cα-substituted prolines
without the aid of external chiral sources, one potential drawback
is that the hydrolysis of proline amide intermediates requires
harsh conditions which hamper easy access to prolines
containing a sensitive functional group.
steric and electronic effects. For these reasons, benzyl-type
groups were considered as N-substituents from the outset.
Scheme 2. N-Alkylation of N-benzyl proline esters 1 and 3.
Table 1. Exploration of appropriate N-substituents in the N-alkylation.[a]
In connection with our studies on the asymmetric synthesis of
proline-derived compounds, we needed an effective and practical
method for synthesis of γ,δ-unsaturated α-substituted proline
esters with a substituent at the β-position. While this type of
compound could be conceivably derived from proline allyl esters
by [3,3]-rearrangements,[9] we opted to synthesize them
employing the methodology of West because strictly anhydrous
conditions or a strong base are not required. However, as
mentioned above, the diastereoselectivity during the N-
quaternization was not high. This circumstance led us to
reinvestigate the N-alkylation of the proline ester with the aim of
improving the diastereoselectivity and thereby the level of C→N
chirality transfer. Eventually, we found that the overall level of
C→N→C chirality transfer, especially C→N, could be greatly
enhanced by introducing a proper protecting group. In this
manuscript, we show that the 2,3-disubstituted benzyl group
induced a high level of diastereoselectivity in the N-quaternization
of the proline ester (C→N chirality transfer), forming
stereodefined proline derivatives with excellent diastereo- and
enantiocontrol. In addition, a mechanistic rationale is discussed
for the improved diastereoselectivity during the N-quaternization.
Entry
1
R
Yield [%][b]
n.d.[d]
100
90
d.r.[c]
-
diphenylmethyl (5a)
2
2-naphthylmethyl (5b)
1-naphthylmethyl (5c)
3-methylbenzyl (5d)
6:1
3
15:1
6:1
4
85
5
2-methylbenzyl (5e)
77
14:1
12:1
6:1
6
2-isopropylbenzyl (5f)
2-methoxybenzyl (5g)
2,6-dimethylbenzyl (5h)
2-methyl-3-methoxybenzyl (5i)
2,3-dimethylbenzyl (5j)
2,3-dimethylbenzyl (5j)
2,3-dimethylbenzyl (5j)
90
7
99
8
n.d.[d]
96
-
9
20:1
20:1
50:1
100:1
10
11[e]
12[f]
93
99
As our initial study, we examined the reaction of West’s N-
benzyl proline substrate 1 with cinnamyl bromide to see the effect
of an allylic electrophile on diastereoselectivity during N-
quaternization (Scheme 2). Similar to the results of West et al.,[8b]
the quaternary ammonium salt 2 was obtained in a diastereomeric
ratio of 5:1. This result suggested that the properties of an allylic
electrophile might not be the essential factor contributing to the
diastereoselectivity. Next, we examined the steric effects of an
ester group. The reaction of proline tert-butyl ester 3 with cinnamyl
bromide proceeded with the same 5:1 diastereoselectivity as
observed with methyl ester 1, which implied that the bulkiness of
the ester group did not have much effect on the outcome.
86
[a] Reaction conditions: 5 (0.3 mmol), cinnamyl bromide (0.3 mmol), MeCN
(1.5 mL), RT, 48 h. [b] Isolated yield. [c] The diastereomeric ratio was
determined by 1H NMR of the crude reaction mixture. [d] n.d. = not detected.
[e] Reaction was performed at a 0.4 M concentration. [f] Reaction was
performed at a 0.4 M concentration and at 0 ˚C. The reaction time was
prolonged to 60 h.
In our search for appropriate N-substituents, proline tert-butyl
ester 5 was treated with cinnamyl bromide in acetonitrile at a 0.2
M concentration at room temperature without any additives. We
first explored the bulky diphenylmethyl and naphthylmethyl
groups. The substrate with an N-substituted diphenylmethyl group
failed to produce the desired N-quaternized product (Table 1,
entry 1), probably because of severe steric hindrance. When the
N-substituent was 2-naphthylmethyl, the N-quaternized product
The above experimental results left us no choice but to alter
the N-substituent to achieve high stereoselectivity in the N-
quaternization. As per the requirement of the N-substituent, it
should be easily removed by various methods. In addition, the N-
substituent should not hamper N-quaternization through adverse
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was produced in quantitative yield, but the selectivity remained
almost the same as that of the substrate with a benzyl group
(entry 2). On the other hand, when the 1-naphthylmethyl substrate
was used, the diastereoselectivity was greatly improved to 15:1
(entry 3). In light of the results from 1- and 2-naphthylmethyl
containing substrates, the benzyl group having a substitution at
the ortho position was expected to induce higher selectivity than
that with meta substitution. This was proven by substrates 5d and
5e (entries 4 and 5); the 3-methyl benzyl group showed the same
diastereoselectivity (6:1) as that observed for the 2-
naphthylmethyl group, while the 2-methyl benzyl group resulted
in a diastereomeric ratio of 14:1, which is similar to the result from
the 1-naphthylmethyl group. The diastereoselectivity obtained
from the substrate with an ortho isopropyl group 5f was also high
(entry 6), albeit slightly lower than that with a methyl group.
However, the methoxy group, which causes less steric stress than
a methyl group, showed only modest (6:1) diastereoselectivity
(entry 7).
configuration where the ester and 2,3-dimethylbenzyl groups are
anti disposed about the pyrrolidine ring.[10] The diastereopurity of
the isolated ammonium salt 6j was unchanged upon standing in
the acetonitrile solution at room temperature, even in the
presence of a nucleophilic iodide anion. Crossover experiments
with ammonium salt 6j and N-2-methoxybenzyl proline 5g
showed that no intermolecular N-substituent exchange occurred
(see the Supporting Information). These results suggested that
the N-quaternization of proline ester 5 was an irreversible reaction.
With the above results in mind, we carried out a Density
Functional Theory (DFT) computational investigation using the
B3LYP[11] functional with the 6-31+G(d) basis set to elucidate the
high diastereoselectivity in N-quaternization of 2,3-dimethylbenzyl
proline 5j. The calculated energy profile for this reaction is
depicted in Figure 2b. The computational results revealed that the
obtained major product anti-6j is thermodynamically less favored
than the minor syn-6j, whereas the anti-configured N-2,3-
dimethylbenzyl proline 5j is more stable than the syn form by 4.2
kcal/mol. The energy profile for the N-quaternization of N-benzyl
proline 3 was similar (Figure 2a). Because most alkyl amines
including pyrrolidine have low activation barriers (5–9 kcal/mol)
for pyramidal inversion of sp3-hybridized nitrogen, and inversion
occurs rapidly,[12] the product ratio of these reactions would be
determined by the relative energies of the transition states
according to the Curtin–Hammett principle.[13] In the case of N-
benzylproline 3, the calculated transition state energy difference
(∆∆G‡) is only 0.7 kcal/mol (Figure 2a), whereas the difference in
5j is 2.4 kcal/mol (Figure 2b). The calculated energy differences
correlated well with the obtained diastereomeric ratios in the N-
quaternization reactions. The increased energy difference by the
introduction of the 2,3-dimethyl moiety onto the benzyl group
arose mainly from the steric clash between the ortho methyl group
and the pyrrolidine ring of proline in the transition state (TS 3),[14]
leading to the minor isomer.
After discovering the importance of ortho substitution, we next
examined several disubstituted benzyl groups having an ortho
methyl group. The substrate with a 2,6-dimethyl benzyl group 5h
did not provide the N-quaternized product, presumably due to
severe steric hindrance (entry 8). Fortunately, the 2-methyl-3-
methoxy and 2,3-dimethyl benzyl groups exhibited improved
(20:1) diastereoselectivity with high yields (entries 9 and 10).
Interestingly, the level of diastereoselection and yield were found
to increase with increasing concentrations (entry 11). By
decreasing the reaction temperature from room temperature to
0 °C, the diastereoselectivity of the 2,3-dimethyl benzyl substrate
5j increased to 100:1, although the reaction rate and yield
decreased (entry 12). Acetonitrile was found to be superior to
other solvents for this quaternization in terms of both yield and
stereoselectivity (see the Supporting Information).
The stereochemistry of quaternary ammonium salt 6j was
established by a NOESY experiment and determined to be the
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Figure 2. Energy profiles of the N-quaternization of proline derivatives a) 3 and b) 5j. The free energies in MeCN were calculated at the B3LYP/6-31+G(d) level of
theory.
With the highly diastereomerically enriched N-allylic
ammonium salt of proline ester 6j, we surveyed the reaction
conditions for the [2,3]-Stevens rearrangement and found that
KOtBu in THF at −78 ˚C was optimal for this transformation, as in
other similar systems.[8,15] Proline derivative 6j gave γ,δ-
unsaturated α-substituted proline ester 7 in 90% yield with
excellent diastereoselectivity (50:1) (Scheme 3a). The
diastereomeric purity of rearrangement substrate 6j was
completely transmitted to the enantiomeric purity of the
quaternary proline product 7 (50:1 d.r. of 6j→98:2 e.r. of 7). Other
possible rearrangements such as the Sommelet–Hauser
rearrangement[16] and the [1,2]-Stevens rearrangement[17] were
not observed to a detectable extent.
although a lower reaction temperature might lead to higher
diastereoselectivity. Without the separation of the ammonium salt
diastereomers, the subsequent [2,3]-rearrangement was
performed with KOtBu in THF at −78 ˚C. Variation of the cinnamyl
aromatic moiety showed that an electron-withdrawing 4-
substituent is well tolerated, giving the α-substituted proline 12a
in a good yield, d.r., and e.r. However, an electron-donating
substituent is less well-tolerated, resulting in a moderate e.r. but
high d.r. (12b). 3-Substituent on the aryl ring is well tolerated,
giving product 12c in a good yield and d.r. The level of C→N→C
chirality transfer was extremely high in the case of product 12d,
which has a thiophene ring instead of a phenyl ring.
Table 2. Scope of C→N→C chirality transfer.[a]
Scheme 3. a) The [2,3]-rearrangement of quaternary ammonium salt 6j. b)
Effect of the steric bulkiness of the ester group on the diastereoselectivity of the
[2,3]-rearrangement.
The absolute and relative stereochemistry of
7 was
established by X-ray crystallography (Scheme 3a). The relative
stereochemistry of 7 indicated that the [2,3]-rearrangement
occurred via an exo transition state, presumably to avoid the
unfavorable steric interaction between the tert-butyl ester and the
aromatic ring in the endo transition state. The importance of the
steric hindrance of the ester group on the diastereoselectivity was
discerned when the corresponding methyl ester substrate 8 was
subjected to the same rearrangement conditions (Scheme 3b).
The selectivity was only 3:1 in favor of the exo product by this
reaction.
[a] Reaction conditions: (1) N-quaternization: 5j (0.3 mmol), 10 (0.3 mmol),
MeCN (0.75 mL), RT, 48 h. (2) [2,3]-rearrangement: 11 (0.1 mmol), KOtBu
in THF (0.2 mmol), THF (2 mL), −78 ˚C, 1 h. [b] Isolated yield of [2,3]-
rearrangement. [c] The enantiomeric ratio was determined by HPLC using a
Chiracel OD-H column. [d] The diastereomeric ratio was determined by 1H
NMR of the crude reaction mixture. [e] N-quaternization was conducted at a
1 M concentration and lower temperature (−15 ˚C). [f] NaI (0.45 mmol) was
added in the N-quaternization to accelerate the reaction.
With the optimal reaction protocols established, the scope of
this process was examined by varying the allylic electrophile 10
(Table 2). For practical reasons, the N-quaternization reaction
was conducted at 0.4 M concentration and at room temperature,
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A. I. Jiménez, C. Cativiela, R. Nussinov, C. Alemán, J. Casanovas, J.
Org. Chem. 2008, 73, 3418–3427.
[3]
[4]
For a selected review, see: R. D. Taylor, M. MacCoss, A. D. G. Lawson,
J. Med. Chem. 2014, 57, 5845–5859.
When the alkyl-substituted allylic bromides were employed as
electrophiles, the corresponding α-substituted proline was also
successfully obtained with good C→N→C chirality transfer, even
though the yield, d.r. and e.r. varied somewhat depending on the
substitution pattern around the double bond. The 3,3-
disubstituted allyl electrophile prenyl bromide afforded 12e in 89%
yield and 95:5 e.r., whereas the 3-monosubstituted allyl
electrophile 10f gave the product 12f in only a modest e.r. but a
high yield and d.r. The N-alkylation with the simple allylic
electrophile allyl bromide 10g was very slow, and thus, it required
NaI to increase the reaction rate. Using allyl bromide and NaI, the
Cα-allyl proline 12g was obtained in a 75% yield and 95:5 e.r.
Dienyl bromide 10h and 2,3-disubstituted allyl bromide 10i were
also selectively quaternized (20:1 d.r.) to give the corresponding
α-substituted prolines 12h and 12i after the rearrangement.
For selected reviews, see: a) P. I. Dalko, L. Moisan, Angew. Chem. Int.
Ed. 2004, 43, 5138–5175; Angew. Chem. 2004, 116, 5248–5286; b) B.
List, Acc. Chem. Res. 2004, 37, 548–557; c) W. Notz, F. Tanaka, C. F.
Barbas III, Acc. Chem. Res. 2004, 37, 580–591; d) G. Guillena, C. Nꢀjera,
D. J. Ramꢁn, Tetrahedron: Asymmetry 2007, 18, 2249–2293; e) M.
Gruttadauria, F. Giacalone, R. Noto, Chem. Soc. Rev. 2008, 37, 1666–
1688.
[5]
a) J. F. Biard, S. Guyot, C. Roussakis, J. F. Verbist, J. Vercauteren, J. F.
Weber, K. Boukef, Tetrahedron Lett. 1994, 35, 2691–2694; b) K. Shin-
ya, J.-S. Kim, K. Furihata, Y. Hayakawa, H. Seto, Tetrahedron Lett. 1997,
38, 7079–7082; c) B. D. Morris, M. R. Prinsep, J. Nat. Prod. 1999, 62,
688–693; d) H. Morita, M. Arisaka, N. Yoshida, J. Kobayashi,
Tetrahedron 2000, 56, 2929–2934; e) H. Morita, M. Yoshinaga, J.
Kobayashi, Tetrahedron 2002, 58, 5489–5495; f) T. S. Bugni, M. Woolery,
C. A. Kauffman, P. R. Jensen, W. Fenical, J. Nat. Prod. 2006, 69, 1626–
1628.
[6]
[7]
For selected reviews, see: a) C. Cativiela, M. D. Díaz-de-Villegas,
Tetrahedron: Asymmetry 2000, 11, 645–732; b) M. I. Calaza, C. Cativiela,
Eur. J. Org. Chem. 2008, 3427–3448.
In summary, we have established an efficient chirality transfer
method for the asymmetric synthesis of α-substituted proline
derivatives via the generation of a nitrogen stereogenic center. To
achieve a high level of C→N chirality transfer, we examined
several benzyl-type auxiliaries as N-substituents and found that
a) D. Seebach, R. Naef, Helv. Chim. Acta 1981, 64, 2704–2708; b) D.
Seebach, M. Boes, R. Naef, W. B. Schweizer, J. Am. Chem. Soc. 1983,
105, 5390–5398; c) T. Weber, D. Seebach, Helv. Chim. Acta 1985, 68,
155–161; e) D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. Int.
Ed. Engl. 1996, 35, 2708–2748; Angew. Chem. 1996, 108, 2881–2921.
For examples on asymmetric synthesis of α-substituted prolines via
C→N→C chirality transfer, see: a) V. Ferey, P. Vedrenne, L. Toupet, T.
Le Gall, C. Mioskowski, J. Org. Chem. 1996, 61, 7244–7245; b) K. W.
Glaeske, F. G. West, Org. Lett. 1999, 1, 31–33; c) A. P. A. Arboré, D. J.
Cane-Honeysett, I. Coldham, M. L. Middleton, Synlett. 2000, 236–238;
d) E. Tayama, S. Nanbara, T. Nakai, Chem. Lett. 2006, 35, 478–479; e)
P. Tuzina, P. Somfai, Org. Lett. 2009, 11, 919–921; f) A. Soheili, U. K.
Tambar, Org. Lett. 2013, 15, 5138–5141; g) J. H. Siitonen, L. Yu, J.
Danielsson, G. Di Gregorio, P. Somfai, J. Org. Chem. 2018, 83, 11318–
11322; h) H. Cho, J. E. Shin, S. Lee, H. Jeon, S. Park, S. Kim, Org. Lett.
2018, DOI: 10.1021/acs.orglett.8b02568.
the
2,3-disubstituted
benzyl
group
induced
high
diastereoselectivity in the N-quaternization of the proline ester.
The increase in the diastereoselectivity was attributed to the steric
clash between the ortho substituent and the pyrrolidine ring of
proline. Our computational studies suggested that the alkylation
reaction follows Curtin-Hammett kinetics, and the product
distribution was determined by the relative energies of the
transition states. The scope of allylic electrophiles was also
investigated under the optimized conditions and provided α,β-
substituted proline esters with good diastereo- and
enantioselectivity. This protocol has been applied for the
synthesis of complex molecules including natural products, and
the results will be presented in due course.
[8]
[9]
Sakaguchi, K.; Yamamoto, M.; Watanabe, Y.; Ohfune, Y. Tetrahedron
Lett. 2007, 48, 4821.
[10] The X-ray structure of 6i also showed the anti-relationship of the ester
and benzyl groups (see the Supporting Information).
Acknowledgements
[11] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[12] a) G. Pfafferott, H. Oberhammer, J. E. Boggs, W. Caminati, J. Am. Chem.
Soc. 1985, 107, 2305–2309; b) R. D. Bach, M. Raban, Cyclic
Organonitrogen Stereodynamics, (Eds.: J. B. Lambert, Y. Takeuchi),
VCH, New York, 1992, pp 63–103.
This work was supported by the Mid-Career Researcher Program
(Grant NRF-2016R1A2A1A05005375) of the National Research
Foundation of Korea (NRF) funded by the Government of Korea
(MSIP).
[13] a) J. I. Seeman, Chem. Rev. 1983, 83, 83–134; b) J. I. Seeman, J. Chem.
Educ. 1986, 63, 42–48.
[14] For the clear perception of the structure of TS3, various views of the
structure are depicted in Figure S2 of the Supporting Information.
Keywords: proline derivatives • chirality transfer •
stereoselective synthesis • Curtin-Hammett principle • [2,3]-
rearrangement
[15] For
a selective review of base-induced [2,3] rearrangements of
ammonium salts, see: J. B. Sweeney, Chem. Soc. Rev. 2009, 38, 1027–
1038.
[16] a) M. C. R. Sommelet, Hebd. Seances Acad. Sci. 1937, 205, 56–58; b)
E. Tayama, Chem. Rec. 2015, 15, 789–800.
[1]
[2]
a) P. Maity, B. König, Biopolymers 2008, 90, 8–27; b) A. A. Morgan, E.
Rubenstein, PLoS One 2013, 8, e53785.
[17] T. S. Stevens, E. M. Creigthon, A. B. Gordon, M. MacNicol, J. Chem.
Soc. 1928, 3193–3197.
a) M. W. MacArthur, J. M. Thornton, J. Mol. Biol. 1991, 218, 397–412; b)
M. P. Williamson, Biochem. J. 1994, 297, 249–260; c) A. Flores-Ortega,
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Hyunkyung Cho, Hongjun Jeon, Jae Eui
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Asymmetric Synthesis of Cα-
Substituted Prolines via Curtin–
Hammett Controlled
C→N→C chirality transfer: An efficient chirality transfer process was established
for the asymmetric synthesis of α-substituted proline derivatives. Using a 2,3-
disubstituted benzyl group as the N-substituent, a high level of C→N chirality
transfer was achieved that enabled enantioselective synthesis of the α-substituted
prolines via [2,3]-Stevens rearrangement (N→C chirality transfer). DFT calculations
suggested that this selective N-alkylation follows Curtin-Hammett kinetics.
Diastereoselective N-Alkylation
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