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Highly Stereoselective Aldol Condensation Using an Enantioselective Chiral Enolate.

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tion at the phosphorus atom, and in the case of (2c) for incorporation of the k C triple bond by thermal elimination of
Received: February 15. 1980 [Z 503 IE]
German version: Angew. Chem. 92, 578 (1980)
I l l a ) G. Becker. Z. Anorg. Allg. Chem. 423. 242 (1976); b) T. C. Klebach. R.
Lourens, F. Bickelhaupr. J . Am. Chem. Soc. ioO,4886 (1978); c) K . Issleib. H.
Schmidt, H . Me-ver, J. Organomet. Chem. 160, 47 (1978); d) R. Appel. Y
Earth. Angew. Chem. 97, 497 (1979); Angew. Chern. Int. Ed. Engl. 18, 469
Appel. J Peters, lecture delivered at the Int. Conf. Phosphorus Chem
Sept. 17-21. 1979 in Halle (GDR).
131 "P: 'H: -NMR (ChDh.32.2 MHz, H3POa ext.): (20): S=235.0: (Zb): 6=273.0:
fk/.i5=272.0. 2740 (cis//rans isomers in the ratio 1 : l ) . "Cj'H:-NMR
(CDCI,, 22.6 MHz. TMS int.): {Zb): 6=!96.1 [d. J(PC)=69.0 Hz, P--C];
( 2 ~ )i5=
; 197.3 [d, J(PC)=82.0 Hz. P--C].
141 R. Appel. A . Westerhaus, unpublished.
17-1 R.
Highly Stereoselective Aldol Condensation Using
an Enantioselective Chiral Enolate[**]
By Satoru Masamune, Sk. Asrof Ali, David L. Snitman,
and David S. Garvey"]
The concept of the diastereomeric transition state is well
documented"]. Thus, in a kinetically controlled reaction
Prof Dr. S. Masamune, Dr. S. A. Ah. Dr. D. L. Snitman, D. S. Garvey
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, Mass. 02139 (USA)
This work was supported by the Sloan Research Funds (MIT), the National
Instilutes of Health NCI Training Grant IT32 CA09112 and NIH A1 15403.
Angew. Chem. Inr. Ed. Engl. 19 (1980) No. 7
R = R,
fhj: R
R =
= R,
Table 1. Aldol condensation of aldehyde (3) with lithium enolate ( I ) .
(3) la1
Chlorophenyl(trimethylsily1)methane (72.4 g, 360 mmol)
is converted with Mg (10.0 g, 400 mmol) in diethyl ether (200
ml) into the Grignard compound, which is then added dropwise slowly to an ice-cooled solution of PC13 (49 g, 360
mmol) in ether (150 ml). MgClz is removed by filtration and
the filtrate is evaporated down under vacuum. Fractional
distillation of the residue furnishes 52.7 g (55%) of (lc), b.p.
53"C/10-3 torr ["P('H)-NMR (C6D6): 6=189].
A solution of (lc) (15.0 g, 57 mmol) in ether (200 ml) is
treated with 25.3 g (220 mmol) of 1,4-diazabicycl0[2.2.2]0~tane and the mixture is stirred for 12 h at room temperature.
The insoluble material is filtered off and washed with ether.
The combined filtrates are then evaporated down under vacuum and the amine hydrochloride which precipitates is removed by filtration. After removal of solvent the residue is
treated with n-pentane, filtered and the filtrate evaporated
down and distilled yield 7.1 g (54%)of (2c), b.p. 51 "C/10-)
(5a - c)
Structures [b]
of products
(4) and (5)
Ratio of
(4) to (5)
[a] Prepared from optically pure 2-cyclohexylpropionic acid LiAIHI reduction
and Collin's oxidation [( +)-S:[a]:;=+ 19.3 ( c = I 185 C2H50H):( - ) - R : [u]i:=
- 18 6 (c= 2.055 C2H50H)] ura methylation. ( + )-S- and ( - )-R-(3) had [a)$ =
+62.8 (c=1.545 CH2CI2) and -63.1 (c=0.950 CH2C12), respectively [b] The
stereochemistry of the aldol products is based on the conversion of (4) and (S)
through acid hydrolysis and oxidation into the corresponding 4-cyclohexyl-3-hydroxy-2-methylpentanoic acids which were compared with those obtained from
acids of known stereochemistry. [c] (4d).
(Sd)-enantiomers of (46). (Sb). [d] (4e). (Se). enantiomers of (4a). lSa).
which leads to the formation of new chiral centers, certain
pairs of optically active substrates react to form one diastereoisomer predominantly, whereas other combinations result
in inferior stereoselection. We have observed this phenomenon in an aldol condensation (Eq. 1) and have consequently
developed a chiral enolate reagent which is highly enantioselective and synthetically useful. A recent report by Heathcock et aI.l'l concerning this subject has prompted us to summarize our independent findings in preliminary formP1.
Initial exploratory work in this area involved the use of
chiral lithium enolates (la) and ( l b ) derived from S- and Ratrolactic acids, respectively. Thus, treatment of the acids14]
with 3.3 equivalents of ethyllithium provided a 65% yield of
the corresponding ethyl ketones, which were in turn silylated
to yield (2a) and (Zb) (Scheme l ) I 5 ] . The aldol condensation
was then carried out in the usual way: after dropwise addition of aldehyde (3)16'to a THF solution ( - 78 " C )of enolate
( I ) , generated from (2) with lithium diisopropylamide, the
reaction mixture was stirred for 25 min and quenched with
aqueous ammonium chloride for workup. The structures and
yields of products (4) and (5) in each reaction are summarized in Table 1.
Two pairs (Table 1, entries 1 and 4) provided a significant
stereoselection of 1:8 in sharp contrast with that (1.5 : 1) observed in the other cases (entries 2 and 3). Thus, only a certain pair of chiral substrates produces predominantly one of
the four possible stereoisomers in an aldol condensation.
The stereochemical course of the above reaction requires
some analysis. While the Z - or E-stereochemistry [only Z
shown in ( I ) ] of the enolate has been shown to be directly
0 Verlag Chemie, GmbH, 6940 Weinheim, 1980
$ O2.sO/O
correlated with the syn- and anti-2,3 s t e r e ~ c h e m i s t r yof
[ ~the
products (4)and (S)[’I, the 3,4-stereochemistry appears to depend on two factors, (a) the selectivity inherent in the reacting aldehyde commonly referred to as Cram/anti-Cram selectivity[’] and (b) the enantioselectivity arising from the chirality present in the enolate. These two selectivities were
evaluated separately.
The reaction of (+)-(3)with the achiral reagent ( l c ) utilized earlier by Heathcock et al.[’‘l provided a 27:73 mixture
of (4c) and (Sc), showing that the selectivity inherent in aldehyde (3)approximates a ratio of 1:31’01.Also, achiral aldehydes (6) and (7) were condensed with ( l a ) to afford products (8) and (9) (1 :3.5 ratio in 80% yield) and (10)and (11)
(1 :6 in 75% yield), respectively[12].Hence the enantioselectivity of ( l a ) can be estimated to be about 1 :5. Therefore, enhanced stereoselection is only achieved when these two factors are acting in concert (entries 1 and 4).
The above results encouraged us to seek a more enantioselective chiral reagent. After investigating a variety of enolates, it was found that the hexahydro derivative (12a) of
demonstrated a significant increase in stereoselection
(ca. 15: 1 ) in the aldol condensation with phenylacetaldehyde, as compared with (la). Also, the high degree of enantioselectivity of (12a) or (12b) can counteract the normally
small Cram/anti-Cram selectivity of aldehydes to the extent
that either the 3,4-anti or the 3,4-syn1’]
aldol adduct can now
be obtained as the predominant product.
A clear demonstration of this fact is the stereoselective
synthesis of both Prelog-Djerassi and iso-Prelog-Djerassi lactonic acid [(l3) and (14),respectively][”].
[ I ] H . B. Kagan, J . C. Fiaud, Top. Stereochem. 10, 175 (1978); J. D. Morrison,
H. S. Mosher. Asymmetric Organic Reactions. Prentice-Hall. Englewood
Cliffs. N. J 1971: K. Mislow: Introduction to Stereochemistry. W . A. Benjamin. New York 1966
[2] C. H. Hearhcock. C. T. White. J. Am. Chem SOC.10;. 7076 (1979). C. H .
Hearhcock. M. C. Pirrug. C. T. Buse. J. P. Hagen, S. Y. Young,J. E. Sohn.
ihid. 101. 7077 (1979).
[3] A lecture presented by S. M. at the University of Virginia on November 20.
1979 included an outline of this work.
[4] S: [a]:: = + 3 6 5 ( C = 1 . 5 2 5 . C~HIOH): Rr [ a ] l : = - 3 6 7 ( < = 2 9 3 2 .
C2H,0H) The reported specific rotations of the S - and R-acids are [a]i:‘ =
+37.7 (r=3.500, C , H 5 0 H ) and [a];:”=-37.7 (c=3.3>4, CIHsOH). respectively: A McKenzie. G. W. Clough. J. Chem. SOC.97, 1016 (1910).
[5] Prepared by T Suro. (2a). [a];;= - 125.9 ( c = 1.290, CH2C12): (Zb):
[a]:;= + 125.5 ( c = 1.535. CHzClz). Both were optically pure to the limit of
detection by NMR using Eu(hfbc),.
[6] D. J. Cram, F D. Greene. J Am. Chem. SOC.75, 6005 (1953). describe the
preparation of (3) of unspecified optical purity.
171 The usage of “threo” and “ervrhro” is often confusing. In this communication, the main chain is drawn in the zig-zag fashion. and two substituents on
the same side are designed ‘syn”. and those which are not, “ann”
[8] For recent examples. see for instance: a) S. Masamune, S. Mort. D. E. Van
Horn, D. W Brooks. Tetrahedron Lett. 1979, 1665; M Hiroma. S M a w
mune, ibid. 1979, 2229; b) R. W. Hoffmann, H. J. Zeiss. Angew. Chem. 91,
329 (1979); Angew. Chem. Int. Ed. Engl. 18,306 ( 1 979); c) C. T. Buse. C. H.
Heathrock, J. Am. Chem. SOC.99. 8109 (1977).
191 This problem has been discussed in the past in terms of several different
conformations of the a-substituent (Cram, Cornforth, Krabatsos and Felkin
rules). See reference 111.
[lo] Somewhat surprisingly. aldehyde (3) prefers the “anti-Cram” approach of
enolates (cf. Table I ) . For an earlier example, see reference [I I].
[ I t ] M Hirama, D. S. Gamey. L. D:L. Lu, S. Masamune, Tetrahedron Lett.
1979, 3937.
[12] Although all of compounds (8)-(11) are syn-2.3 stereoisomers (71. the absolute configurations of these chiral centers have not been unambiguously established.
[I31 The corresponding ethyl ketones were obtained from R~ and S-hexahydroatrolactic dcid ([a]:;= - 15 9 ( c = 1.240. C2HrOH) and [a]f:= + 16.3 (c=
1.690. CzH50H).respectively) in the same manner as for (Za).
[I41 Aldehyde (15) was prepared from the optically pure monomethyl ester of
meso-2,4-dimethylglutaric acid. [a];’:=
-4.61 (c=7.050, CHCI,).
[IS] The lactonic acids (13) and (14) were formed from their corresponding aldol
products by: a ) lactonization with trifluoroacetic acid/methanol/dichloromethane, b) reduction with Zn(BH&, and c) oxidation with Jones’ reagent.
Outer Sphere Electron Transfer Reactions:
A Novel Linear Relationship between the
Selectivity and the Normal Potential of the Reducing
117a, h)
By Hans-Michael Huck and Karl Wieghardt“’
In the simplest mechanism of electron transfer (ET) between two transition metal complexes (the outer-sphere
mechanism) the reactants form a n encounter complex in a
preceding equilibrium. In the rate-determining step, the electron is transferred through the intact first coordination
spheres of the two complexes; the resulting complex then decomposes to the products“]:
Scheme 2
[Ox] + [Red] 6 [[Ox][Red]j
As shown in Scheme 2, aldehyde (1.5)[t41was condensed
with (1Za) in T H F at - 78 “C to yield a mixture of (16a) and
(1 7a) in a ratio of 15: 1 . Conversion of (16a) into ( + ) - ( 1 3 )
was accomplished via a three-step sequence[15]. In a similar
fashion, the iso-acid (14)could also be obtained as the major
product. Condensation of (15) and (1 Zb) provided (1 6b) and
(1 7b) in a ratio of 1 : 10. Thus, this new, readily available reagent can be used to control the 3,4 stereochemistry of aldol
products with high diastereoselection, a n achievement which
has not been realized before.
Received: January 2, 1980 [Z 504 IE]
German version: Angew. Chem. 92, 573 (1980)
0 Verlag Chemie, GmbH, 6940 Weinheim, 1980
Encounter complex
1 k,,
Fast\ Products
Successor complex
Equation (a) can then be derived for this scheme:
Prof Dr. K. Wieghardt, DipLChem. H. M. Huck
Institut fur Anorganische Chemie der Universitat
Callinstrasse 9, D-3000 Hannover I (Germany)
$ 02.50/0
Angew. Chem. Int. Ed. Engl. I9 (1980) No. 7
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chiral, stereoselective, using, condensation, enolate, aldon, enantioselectivity, highly
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