Facile access to (Z)-alkene-containing diketopiperazine mimetics utilizing organocopper-mediated anti-SN2′ reactions

Article abstract of DOI:10.1016/j.tetlet.2005.04.057

Regio- and stereoselective anti-S_N2′ alkylation of γ-phosphoryloxy-α,β-unsaturated-δ-lactams with organocopper reagents allowing the preparation of N-alkylated-α,δ- substituted-β,γ-unsaturated-δ-lactams as highly functionalized diketopiperazine

Full text of DOI:10.1016/j.tetlet.2005.04.057

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4183–4186
Facile access to (Z)-alkene-containing diketopiperazine mimetics
utilizing organocopper-mediated anti-SN20 reactions
Ayumu Niida,a Shinya Oishi,a Yoshikazu Sasaki,a Makiko Mizumoto,a
Hirokazu Tamamura,a Nobutaka Fujiia and Akira Otakaa,b,
*
aGraduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
bGraduate School of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, Japan
Received 18 March 2005; revised 11 April 2005; accepted 13 April 2005
Available online 29 April 2005
Abstract—Regio- and stereoselective anti-SN20 alkylation of c-phosphoryloxy-a,b-unsaturated-d-lactams with organocopper reagents
allowing the preparation of N-alkylated-a,d-substituted-b,c-unsaturated-d-lactams as highly functionalized diketopiperazine
mimetics is presented.
Ó 2005 Elsevier Ltd. All rights reserved.
2,5-Diketopiperazine 1 is the smallest possible cyclic
peptide consisting of two a-amino acid residues. This
highly constrained scaffold is seen in large numbers of
biologically active compounds and serves as a privileged
structure in medicinal chemistry.1 Recently, we engaged
in the development of synthetic methodologies for the
preparation of (E)-alkene dipeptide isosteres (EADIs)
as potential trans-peptide bond mimetics2 along with
their application to biologically active peptides.3 On
the basis of our research into EADIs, we envisioned that
incorporation of (Z)-alkene units structurally similar to
the cis-amide bonds in 2,5-diketopiperazines would pro-
vide diketopiperazine mimetics 2 as a novel promising
scaffold for drug discovery (Fig. 1). This type of mimetic
would be able to dissolve well in various media by pre-
venting the formation of hydrogen-bonding networks
that would otherwise result from the two peptide bonds.
´
Pioneering studies were recently reported by Guibe and
co-workers4 and Knight et al.5 for the preparation of
similar structures that led to (Z)-alkene dipeptide iso-
steres and ergot alkaloids, respectively. However, stereo-
selective incorporation of divergent a-substituents into a
common key intermediate has yet to be reported.
Our synthetic approach toward EADIs utilizes organo-
copper-mediated anti-SN20 reaction of acyclic a,b-enoates
possessing leaving groups at the c-position. Proper
choice of organocopper reagents allows a common
substrate to be converted to various a-alkylated pro-
ducts. Development of a facile and efficient synthetic
method toward functionalized diketopiperazine mimet-
ics such as 2 is strongly desirable, since this class of com-
pounds is of medicinal and synthetic value. In this letter,
novel organocopper-mediated synthetic protocols are
presented for highly functionalized diketopiperazine
mimetics possessing a wide variety of a-substituents.
These are discussed from the viewpoint of choice of the
cyclic substrates and reagents.
O
Incorporation of
(Z)-alkene unit
1
R
1
R
NH
N
3
2
N
R
R
3
2
R
R
O
O
1
2
2,5-Diketopiperazines
Diketopiperazine mimetics
Figure 1. Diketopiperazine mimetics possessing substituted (Z)-alk-
enes as cis-amide bond.
The synthesis of requisite substrates for organocopper
reactions is summarized in Scheme 1. The easily
obtainable N-Boc allyl alcohol derivatives6 syn-3 and
anti-3 were chosen as starting materials. Conversion of
the N-protecting group of syn-3 to N-Ns (Ns =
2-nitrobenzenesulfonyl) followed by O-derivatization
Keywords:
Organocopper;
anti-SN20
reaction;
Phosphate;
Peptidomimetic.
*
Corresponding author. Tel.: +81 88 633 7283; fax: +81 88 633
9505; e-mail: aotaka@ph.tokushima-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.057

4184
A. Niida et al. / Tetrahedron Letters 46 (2005) 4183–4186
OTBS
Bn
Me
O
OH
OTBS
Bn
i, ii, iii
89%
iv
Bn
Bn
Bn
Bn
OH
O
N
N
91%
Me
R
Me
R
N
N
NHBoc
NHNs
Me
Ns
Me
O
O
syn-3
4
5
22
10 R = Me
11 R = i-Bu
12 R = Bn
13 R = i-Pr
16 R = Me
17 R = i-Bu
18 R = Bn
19 R = i-Pr
20 R = (CH ) OTBS
21 R = (CH ) CO Et
OR
Bn
Bn
Bn
v, vi, vii
80%
viii
84%
N
Me
N
N
14 R = (CH ) OTBS
15 R = (CH ) CO Et
2 4
2 4
Me
Me
O
2 2
2
2 2
2
23
O
7 R = H
8 R = P(O)(OPh)
6
Figure 2. Structures of compounds obtained from the reaction of
phosphates 8 and 9 with organocopper reagents.
ix, 85%
2
OP(O)(OPh)
2
OH
Bn
Bn
Table 1. Organocopper-mediated reactions of phosphates 8 and 9
N
Entry Substrate Reagent (2 equiv)a,b
Product(s)
(%)c
Me
NHBoc
9 Steps, 46%
O
anti-3
1
2
8
8
MeCuIÆMgClÆ2LiCl
MeCuIÆMgCl
10 (93)
10 (24),
22 (40)
10 (83)
11 (82)
12 (80)d
23 (62)
13 (81)d
9
Scheme 1. Synthesis of key substrates. Reagents: (i) 4 M HCl–dioxane;
(ii) Ns-Cl, 2,4,6-collidine, CHCl3; (iii) TBS-OTf, 2,6-lutidine, CH2Cl2;
(iv) K2CO3, MeI, DMF; (v) HSCH2CO2H, LiOH, DMF; (vi)
CH2@CHCOCl, Et3N, CH2Cl2; (vii) TBAF, THF; (viii) Grubbsꢀ
catalyst second generation, CH2Cl2; (ix) (PhO)2P(O)Cl, pyridine,
CH2Cl2. Abbreviations: Ns: 2-nitrobenzenesulfonyl; TBS: tert-
butyldimethylsilyl.
3
8
8
8
8
8
8
8
9
9
9
9
9
9
MeCuÆLiIÆLiBr
4
i-BuCuÆ2LiIÆ2LiCl
BnCuIÆMgClÆ2LiCl
i-PrCuIÆMgClÆ2LiCle
i-PrCu(CN)ÆMgClÆ2LiCl
5
6
7
8
TBSOCH2(CH2)2CH2CuÆ2LiIÆ2LiCl 14 (80)
9
BrZnCu(CN)ÆCH2CH2CO2EtÆ2LiClf 15 (80)
10
11
12
13
14
15
MeCuIÆMgClÆ2LiCl
i-BuCuIÆMgClÆ2LiCl
BnCuIÆMgClÆ2LiCl
i-PrCu(CN)ÆMgClÆ2LiCl
TBSOCH2(CH2)2CH2CuÆ2LiIÆ2LiCl 20 (81)
BrZnCu(CN)ÆCH2CH2CO2EtÆ2LiClf 21 (79)
16 (73)
17 (81)
18 (85)
19 (89)
with TBS group gave N-Ns amide derivative 4. Treat-
ment of 4 with MeI in the presence of K2CO3 afforded
the N-Me sulfonamide 5.7 After removal of the Ns
group by treatment with a thiol under basic conditions,
the resulting secondary amine was acylated with acryloyl
chloride followed by O-TBS deprotection with TBAF to
afford acrylamide 6. Ring-closing metathesis reaction of
6 with Grubbsꢀ second-generation catalyst8 proceeded
smoothly at room temperature to yield c-hydroxy-a,b-
unsaturated-d-lactam 7. Although the activation of
c-hydroxy units in the acyclic enoates with the
methanesulfonyl (Ms) group has afforded satisfactory
results in organocopper-mediated synthesis of EADIs,
attempted O-methanesulfonylation of 7 failed to afford
any desired product due to its instability during purifica-
tion over silica gel. Furthermore, O-acetylated deriva-
tives proved to be inadequate for the subsequent
copper-mediated a-alkylation, even though the
acetylated compounds could be obtained in high yield.
After extensive survey of c-activation methodologies,
we found that lactam c-phosphoryloxy functionality9–11
was suitable as a leaving group in terms of its stability
and reactivity. Reaction of 7 with diphenylphosphoryl
chloride in the presence of pyridine yielded the requisite
key intermediate 8 in satisfactory isolated yield. The cor-
responding diastereomer 9 was also synthesized from
anti-3 by a sequence of reactions identical to those used
for the preparation of 8.
a Reaction condition (ꢀ78 °C, 20 min) was used except for entries 6, 9,
and 15.
b THF or mixed solvent consisting of THF and Et2O (or Et2O–pen-
tane) was used.
c Isolated yield.
d Small amount of SN2 product was isolated.
e Reaction at ꢀ78 °C for 20 min, then at 0 °C for 40 min.
f Reaction at 0 °C for 60 min.
of LiCl proceeded at ꢀ78 °C in anti-SN20 manner with
high regio- and stereoselectivity to yield the desired
a-alkylated mimetic 10 in high chemical yield (Table 1,
entry 1). In contrast, organocopper-mediated reaction
in the absence of LiCl afforded a mixture of anti-SN20-
(10, 24%) and SN2-product (22, 40%) (entry 2), which
indicated the critical involvement of the Li salt in high
a-selectivity. Whereas the role of the Li salt in affecting
reaction regioselectivity is not well understood, we spec-
ulate that structural changes of the reagent/substrate
complex induced by the Li salt were responsible for
the observed high regioselectivity. MeCuÆLiIÆLiBr in
THF–Et2O derived from an equimolar mixture of
MeLiÆLiBr and CuI was also a useful reagent for anti-
SN20 alkylation of 8 (entry 3). Encouraged by these
results, we examined the synthesis of other a-functional-
ized diketopiperazine mimetics utilizing several kinds
of organocoppers prepared from equimolar amounts
of organometallic reagent and copper(I) salt in the pres-
Next, we investigated a-alkylation of phosphate 8 with
organocopper reagents (Fig. 2 and Table 1).12 Reaction
in THF of 8 with organocopper reagent prepared from
equimolar amounts of MeMgCl and CuI in the presence

A. Niida et al. / Tetrahedron Letters 46 (2005) 4183–4186
4185
ence of Li salt. Treatment of 8 with i-BuCuÆ2LiIÆ2LiCl
and BnCuIÆMgClÆ2LiCl gave the corresponding anti-
SN20 alkylation products 11 and 12 in reasonable yields,
respectively (entries 4 and 5). Reaction of i-PrCuIÆMg-
ClÆ2LiCl did not proceed at ꢀ78 °C, but gave predomi-
nantly the pyridinone derivative 23 at room
temperature. This was probably due to the poor nucleo-
philicity of the reagent attributable to its steric bulkiness
(entry 6). On the other hand, use of the cyanocuprate
reagent, i-PrCu(CN)ÆMgClÆ2LiCl, drastically improved
the yield of desired anti-SN20 alkylation product 13
(entry 7).
the choice of organocopper reagents. Diversity of sub-
stituents at the 1- or 6-positions of the ring can also
be assured by the selection of N-alkylating reagents or
starting amino acids. Enhancement of a-selectivity in
the organocopper-mediated reaction is attributable to
the addition of Li salt, even though the basis for this ef-
fect is not well understood. Investigating the effects of Li
salts and biological evaluation of these mimetics, includ-
ing the conversion to linear (Z)-alkene-type dipeptide
isosteres as a counterpart to EADIs, will be presented
in due course.
Introduction of functional groups amenable to further
chemical manipulation was examined next. a-Alkylation
of 8 with an O-TBS-protected hydroxybutyl group was
possible by the use of TBSOCH2(CH2)2CH2CuÆ2LiIÆ
2LiCl (entry 8). Copper–zinc mixed reagents possessing
functional groups have shown synthetic usefulness
through the application to various types of activated
allylic compounds.13 Recently, Knochel et al. reported
that cyclic allylic phosphonates were alkylated in
anti-SN20 fashion by the action of functionalized
copper–zinc reagents.10 Independently, we also found
that the reaction of 8 with a copper–zinc mixed reagent
(BrZnCu(CN)CH2CH2CO2EtÆ2LiCl) proceeded unequivo-
cally in anti-SN20 manner to yield a-substituted
compound 15 possessing ester functionality (entry 9).14
Furthermore, diastereomeric 9 was also alkylated in
anti-SN20 manner with various organocopper reagents
to yield functionalized diketopiperazine mimetics
(entries 10–15).
Acknowledgments
We thank Dr. Motoo Shiro, Rigaku International
Corporation, Japan, and Dr. Terrence R. Burke Jr.,
NCI, NIH, USA, for X-ray analysis and for proofread-
ing this manuscript, respectively. This research was
supported in part by 21st Century COE Program
ꢁKnowledge Information Infrastructure for Genome Sci-
enceꢀ, a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan, the Japan Society for the Promotion
of Science (JSPS), and the Japan Health Science Foun-
dation. A.N. is grateful for Research Fellowships of
the JSPS for Young Scientists.
Supplementary data
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.04.057.
The absolute configurations of diketopiperazine mimet-
ics 12 or 16 were unambiguously determined to be 3,6-
trans (3S,6S) or 3,6-cis (3R,6S) by X-ray analyses.15
Based on these results, relative configuration of the
corresponding diastereomer 10 (vs 16) or 18 (vs 12)
References and notes
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derived from 5,6-cis-8 and 5,6-trans-phosphate 9,
respectively, indicating that the organocopper-mediated
SN20 reactions proceeded in high anti-selectivity. Other
SN20-products resulting from 5,6-cis-phosphate 8 also
exhibited upfield chemical shifts of a-protons as com-
pared to those of the corresponding 5,6-trans-derived
compounds. Based on these results and the high level
of stereoselectivity observed in organocopper-mediated
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´
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In summary, reported herein are new and practical syn-
thetic methodologies for preparation of functionalized
diketopiperazine mimetics 2 containing (Z)-alkene units.
Of note are the use of organocopper-mediated anti-SN20
reactions to c-phosphoryloxy-a,b-unsaturated-d-lac-
tams, which proceed with high regio- and stereoselecti-
vities. Unequivocal access to various diastereomerically
pure a-substituted mimetics is possible depending on

4186
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12. Representative procedure for organocopper-mediated
anti-SN20 reaction of c-phosphoryloxy-a,b-unsaturated-d-
lactams: To a stirred solution of CuI (37.3 mg, 0.196
mmol) and LiCl (16.6 mg, 0.392 mmol) in dry THF
(0.75 mL) was added MeMgCl in THF (3.0 M, 0.0653
mL, 0.196 mmol) under argon at ꢀ78 °C, and the mixture
was stirred for 10 min at 0 °C. To the solution of
organocopper reagent was added dropwise a solution of
the phosphate 8 (44.1 mg, 0.0981 mmol) in dry THF
(0.75 mL) at ꢀ78 °C, and the mixture was stirred for
20 min. The reaction was quenched with a 1:1 saturated
NH4Cl–28%NH4OH solution (2 mL). The mixture was
extracted with Et2O, and then the extract was washed with
water, and dried over MgSO4. Concentration under
reduced pressure followed by flash chromatography over
silica gel with n-hexane–EtOAc (1:1) yielded mimetic 10
(19.6 mg, 0.0910 mmol, 93%) as colorless oil.
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15. Crystal data for 12 (ref. CCDC 259902) and 16 (ref.
CCDC 259903) can be obtained on request form the
Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EW, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].