Highly stereoselective asymmetric construction of an acyclic carbon skeleton having two adjacent alkyl substituents by Michael addition of optically active allenyltitaniums to alkylidenemalonates

Article abstract of DOI:10.1021/ol016652p

(matrix presented) Enantio-enriched allenyltitaniums prepared in situ by the reaction of optically active secondary propargyl phosphates with a divalent titanium reagent Ti(O-i-Pr)₄/2i-PrMgCl react readily with alkylidenemalonates with excellen

Full text of DOI:10.1021/ol016652p

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3543-3545
Highly Stereoselective Asymmetric
Construction of an Acyclic Carbon
Skeleton Having Two Adjacent Alkyl
Substituents by Michael Addition of
Optically Active Allenyltitaniums to
Alkylidenemalonates
Yongcheng Song, Sentaro Okamoto, and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho Midori-ku, Yokohama, Kanagawa 226-8501, Japan
fsato@bio.titech.ac.jp
Received August 27, 2001
ABSTRACT
Enantio-enriched allenyltitaniums prepared in situ by the reaction of optically active secondary propargyl phosphates with a divalent titanium
reagent Ti(O-i-Pr)4/2i-PrMgCl react readily with alkylidenemalonates with excellent regio- and diastereoselectivities to afford the Michael addition
products with a high optical purity, thus opening up a new asymmetric method for construction of an acyclic carbon skeleton bearing two
adjacent alkyl substituents.
Recently, we reported the synthesis of optically active
allenyltitaniums bearing axial chirality by the reaction of
optically active secondary propargyl phosphates with a
divalent titanium reagent Ti(O-i-Pr)4/2i-PrMgX (1),1 which
proceeds with 97% enantiospecificity.2a In our continuing
study to utilize the allenyltitaniums thus produced in asym-
metric synthesis,2 we have now found that they react readily
with alkylidenemalonates with excellent regio- and diastereo-
selectivities to afford the Michael addition products with a
high optical purity. Thus, the reaction opens up a new
asymmetric method for construction of an acyclic carbon
skeleton bearing two adjacent alkyl substituents, the structure
of which is widely found, as a main unit or subunit, in natural
and man-made biologically important compounds.3 It should
be noted that this is the first example of asymmetric Michael
addition reaction of an allenylic metal reagent.4,5
The allenyltitanium prepared from diethyl (S)-1-methyl-
3-trimethylsilylprop-2-ynyl phosphate (2)6 and 1 (at -50 to
-40 °C for 2 h in ether) reacted smoothly with diethyl
ethylidenemalonate (4) with excellent regio- and diastereo-
(1) Reviews for synthetic reactions mediated by a Ti(O-i-Pr)4/2i-PrMgX
reagent: Sato, F.; Urabe, H.; Okamoto, S. Pure Appl. Chem. 1999, 71,
1511-1519. Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000, 753-775. Sato,
F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835-2886. Sato, F.;
Okamoto, S. AdV. Synth. Catal., in press.
(2) (a) Okamoto, S.; An, D. K.; Sato, F. Tetrahedron Lett. 1998, 39,
4551-4554. (b) An, D. K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1998,
39, 4555-4558. (c) An, D. K.; Hirakawa, K.; Okamoto, S.; Sato, F.
Tetrahedron Lett. 1999, 40, 3737-3740. (d) Okamoto, S.; Matsuda, S.;
An, D. K.; Sato, F. Tetrahedron Lett. 2001, 42, 6323-6326.
(3) For asymmetric synthesis of an acyclic carbon skeleton with two
adjacent alkyl groups by conjugate addition of chiral enolates to R,â-
unsaturated carbonyl compounds, see: (a) Corey, E. J.; Peterson, R. T.
Tetrahedron Lett. 1985, 26, 5025-5028. (b) Yamaguchi, M.; Hasebe, K.;
Tanaka, S.; Minami, T. Tetrahedron Lett. 1986, 27, 959-962. By conjugate
addition of chiral allyllithiums, see: (c) Curtis, M. D.; Beak, P. J. Org.
Chem. 1999, 64, 2996-2997. (d) Johnson, T. A.; Curtis, M. D.; Beak, P.
J. Am. Chem. Soc. 2001, 123, 1004-1005. By catalytic asymmetric Michael
addition, see: (e) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas,
C. F., III. Tetrahedron Lett. 2001, 42, 4441-4444 and references therein.
10.1021/ol016652p CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/02/2001

selectivity (at -40 °C to room temperature over 1 h) to afford
92% yield of the corresponding Michael addition product 9
having the structure shown in Scheme 1 and entry 1 in Table
trimethylsilylprop-2-ynyl phosphate (3)6 and alkylidene-
malonates 4-8, the reaction appears reasonably general.
Thus, the allenyltitanium derived from 2 reacted with, in
addition to 4 where R2 is methyl, alkylidenemalonates in
which R2 is a primary alkyl (5, entry 2) and aryl groups (6
and 7, entries 3 and 4) to afford the corresponding Michael
adduct with more than 97% diastereoselectivity and more
than 92% enantiospecificity. Similarly, the reaction of the
titanium reagent derived from 3 also proceeded with excellent
selectivities (entries 5 and 6). It is noteworthy that the
reaction proceeds smoothly with alkylidenemalonates having
a functional group such as an ester or a halide group (entries
4 and 6).
Scheme 1. Generation of Optically Active Allenyltitaniums
and Their Reaction with Alkylidenemalonates
The resulting Michael addition products can be readily
transformed into a variety of bifunctional compounds such
as 15-18 by conventional reaction sequences, as represented
by the reaction starting with 9, by taking advantage of the
reactivity of the silylacetylene and malonate functionalities
present at each of the terminal positions (Scheme 2). The
1. The enantiomeric ratio (er) of 9 thus obtained was
determined to be 96:4 by GC analysis with use of a chiral
column after derivatization (vide infra).
Scheme 2. Synthetic Transformation Starting with 9 Where
R1 and R2 Are Mea
Table 1. Michael Addition Reaction of Optically Active
Allenyltitaniums with Alkylidenemalonates
a (i) LiCl, dimethyl sulfoxide/H2O, 150 °C; (ii) NaIO4, cat. RuCl3,
CCl4/CH3CN/H2O; (iii) BH3, tetrahydrofuran; (iv) H3O+; (v)
n-Bu4NF, tetrahydrofuran; (vi) H2, Pd/BaSO4/quinoline; (vii) 2 N
HCl, reflux.
anti stereochemistry of 9 was confirmed by the production
1
of the known compound 185 and also by the H NMR
analysis of δ-lactone 16.7 Meanwhile, the absolute config-
uration of 9 was determined by comparison of the sign of
a 2: 97.8% ee. 3: 95.2% ee. b Isolated yield. c Ratio was determined by
GC analysis. d Enantiomeric ratio of the anti isomer. The er values given
in parentheses are simply extrapolated when the starting propargylic
phosphates 2 and 3 are 100% ee. e Determined by GC analysis of 15.
f Determined by GC analysis of the corresponding acid of the type 15.
g Determined by GC analysis of the diol prepared by the reaction of the
compound of the type 15 with LiAlH4. h Determined by HPLC analysis.
i Determined by GC analysis of the diol prepared by the reduction with
LiAlH4 of the compound of the type 15 in which R2 is Ph (debromination
occurred upon treatment with LiAlH4).
optical rotation of 17 with that reported [[R]29 -13.8 (c
D
0.60, CHCl3); lit.3b [R]24 -11 (c 1.0, CHCl3)].
D
Determination of the stereochemistries of other products
10-14 shown in Table 1 was carried out as follows. The
(4) Michael addition reaction of nonchiral or racemic allenylstannanes
and allenylsilanes to R,â-unsaturated carbonyl compounds in the presence
of Lewis acid have been reported: Danheiser, R. L.; Carini, D. J.; Basak,
A. J. Am. Chem. Soc. 1981, 103, 1604-1606. Santelli, M.; El Abed, D.;
Jellal, A. J. Org. Chem. 1986, 51, 1199-1206. Haruta, J.; Nishi, K.;
Matsuda, S.; Tamura, Y.; Kita, Y. J. Chem. Soc., Chem. Commun. 1989,
1065-1066.
(5) Yamamoto reported that Michael addition of allyltitaniums to
alkylidenemalonates proceeds with high anti stereoselectivity: Yamamoto,
Y.; Nishii, S. J. Org. Chem. 1988, 53, 3597-3603. Yamamoto, Y.; Nishii,
S.; Maruyama, K. J. Chem. Soc., Chem. Commun. 1985, 386-388.
(6) Optically active propargyl phosphates 2 and 3 could be readily
prepared, respectively, from naturally occurring lactates or 2,3-epoxyheptan-
1-ol derived from 2-heptenol by Sharpless asymmetric epoxidation. See
ref 2 for the synthesis and determination of the optical purities.
Since we used 2 with 97.8% enantiomeric excess (ee), the
overall enantiospecificity from 2 to 9 was calculated to be
94%, and as the enantiospecificity from 2 to the allenyl-
titanium is 97%,2a the degree of enantiospecificity for the
Michael addition reaction was estimated to be 97%.
As revealed from entries 2-6 in Table 1, which shows
the results of the reaction using 2 or diethyl (S)-1-butyl-3-
3544
Org. Lett., Vol. 3, No. 22, 2001

1
anti stereochemistry of all products was confirmed by H
NMR analysis after converting to the corresponding δ-lactone
of the type 16.7 X-ray crystallography of the bis-amide 19
derived from 12 and (S)-1-phenylethylamine by the procedure
shown in Scheme 3 determined the relative and absolute
Scheme 4. Proposed Transition Structures for Michael
Addition of Allenyltitaniums to Alkylidenemalonates
Scheme 3a
selectivity in a single step have attracted much interest in
organic synthesis. The present one-pot procedure for syn-
thesizing optically active diethyl anti-1,2-dialkyl-4-trimethyl-
silyl-3-butynylmalonates starting from readily available
optically active 1-alkyl-3-trimethylsiliy-2-propynyl phos-
phates and alkylidenemalonates certainly opens up a new
efficient method, by taking advantage of the versatile
reactivity of the silylacetylene and malonate groups present
at each of the terminal positions. Further exploration of the
synthetic utility of the reaction is underway in our laboratory.
a (i) 1 N KOH, MeOH; (ii) H+; (iii) reflux, 4 h, EtOH; (iv)
PyBOP (1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexaflu-
orophosphate), (i-Pr)2NEt, (S)-1-Phenylethylamine, DMF.
configurations of 12.8 For compounds 10, 11, 13, and 14,
the absolute configuration was assigned from analogy with
9 and 12.
The stereochemical outcome of the reaction can be
rationalized by assuming that the Michael addition reaction
of the allenyltitanium with alkylidenemalonate proceeds
preferentially via the anti coplanar transition structure A
shown in Scheme 4 rather than B, which may be destabilized
by the steric repulsion between the substituents R1 and R2.9,10
Carbon-carbon bond-forming reactions that create two
adjacent stereogenic centers with high diastereo- and enantio-
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Science and Technology (Japan) for financial
support and the Japan Society for the Promotion of Science
(JSPS) for a grant to Y.S. We thank Prof. Munetaka Akita
of this institute for X-ray crystallography of 19.
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 9-19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) The cis stereochemistry of δ-lactones of the type 16 was determined
on the basis of the 1H-1H coupling constant (3.9-4.2 Hz) and/or the nuclear
overhauser enhancement (NOE) between the protons at the â- and
γ-positions. Ozegowski, R.; Kunath, A.; Schick, H. Liebigs Ann. 1996,
1443-1448. Hanessian, S.; Gomtsyan, A.; Malek, N. J. Org. Chem. 2000,
65, 5623-5631.
(8) Recrystallization from chloroform provided crystalline 19 as a
chloroform-solvate. Crystallographic data (excluding structure factors) for
structure 19 has been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-166668. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB21EZ, U.K. (Fax: (44) 1223-336-033. E-mail: deposit@
ccdc.cam.ac.uk).
OL016652P
(9) A similar anti coplanar transition structure was proposed to explain
the predominant production of the anti adduct for the conjugate addition
of allyltitaniums to alkylidenemalonates; see ref 5.
(10) The cyclic transition structure in which the Ti atom of allenyltitanium
is coordinated by one or both of the carbonyl oxygen atom(s) of malonate
can be ruled out because it might afford the Michael adduct(s) having an
opposite stereochemistry at the propargyl carbon to one obtained here.
Org. Lett., Vol. 3, No. 22, 2001
3545