Samarium-promoted asymmetric aldol-Tishchenko reaction: Synthesis of amino acid-derived 4-amino-1,3-diols

Article abstract of DOI:10.1002/adsc.201100952

A samarium-mediated novel synthesis of enantiopure 4-amino-1,3-diols is carried out through a samarium-promoted aldol-Tishchenko reaction starting from chiral α'-amino-α-chloro ketones (derived from natural α-amino acids) and aldehydes. The process takes place with moderate levels of stereoselectivity and in high yields. A mechanism is proposed to explain these results while the absolute configuration and structure of the aldol-Tishchenko adducts were established by X-ray analysis. This method has also been utilized for the synthesis of enigmols, 1-deoxysphingoid base analogues. Copyright

Full text of DOI:10.1002/adsc.201100952

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DOI: 10.1002/adsc.201100952
Samarium-Promoted Asymmetric Aldol–Tishchenko Reaction:
Synthesis of Amino Acid-Derived 4-Amino-1,3-diols
Humberto Rodrꢀguez-Solla,a,* Carmen Concellꢁn,a Paula Tuya,a
Santiago Garcꢀa-Granda,b and and M. Rosario Dꢀazb
a
Departamento de Quꢀmica Orgꢂnica e Inorgꢂnica, Facultad de Quꢀmica, Universidad de Oviedo, Juliꢂn Claverꢀa 8, 33071
Oviedo, Spain
E-mail: hrsolla@uniovi.es
b
Departamento de Quꢀmica Fꢀsica y Analꢀtica, Facultad de Quꢀmica, Universidad de Oviedo, Juliꢂn Claverꢀa 8, 33071
Oviedo, Spain
Received: December 6, 2011; Revised: March 5, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100952.
Abstract: A samarium-mediated novel synthesis of
enantiopure 4-amino-1,3-diols is carried out through
a samarium-promoted aldol–Tishchenko reaction
starting from chiral a’-amino-a-chloro ketones (de-
rived from natural a-amino acids) and aldehydes.
The process takes place with moderate levels of ste-
reoselectivity and in high yields. A mechanism is
proposed to explain these results while the absolute
configuration and structure of the aldol–Tishchenko
adducts were established by X-ray analysis. This
method has also been utilized for the synthesis of
enigmols, 1-deoxysphingoid base analogues.
chemistry. Enantiopure a-amino ketones are easily
obtained from readily available natural a-amino acids
and they have been extensively utilized as building
blocks in organic synthesis. In this sense, our group
has previously described the synthesis of chiral a’-
amino a-chloro ketones 1 by treatment of easily avail-
able a-amino esters with in situ generated chlorome-
thyllithium.[13] We have also described some synthetic
applications of these a-amino chloromethyl ke-
tones,[14] such as the preparation of enantiopure threo-
aminoalkylepoxides,[15] 3-azetidinols,[16] amino epihalo-
hydrins,[17] a’-amino-a,b-epoxy ketones,[18] aminoaziri-
dines (from their ketimine derivatives),[19] g-amino
ester azetidinium salts and epoxy esters,[20] amino-g-
butyrolactones and butenolides,[21] pseudo-C2-symmet-
ric diepoxides,[22] and chiral trisubstituted piperi-
dines.[23]
Keywords: aldol reaction; amino acids; enolates; sa-
marium; Tishchenko reaction
In recent years samarium diiodide has rapidly
become an important reagent in organic chemistry be-
The 4-amino-1,3-diol moiety belongs to a family of cause of its versatility in one- and two-electron trans-
compounds – enigmols – which are known as 1-deoxy- fer reactions. Thus, since the pioneering studies of
sphingoid base analogues; they have demonstrated Kagan,[24] many synthetic applications of this reagent
promising activity against prostate[1] and colon[2] were reported from our group and others.[25]
cancer. These compounds are generally identified as
Encouraged by the pharmacological interest in
a potential new class of anticancer principles.[3]
enigmols,[1,2] and motivated by our studies on the syn-
The aldol–Tishchenko reaction (aldol/Tishchenko thetic applications of a’-amino-a-chloro ketones and
tandem process)[4] allows the conversion of aldehydes the development of new applications of samarium
and ketones into 1,3-dihydroxy compounds. This reac- diiodide in organic synthesis, in this communication
tion has been previously reported employing different we report the employment of a-amino chloromethyl
catalysts such as samarium,[5] yttrium,[6] lithium,[7] tita- ketones and aldehydes as starting materials for the
nium,[8] ytterbium,[9] zirconium,[10] aluminium,[11] and synthesis of enigmol targets through an aldol–Tish-
lanthanum[12] species.
One of the most frequently used strategies to pre- marium diiodide.
chenko reaction, this process being promoted by sa-
pare enantiopure compounds is based on the use of
Our first attempts were performed using the N,N-
optically active natural products as starting materials. dibenzylamino chloromethyl ketone derived from l-
Thus, a-amino acids have been one of the most uti- alanine 1a and n-octanal 2a. After searching for the
lized sources of chiral compounds in synthetic organic optimum conditions for this reaction, 1.0 equiv. of 1a
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Table 1. Synthesis of aldol–Tishchenko adducts 3.
crude reaction mixtures. The analyses of the spectra
showed that all aldol–Tishchenko adducts 3 were iso-
lated with a diastereoisomeric ratio ranging between
1.5/1 to 3.5/1. These dr values should be analyzed
taking into account that there are three stereogenic
centers in aldol–Tishchenko adducts 3, two of them
being generated during the reaction. Thus, given that
the stereochemistry of the CHN carbon center is
fixed on the starting material, these results indicated
that the moderate stereoselectivity observed is a con-
sequence of the aldol process. This fact will be con-
veniently explained in the mechanistic proposal.
It is noteworthy that, although moderate stereose-
lectivity was observed in products 3a–i, major and
minor stereoisomers were separately isolated after
chromatography (hexane/EtOAc=10/1). The absolute
configuration of the major stereoisomer of compound
3i was unambiguously confirmed by a single-crystal
X-ray diffraction study (Figure 1) and was therefore
assigned as 3i-(1S,3S,4S).[27] The absolute configura-
tions of other aldol–Tishchenko adducts 3 were as-
signed by analogy and also confirmed the absence of
racemization by HPLC chiral analysis (see below).
Entry
3
R1
R2
dr[a] 1,2-syn/1,2-anti Yield [%][b]
1
2
3
4
5
6
7
8
9
3a Me n-C7H15 2.5/1
3b Me i-Bu 2.5/1
3c Me c-C6H11 3/1
3d i-Bu n-C7H15 3/1
80
81
80
91
90
88
79
90
85
3e i-Bu i-Bu
3/1
3f i-Bu c-C6H11 3.5/1
3g Bn n-C7H15 1.7/1
3h Bn i-Bu
1.5/1
3i Bn c-C6H11 2.5/1
[a]
Diastereoisomeric ratio (dr) 1,2-syn/1,2-anti was deter-
mined by 300 MHz H NMR analysis of crude products
1
3. Stereogenic centers 2, and 4 are always present in a rel-
ative trans-configuration.
Isolated yields of analytically pure compounds 3.
[b]
and 2.5 equiv. of 2a in THF were added dropwise to
a solution of SmI2 (3.0 equiv., 0.1M in THF) at
À788C. The reaction mixture was stirred for one addi-
tional hour at À788C. The solution was finally al-
lowed to warm to room temperature and poured into
a mixture of saturated aqueous Na2S2O3/NaHCO3 and
washed with brine. The aldol–Tishchenko adduct 3a
was isolated in 80% yield and in a diastereoisomeric
ratio 2.5/1 (Table 1).
Using these conditions, other aliphatic aldehydes
(branched 2b and cyclic 2c) were employed. In all
cases aldol–Tishchenko adducts 3a–c were obtained in
high yields with moderate stereoselectivities. When
the reaction was carried out with aromatic aldehydes,
products derived from a pinacol coupling reaction
were obtained instead, due to the reductive coupling
reaction of aromatic aldehydes in the presence of sa-
marium diiodide.[26]
Under the above-mentioned reaction conditions, 1-
aminoalkyl chloromethyl ketones derived from l-leu-
cine 1b and l-phenylalanine 1c also afforded with
moderate stereoselectivities the corresponding aldol–
Tishchenko adducts in high yields ranging between
79–91% (Table 1). The degree of stereoselectivity was
only moderately affected by the steric demand of R2
on aldehydes 2. So, the stereoselectivity observed in
the aldol–Tishchenko reaction was slightly higher in
the case of cyclohexanecarbaldehyde 2c, and similar
for n-octanal 2a or 3-methylbutanal 2b (Table 1). The
structure of aldol–Tishchenko adducts 3 was assigned
1
based on H, 13C, HMBC and HSQC NMR experi-
ments. The diastereoselectivity of the reaction was es-
1
tablished by H NMR spectroscopy experiments on Figure 1. ORTEP diagram for 3i-(1S,3S,4S).
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Samarium-Promoted Asymmetric Aldol–Tishchenko Reaction
Scheme 1. Mechanistic proposal for the synthesis of 3a from 1a.
A plausible mechanism for this samarium-promoted tive samarium-catalyzed Tishchenko reduction of b-
aldol-Tishchenko reaction involves an initial metala- hydroxy ketones.
À
tion of the C Cl bond on aminoalkyl chloromethyl
To illustrate some synthetic possibilities of this
ketone 1a to afford samarium enolate 4. The addition method, aldol–Tishchenko adducts 3d–f (major ste-
of this samarium enolate to the corresponding alde- reoisomers) were transformed into the corresponding
hyde (2a) would generate stereoisomeric samarium b- diols 8a–c by reaction with LiAlH4, in THF, at 08C
alkoxy ketones 5 in which the samariumACTHNUGRTNEUNG(III) atom for 6 h. After these reaction conditions, amino diols 8
would act as a Lewis acid, due to its high oxophilici- were isolated without any loss of diastereoisomeric
ty,[28] to coordinate with one molecule of the alde- purity and in high yields (Table 2).
hyde, and to facilitate the addition of a second equiv-
The enantiomeric purity of compounds 8 was deter-
alent of aldehyde generating hemiacetal intermediates mined by chiral HPLC chromatography of 8d showing
6. These species 6 would undergo an intramolecular an enantiomeric excess (ee) >98%. A racemic mix-
1,5-hydride shift that would result in the production
of samarium alcoholates 7 which, after hydrolysis,
would finally afford the corresponding aldol–Tish-
Table 2. Synthesis of enantiopure amino diols 8.
chenko adducts 3a-(2S,3S,5R) and 3a-(2S,3R,5S) in
80% yield (see Experimental Section).
The moderate stereoselectivity observed in adducts
3 could be explained as a consequence of the aldol
process rather than the Tishchenko reaction, since it
has been previously reported that for the samarium-
catalyzed intramolecular Tishchenko reduction of b-
hydroxy ketones, the transformation affords the cor-
responding anti diol monoesters in high yield and
with excellent levels of stereochemical control.[5d]
These high levels of stereochemical control are ex-
plained using a six-membered transition state (depict-
ed as A in Scheme 1) and it is similar to that pro-
posed by Evans[5d] and Schreiber.[5c] for the anti selec-
Entry
8
R1
R2
Yield [%][a]
1
2
3
4
8a
8b
8c
8d
i-Bu
i-Bu
i-Bu
PhCH2
n-C7H15
i-Bu
c-C6H11
i-Bu
91
92
95
94
[a]
Isolated yield of pure compounds 8 after column chroma-
tography based on compounds 3.
Adv. Synth. Catal. 2012, 354, 1679 – 1684
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Scheme 2. Synthesis of 10-(2S,3S,5R) and 10-(2S,3R,5S).
ture of 8d was prepared from racemic phenylalanine Experimental Section
to exclude the possibility of coelution of both enantio-
mers in HPLC.[29]
Synthesis of (2S,3S,5R)/ACTHNGUTER(NNUG 2S,3R,5S)-2-Dibenzylamino-
As it has been previously indicated, enigmols are 3-hydroxydodecan-5-yl Octanoate (3a)
interesting compounds due to their pharmacological
A 0.1M solution of samarium diiodide in tetrahydrofuran
utilities. In this sense, our next efforts were directed
towards the synthesis of enigmol analogues using this
samarium-promoted aldol–Tishchenko methodology.
So, N,N-dibenzylamino chloromethyl ketone derived
from l-alanine 1a and n-tetradecanal 2d was added
(3 equiv., 1.5 mmol, 15 mL) was prepared and cooled to
À788C. Then, a solution of the (S)-3-dibenzylamino-1-chlor-
obutan-2-one 1a (1 equiv., 0.5 mmol, 151 mg) and octanal
(2.5 equiv., 1.25 mmol, 0.2 mL) in 25 mL THF was added
dropwise to the SmI2 solution. The reaction mixture was
dropwise to a solution of SmI2 (3.0 equiv., 0.1M in stirred for an additional 1 h at À788C. Then the solution
was allowed to warm to room temperature, air was bubbled
through, and it was finally poured into a mixture of saturat-
ed aqueous Na2S2O3/NaHCO3 and brine. The aqueous layer
was extracted with Et2O (2ꢄ20 mL), and the combined or-
THF) at À788C (Scheme 2). After stirring for one
hour the solution was finally allowed to warm to
room temperature. After work-up adducts 9-
(2S,3S,5R) and 9-(2S,3R,5S) were isolated in 83%
yield and in a diastereoisomeric ratio 2.5/1. Column
ganic layers washed with brine, dried over Na2SO4, filtered
and concentrated under reduced pressure. The resulting
chromatography separation and further reduction of
crude material was purified by column chromatography
both stereoisomers allowed the synthesis of enigmol
analogues 10-(2S,3S,5R) and 10-(2S,3R,5S) which
were fully characterized and, in the case of compound
(hexane/AcOEt=10:1), to afford pure 3a-(2S,3S,5R), and
3a-(2S,3R,5S) as major an minor stereoisomers, respectively.
Major stereoisomer 3a-(2S,3S,5R): yellow oil; [a]2D0: À1.6
1
10-(2S,3R,5S), compared with the data previously re-
ported in the literature for the same compound.[1b]
In conclusion, we have a described new samarium-
mediated aldol–Tishchenko protocol for the synthesis
of 4-amino-1,3-diol targets starting from chiral a’-
amino-a-chloro ketones (derived from natural a-
amino acids) and aldehydes. This process took place
with moderate levels of stereoselectivity and the dia-
steroisomers were easily separated by column chro-
matography. The absolute configuration and structure
of aldol-Tishchenko adducts have been well estab-
lished by X-ray analysis. This method has also been
utilized for the stereoselective preparation of enigmol
analogues.
(c 0.50, CHCl3); H NMR (300 MHz, CDCl3): d=7.36–7.22
(m, 10H), 5.22–5.13 (m, 1H), 3.85 (d, J=13.3 Hz, 2H), 3.49
(t, J=9.3 Hz, 1H), 3.34 (d, J=13.3 Hz, 2H), 2.61–2.50 (m,
1H), 2.30 (t, J=7.3 Hz, 2H), 1.69–1.24 (m, 24H), 1.05 (d,
J=6.6 Hz, 3H), 0.92–0.84 (m, 6H); 13C NMR (75 MHz,
CDCl3): d=173.2 (C), 138.8 (2 ꢄ C), 128.9 (4 ꢄ CH), 128.4
(4 ꢄ CH), 127.1 (2 ꢄ CH), 71.6 (CH), 67.5 (CH), 58.5 (CH),
53.3 (2ꢄCH2), 38.9 (CH2), 35.0 (CH2), 34.6 (CH2), 31.7 (2ꢄ
CH2), 29.4 (CH2), 29.0 (2ꢄCH2), 28.9 (CH2), 25.1 (2ꢄCH2),
22.5 (2ꢄCH2), 14.0 (2 ꢄCH3), 8.0 (CH3); MS (ESI+-TOF):
m/z (%)=565 (16), 524 ([M+H]+, 100), 483 (73), 338 (15);
HR-MS: m/z=524.4102, calcd. for C34H54NO3 [M+H]+:
524.4098; IR (neat): n=2927, 2856, 1732 cmÀ1; Rf =0.48
(hexane/EtOAc=10:1).
Minor stereoisomer 3a-(2S,3R,5S): yellow oil; [a]2D0: À1.3
1
(c 1.00, CHCl3); H NMR (300 MHz, CDCl3): d=7.39–7.06
(m, 10H), 5.00–4.88 (m, 1H), 3.62 (d, J=13.6 Hz, 2H),
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Samarium-Promoted Asymmetric Aldol–Tishchenko Reaction
3.46–3.31 (m, 1H), 3.33 (d, J=13.7 Hz, 2H), 3.05 (br s, 1H),
2.52 (m, J=6.6 Hz, 1H), 2.27–2.17 (m, 2H), 1.50–1.13 (m,
24H), 1.05 (d, J=6.6 Hz, 3H), 0.82–0.76 (m, 6H); 13C NMR
(75 MHz, CDCl3): d=175.2 (C), 140.0 (2ꢄC), 128.7 (4ꢄ
CH), 128.1 (4ꢄCH), 126.7 (2ꢄCH), 71.7 (CH), 69.0 (CH),
57.0 (CH), 54.2 (2ꢄCH2), 40.3 (CH2), 34.9 (CH2), 34.5
(CH2), 31.6 (2ꢄCH2), 29.2 (CH2), 29.1 (CH2), 29.0 (CH2),
28.8 (CH2), 25.4 (CH2), 25.1 (CH2), 22.5 (CH2), 14.0 (CH2),
8.5 (CH3); MS (ESI+-TOF): m/z (%)=524 ([M+H]+, 100);
HR-MS: m/z=524.4115, calcd. for C34H54NO3 [M+H]+:
524.4104; Rf =0.42 (hexane/EtOAc=10:1)
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105 mg) was dissolved in THF (2 mL) and cooled to 08C,
Then a 1.0M solution of LiAlH4 in diethyl ether (1.1 equiv.,
0.22 mmol, 0.22 mL) was added dropwise and the reaction
mixture was stirred for 6 h. After that, the solution was
quenched with ice-water and filtered through a Celiteꢅ pad.
The aqueous layer was extracted with Et2O (2ꢄ5 mL), and
the combined organic layers dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude material
was purified by column chromatography (hexane/AcOEt=
5:1), affording pure amino diol 8a; yield: 91%; [a]2D0: +16.4
1
(c 0.50, CHCl3); H NMR (300 MHz, CDCl3): d=7.42–7.11
(m, 10H), 4.72 (br s, 1H), 3.79 (d, J=13.4 Hz, 2H), 3.65
(dq, J=8.5, 3.8 Hz, 2H), 3.37 (d, J=13.4 Hz, 2H), 2.91 (br s,
1H), 2.54 (dt, J=9.8, 5.7 Hz, 1H), 1.76–1.02 (m, 17H), 0.88
(d, J=6.4 Hz, 6H), 0.85–0.76 (m, 3H); 13C NMR (75 MHz,
CDCl3): d=138.9 (2ꢄC), 128.9 (4ꢄCH), 128.5 (4ꢄCH),
127.3 (2ꢄCH), 68.8 (2ꢄCH), 60.3 (CH), 53.8 (2ꢄCH2), 39.2
(CH2), 37.3 (CH2), 35.7 (CH2), 31.8 (CH2), 29.5 (CH2), 29.2
(CH2), 26.6 (CH), 25.7 (CH2), 23.2 (CH3), 23.0 (CH3), 22.6
(CH2), 14.0 (CH3); MS (ESI-TOF): m/z (%)=440 ([M+
H]+, 100), 422 ([M+ÀH2O], 20); HR-MS: m/z=440.3533,
calcd. for C29H46NO2 [M+H]+: 440.3529; Rf =0.23 (hexane/
EtOAc=5:1)
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Supporting Information
Characterization data as well as H/13C NMR spectra of all
new compounds 3, 8 and 10 are available in the Supporting
Information.
1
´
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Acknowledgements
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We thank financial support from Spanish Ministerio de Cien-
cia
e
Innovacion (CTQ2010-14959, MAT2006-01997,
MAT2010-15094 and Factorꢀa de Cristalizaciꢁn Consolider
Ingenio 2010), and FEDER funding. C.C. and P.T. thank
MICINN for a Juan de la Cierva contract and a predoctoral
FPU fellowship, respectively.
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1684
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ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1679 – 1684