Flexible, phase-transfer catalyzed approaches to 4-substituted prolines

Article abstract of DOI:10.1021/ol502239g

A range of 4-substituted prolines can be rapidly synthesized from a protected glycine Schiff base in only four steps and in 27-55% overall yield. Phase transfer catalysis allows direct access to both enantiomeric series, and the relative stereochemistry at the 4-position is readily controlled (>10:1 dr) through the choice of hydrogenation conditions.

Full text of DOI:10.1021/ol502239g

Letter
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Flexible, Phase-Transfer Catalyzed Approaches to 4‑Substituted
Prolines
Heather J. Johnston, Fergus S. McWhinnie, Felicetta Landi, and Alison N. Hulme*
EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, U.K.
S
* Supporting Information
ABSTRACT: A range of 4-substituted prolines can be rapidly
synthesized from a protected glycine Schiff base in only four steps
and in 27−55% overall yield. Phase transfer catalysis allows direct
access to both enantiomeric series, and the relative stereochemistry at
the 4-position is readily controlled (>10:1 dr) through the choice of
hydrogenation conditions.
natural products which exhibit antibiotic, anticancer, and
roline is unique among the 20 proteinogenic amino acids in
Pthat it forms a conformationally restrained tertiary amide
bond.1 Proline residues thus form an important part of protein
structural features such as loops, turns, and polyproline helices;2
substituted proline derivatives3 can enhance the inherent
structural constraints which proline imparts upon a peptide, or
peptide mimic. Our interest in 4-substituted prolines 1 was
sparked by the incorporation of cis 4-methyl proline (cis 4-
MePro) in bisebromoamide (2, Figure 1), a natural product
isolated from marine cyanobacteria Lyngbya sp. that exhibits
promising anticancer activity.4 Existing routes to the synthesis of
this proline analogue were lengthy, reliant on expensive starting
materials, poorly stereoselective or did not allow access to either
enantiomeric series.5 Since 4-MePro is present in other classes of
immunosuppressant activities,6 and 4-substituted proline de-
rivatives are found in several classes of ACE inhibitor, e.g. trans 4-
ChxPro in the prodrug Fosinopril (3, Figure 1),7 we set out to
develop a general synthetic route which would allow ready access
to both enantiomeric series of 4-substituted proline as either the
cis or trans diastereomer.
Retrosynthesis of the 4-substituted prolines cis and trans 1 led
us to identify the corresponding 4-substituted dehydroprolines 4
as a key target (Figure 2), since literature precedent exists for
Figure 2. Retrosynthesis of 4-substituted proline derivatives; illustrated
for 2S enantiomeric series.
their highly selective hydrogenolytic conversion to either the cis
or trans 4-substituted prolines.5a Two approaches were
investigated: (i) C−N bond disconnection with backbone
formation via Michael addition to an α,β-unsaturated aldehyde
and (ii) CC bond disconnection preceded by C-allylation and
N-functionalization. In each case it was anticipated that the
Figure 1. Marine natural product bisebromoamide 2 and ACE inhibitor
prodrug Fosinopril 3.
Received: July 29, 2014
Published: September 5, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
required acyclic precursor (5 and 7) would be readily synthesized
from commercial N-(diphenylmethylene)glycine tert-butyl ester
8 and that access to either enantiomeric series might be achieved
using asymmetric phase transfer catalysis (PTC).8
Although PTC has been widely used to mediate Michael
additions of a range of nucleophiles to α,β-unsaturated ketones,
esters, amides, and nitriles,9 its use to control the addition of
nucleophiles to highly reactive α,β-unsaturated aldehydes is less
common.8a We were attracted to the pseudoenantiomeric pairing
of cinchonidine 9 and cinchonine 10 based catalysts (Figure 3)
either enantiomeric series, this sequence was repeated using
cinchonine-based catalyst 10, and the corresponding N-Cbz
protected enamine ent-4a was synthesized in 38% overall yield
and 95% ee.
The alternate retrosynthetic disconnection (ii, Figure 2) was
then investigated. Ring closing metathesis (RCM) is commonly
used in the formation of six-membered cyclic amino acids, but to
the best of our knowledge, there is only one successful example
which has utilized RCM for the synthesis of the five-membered
ring of substituted prolines.17 Thus, glycine Schiff base 8 was
alkylated in the presence of TBAB with 2-methylallyl bromide to
give imine 13a which was again deprotected using aqueous acid
to give the corresponding primary amine 6a (Scheme 2). This
Scheme 2. RCM-Based Route to Enamine Intermediate 4a
Figure 3. Cinchona alkaloid based phase transfer catalysts 9 and 10.
reported by the Lygo group10 and others,11 as their use has
precedent in the synthesis of unnatural amino acids.12 Indeed,
the PTC mediated synthesis of 5-substituted proline derivatives
through the Michael addition of a glycine Schiff base to enones10a
gave us confidence that this approach would allow ready access to
either enantiomeric series (2S and 2R) in high ee.
Our attention focused initially on the synthesis of protected cis
4-MePro (cis 1a) which we required for a Solid Phase Peptide
Synthesis (SPPS)-based synthesis of bisebromoamide 2. Michael
addition of glycine Schiff base 8 to methacrolein in the presence
of cinchonidine based PTC 9 (Scheme 1) gave access to the 2S
Scheme 1. Synthesis of cis 4-MePro (cis 1a) via a Michael
Addition Sequence
amine was protected as either its Boc or Cbz carbamate;18 N-
allylation of 14a introduced the second alkene moiety which was
readily isomerized in the presence of the Ru(II) catalyst,
RuClH(CO)(PPh3)3 15, to give the RCM precursor as a
rotameric mixture of E- and Z-isomers.19 Treatment of this diene
with Grubbs’ second generation catalyst20 gave the RCM
product, enamine 4a, in good yield (55% P = Cbz; 44% P =
Boc, over two steps).21 Hydrogenation (H2, Pd/C) of 4a (P =
Cbz) gave cis 1a in only seven steps from commercial starting
materials. Once again, this route lends itself to the production of
either enantiomeric series through the appropriate choice of
cinchonidine or cinchonine-based PTCs. To confirm that
asymmetric synthesis was compatible with the RCM route, the
synthesis was repeated as far as 14a (P = Cbz) with chiral PTC 9.
Chiral HPLC of 14a (P = Cbz) confirmed the enantioselectivity
of the unoptimized PTC-catalyzed reaction as 89% ee.
Of the two approaches, the PTC-catalyzed Michael addition
gives more direct access to 4-substituted proline derivatives. We
thus expanded this route to encompass the synthesis of a number
of cis-substituted targets 1b−e (Table 1),22 noting that high
yields and % ee were maintained in the PTC reaction, and high
diastereoselectivity (cis:trans) was observed in the Pd/C
catalyzed hydrogenation.23 In cases where the % ee dropped
slightly (e.g., for the 4-cyclohexyl substituted proline, 4-ChxPro),
lowering the reaction temperature from −78 to −95 °C gave rise
to a significant improvement in % ee, albeit accompanied by a
reduction in yield. Although the synthesis of protected 4-EtPro
has been reported using two different Wittig/reduction
intermediate 11a as an ∼1:1 mixture of diastereomers. The
diphenylmethylene protecting group was removed using
aqueous acid,13 and the resultant free amine 5a spontaneously
cyclized to form an unstable imine 12a. The imine was
isomerized in situ to enamine 4a through base-promoted Cbz
protection.14 This stable species was isolated in 42% yield over
three steps; the enantiomeric excess of 4a was confirmed as 97%
ee by chiral HPLC.15 Selective hydrogenation, using H2 and Pd/
C,11 provided the desired cis-stereoisomer, cis 1a, in high yield
and 19:1 selectivity. TFA-mediated deprotection of 1a to give the
free acid confirmed the absolute configuration of the major
diastereomer [(2S,4S)-4-MePro [α]D = −84 (c 0.1, H2O); lit.16
[α]D = −83 (c 0.53, H2O)]. To demonstrate ready access to
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Table 1. Synthesis of 4-Substituted Proline Derivatives, cis 1
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for the preparation of α,β-unsaturated
aldehydes, 4a−e, 1a−e, and 18. Chiral HPLC traces for 4a−e
1
and ent-4a. H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
a
R
yield 4 (%)
ee 4 (%)
dr 1 (cis:trans)
a
b
c
d
e
e
Me
Et
42
35
57
31
66
97
95
93
82
80
93
19:1
14:1
10:1
10:1
20:1
20:1
AUTHOR INFORMATION
Corresponding Author
■
iPr
Bn
*E-mail: Alison.Hulme@ed.ac.uk.
Notes
Chx
Chx
b
54
a
b
The authors declare no competing financial interest.
Yield over three steps from 8. PTC reaction conducted at −95 °C.
strategies,24 4-iPrPro has not been reported previously. However,
cis 4-BnPro has been investigated as a constrained analogue of the
α2δ ligands pregabalin and gabapentin for the treatment of
neuropathic pain.25 In each case, our PTC route allows
substantially more efficient access to these interesting substituted
proline derivatives.
To demonstrate the applicability of this method to the
synthesis of trans 4-substituted prolines (trans 1, Figure 2), such
as the 4-ChxPro species found in Fosinopril, Chx substituted
enamine 4e was treated with H2 in the presence of Crabtree’s
Ir(I) catalyst,5a generating 18 in 75% yield as a single
diastereomer (Scheme 3). Cbz deprotection (H2, Pd/C) gave
trans 1e also in high yield (72%),26,27 allowing direct comparison
with the previously synthesized diastereomer cis 1e.28
ACKNOWLEDGMENTS
We thank Cancer Research UK (Grant ref C21383/A6950) and
the EC (Contract: MEST-CT-2005-020744) for funding.
■
REFERENCES
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materials. This should allow the application of this interesting
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