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Direct Catalytic Asymmetric Aldol Reactions of Aldehydes with Unmodified Ketones.

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Direct Catalytic Asymmetric Aldol Reactions of
Aldehydes with Unmodified Ketones
Yoichi M. A. Yamada, Naoki Yoshikawa,
Hiroaki Sasai, and Masakatsu Shibasaki*
The aldol reaction is one of the most powerful ofcarbon-carbon bond-forming reactions, and the development of a range of
catalytic asymmetric aldol-type reactions has thus proven to be
a valuable contribution to asymmetric synthesis.['] In all of
these asymmetric aldol-type reactions, however, pre-conversion
of the ketone moiety to a more reactive species such as an enol
silyl ether, enol methyl ether, or ketene silyl acetal is an unavoidable necessity. Development of a direct catalytic asymmetric
aldol reaction, starting from aldehydes and unmodzfed ketones
is thus a worthwhile endeavor.I2] Such reactions are known in
enzyme chemistry:[31 the fructose-I ,6-bisphosphate and dihydroxyacetone phosphate (DHAP) aldolases are characteristic
examples. The mechanism of these is thought to involve cocatalysis by a Zn2' ion and a basic functional group in the enzyme's
active site; the latter abstracts a proton in proximity to a carbony1 compound while the former functions as a Lewis acid to
activate the second carbonyl component. These aldolases can
thus be thought of as multifunctional catalysts displaying both
Lewis acidity and Br~nstedbasicity, so making possible efficient
catalytic asymmetric aldol reactions under typically mild in vivo
conditions. An analogous cooperative mode of action can be
seen in reactions mediated by any of several heterobimetallic
asymmetric catalysts having both Lewis acidity and Brsnsted
basicity, which have been developed by our research gr0~1p.I~.
We speculated that it might be possible to develop a direct
catalytic asymmetric aldol reaction of aldehydes with unmodified ketones by employing catalysts like I (Scheme 1). A
R2
,.
Figure 1. The structure of LnLi,trls[ (R)-binaphthoxide] ((R)-LnLB)
Table 1. Direct catalytic asymmetric aldol reactions promoted by (R)-LLB
(20 mol %)
Entry
1 la1
2
3
4
5
6
7
8 Ibl
9
10
11
12
Aldehyde Ketone
(equiv)
Product
la
la
la
la
la
lb
lc
Id
le
lb
la
lb
3a
3a
3a
3a
3b
3c
3d
3e
3f
3g
3b
3i
2a ( 5 )
2a ( 5 )
2 a (1.5)
Za (10)
2b (8)
2a (7.4)
2a (8)
2a (8)
2 a (8)
2 c (10)
2 c (10)
Zd (50)
f
Yield
re
IhI
[Y"]
["A]
88
88
135
91
253
87
169
277
12
185
100
185
43
76
43
81
55
90
72
59
28
82
53
71
89
88
87
91
76
69
44
54
52
74
73
94
[a] (R)-LLB and addition of 1 equiv of H,O to LLB, see ref. [lo]. [b] The reaction
was carried out at - 30 "C
0-M
*6-,
I
OH
a ketone could then generate an optically active aldol adduct
with regeneration of the catalyst I. We now wish to report the
first example of such a reaction,l6] in which we have obtained
optically active aldol adducts in up to 94% ee.
We were initially concerned that our heterobimetallic asymmetric catalysts would be ineffective at promoting aldol reactions as a result of their rather low Brernsted basicity and were
thus pleased to find that aldol reactions of the desired type
proceeded quite smoothly with LaLi,tris(binaphthoxide)
(LLB)[4d1as catalyst (Figure 1). As shown in Table 1, when the
n
O\
LA : Lewis acid
R
M : Metal of Brensted
0-LA,
N
*
c0
base
: Chiral ligand
Scheme 1. Catalytic cycle of the direct catalytic asymmetric aldol reactions.
Brsnsted base unit (OM) of catalyst I could deprotonate an
or-proton of a ketone to generate the metal enolate 11, while at
the same time a Lewis acid unit (LA) could activate an aldehyde
to give 111. These reaction partners might react in the chelationcontrolled, asymmetric environment to afford a P-keto metal
alkoxide (IV). Proton exchange between the metal alkoxide
moiety and a hydroxy proton of the aryl unit or an a-proton of
[*I Prof. Dr. M. Shibasaki, Y M . A. Yarnada, N. Yoshikawa, Prof. Dr. H. Sasai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113 (Japan)
Fax: Int. code +(3)5684-5206
e-mail: rnshibasairr mol.fu-tokyo.ac.jp
Anh'enz. Chem. Int. Ed. Engl. 1997,36, No. 17
direct catalytic asymmetric aldol reaction of pivalaldehyde (la)
with 5.0 equivalents of acetophenone (Za) was carried out in the
presence of 20 mol% of (R)-LLB and 1.0 equivalent of H,O
(relative to LLB) in THF at -20°C for 88 h, we obtained the
desired adduct 3ar7,*]in 43% yield with 89% ee (entry
Anhydrous LLB was more efficient than hydrated LLB, affording 3a with 88% ee in 7 6 % yield after stirring for 88 h (entry 2).['01 Furthermore, the use of 1.5 equivalents of 2a gave 3a
with 87% ee, albeit in 43% yield (entry 3 ) , and increasing the
amount to 10 equivalents afforded 3a with 91 % ee in 81 % yield
after stirring for 91 h (entry 4) .I''I
R'CHO
+
'kf
la: R' = 1 ~ u
(R)-LLB
(20mol %)
THF,-ZO"C *
2a: R' = Ph
lb: R' = PhCH2C(CH3)2 2 b R' = 1-naphthyl
2c: R2 = CH,
lc: R' =cycloheryl
2d: R' = Et
l d R' = Rr
le:R'
= Ph(CH&
0 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1997
R'
38:R'
=i%U,
3b: R'
=Bu,R' = 1-naphthyl
R' = Ph
3C: R' =PhCHzC(CH&. R2 = Ph
3d: R' =cyclohexyl. R' = Ph
3e:R' =Pr. R2 = Ph
3f: R' =Ph(CH2)2, R' = Ph
39:R' =PhCH&(CH3)2, R' = CH,
3 h R' =Bu,R2 = CH3
3i: R' =PhCH,C(CH,),.
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R2=
Et
1871
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Following on from these results we turned our attention to
broadening the range of substrates. The reaction of l a with 2b
at - 20 "C proceeded satisfactorily to give 3b with 76% ee in
55% yield (entry 5 ) , as did the reaction of l b with 2a at -20°C
to afford the aldol adduct 3c with 69% ee in 90% yield (entry 6). The achievement of efficient catalytic asymmetric aldol
reactions of aldehydes with a-hydrogen atoms clearly represents
a much greater challenge than for cases such as those above,
since self-aldol products can easily be produced as by-products.
However, the reaction of cyclohexanecarbaldehyde (Ic) with 2a
proceeded smoothly without significant self-aldol of Ic. Thus,
after optimization, the reaction of l c with 8.0 equivalents of 2a
in the presence of 20 mol YOof LLB gave 3d with 44 % ee in 72 Yo
yield, with no detectable self-condensation products of lc (entry 7).[1z,131The reaction of isobutyraldehyde ( I d ) also proceeded smoothly, giving 3e with 54 YOee in 59 YOyield at 30 "C
(entry 8). The reaction of hydrocinnamaldehyde (le), which
possesses two a-hydrogen atoms, with 2a proved more difficult;
3f was obtained with 52 YOee; however, the yield was low (28 %)
due to the formation of self-condensation by-products (entry 9).
Aldol reactions that utilize acetone (2c) as a starting material
are generally difficult to control. However, in this case the reaction of aldehyde (lb) and 10 equivalents of 2c with LLB gave 3g
with 74% ee in 82% yield (entry lo), the reaction of l a with
10 equivalents of 2c at - 20 "C product 3h with 73 YOee in 53 Yo
yield (entry 1l), and the reaction of l b and 50 equivalents of
2-butanone (2d) at - 20 "C adduct 3i with excellent ee (94 %) in
71 YOyield (entry 3 2) .[143 Acetone and 2-butanone are widely
used as solvents and are much cheaper than the corresponding
enol silyl ethers and/or methyl enol ethers, which are used as
substrates in the catalytic asymmetric Mukaiyama aldol reaction;"] the use of large excesses of ketone can thus be justified
in this particular case.
As outlined above (Scheme 1) in these reactions the lanthanum atom is believed to function as a Lewis acid and a
lithium binaphthoxide moiety as a Bransted base. The nature of
the coordination of the aldehyde appears to be of first importance, as the accompanying activation makes possible a smooth
reaction of the hypothetical LLB enolate (II), which on the basis
of pK, values can be expected to be present at only low concentrations, and also enables control of the orientation of the aldehyde and so facilitates the enantioselective reaction. To determine the extent of coordination between aldehydes and the
lanthanum cation we carried out a 'H NMR study on a mixture
of PrLi,tris(binaphthoxide) (PrLB)[4dl and l a (Figure 2).r4a1
The propensity of Pr complexes to induce upfield shifts is
and in fact reaction of l a with 2a in the presence of
(R)-PrLB gave (S)-3a in 79%
ee, indicating that Pr-containing catalysts are also a reasonable model for those containing La in terms of chemical
reactivity. In the relevant
____
'H NMR spectra the chemical
shift of the formyl hydrogen of
l a appears at 6 = 9.37 in THF;
however, when 20molY0 of
PrLB was added, an upfield
7
--?
9.5
9.4
9.2
9.0
shift of this signal to 6 = 9.27
-6
was observed. In contrast,
~
-/\
i
.
L
Figure 2 Chemical shift of the
formyl hydrogen in l a in TH F (hottom) as well as in the presence of
60 mol% of (R)-dilithium binaphthoxide (center), and 2 0 m o ~ %of
(R)-PrLB (top).
1872
adding 60 mol%
Of
the dilithi-
um salt of (R)-binaphthol
. .
alone gave n o detectable chemical shift of la, and moreover,
reaction of l a with 2a catalyzed
0 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1997
by this salt gave roc-3a. These results clearly indicate that coordination of the aldehyde to Pr is indeed occurring, allowing
activation and stereocontrol to occur as proposed.["]
In conclusion, we have succeeded in carrying out the first
catalytic asymmetric aldol reaction of aldehydes with unmodified ketones by using heterobimetallic multifunctional catalysts.
Although the present catalytic asymmetric reaction is still being
developed, the results reported here should provide a solid foundation for further work.
Experimental Section
General procedure: To a stirred solution of(R)-LLB (0.10 mmol) in TH F (1.67 mL)
was added 2-butanone (Zd, 25 mmol) at - 20°C. After 30 min, 2,2-dimethyl-3phenylpropanal (lb, 0.50 mmof) was added to the solution, which was then stirred
for 185 h at -20°C. The reactlon was quenched by adding 2 mL of 1 N HCI and
extracted with Et,O (3 x 10 mL). The combined organic layers were washed with
brine and dried over Na,SO, The solvent was removed under reduced pressure,
and the residue purified by flash chromatography (SiO,, Et,O/hexane 1/12) to give
(S)-3i with 94% ee in 71 % yield.
Received: March 4, 1997 [Z10195IE]
German version: Angew. Chem. 1997, 109, 1942-1944
Keywords: aldol reactions * asymmetric catalysis - asymmetric
synthesis homogeneous catalysis lanthanum
-
-
[l] For recent developments, see the following papers and the references cited
therein: a) S. E. Denmark, S. B. D. Winter, X. Su, K.-T. Wong, J Am. Chem.
SOC.1996, 118, 7404-7405; b) D. A. Evans, J. A. Murry, M. C. Kozlowski,
ibid. 1996, f18,5814-5815; c) R. A. Singer, E. M. Carreira, ibid. 1995, f f 7 ,
12360-12361; d) G. E. Keck, D. Krishnamurthy, ibid. 1995,117, 2363-2364;
e) M. Sodeoka, K. Ohrai, M. Shibasaki, L Org. Chem. 1995,60, 2648-2649;
f ) K. Mikami, S. Matsukawa, J Am. Chem. SOC.1994,116,4077-4078; g) S.
Kobayashi, H. Uchiro, I. Shiina, T. Mukaiyama, Tetrahedron 1993,49, 17611772; h) E. J. Corey, C. L. Cywin, T. D. Roper, Tetrahedron Left. 1992, 33,
6907-6910; i) E. R. Parmee, Y. Hong, 0. Tempkin, S. Masamune, ibid. 1992,
33,1729- 1732;~)S. Kiyooka, Y. Kaneko, K. Kume, ibid. 1992,33,4927-4930;
k) K. Furuta, T. Maruyama, H. Yamamoto, J Am. Chem. So?. 1991, 113,
1041-1042; I) E. R. Parmee, 0.Tempkin, S. Masamune, A. Abiko, ibid. 1991,
113,9365-9366; m) K. Uotsu, H. Sasai, M. Shibasaki, Tetrahedron: Asymmefry 1995, 6, 71 -74.
[2] a) R. Noyori, Asymmetric Catalytsis in Organic Synthesis, Wiley, New York,
1994; b) M. Sawamura, Y. Ito in Catalytic Asymmetric Synthesis (Ed.: I.
Ojima), VCH, New York, 1993, pp. 367-388.
[3] W.-D. Fessner, A. Schneider, H. Held, G. Sinerius, C. Walter, M. Hixon, J. V.
Schloss, Angew. Chem. 1996, 108, 2366-2369; Angew. Chem. Int. Ed. Engl.
1996, 35, 2219-21, and references therein.
[4] a) H. Sasai, T. Arai, Y. Satow, K. N. Houk, M. Shibasaki, J Am. Chem. SOC.
1995, 117,6194-6198; b) T. Arai, Y. M. A. Yamada, N. Yamamoto, H. Sasai,
M. Shibasaki, Chem. Eur. J. 1996, 2, 1368-1372; c) H. Sasai, S. Arai, Y
Tahara, M. Shibasaki, L Org. Chem. 1995, 60, 6656-6657; d) H. Sasai, T
Suzuki, N. Itoh, K. Tanaka, T. Date, K. Okamura, M. Shibasaki, J Am. Chem.
SOC.1993, lf5, 10372-10373; e) H. Sasai, T. Suzuki, S, Arai, T. Arai, M.
Shibasaki, ibid. 1992, 1 f 4 , 4418-4420; f ) For review, see; M. Shibasaki, H.
Sasai, T. Arai, Angen,. Chem. 1997, 109, 1290-1310; Angew. Chem. Int. Ed.
Engl. 1997,36, 1236-1256.
[5] For an excellent review, see H. Steinhagen, G Helmchen, Angew. Chem. 1996,
108,2489-2492; Angen,. Chem. Int. Ed. Engl. 19%, 35, 2339-2342.
[6] A partially successful attempt to develop a direct catalytic, asymmetric aldol
reaction has been reported; however, only one reactive aldehyde and acetone
were used and the ee value of the corresponding product was not determined:
M. Nakagawa, H. Nakao, K.-I. Watanabe, Chem. Lett. 1985, 391-394.
[7] The spectral data of the compounds 3a, M-3f, and 3h resemble those previously reported. See ref. [8].
[S] a) K. Narasaka, T. Miwa, H. Hayashi, M. Ohta, Chem. Len. 1984,1399-1402;
b) P. V. Ramachandran, W.-C. Xu, H. C. Brown, Tetrahedron Letf. 1996, 37,
491 1-4914.
[9] The enantiomeric excess of all the aldol adducts was determined by HPLC
analysis with DAICEL CHIRALPAK AS, AD, or CHIRALCEL OJ; absolute
configurations were determined to be (S)-form. Absolute configurations of 3b,
3c, 3g, and 3i were determined by Mosher's method: J. A. Dale, H. S. Mosher
J. Am. Chem. Soc. 1973,95, 512-519.
[lo] To (R)-LLB in THF was added 1.0equiv of H,O in TH F ( 1 . 0 ~ )to give
hydrated (R)-LLB, which had been found to be a more effective catalyst for
previously reported catalytic asymmetric nitroaldol reactions [4b].
[ l l ] Results with 5 or 10 mol% of (R)-LLB: 42% yield, 77% ee and 52% yield,
88% ee, respectively.
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Angew. Chem. int. Ed. Engl. 1997,36, No. 17
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[12] Results with 20 molY0 of other catalysts at -20 "C: LaNa,tris(binaphthoxide)
(LSB)[4a] i n T H F ( t 6 % , 13% ee), LaK,tris(binaphthoxide) (LPB)[4c]inTHF
(49%, 0 % e r ) , AILibis(binaphth0xide) (ALB)[4b] in THF (quite low yield),
LLB in toluene (25'Yo. 31 % ee), LLB in CH,CI, (33%, 15% ee), LnLB where
Ln = Pr. Sm. Gd, Dy. or Yb in T H F (low ee values), LLB* in T H F
(B* = 6,6'-bis((triethylsilyl)ethynyl(binaphthoxide)) (low ee), 6,6'-dibromo(binaphthoxide) (low e e ) , 6,6'-dimethoxy(binaphthoxide)(low ee)).
[I31 The moderate yield is mainly due to the low reactivity of LLB. A small amount
of dehydrated product was detected.
was detect[14] A trace amount of 4-hydroxy-3.5,5-trimethyl-6-phenyl-2-hexanone
ed.
[15] The reaction of benzaldehyde and 8 equiv of 2a in the presence of 20 m o l % of
(R)-LLB at 198 h gave the desired aldol adduct with only 3 % ee ( S ) in 41 %
yield. but the reaction under the same conditions except in the presence of
YbLi,tris((R)-binaphthoxide) ((R)-YbLB) instead of (R)-LLB gave the aldol
product with 36% m (R) in 47% yield.
[16] Review: A. F. Cockerill, L. 0 Davies, R. C. Harden, D. M. Rackham. Chem.
Rer. 1973. 73. 553 - 588, and references therein.
[I 71 I t is unlikely. even if the aldehyde coordinates to a Li atom of the Pr complex,
that proximity to the Pr or the positioning of the formyl C-H in the shielding
region of the naphthyl ring could produce a shift of such magnitude, as no such
chemical shift is observed in the presence of LLB.
We have now synthesized single-phase a-P3N, by thermal
condensation of tetraaminophosphonium iodide lP(NH,),]I according to Equation (2) .I4] The NH,I atmosphere that develops
during the decomposition of [P(NH,),]I evidently is significant
for the formation of ordered a-P,N,, because heavily disordered
P3N5 is formed when [P(NH,),]Cl is used under comparable
experimental conditions. During our procedure a-P,N, is
formed as a microcrystalline, beige powder, which is insoluble in
common solvents as well as in hot acids and alkaline solutions.
a z 5 ~
3[P(NH,),JI
t
Dedicated to Professor Hans Georg von Schnering
Polymeric nonmetal nitrides are of considerable interest for
the development of inorganic materials.['I Among the binary
members of this class of compounds dimorphic boron nitride
(BN) and silicon nitride (Si,N,) have gained significance. Their
potential applications include use as substrate for semiconductors (Si,N,) and as high-temperature materials (for example
crucibles made of hexagonal BN or valve tappets and turbochargers made of Si,N,).
Chemically and structurally related phosphorus(v) nitride
P,N, was assumed to be built up by a polymer network structure
of connected TN, tetrahedra (T = B, Si, P) similar to that of
cubic BN and Si,N,. The crystal structures of BN and Si,N,
have already been investigated in detail."] However, no structural model of P,N, was available in spite of many intensive
efforts,12. because neither monocrystalline nor pure polycrystalline samples of P3N5had been obtained. In our recently developed synthesis of phosphorus(v) nitride [Eq. (l)] we always obtained mixtures of the polymorphs a- and B-P3N5,which were
characterized by electron diffraction (ED), high-resolution
transmission electron microscopy (HRTEM), EXAFS (extended X-ray absorption tine structure) spectroscopy, and 31Pand
' ,N solid-state NMR spectr~scopy.~~]
--
P3NS
+ 8HC1
I*] Prof. Dr
['*I
4000i
I
I 2oaoji I
I
'
10
.
20
40
30
50
281"Figure 1. Observed (crosses) and calculated (line) X-ray powder diffraction pattern
as well as difference profile of the Rietveld refinement of or-P,N5 (only section until
26 = 50" is shown). Possible positions of the peaks are marked by vertical lines. The
powder pattern was obtained at the ESRF, Grenoble, on the Beamline BMl
( i = 99.963(4) pm)
methods and refined by the Rietveld method (Table 1, see Experimental Section).
In the solid state a-P,N, has a three-dimensional network
structure of connected PN, tetrahedra (Figure 2). As a consequence of the molar ratio P:N = 3:5 two fifths of the nitrogen
atoms
are bound to three neighboring P atoms and the
remaining nitrogen atoms ("I')
to two P atoms according to
Table 1. Atomic coordinates and isotropic displacement factors [A2]of a-P,N,.
(11
W. Schnick. Dip].-Chem. S. Horstmann, Mag. E. lrran
Ldboratorium fur Anorganische Chemie der UniversitHt
D-95440 Bayreuth (Germany)
Fax: Int. code +(9?1)55-2788
e-mail: wolfgang.schnick(wuni-bayreuth.de
This work was supported by the Fonds der Chemmhen Industrie, the Deutsche
Forschungsgemeinschaft (project SCHN 377/2-2, and Gottfned-WilhelmLeibniz-Progrdmm), the Bundesministerium fur Bildung, Wissenschaft,
Forschung und Technologie in the Verbundprojekt "Erforschung kondensierter Mdterie" (project 03-SC4 BAY), and the ESRF Grenoble. The authors
thank Dr P. Pattison (ESRF, Grenoble) for his help during the synchrotron
exueriment.
Angeb Chem In[ Ed Eqg/ 1997,36, No 17
(2)
" ol I
Stefan Horstmann, Elisabeth Irran, and
Wolfgang Schnick*
+ 2NH,CI
+ 3NH,I + 4 N H ,
The crystal structure of a-P,N, was determined and refined
on the basis of powder X-ray diffraction data. Due to numerous
overlapping peaks the resolution of conventional powder diffractometers (typical full width of half maximum height
(FWHM) of the peaks: 0.09') did not allow us to deconvolute
the diffraction pattern of a-P3N,. Therefore we performed powder diffraction investigations with higher resolution by using
synchrotron radiation at the European Synchrotron Radiation
Facility in Grenoble (ESRF, Beamline BMI, typical FWHM:
0.03"). We could index the powder pattern obtained unambiguously (Figure 1) and the structure was determined by direct
Synthesis and Crystal Structure of
Phosphorus(v) Nitride a-P3N5**
(PNCI,),
P3N5
0.0 [b]
0.136(1)
0.365(2)
0.009(2)
0.129(1)
0.370(1)
0.142(2)
0.356(2)
0.5182(3)
0.2000(8)
0.2924(8)
-0.003(2)
0.341(1)
0. I19(1)
0.351(2)
0.135(2)
0.0 [b]
0.309(1)
0.196(1)
0.269(1)
0.450(1)
0.066(1)
0.147(1)
0.348(1)
0 0036(4)
0 0036(4)
0 0036(4)
0 0017(7)
0 0017(7)
00017(7)
0 0017(7)
0 0017(7)
[a] U,,, is defined as exp(-8nzU,,,sin'O/i), the displacement factors of P and N
were constrained to be equal. [b] Atomic coordmations were fixed during the
refinement.
8 WILEY-VCH Verlag GmbH, D-69451 Wemheim, 1997
057O-OX33~97/3617-iX73
S 17 50+ 5010
1873
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