Enantioselective synthesis of C11-C17 segment of mycinolide IV using samarium(II) iodide-mediated aldol reaction

Article abstract of DOI:10.1246/cl.2005.698

δ,β′-Dihydroxy-β,γ-unsaturated esters were stereoselectively synthesized by aldol reaction of aldehydes with samarium enolates that were generated by epoxide-fragmentation of γ,δ- oxiranyl-α,β-unsaturated esters using two moles of samarium(II) iodide. Thi

Full text of DOI:10.1246/cl.2005.698

698
Chemistry Letters Vol.34, No.5 (2005)
Enantioselective Synthesis of C11–C17 Segment of Mycinolide IV
Using Samarium(II) Iodide-mediated Aldol Reaction
Yasuyuki Ogawa,y;yy Kiichi Kuroda,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received March 4, 2005; CL-050296)
ꢀ,ꢁ0-Dihydroxy–ꢁ,ꢂ-unsaturated esters were stereoselec-
ed esters instead of ꢂ,ꢀ-aziridinyl–ꢃ,ꢁ-unsaturated esters was
studied and aldol adducts thus formed here were considered to
be ꢀ,ꢁ0-dihydroxy–ꢁ,ꢂ-unsaturated esters (Scheme 2). As three
functional groups and trans double bond are involved in these
compounds, they can be considered new building blocks for
the synthesis of natural products or bioactive compounds.
In the first place, SmI2-mediated aldol reaction of (20R,2E)-
3-(oxiran-20-yl)acrylic ethyl ester (1)6 with several aldehydes
was examined (Table 1). Reaction of 1 with benzaldehyde gave
the corresponding ꢀ,ꢁ0-dihydroxy–ꢁ,ꢂ-unsaturated ester 1a (32/
68 mixture of syn and anti isomers) in moderate yield along with
a small amount of ꢀ-hydroxy–ꢁ,ꢂ-unsaturated ethyl ester (En-
try 1). The yield of 1a slightly decreased because reduction of
benzaldehyde simultaneously took place under these conditions.
On the other hand, reaction of 1 with aliphatic aldehydes pro-
ceeded smoothly to give the corresponding ꢀ,ꢁ0-dihydroxy–
ꢁ,ꢂ-unsaturated esters 1b–1f in excellent yields (Entries 2–6).
This aldol reaction proceeded to form E-olefin selectively
with complete ꢃ-regioselectivity but diastereoselectivity (syn=
anti ¼ 23=77{49=51) was not observed.
tively synthesized by aldol reaction of aldehydes with samarium
enolates that were generated by epoxide-fragmentation of ꢂ,ꢀ-
oxiranyl–ꢃ,ꢁ-unsaturated esters using two moles of samarium-
(II) iodide. This samarium(II) iodide-mediated aldol reaction
was applied successfully to the enantioselective synthesis of
C11–C17 segment of Mycinolide IV.
Samarium(II) iodide (SmI2) is known as a powerful one-
electron reducing agent and is widely used in organic synthesis.1
Preparation of 3-hydroxy-2-(1-hydroxyalkyl)alkyl ketones (dou-
ble-aldols) or 3-amino-2-(1-hydroxyalkyl)alkyl ketones (ꢁ-
amino–ꢁ0-hydroxy ketones) by SmI2-mediated aldol reaction
of aldehydes with oxiranyl ketones or aziridinyl ketones was
recently reported (Scheme 1),2,3 which were then successfully
applied to synthesis of taxane skeleton.4
O
XH
R2
I2Sm
R1
SmI2
R2
SmI2
O
R3CHO
O
X
X
R1
HO
R1
R2
R3
Table 1. SmI2-mediated aldol reaction of ꢂ,ꢀ-oxiranyl–ꢃ,ꢁ-
unsaturated ester 1 and various aldehydes
X = O, NR
X = O; double-aldol
X = NR; -amino−
ketone
β
β
'-hydroxy
OH
O
OH
O
O
SmI / THF
2
OEt
OH
O
OEt
+
Scheme 1.
OEt
RCHO
R
R
OH
In addition, preparation of ꢀ-amino–ꢁ0-hydroxy–ꢁ,ꢂ-unsat-
urated esters by SmI2-mediated aldol reaction of aldehydes with
ꢂ,ꢀ-aziridinyl–ꢃ,ꢁ-unsaturated esters was reported.5 Further,
this SmI2-mediated aldol reaction was successfully applied to
the asymmetric one by introducing chiral oxazolidinone to un-
saturated aziridine. Next, the use of ꢂ,ꢀ-oxiranyl–ꢃ,ꢁ-unsaturat-
−78 °C
1
syn
anti
Aldehyde
R
Entry
Product
Yield/%
(syn/anti)
1
2
3
4
5
6
Ph
Et
Ph(CH2)2
i-Pr
c-Hex
t-Bu
1a
1b
1c
1d
1e
1f
65
85
86
91
95
89
(32/68)
(40/60)
(49/51)
(43/57)
(37/63)
(23/77)
SmI2
O
O
SmI2
SmI2
O
O
R1
R2
R1
γ,δ-oxiranyl−α,β
unsaturated ester
SmI2 SmI2
R2
-
Then, this aldol reaction was applied to the asymmetric one
by introducing a chiral oxazolidinone to the unsaturated epoxide
as in the cas0e of unsaturated aziridine. In the first place, the re-
action of (2 R,400R,2E)-400-benzyl-300-[3-(oxiran-20-yl)acryloyl]-
oxazolidin-200-one (2) with 3-phenylpropanal was examined
(Table 2, Entry 1).7 This asymmetric aldol reaction proceeded
smoothly and afforded the corresponding product 2a in high
yield with high syn diastereoselectivity (dr ¼ 7:8=1). In addi-
tion, the corresponding products were also obtained in good to
high yields with high diasteoselectivities when other aldehydes
were used (Entries 2–4).
H3O+
OH
OH
O
O
O
R1
R1
R2
R1
R2
R3CHO
O
R2
R3
OH
δ,β'-dihydroxy−β,γ
unsaturated ester
-
Scheme 2.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.5 (2005)
699
Table 2. SmI2-mediated asymmetric aldol reaction
O
O
O
O
b
a
O
O
O
OH
O
N
O
O
SmI / THF
2
OEt
O
N
O
N
O
RCHO
4
2
Bn
R
OH
2
Bn
−78 °C
Bn
O
c
SEMO
Aldehyde
R
OH
OH
C11-C17 segment (3)
HO
N
O
Entry
Product
Yield/%
dra
OH
Bn
1
2
3
4
Ph(CH2)2
Et
i-Pr
2a
2b
2c
2d
85
89
72
68
7.8/1
9.3/1
8.1/1
7.9/1
2b
[α]D19 = −10.6 (c 0.89, CHCl3)
lit. [α]D30 = −12.8 (c 0.98, CHCl3)
c-Hex
aDiasteromeric ratio
Scheme 4. Reagents and conditions: a) mCPBA, ClCH2CH2Cl,
60 ꢂC (60%); LiOH, dioxane-MeOH-H2O, 0 ꢂC; PivCl, Et3N,
(4R)-4-benzyl-2-oxazolidinone, LiCl, 0 ꢂC (52% in 2 steps). b)
SmI2, EtCHO, THF, ꢁ78 ꢂC (85%, dr = 8.7:1). c) SEMCl,
iPr2NEt, CH2Cl2, 0 ꢂC (85%); LiBH4, THF–EtOH, 0 ꢂC (87%).
O
OH
11
11
SEMO
OH
was successfully applied to the enantioselective synthesis of
C11–C17 segment of Mycinolide IV. Further investigation of
this reaction is now in progress.
17
OH
1
HO
O
C -C segment (3)
11 17
17
O
The present work was partially supported by Grant of the
21st Century COE Program from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan.
Mycinolide IV
Scheme 3.
As the asymmetric SmI2-mediated aldol reaction was thus
established, this aldol reaction was applied to the synthesis of
natural products to show its utility. Then, synthesis of C11–
C17 segment of Mycinolide IV (3) was tried. Mycinolide IV,
isolated from Micromonospora griseorubida sp. nov., is the
16-membered macrolide antibiotic and the aglycon of mycina-
micin IV. As C11–C17 segment (3) has two chiral centers and
trans double bond, the above mentioned aldol reaction would
be effectively employed in the construction of this compound
(Scheme 3).
References
1
a) G. A. Molander, Chem. Rev., 92, 29 (1992). b) G. A.
Molander and C. R. Harris, Chem. Rev., 96, 307 (1996).
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(1998).
2
a) T. Mukaiyama, H. Arai, and I. Shiina, Chem. Lett., 2000,
580. b) T. Mukaiyama, K. Pudhom, K. Yamane, and H. Arai,
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3
4
T. Mukaiyama, Y. Ogawa, and K. Kuroda, Chem. Lett., 33,
1472 (2004).
a) K. Pudhom, H. Arai, K. Yamane, and T. Mukaiyama,
Chem. Lett., 2002, 87. b) J. Matsuo, Y. Ogawa, K. Pudhom,
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First, 2,4-pentadienoic acid ethyl ester (4) was treated with
m-CPBA and ꢂ,ꢀ-oxiranyl–ꢃ,ꢁ-unsaturated ester was obtained
(Scheme 4). Then, it was converted to ꢂ,ꢀ-oxiranyl-ꢃ,ꢁ-unsatu-
rated imide as a mixture of two diastereomers by hydrolysis and
successive introduction of chiral oxazolidinone that followed.
Next, asymmetric SmI2-mediated aldol reaction was attempted.
Treatment of 2 and propanal with 2 equiv. of SmI2 at ꢁ78 ꢂC
cleanly afforded the aldol adduct 2b in high yield (85%) with
high diastereoselectivity (dr ¼ 8:7=1). Concerning the reactivity
and stereoselectivity, the results were the same either when a
mixture of diastereomers or a single isomer was used. Undesired
isomers were separated easily by column chromatography. The
primary hydroxy group of 2b was selectively protected with
2-(trimethylsilyl)ethoxymethyl (SEM) group followed by reduc-
tion with LiBH4 afforded C11–C17 segment of Mycinolide IV
(3). This compound had already been obtained by an entirely dif-
ferent procedure in the total synthesis of Mycinolide IV.8 Suc-
cessful use of the aldol adduct 2b in the enantioselective synthe-
sis of C11–C17 segment of Mycinolide IV also confirmed ster-
eochemical assignment of this compound.
5
6
7
Y. Ogawa, K. Kuroda, and T. Mukaiyama, Chem. Lett., 34,
372 (2005).
M. Miyazawa, N. Ishibashi, S. Onhuma, and M. Miyashita,
Tetrahedron Lett., 38, 3419 (1997).
Typical experimental procedure is as follows (Table 2,
Entry 1): to a mixture of 2 (36.3 mg, 0.133 mmol) and 3-phe-
nylpropanal (26.7 mg, 0.200 mmol) in THF (4 mL) at ꢁ78 ꢂC
under an argon atmosphere was added a solution of SmI2 in
THF (0.1 M, 3.30 mL, 0.330 mmol). After the reaction mix-
ture was stirred for 30 min at ꢁ78 ꢂC, the reaction mixture
was quenched with saturated aq ammonium chloride and
was diluted with ethyl acetate. It was extracted with ethyl ace-
tate, and the organic layer was washed with brine and dried
over anhydrous sodium sulfate. The crude product was
obtained after evaporation of the solvent under reduced pres-
sure and purification by thin-layer chromatography afforded
syn-2a (41.2 mg, 76%) and other isomer (5.3 mg, 9.7%).
a) K. Suzuki, T. Matsumoto, T. Tomooka, K. Matsumoto,
and G. Tsuchihashi, Chem. Lett., 1987, 113. b) S. Takano,
Y. Sekiguchi, and K. Ogawasawara, Heterocycles, 33, 743
(1992).
It is noted that the stereoselective synthesis of ꢀ,ꢁ0-dihy-
droxy–ꢁ,ꢂ-unsaturated esters from ꢂ,ꢀ-oxiranyl–ꢃ,ꢁ-unsaturat-
ed esters and aldehydes was developed via the samarium eno-
lates by using two moles of SmI2. In addition, this aldol reaction
8
Published on the web (Advance View) April 9, 2005; DOI 10.1246/cl.2005.698