Process for making intermediate aldehydes

Details Process for making intermediate aldehydes Process for making intermediate aldehydes

1999-05-27

2001-03-13

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C546S344000, C548S570000, C568S874000

Reexamination Certificate

active

06201158

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention disclosed herein concerns a process for making propargylic alcohols by zinc-mediated catalytic, asymmetric addition of acetylenes to aldehydes. Enantioselective addition of organometallic reagents to aldehydes affords optically active secondary alcohols. Such optically active secondary alcohols serve as intermediates in many naturally occurring compounds, biologically active compounds, and materials such as liquid crystals. The resultant alcohols are also important as synthetic intermediates of various fuctionalities which include halide, amine ester and ether.
Various publications of related zinc mediated and zinc acetylide procedures have been cited in the literature. See Noyori, R., et al.,
Angewandte Chemie Int. Ed.,
30 ,49-68, (1991); Soai, K., et al.,
Chemical Review,
92, 833-856, (1992); Seiji, N. et al.,
J. of Chemical Society Perkin Trans.,
1, 937-943, (1990); Ramos Tombo, G. S., et al.,
Synlett,
547, (1990); Thompson, A., et al,
Tetrahedron Letters,
36, 8937-8940, (1995); Huffman, M., et al,
J. of Organic Chemistry,
60 (6), 1590-1594 (1995); Miyuki, I. et al.,
Tetrahedron Assymetry,
5, No. 10, 1901-1904 (1994); and Corey, E. J., et al.,
J. of American Chemical Society,
116, 3151-3152, (1994).
In the past, asymmetric acetylide additions to carbonyl compounds were performed in either of two ways, stoichiometrically or catalytically. In the stoichiometric case, a large amount of the chiral ligand is required. Even with high enantiomeric excess (ee), this is undesirable from the point of view of cost and additional equipment needed to recover the ligand. In addition, many methods use the intermediacy of a strong base to generate an acetylide species, leading to limits on the functionality present in the substrates.
In the catalytic cases reported, the enantiomeric excesses obtained have been low. In addition, the reported procedures use a two-fold excess of a difficult to prepare diacetylenic zinc species. In effect, three acetylene groups are discarded. Although this particular catalytic methods produces high % ee, this method is limited in that a preformed dialkylzinc species must be used.
The disadvantages of the processes employed in the prior art are the use of a stoichiometric quantity of a chiral ligand or in the catalytic mode, the preformation of a diacetylenic zinc species.
The advantages of the process employed in the present invention include:
(1) no preformation of zinc reagents, the free acetylene is used in the reaction.
(2) a catalytic quantity, typically 10 mole %, of the chiral ligand is used.
(3) ee's are moderate to high.
The invention disclosed herein provides a process for the catalytic asymmetric addition of substituted acetylenes to aldehydes, furnishing propargylic alcohols in moderate to high ee.
SUMMARY OF THE INVENTION
An acetylene, a dialkylzinc, and a catalytic amount of chiral ligand, are reacted and added to an aldehyde, to form a propargylic alcohol product in moderate to high % ee. The fundamental principle involves the novel mode of formation of the asymmetric zinc acetylenic intermediate that adds to the aldehyde. Direct exposure of the acetylene to dialkylzinc in the presence of a catalytic amount of a chiral aminoalcohol ligand generates a reactive, asymmetric zinc acetylide species, rendering the reaction catalytic in the chiral ligand.
The generation of the reactive asymmetric zinc acetylide reagent can be generally be carried out in from about 5 minutes to 1 hour at temperature of from about 0° C. to about 30° C. The addition of the asymmetric zinc acetylenic reagent to the aldehyde can generally be carried out over a period of about one hour to about twenty-four hours at temperatures of from about −70° to room temperature.
In one embodiment of the invention a process of synthesizing a compound of formula (I) is described:
wherein R
1
represents aryl, alkyl, alkynyl, alkylsilyl, ester or ether; said aryl, alkyl and alkynyl being optionally substituted with one to three groups selected from R
a
, R
2
is aryl or C
1-6
alkyl; said aryl and C
1-6
alkyl being optionally substituted with one to three groups selected from R
a
, comprising:
reacting a compound of formula (II):
wherein R
1
is defined above;
with a compound of formula (III):
 R Zn R  (III)
wherein, R is C
1-6
alkyl or aryl;
in the presence of a chiral ligand of formula (IV) at a temperature of about 0° C. to about 30° C.:
wherein, R
3
and R
4
are independently aryl, alkylaryl, alkyl, or H; said aryl, akylaryl and alkyl being optionally substituted with one to three groups of R
a
, or R
3
and R
4
together can form a 5- or 6-membered ring, which can be optionally substituted with one to three groups of R
a
;
R
5
and R
6
are independently, H, alkyl, aryl, said alkyl and aryl being optionally substituted with one to three groups of R
a
, or R
5
and R
6
together with the N atom to which they are attached form a 5- or 6-membered heterocyclic ring, which can be optionally substituted with one to three groups of R
a
and;
R
a
is H, C
1-10
alkyl, halogen, NO
2
, OR, —NR, C
5-10
aryl or C
5-10
heteroaryl;
adding the resultant mixture to a compound of formula (V) at a temperature of about −70° C. to room temperature:
wherein, R
2
is defined above to produce a compound of formula (I).


REFERENCES:
patent: 4309438 (1982-01-01), Christensen et al.
patent: 4479947 (1984-10-01), Christensen et al.
patent: 5292929 (1994-03-01), Sullivan
patent: 6015926 (2000-01-01), Chen
Noyori, R., et al.,Angewandte Chemie Int. Ed., 30 ,49-68, (1991).
Soai, K., et al.,Chemical Review, 92, 833-856, (1992).
Seiji, N. et al.,J. of Chemical Society Perkin Trans., 1, 937-943, (1990).
Ramos Tombo, G.S., et al.,Synlett, 547, (1990).
Thompson, A., et al,Tetrahedron Letters, 36, 8937-8940, (1995).
Huffman, M., et al,J. of Organic Chemistry, 60 (6), 1590-1594 (1995).
Miyuki, I. et al.,Tetrahedron Assymetry, 5, No. 10, 1901-1904 (1994).
Corey, E. J., et al.,J. of American Chemical Society, 116, 3151-3152, (1994).

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