Application of samarium diiodide (SmI2)-induced reduction of α-acetoxy-α,β-enoates with α-specific kinetic electrophilic trapping for the synthesis of amino acid derivatives

Article abstract of DOI:10.1039/b303718e

γ-Acetoxy-α,β-enoates were easily reduced by samarium diiodide (SmI₂) in THF to generate samarium dienolates which were kinetically trapped with ease at their α-positions by electrophiles (proton, aldehydes or ketones) to yield (E)-alkene dipep

Full text of DOI:10.1039/b303718e

Application of samarium diiodide (SmI2)-induced reduction of
g-acetoxy-a,b-enoates with a-specific kinetic electrophilic trapping for
the synthesis of amino acid derivatives
Akira Otaka,* Akira Yukimasa, Junko Watanabe, Yoshikazu Sasaki, Sinya Oishi, Hirokazu
Tamamura and Nobutaka Fujii
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
E-mail: aotaka@pharm.kyoto-u.ac.jp; Fax: +81-75-753-4570; Tel: +81-75-753-4571
Received (in Cambridge, UK) 4th April 2003, Accepted 28th May 2003
First published as an Advance Article on the web 18th June 2003
g-Acetoxy-a,b-enoates were easily reduced by samarium
diiodide (SmI2) in THF to generate samarium dienolates
which were kinetically trapped with ease at their a-positions
by electrophiles (proton, aldehydes or ketones) to yield (E)-
alkene dipeptide isosteres or g-amino acid derivatives in
high chemical yields.
mechanism, we expected that kinetic trapping of the dienolate
with electrophiles such as aldehydes or ketones should give a-
substituted (E)-alkene isosteres via aldol reactions at the a-
carbon as shown in Fig. 1 (4 to 6). However, SmI2-mediated
reactions between aldehydes or ketones and electron deficient
alkenes such as a,b-enoates have been reported to give g-
lactone derivatives through attack to the b-position of ketyls
derived from the carbonyl compounds by reaction with SmI2.7
In our envisioned reaction system, a,b-enoates would be
employed that have electron withdrawing leaving groups at the
g-position, which, in comparison with aldehydes or ketones,
would allow the enoates to receive electrons more easily from
SmI2 to form dienolate intermediates. Indeed as shown in Table
1, reaction of 7 with SmI2 in THF in the presence of aldehydes
or ketones proceeded smoothly at 0 °C within 30 min to give a-
hydroxyalkylated (E)-alkene isosteres (9–11) in reasonable
chemical yields with accompanying small amounts of reduction
product 8. Such a-hydroxymethylation could be of great
synthetic value since hydroxymethyl groups can be transformed
to side chain functionalities of various amino acids. Trapping
with formaldehyde under aprotic conditions of the dienolate
resulting from SmI2-mediated reduction should give the desired
a-hydroxymethylated isostere. Treatment of 7 with SmI2 in the
presence of a stable reactive formaldehyde-complex, prepared
from s-trioxane and methylaluminium bis(2,6-diphenylphen-
oxide),8 gave the desired a-hydroxymethylated isostere 12 in an
acceptable yield (Table 1, run 6). Observation of the a-specific
kinetic trap can probably be rationalized by the fact that the p-
electron density of a dienolate species is higher at the a-carbon
Samarium diiodide (SmI2) is a one-electron reducing agent
which meets the demands of a wide range of chemical
transformations.1 During the course of our synthetic efforts
directed at fluoroalkene dipeptide isosteres, we found that g,g-
difluoro-a,b-enoates can be reduced to g-fluoro-b,g-enoates by
SmI2–ButOH in THF by two successive electron transfers.2
This reaction appears to be classifiable into the same class of
reaction where g,d-epoxy-a,b-enoates3 or g,d-dihydroxy-a,b-
enoate derivatives4 undergo a reductive elimination by SmI2 to
yield d-hydroxy-b,g-enoates through the probable intermediary
of dienolate species. These findings prompted us to examine the
reductive formation by SmI2 of dienolates 4 from g-acetoxy-
a,b-enoates5 1 with application of a kinetic electrophilic trap to
the synthesis of amino acid derivatives including (E)-alkene
dipeptide isosteres and g-amino acids (Fig. 1).
Table 1 Synthesis of (E)-alkene dipeptide isosteres by SmI2 in the presence
of various electrophiles
Fig. 1 Plausible mechanism for SmI2-induced formation of dienolates from
g-acetoxy-a,b-enoates and their trap with electrophiles.
(E)-Alkene dipeptide isosteres with substitution of trans-
olefins for peptide bonds have recently become of great interest
in medicinal or synthetic organic chemistry owing to their
structural similarity to parent peptide bonds.6 The d-amino-g-
acetoxy-a,b-enoate6 7 was rapidly reduced with SmI2–MeOH
Isolated
Run
Electrophile
Condition
yield (%)a
8 (32)b
8 (91)
9 (83), 8 (3)
10 (69)e, 8 (2)
11 (86), 8 (3)
12 (64), 8 (11)
in THF to yield an -Phe–Gly-type (E)-alkene dipeptide isostere
L
1
2
3
4
5
6
None
0 °C, 10 min
0 °C, 10 min
0 °C, 10 min
0 °C, 20 min
0 °C, 15 min
0 °C, 30 min
8 in 91% isolated yield (Table 1, run 2).† In this reaction, the
presence of a proton source (MeOH) is necessary for clean
conversion of 7 to 8 (in the absence of MeOH: 32%).
Consecutive transfer of two electrons from SmI2 into the p-
electron system adjacent to an acetoxy group is likely to result
in the formation of a dienolate species resulting from loss of the
acetoxy group as shown in Fig. 1. Here, presence of a proton
source leads to the kinetic trapping of the plausible dienolate
intermediate to give an Xaa–Gly-type (E)-alkene isostere (Xaa
= amino acid) (Fig. 1, 4 to 5). Based on such a reaction
MeOHc
Acetoned
Acetaldehyded
Isobutyraldehyded
Formaldehydef
a Combined yield of diastereomers except for 8. b Unidentified products
were formed. c In THF : MeOH = 7 : 1. d 3 equiv. e (Z)-isomers (4%) were
detected. f Formaldehyde complex was prepared from s-trioxane (2 equiv.),
2,6-diphenyl phenol (12 equiv.), and Me3Al (6 equiv.) in CH2Cl2–
hexane.
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This journal is © The Royal Society of Chemistry 2003

than the g-carbon.9 The use of alkyl halides such as methyl
iodide as electrophiles did not give the desired a-alkylated
products. It is worth noting that organocopper-mediated SN2A
reactions used for the preparation of (E)-alkene dipeptide
mimetics does not afford the a-hydroxyalkylated isosteres via
single step manipulations.10 As with enoate 7, almost no
stereoselectivity was noted for coupling reactions with the
carbonyl compounds examined, making stereoselective in-
troduction of carbonyl compounds an issue yet to be solved.
Next, we examined the use of N-Boc protected a-aminal
derivatives as trapping agents (Scheme 1). Reductive coupling
between the aminal derivatives and the simple g-acetoxy-a,b-
enoate 15, readily available from cis-2-butene-1,4-diol 13, with
SmI2 provides unprecedented facile access to functionalized g-
amino acid derivatives that are useful for design of foldamers11
or five-membered lactams. Generally, reaction of the Boc-
protected aminal derivatives with organometallic reagents
proceeds within a range of from poor to modest yields due to the
enolizable nature of the aminals and the presence of NH
hydrogens.12 However SmI2-mediated coupling reactions be-
tween g-acetoxy-a,b-enoate 15 and aminal derivatives gave
diastereomeric mixtures of g-amino acid derivatives (16–18) in
good yields although without diastereoselection.‡ These reac-
tions occur under essentially neutral conditions, which could
contribute to the observed high chemical yields. The resulting g-
amino acid derivatives possess functional groups amenable to
further chemical transformation that could easily lead to
additional structural units. For example, compound 18 was
subjected to a further sequence of reactions composed of
dehydration followed by an intramolecular Diels–Alder reac-
tion to afford the tricyclic compound 23,§ which represents a
potential synthetic precursor of a lactam analogue of galiella-
lactone, an antagonist of IL-6 signalling.13 Furthermore,
conversion of 18 to a seven-membered cyclic g-amino acid 24
was achieved using a second generation Grubbs’ catalyst
coordinated with the 1,3-dimesityl-4,5-dihydroimidazol-2-yli-
dene ligand.14
acetoxy-a,b-enoates as substrates resulted in the formation of
a-hydroxyalkylated (E)-alkene dipeptide isosteres (9–12).
Combination of 15 with N-Boc-protected aminal derivatives in
SmI2-mediated reduction leads to a highly efficient coupling
reaction that is applicable to the synthesis of a variety of g-
amino acid derivatives. To our knowledge, reductive dienolate
formation using SmI2 and its practical application to the
preparation of compounds of synthetic and medicinal value
have rarely been reported previously in the literature.15 We
believe that dienolate formation from readily available g-
acetoxy-a,b-enoates with SmI2 under neutral conditions fol-
lowed by kinetic trapping by electrophiles may be of significant
synthetic value.
We thank Dr. Terrence R. Burke Jr., NCI, NIH, Frederick,
MD., USA, for proofreading this manuscript. Research was
supported in part by 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, and the Japan Health Science Foundation.
Notes and references
† Alkene dipeptide isosteres obtained in this study have alkene coupling
constants (3JHH = 15.5–16.1 Hz) which are consistent with those of alkenes
possessing (E)-configurations.6 For ease of determination of geometry of 9,
10, and 11, a mixture of diastereomers was converted to the corresponding
diens by treatment with MsCl–pyridine followed by treatment with DBU–
Et3N.
‡ To a mixture consisting of enoate 15 (500 mg, 2.90 mmol) and Boc-(S)-
phenylalaninal (1.16 g, 4.64 mmol) in THF (12 cm3) was added a solution
of SmI2 in THF (0.1 mol dm23, 87 cm3) at 0 °C under argon. After being
stirred at 0 °C for 30 min, the reaction was quenched by addition of saturated
aqueous NH4Cl at this temperature. The whole was extracted with Et2O, and
the extract was washed with aqueous HCl (0.1 mol dm23) and brine and
dried over MgSO4. Concentration under reduced pressure followed by flash
chromatography gave the g-amino acid derivative 16 (855.1 mg, 81%
yield).
§ Relative configurations have yet to be completely assigned. However, the
lactone counterpart (reverse configuration) of 22 was used for the
preparation of a synthetic intermediate of galiellalactone. Therefore,
relative configurations were tentatively assigned as shown in Scheme 1.
In conclusion, as described herein, electrophilic g-acetoxy-
a,b-enoates 1 were easily reduced by SmI2, potentially yielding
Sm(III)-dienolate intermediates 4. Subsequent a-specific kinetic
proton trapping of this intermediate was utilized successfully
for the synthesis of the Phe–Gly-type (E)-alkene dipeptide
isostere 8. Furthermore, the expected dienolates resulting from
such SmI2-mediated reduction were also efficiently trapped in
situ by aldehydes and ketones, where the use of d-amino-g-
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Scheme 1 Reagents: (i) Ac2O, pyridine, DMAP; (ii) O3 gas then Me2S,
AcOEt, then (EtO)2P(O)CH2CO2Et, LiCl, Pri2NEt, CH3CN; (iii) 4 mol
dm23 HCl in dioxane then NaHCO3 (aq) and extraction, then AcOH (2
equiv.), CH2Cl2; (iv) MsCl, Et3N, CH2Cl2; (v) 110 °C, DMF; (vi) Grubbs’
catalyst (second generation, 0.05 equiv.), reflux, CH2Cl2.
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CHEM. COMMUN., 2003, 1834–1835
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