Stereoselective SN2′ alkylation reaction sequence of the γ,δ-epoxy α,β-unsaturated ester system via γ,δ-chlorohydrin intermediates by the use of a R3Al-CuCN reagent

Article abstract of DOI:10.1016/j.tetlet.2009.06.106

A novel stereoselective S_N2′ alkylation reaction sequence of the γ,δ-epoxy α,β-unsaturated ester system has been developed which involves a regioselective substitution reaction with chloride ions at the γ-position and a subsequent S_N

Full text of DOI:10.1016/j.tetlet.2009.06.106

Tetrahedron Letters 50 (2009) 5126–5129
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective SN20 alkylation reaction sequence of the
,b-unsaturated ester system via ,d-chlorohydrin intermediates
by the use of a R3Al–CuCN reagent
c,d-epoxy
a
c
*
*
Fumihiko Yoshimura, Atsushi Matsui, Atsushi Hirai, Keiji Tanino , Masaaki Miyashita
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
a r t i c l e i n f o
a b s t r a c t
A novel stereoselective SN20 alkylation reaction sequence of the
c
,d-epoxy
a
,b-unsaturated ester system
-posi-
-chloro-d-hydroxy derivatives with a
R3Al–CuCN reagent. The new methodology was demonstrated to be applicable to a variety of substrates
and to provide various d-hydroxy- -alkyl-b, -unsaturated esters including those bearing a quaternary
asymmetric carbon atom at the
Article history:
Received 2 June 2009
Revised 20 June 2009
Accepted 23 June 2009
Available online 26 June 2009
has been developed which involves a regioselective substitution reaction with chloride ions at the
c
tion and a subsequent SN20 alkylation reaction of the resulting
c
a
c
a-position in a highly stereoselective manner and high yields.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Epoxy unsaturated ester
SN20 alkylation reaction
Chlorohydrin
R3Al–CuCN reagent
Quaternary asymmetric carbon atom
Stereoselective construction of the polypropionate-derived
chains, that are found in many macrolide and ansamycin antibiotics,
has been of great importance in the community of medicinal chem-
istry and synthetic organic chemistry.1 While aldol-type reactions
are widely used in this area, substitution reactions of epoxides with
a methyl anion equivalent also provide a powerful methodology for
this purpose. In this context, we have already developed two new
On the other hand, to synthesize the corresponding syn-SN20
product 2-syn from the trans-epoxy ester 1, an epoxide-opening
reaction that occurs in a syn-SN20 manner is required. However,
such transformation in one-step is extremely difficult, because
the copper-mediated or the copper-catalyzed SN20 reaction gener-
ally occurs by an anti-attack of a nucleophile with respect to a leav-
ing group.5 In order to realize this particular syn-SN20 alkylation
synthetic methodologies that involved the highly
alkylation reaction of ,d-epoxy- ,b-unsaturated esters with
Me3Al–H2O2 and R3Al–R03SiOTf3 reagents, resulting in the formation
of d-hydroxy- -methyl- and d-hydroxy- -alkyl- ,b-unsaturated
esters, respectively, in a stereospecific manner.
On the contrary, it has been known that stereoselective intro-
c
-selective SN2
reaction of the
designed the two-step reaction sequence involving a regioselective
substitution reaction of 1 with chloride ions at the -position and a
c,d-epoxy-a,b-unsaturated ester system, we newly
c
a
c
c
c
a
subsequent SN20 alkylation reaction of the resulting anti-chlorohy-
drin 3 with a R3Al–CuCN reagent, as shown in Scheme 1. In this
context, Dieter and Guo recently reported tandem regio- and ster-
eoselective bis-allylic substitution reactions of anti-5-acetoxy-4-
duction of a methyl group at the a-position of the c,d-epoxy-a,b-
unsaturated ester system via an SN20 reaction is quite difficult. To
overcome this synthetic problem, we have successfully developed
halo-a,b-unsaturated esters, prepared from trans-c,d-epoxy-a,
b-enoates, with alkyl magnesium cuprates, in which the first sub-
the first stereoselective SN20 methylation reaction of
a
c,d-epoxy-
stitution reaction with alkyl magnesium cuprate occurred at the
,b-unsaturated esters with a Me2Zn–CuCN reagent.4 For example,
a
-position in an SN20 manner followed by the second SN20 reaction
the reaction of an epoxy ester 1 with a Me2Zn–CuCN reagent in
DMF gave rise to the anti-SN20 product 2-anti with remarkable high
regio- and stereoselectivity (Scheme 1).4
of the resulting allylic acetate at the b-position.6 On the other hand,
Tamamura has reported the two-step syn-SN20 alkylation reaction
of
c,d-aziridinyl-a,b-enoates which involved the first regioselective
SN2 reaction with methanesulfonic acid followed by an anti-SN20
alkylation of the resulting d-amino-c-mesyloxy-a,b-enoates with
an organocopper reagent.7
* Corresponding authors. Present address: Department of Applied Chemistry,
Faculty of Engineering, Kogakuin University, Hachioji 192-0015, Japan. Tel./fax: +81
42 628 4870 (M.M.).
In this Letter, we report a highly stereoselective syn-SN20 alkyl-
ation reaction sequence of the
c,d-epoxy a,b-unsaturated ester
E-mail address: bt13149@ns.kogakuin.ac.jp (M. Miyashita).
system which involves the charcoal-promoted substitution
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.106

F. Yoshimura et al. / Tetrahedron Letters 50 (2009) 5126–5129
5127
Me
Since commercially available charcoal adsorbs water on the
surface, HCl generated from TMSCl and water would probably act
as an acid catalyst and promote the chloride substitution reaction
on the solid surface.
Me Zn, CuCN
O
2
R
R
R
R
(ref. 4)
CO R'
CO R'
2
2
S 2'
N
OH
1
2-anti
Next, we examined the key SN20 methylation reaction of 3a un-
der various conditions and the results are summarized in Table 1.
The reaction of 3a with Me2CuLi in THF produced the desired
syn-methylation product 2a-syn in 71% yield (entry 1), although
a considerable amount of the reduction product 4a (12% yield)
was accompanied. On the other hand, the reaction of 3a with a
Me2Zn–CuCN reagent4 in DMF afforded a 5:1 mixture of 2a-syn
and 5a in 92% combined yield (entry 2), whereas the reaction with
lithium trimethyl zincate did not produce 2a-syn at all (entry 3). To
our great pleasure, the reaction of 3a with an organocopper
reagent prepared from Me3Al and CuCN9 in THF gave the desired
product 2a-syn in complete regio- and stereoselectivity in 95%
yield (entry 4). While the reaction of chlorohydrin 3b-anti bearing
a benzyloxy group on the side chain, which was prepared from 1b
in 99% yield (dr >99:1), with Me3Al–CuCN in THF proceeded simi-
larly, the yield of 2b-syn was variable and lacked reproducibility
(entry 5). Therefore, we next examined the solvent effect of the
reaction with the Me3Al–CuCN reagent (entries 6–9). As a result,
while the reactions in CH2Cl2 and in Et2O were not effective at
all, use of a more polar solvent, for example, DMF, exhibited higher
reactivity. In particular, MeCN was found to enhance the reaction
γ-selective substitution
reaction with Cl ion
–
Cl
Me
CO R'
"Me-Cu reagent"
CO R'
2
2
S 2'
N
OH
OH
2-syn
3
Scheme 1. SN20 methylation reactions of
c,d-epoxy a,b-unsaturated ester 1.
reaction with TMSCl at the
c
-position and a subsequent SN20 alkyl-
-chloro-d-hydroxy derivatives with
a R3Al–CuCN reagent with remarkably high stereoselectivity.
Initially, we chose methyl trans-4,5-epoxy-2-hexenoate (1a)
readily obtainable from methyl sorbate as a model substrate and
examined the above two-step reaction sequence. Thus, the reaction
of 1a with TMSCl in the presence of charcoal in THF at 0 °C afforded
ation reaction of the resulting
c
anti-c-chloro-d-hydroxy-a,b-unsaturated ester 3a (dr = 91:9) in
96% yield (Scheme 2).8 Although other additives such as MS4A,
silica gel, and one equivalent of water were examined to effect
c
-selective chlorination, charcoal was the promoter of choice.
Cl
TMSCl
O
reagent
O
charcoal
R
R
CO2Et
CO2R'
or
CO2R'
conditions
THF, 0 °C
R
OH
3
1a: R = R' = Me
1b: R = CH2OBn, R ' = Et
1c: R = Pr, R' = Et
1d: R = CH2OBn
1e: R = Pr
R''
R''
R
R
R
R
CO2R'
Me
CO2R'
CO2R'
CO2R'
OH
OH
OH
OH
2-anti
4
2-syn
5
Scheme 2. SN20 alkylation reaction sequence of
c
,d-epoxy
a,b-unsaturated esters 1a–e.
Table 1
Reactions of chlorohydrins 3 with various methylating agentsa
Cl
R
Me
Me Al / CuCN
3
R
CO R'
CO R'
2
2
solvent
OH
OH
3a R = R' = Me
3b R = CH OBn, R' = Et
2a-syn R = R' = Me
2b-syn R = CH OBn, R' = Et
2
2
Entry
Chlorohydrin
Me-Metal (equiv) CuX (equiv)
Solvent
2-synb (%)
1
2
3
4
5
6
7
8
9
3a-antic
3a-antic
3a-antic
3a-antic
3b-anti
3b-anti
3b-anti
3b-anti
3b-anti
Me2CuLi (2)
THF
DMF
THF
THF
THF
CH2Cl2
Et2O
DMF
MeCN
2a-syn 71d
2a-syn 92e
2a-syn 0g
Me2Zn (2), CuCN (2)
Me3ZnLi (1.1)f
Me3Al (2.2), CuCN (1.1)
Me3Al (2.2), CuCN (1.1)
Me3Al (2.2), CuCN (1.1)
Me3Al (2.2), CuCN (1.1)
Me3Al (2.2), CuCN (1.1)
Me3Al (2.2), CuCN (1.1)
2a-syn 95
2b-syn 20ꢀ70
Complex mixture
2b-syn 0h
2b-syn 70i
2b-syn 88
a
The reaction was carried out at 0 °C for 1 h unless otherwise noted.
Determined by 1H NMR using pyrazine as an internal standard.
dr = 91:9.
b
c
d
e
f
Allylic alcohol 4 was accompanied in 12% yield.
A mixture of stereoisomers (2/5 = 5:1) was produced.
The reaction was carried out at ꢁ78 °C for 1 h.
g
h
i
A mixture of allylic alcohol 4 (10%) and the starting material (24%) was obtained.
The starting material was recovered unchanged.
An inseparable mixture of by-products was formed along with the starting material.

5128
F. Yoshimura et al. / Tetrahedron Letters 50 (2009) 5126–5129
Table 2
The SN20 alkylation reaction of various
c
,d-epoxy
a
,b-unsaturated esters with a R3Al–CuCN reagent via chlorohydrins 3a
Entry
Epoxide
Yield of 3b (%)
R3Al
Product
Yield of 2b (%)
2-syn:2-antic
1
2
3
4
5
6
1b
1c
1d
1e
1a
1a
99
99
Me3Al
Me3Al
Me3Al
Me3Al
Et3Al
2b-syn
2c-syn
2d-anti
2e-anti
2f-syn
2g-syn
88
99
79
96:4
96:4
4:96
1:>99
>99:1
>99:1
97d
84d,e
96f
96f
68
90g
86g,h
i-Bu3Al
a
The reaction was carried out with R3Al (2.2 equiv) and CuCN (1.1 equiv) in MeCN at 0 °C for 18 h unless otherwise noted.
b
c
d
e
f
Combined isolated yield by silica gel column chromatography.
Determined by 13C NMR (quantitative integration).
DMF was used as solvent.
dr = 80:20.
dr = 91:9.
g
h
THF was used as solvent.
c
-Alkylation product was formed in 4% yield.
rate remarkably and to give the best result in this reaction (entry
9).
The excellent results of the preliminary experiments led us to
investigate the scope of the present SN20 alkylation reaction
sequence (Table 2).10,11 Thus, the SN20 methylation reaction
ated the rate of the SN20 reaction significantly, maybe due to
enhancement of the Lewis acidity of the organocopper species
and promotion of elimination of chloride ions. It should be noted
that anti- and syn-SN20 alkylation products bearing an
a-quater-
nary asymmetric carbon atom are available from the same start-
ing material by the use of the requisite organocopper species. For
example, the two-step SN20 reaction of methyl 4,5-epoxy-2-cyclo-
hexene carboxylate 815 produced 9-syn (syn/anti = 96:4), while
the reaction of 8 with a Me2Zn–CuCN reagent in DMF furnished
9-anti16 as the sole product in 88% yield. These two methodolo-
gies provide very useful technologies for the synthesis of tertiary
sequence of trans-c,d-epoxy unsaturated esters (1b, c) bearing a
benzyloxy or a propyl side chain efficiently occurred giving rise
to the desired products 2b-syn and 2c-syn, respectively, in high ste-
reoselectivity (syn/anti = 96:4) and high yields (entries 1 and 2).
The methodology was also applicable to cis-epoxy congeners 1d
and 1e (entries 3 and 4), although DMF was the choice of solvent
in the substitution reaction with chloride ions12 and the SN20 reac-
tion of the chlorohydrin derived from 1e resulted in a slightly
lower yield.
carboxylic acid esters bearing an
stereoselective manner.
a-quaternary carbon center in a
In conclusion, we have developed a highly regio- and stereose-
lective syn- -methylation reaction sequence of the ,d-epoxy- ,b-
unsaturated ester system which involved a substitution reaction
with chloride ions at the
-position and a subsequent SN20 alkyl-
It is noteworthy that the SN20 alkylation reactions of 1a with
more bulky trialkylaluminum reagents such as triethylaluminum
and triisobutylaluminum smoothly occurred in the presence of
CuCN to furnish the ethyl and isobutyl substitution products,
respectively, in complete stereoselectivity and high yields (entries
5 and 6).
In order to demonstrate the potential of the new synthetic
methodology, we designed stereoselective construction of a qua-
ternary carbon center by the use of the present method (Scheme
3). Thus, the substitution reaction of epoxy methacrylate 6 with
TMSCl followed by treatment of the resulting chlorohydrin with
a
c
a
c
ation reaction of the resulting chlorohydrins with a R3Al–CuCN
reagent. It is noteworthy that three types of methylation products
with a different substitution pattern are obtainable from the same
a
,b-epoxy unsaturated ester by the reaction with Me3Al–H2O2
leading to an SN2-methylation product at the
Me2Zn–CuCN reagent4 giving rise to an anti-SN20 methylation
product at the -position, and with TMSCl followed by
Me3Al–CuCN reagent leading to a syn-SN20 methylation product,
respectively. Since the optically active ,b-epoxy unsaturated es-
c-position, with a
a
a
a Et3Al-CuCN reagent produced tertiary ester 7 bearing an
a-qua-
a
ternary asymmetric carbon atom (syn/anti = 91:9) in 94%
ters are readily available by the Katsuki-Sharpless asymmetric
epoxidation17 of allylic alcohols and the Shi asymmetric epoxida-
tion18 of dienoates, the new methodologies provide very useful
technologies in the synthesis of natural products, particularly,
those including the polypropionate-derived structures. Applica-
tion of these methods to natural product synthesis is now on
going in our laboratory.
yield.13,14 Interestingly, addition of toluene as co-solvent acceler-
Et Al (4 equiv.)
3
CuCN (2 equiv.)
TMSCl
Me
CO Et
Et Me
CO Et
O
charcoal
BnO
BnO
2
2
THF
0 °C to rt
MeCN, toluene
(2 : 5), 0 °C, 18 h
94% for 2 steps
OH
syn/anti 91 : 9
6
7
=
Acknowledgments
Me
CO Me
Me Zn (2 equiv.)
2
CuCN (2 equiv.)
The authors thank Dr. Eri Fukushi and Mr. Kenji Watanabe (GC–
MS & NMR Laboratory, Graduate School of Agriculture, Hokkaido
University) for their mass spectrometric analyses. Financial sup-
port from the Ministry of Education, Culture, Sports, Science and
Technology, Japan (a Grant-in-Aid for Scientific Research (B) (No.
16350049)) is gratefully acknowledged.
CO Me
2
2
O
DMF, –23 °C, 1 h
88%, single isomer
HO
8
9-anti
9-syn
TMSCl
charcoal
THF, 0 °C
95%
Me
CO Me
Me Al (2 equiv.)
3
CuCN (2 equiv.)
Cl
CO Me
2
2
Supplementary data
MeCN, 0 °C, 18 h
77%
HO
HO
10
Supplementary data (characterization data) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.06.106.
syn
/anti = 96 : 4
Scheme 3. Stereoselective construction of asymmetric quaternary carbon atoms.

F. Yoshimura et al. / Tetrahedron Letters 50 (2009) 5126–5129
5129
extracted with EtOAc. The combined organic layers were washed with
water and brine, dried over MgSO4, and concentrated under reduced
pressure. Purification of the residue by flash column chromatography on
References and Notes
1. For representative reviews, see: (a) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New
York, 1991; Vol. 2, p 239; (b) Macrolide Antibiotics: Chemistry, Biology, and
Practice; Omura, S., Ed.; Academic Press: New York, 2002; (c) Schetter, B.;
Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506.
2. (a) Miyashita, M.; Hoshino, M.; Yoshikoshi, A. J. Org. Chem. 1991, 56, 6483; (b)
Miyashita, M.; Shiratani, T.; Kawamine, K.; Hatakeyama, S.; Irie, H. Chem.
Commun. 1996, 1027; (c) Miyashita, M.; Tanino, K. J. Synth. Org. Chem. Jpn. 2004,
62, 1080.
3. Shanmugam, P.; Miyashita, M. Org. Lett. 2003, 5, 3265.
4. Hirai, A.; Matsui, A.; Komatsu, K.; Tanino, K.; Miyashita, M. Chem. Commun.
2002, 1970.
5. (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063; (b) Ibuka, T.;
Tanaka, M.; Nemoto, H.; Yamamoto, Y. Tetrahedron 1989, 45, 435; (c) Marshall,
J. A. Chem. Rev. 1989, 89, 1503; (d) Lipshutz, B. H.; Sengupta, Z. Org. React. 1992,
41, 135.
6. Dieter, R. K.; Guo, F. Org. Lett. 2008, 10, 2087.
7. Tamamura, H.; Yamashita, M.; Muramatsu, H.; Ohno, H.; Ibuka, T.; Otaka, A.;
Fujii, N. Chem. Commun. 1997, 2327.
8. Since the crude product contained a mixture of chlorohydrin and its TMS–
ether, aqueous HCl was added to the reaction mixture to hydrolyze the TMS–
ether upon workup.
9. Flemming, S.; Kabbara, J.; Nickisch, K.; Westermann, J.; Mohr, J. Synlett 1995,
183.
silica gel (hexane/EtOAc = 7:2) gave chlorohydrin 3a-anti (c/d = 91:9) as a
pale yellow oil (2.50 g, 99% yield).
11. Typical procedure for the SN20 reaction of a chlorohydrin with a Me3Al–CuCN
reagent: To
a mixture of chlorohydrin 3a-anti (1.0 g, 5.6 mmol), CuCN
(551.5 mg, 6.2 mmol), and MeCN (28 mL) was added a solution of Me3Al
(2.0 M solution in hexane, 6.2 mL, 12.3 mmol) at 0 °C and the mixture was
stirred at same temperature for 18 h. Then, water was added and the reaction
mixture was filtered through a pad of Celite. The organic layer was separated
and the aqueous layer was extracted with EtOAc. The combined organic layers
were dried over MgSO4 and concentrated under reduced pressure. Purification
of the residue by flash column chromatography on silica gel (hexane/
EtOAc = 3:1) afforded the
a-methylated product 2a-syn (single isomer) as a
pale yellow oil (781 mg, 89% yield).
12. For example, the substitution reaction of 1e in THF afforded chlorohydrin 3e as
a mixture of regioisomers (dr = 66:34) in 63% yield.
13. An excess amount of a Me3Al–CuCN reagent was required for completion of the
reaction.
14. The tertiary ester 7 was also synthesized by the reaction of the
substituted epoxy unsaturated ester 11 with a Me2Zn–CuCN reagent.
a-ethyl-
Me Zn (2 equiv.)
2
CuCN (2 equiv.)
Et Me
CO Et
Et
O
BnO
BnO
CO Et
2
2
10. Typical procedure for the substitution reaction of a
c,d-epoxy-a,b-unsaturated
DMF, 0 °C, 1 h
86%, α/γ = 95 : 5
OH
11
7
ester with TMSCl in the presence of charcoal: To a mixture of methyl trans-
4,5-epoxy-2-hexenoate (1a) (2.0 g, 14.1 mmol), charcoal (1.41 g), and THF
(70 mL) was added TMSCl (3.57 mL, 28.1 mmol) at 0 °C and the mixture
was stirred at the same temperature for 1.5 h. After the reaction mixture
was filtered through a pad of Florisil, MeOH and a 1 M aqueous solution
of HCl were added to the filtrate in order and the mixture was stirred for
15 min. The organic layer was separated and the aqueous layer was
15. Wolfgang, E.; Claude, C. J. Chem. Ber. 1981, 114, 1027.
16. Stork, G.; Franklin, P. J. Aust. J. Chem. 1992, 45, 275.
17. For a review, see: Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
18. For a review, see: Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958.