A novel enantioselective (2Z)-alk-2-enylation of aldehydes via an allyl-transfer reaction from chiral allyl donors prepared from (+)-isomenthone

Article abstract of DOI:10.1021/ol0400140

A highly enantioselective (22)-alk-2-enylation of aldehydes was successfully achieved by an allyl-transfer reaction from a chiral allyl donor, which was easily obtained by separation of a diastereomeric mixture of the corresponding homoallylic alcohol γ-adducts derived from (+)-isomenthone with alk-2-enylmagnesium chloride.

Full text of DOI:10.1021/ol0400140

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1261-1264
A Novel Enantioselective
(2Z)-Alk-2-enylation of Aldehydes via an
Allyl-Transfer Reaction from Chiral Allyl
Donors Prepared from (+)-Isomenthone
Junzo Nokami,* Kenta Nomiyama, Siddiqi M. Shafi, and Kazuhide Kataoka
Department of Applied Chemistry, Okayama UniVersity of Science, Ridai-cho,
Okayama 700-0005, Japan
nogami@dac.ous.ac.jp
Received January 29, 2004
ABSTRACT
A highly enantioselective (2Z)-alk-2-enylation of aldehydes was successfully achieved by an allyl-transfer reaction from a chiral allyl donor,
which was easily obtained by separation of a diastereomeric mixture of the corresponding homoallylic alcohol γ-adducts derived from (+)-
isomenthone with alk-2-enylmagnesium chloride.
Asymmetric allylation of aldehydes (1, RCHO) is one of
the most useful carbon-carbon bond formation reactions in
organic synthesis because of the high and reactive function-
ality and high stereoselectivity.1 For example, highly optically
active homoallylic alcohols 3 [RC*H(OH)CH2CHdCH2]
have been prepared by using allylic organometallic reagents
2 (CH2dCHCH2M; M ) metal) with a stoichiometric
Recently, we discovered an efficient stereoselective alk-
2-enylation reaction of aldehydes to give the R-adduct 5, in
which no allyl(ic) metal nucleophiles are required and a
homoallylic alcohol 6 served as an allyl donor in the presence
amount of a chiral auxiliary2 or a catalytic amount of a chiral
promoter.3 Furthermore, allylation reactions with γ-substi-
tuted organometallic reagent 2 (RCHdCHCH2M; R ) alkyl),
in the presence of a chiral auxiliary or catalyst, afford the
of an acid catalyst. To understand this unusual allylation
γ-adduct 4 diastereo- and enantioselectively.4 This C-C
reaction, we proposed a reaction mechanism via a 2-oxonium
[3,3]-sigmatropic rearrangement with a six-membered chair-
bond formation reaction is particularly useful for the
construction of vicinal stereogenic centers in a flexible
hydrocarbon chain [eq 1].
like transition state (TS-1) as shown in Scheme 1, which
5a
we termed an “allyl-transfer reaction.”
We succeeded in employing the allyl-transfer reaction to
highly enantioselective (E)-alk-2-enylation of aldehydes to
give optically pure (E)-R-adducts of homoallylic alcohols
(E)-7 using optically pure menthone as a chiral auxiliary.5d,f
In this reaction, chiral allyl-donors 8 (γ-adducts of homoal-
lylic alcohols) were prepared by reaction of alk-2-enylme-
(1) For reviews on the reaction using allyl(ic) metals: (a) Yamamoto,
Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. (b) Marshall, J. A. In Lewis
Acids in Organic Synthesis; Yamamoto, H., Ed.; Willey-VCH: New York,
2000; Vol. 1. For reviews on asymmetric allylation and related reactions:
(c) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Willey-VCH: New York, 2000. (d) Chemler, S. R.; Roush, W. R.
In Modern Carbonyl Chemistry; Otera, J., Ed.; Willey-VCH: New York,
2000.
10.1021/ol0400140 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/23/2004

Scheme 1. Stereospecific Allyl-Transfer Reaction from
γ-Adduct 6 to Aldehyde 1 to Give R-Adduct (E)-5
Table 1. Preparation of Allyl Donor 11 from
(+)-Isomenthonea
11 yield/%b (Rf value)c
entry
R1
Me
Et
n-Pent
(R)-11
(S)-11
R/S
1
2
3
b
c
d
61 (0.41)
52 (0.49)
48 (0.54)
35 (0.51)
40 (0.59)
47 (0.63)
64/36
56/44
51/49
a Reactions were performed with (+)-isomenthone (10 mmol) and alk-
2-enylmagnesium chloride, derived from magnesium (15 mmol) and
1-chloroalk-2-ene (15 mmol), in THF at 0 °C for 2 h. b Isolated yield. c Rf
value on TLC (Merk silica gel 60 F254, aluminum sheet) using a mixed
solvent (hexane/ether ) 10/1) as the eluent.
tallic reagents 2 (R * H; M ) MgCl, ZnBr, Ti(OiPr)3) with
optically pure (-)- or (+)-menthone 9, in which the desired
chiral allyl donors (R)-8 (assignment by analogy) were
selectively obtained in 77-82% yield after column chro-
matography on silica gel. The minor product (S)-8 did not
react with aldehyde at all (Scheme 2).
Table 2. Allyl-Transfer Reaction from (R)-11 to Give
Homoallylic Alcohol R-Adduct (Z)-5a
Scheme 2. Allyl-Transfer Reaction from (R)-8 to Give
(E,R)-7
(R)-11
mol equiv
RCHO 1
(Z)-5
entry
R1
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
R
yield, %b,c
1
2
3d
4
5
6
7
8d
9
10
11
12
13
14d
15
16
b
b
b
b
b
c
c
c
c
c
c
c
d
d
d
d
1.0
2.0
2.0
2.0
2.0
1.0
2.0
2.0
1.0
1.5
1.0
1.5
1.0
2.0
1.0
1.0
u
u
v
w
x
u
u
v
w
w
x
x
u
v
w
x
PhCH2CH2 5bu 69 (>99)
PhCH2CH2 5bu 88 (>99)
Ph
BnO(CH2)5 5bw 88 (>99)
PhSCH2CH2 5bx 90 (>99)e
PhCH2CH2 5cu 88 (>99)
PhCH2CH2 5cu 92 (>99)
5bv 68 (>99)
Ph
5cv 74 (>99)
BnO(CH2)5 5cw 77 (>99)
BnO(CH2)5 5cw 90 (>99)
PhSCH2CH2 5cx 77 (>99)e
PhSCH2CH2 5cx 88 (>99)e
PhCH2CH2 5d u 89 (>99)
C2H5
n-C5H11
n-C5H11
n-C5H11
n-C5H11
Ph
5d v 78 (>99)
BnO(CH2)5 5d w 90 (>99)
PhSCH2CH2 5d x 93 (>99)e
a Reactions were performed with allyl donor 11, 1 mmol (2.0 equiv),
0.75 mmol (1.5 equiv), or 0.5 mmol (1.0 equiv), aldehyde (0.5 mmol), and
p-TsOH‚H2O (10 mol % to aldehyde) in CH2Cl2 (1 mL), at 20 °C for 20
h, unless otherwise noted. b Isolated yield. c Values in parentheses show %
ee of the product, determined by HPLC analysis (CHIRALCEL OD, 5%
iPrOH in hexane as the eluent) unless otherwise noted. >99 means that no
signal of the corresponding enantiomer was observed. d p-TsOH‚H2O (40
mol %) was used. e Determined by HPLC analysis (CHIRALCEL OJ, 2%
iPrOH in hexane as the eluent).
In this paper, to extend the applicability of this asymmetric
allyl-transfer reaction further, we used (+)-isomenthone 10
derived from inexpensive (+)-(1S,2R,5R)-isomethol (>99%
ee) as a chiral auxiliary. Reaction of (+)-isomenthone 10
with alk-2-enylmetallic reagents 2 did not give a γ-adduct
selectively, but gave an easily separable diastereomeric
mixture of the corresponding γ-adducts 11 in good yield as
shown in Table 1.
Surprisingly, we discovered that one of the isolated
isomers served as an allyl donor for the (Z)-alk-2-enylation
to give only the (Z)-olefin of the corresponding R-adduct
(Z)-5, and the other isomer gave the corresponding (E)-olefin,
(E)-5. We believe that the former is the first, direct, and
enantioselective (Z)-alk-2-enylation reaction of an aldehyde
to give the corresponding enantiomerically pure (Z)-homoal-
lylic alcohol. Here, we predict that (R)-11 serves as the allyl
donor, as shown in Scheme 3. The (E)-alk-2-enylation is
similar to an allyl-transfer reaction derived from (2R,5R)-
1262
Org. Lett., Vol. 6, No. 8, 2004

In summary, an asymmetric alk-2-enylation reaction of
aldehydes by a p-TsOH‚H2O catalyzed allyl-transfer reaction
from (+)-isomenthone adducts as chiral allyl-donors gave
(E)- and (Z)-homoallylic alcohol R-adducts, via a six-
membered chairlike transition state, in good yield with >99%
ee. This is the first example of an asymmetric (Z)-alk-2-
enylation of aldehydes. The chiral allyl donors were conve-
niently prepared using an environmentally friendly Grignard
reagent with easily available (+)-isomenthone. Therefore,
there was no need to prepare an allylmetallic reagent such
as allyltin by transmetalation with a Grignard reagent and
so on. Finally, it is noteworthy that the conformational
analysis of the six-membered chairlike transition state is
Scheme 3. Configuration of 11 (Assignment by Analogy)
which Gives (Z)-5 via Allyl-Transfer Reaction
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(S)-11 will give (E)-5.
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useful to estimate the reactivity and stereochemistry of this
reaction.
Supporting Information Available: Experimental pro-
cedures and complete characterization (1H and 13C NMR,
IR, and mass spectra or elemental analysis) for compounds
5 and 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was financially supported
by a Grant in Aid for Scientific Research from the Ministry
of Education, Science, Culture, and Sports, Japan (No.
12450357), and the Okayama Foundation for Science and
Technology.
OL0400140
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Org. Lett., Vol. 6, No. 8, 2004