Highly enantiomerically enriched ketone homoenolate reagents prepared by (-)-sparteine-mediated γ-deprotonation of achiral 1-alkenyl carbamates

Article abstract of DOI:10.1002/anie.200352966

Homoenolate equivalents: Enantiotopos-differentiating deprotonation of achiral 1-alkenyl carbamates with the chiral base n-butyllithium/(-)-sparteine yields configurationally stable lithium homoenolate equivalents. In a subsequent syn or anti substitution (see scheme), γ-substituted O-(1-aryl-1-alkenyl) N,N-diisopropylcarbamates are formed with high enantio- and diastereoselectivity.

Full text of DOI:10.1002/anie.200352966

Angewandte
Chemie
[
2b,7]
Asymmetric Synthesis
cient configurational stability.
Alternatively, chiral auxil-
[
8]
iaries were used for residue X.
Highly Enantiomerically Enriched Ketone
Homoenolate Reagents Prepared by
We now report on a surprising, simple, and efficient
approach to 1-aryl ketone homoenolate reagents by enantio-
topos-differentiating g-deprotonation of 1-aryl-1-alkenyl
N,N-diisopropylcarbamates by n-butyllithium/(À)-sparteine.
When we attempted the asymmetric carbolithiation of enol
(
À)-Sparteine-Mediated g-Deprotonation of
Achiral 1-Alkenyl Carbamates**
[
10,11]
carbamate 4a (Z/E = 92:8)
and trapped the lithiated
Michael Seppi, Rainer Kalkofen, Jens Reupohl,
Roland Fröhlich, and Dieter Hoppe*
intermediate 6a with acetone, we isolated the homoaldol
product 8aa in 69% yield and with 97% ee (Scheme 2).
Subsequent experiments indicated that 8aa has R configu-
ration and is formed from the enantiomerically enriched
homoenolate reagent (S)-6a. In turn, reagent (S)-6a arises
from 4a by deprotonation under the influence of the chiral
base via the ternary complex 5a. During the removal of the
pro-R proton at C3 in the nine-membered cyclic transition
state, the lithium cation migrates along the p system to
position 1 to form the five-membered chelate (S)-6a. The
prerequisites for intramolecular deprotonation are met only
in the isomer (Z)-4a, since (E)-4a remains unchanged.
Carbamates 4b–d react analogously. The electrophiles 7
investigated—the dialkyl ketones 7a and 7b, triphenyltin
chloride (7c), the acid chlorides 7d and 7e, the arene
carboxaldehydes 7h and 7i, and alkanal 7l—are added
exclusively at the g-position (Table 1).
Dedicated to Professor Manfred T. Reetz
on the occasion of his 60th birthday
Enantiomerically enriched, 1-hetero-substituted 2-alkenyl-
metal compounds 1 (e.g., M = Li, Ti(OiPr) , Ti(NEt ) )are
3
2 3
[
1]
powerful homoenolate reagents. They react with aldehydes
and ketones with virtually complete 1,3-transfer of chirality to
[
2]
[3]
form optically active homoaldol products 2 (Scheme 1). In
The reactions of 4a with triphenyltin chloride (7c)and p-
bromobenzaldehyde (7h)(and subsequent oxidation of ent-
8
ah)afforded crystalline products ent-8ac and ent-8af,
respectively, each with > 90% ee. In X-ray crystal structure
analyses with anomalous dispersion both of them had the S
Scheme 1. Addition of homoenolate reagents to aldehydes.
[12]
configuration (Figure 1).
[
13]
Since all of the investigated stannylations of allyllithium
[
14]
the best homoenolate reagents 1 the substituent X is a
and benzyllithium derivatives proceed in an antarafacial
[
2a–d]
complexing N,N-dialkylcarbamoyloxy group
or a tert-
manner by anti-S ’ or stereoinvertive processes, the carban-
ionic intermediate 6a has to be assigned the 1S configuration.
Our experiments (Scheme 3)indicate that even p-bromoben-
E
[
2e]
butoxycarbonylamino group, both of which enhance the
kinetic acidity in the deprotonation of the allylic precursor
and are able to hold the counterion in compound 1 at the a-
position.
zaldehyde (7h)undergoes an anti-S ’ addition. Further
E
evidence for this unusual result was provided by the following
The first known chiral allyllithium derivative configura-
tionally stable below À708C was generated by deprotonation
of an enantiomerically enriched, secondary allylic carbamate
experiments: The lithium cation in 6a was exchanged by
reaction with chlorotris(diethylamino)titanium (inversion
[
15]
of configuration), and the resulting ent-9a added onto
[
2]
by
n-butyllithium/N,N,N’,N’-tetramethylethylenediamine
aldehyde 7h (syn addition). Oxidation of the epimeric
secondary alcohols ent-8ah yielded the ketone ent-8af, which
was identical to a sample obtained from the lithium inter-
mediate. This fact means that an antarafacial reaction step—
the carbonyl addition—is involved in the lithium pathway B,
[
4]
(
TMEDA). We also reported on the preparation of lithium
compounds 1 obtained by kinetic resolution of racemic
precursors by deprotonation with n-butyllithium/(À)-spar-
[
5,6]
1
teine. Lithium carbanions 1 (R = H)derived from primary
precursors could be generated by enantiotopos-differentiat-
ing deprotonation, but these only occasionally exhibit suffi-
[
16]
as well. In contrast, 6a and acetone (7a)(Scheme 4)yield
opposite enantiomers (S)-ent-8aa (pathway B)and ( R)-8aa
(pathway A), demonstrating that the lithium intermediate 6a
adds to dialkyl ketones in a syn-S ’ process. The acylation by
E
means of methyl chloroformate (7e)also proceeds predom-
[
*] Dr. M. Seppi, Dipl.-Chem. R. Kalkofen, J. Reupohl, Dr. R. Fröhlich,
Prof. Dr. D. Hoppe
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
Fax: (+49)251-83-36531
inantly in a syn-S ’ process, as could be shown by trans-
E
formation of the carboxylic ester (À)-8ae into alcohol (+)-
8
aa (Scheme 4).
The addition of the lithium compound 6a to 2,2-dime-
thylpropanal (7l)and 2,2-dimethylpropanoyl chloride ( 7d)is
E-mail: dhoppe@uni-muenster.de
also a syn-S ’ process, as was concluded from an experiment
E
similar to that depicted in Scheme 3. The aliphatic ketones,
aldehydes, and acid chlorides are added to the lithium–
[
**] This work was supported by the Deutsche Forschungsgemeinschaft
(
SFB424) and the Fonds der Chemischen Industrie.
Angew. Chem. Int. Ed. 2004, 43, 1423 –1427
DOI: 10.1002/anie.200352966
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Communications
Scheme 2. Enantiotopos-differentiating g-deprotonation of the pro-R protons by means of the chiral base nBuLi/(À)-sparteine. For ElX (7) see
Table 1, Cb=carbamoyl.
Table 1: Reaction of lithium compounds 6 with different electrophiles.
[
a]
20[a]
Entry
Starting materials
Product
Yield [%]
69
ee [%]
[a]D
1
97
+87
À83
[
b]
2
80
92
3
4
5
57
78
81
93
94
77
+49
+54
À91
6
7
78
49
78
À52
+64
[
c,d]
>90
[
[
c,d]
c,d]
8
70
86
+85
9
0
1
73
74
75
86
>95
>90
À105
+84
+51
1
1
1
424
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Chemie
Table 1: (Continued)
[
a]
20[a]
Entry
Starting materials
Product
Yield [%]
83
ee [%]
[a]D
12
13
14
>95
À120
À64
76
72
92
[
c,d]
>95
À129
15
16
17
77
58
50
88
>95
>95
+84
+63
+81
1
8
58
>95
+57
[
a] c=0.5–1.28, CHCl . [b] Lithium species 6a was treated with 3 equiv [ClTi(NEt ) ] (Scheme 5). [c] Mixture of diastereomeric homoaldol adducts (ca.
3
2 3
1
:1). [d] Oxidation of the crude product with pyridinium dichromate (PDC).
[
17]
sparteine complexes in a suprafacial manner. Apparently
the lithium cation provides electrophilic assistance for the
addition of carbonyl electrophiles. Aromatic aldehydes such
as 7h and 7i undergo anti additions (Table 1, entries 7, 8);
Figure 1. Formulas of the g-products ent-8ac and ent-8af, which were
Scheme 4. Additions of (S)-9a and (S)-6a to acetone (7a) yield prod-
analyzed by X-ray diffraction.
ucts of opposite configuration.
presumably, an open-chain transition state is pro-
moted by the formation of an intermediate p–p*
[
18,14]
complex.
Here, the approach from the face not
covered by the solvated lithium cation is favored.
The titanium compound (S)-9a, which generally is
formed from 6a with stereoinversion, adds to
aldehydes reliably via a Zimmerman–Traxler tran-
[
19]
sition state and leads, combined with 1,3-chirality
transfer, diastereoselectively to optically active
homoaldol adducts anti-ent-8 (Scheme 5, Table 2).
Hydrolysis of 1-aryl-1-alkenyl carbamates to ketones
is possible by treatment with trimethylsilyl triflate
Scheme 3. Additions of (S)-9a and (S)-6a to p-bromobenzaldehyde (7h). Subse-
quent oxidation by pyridinium dichromate (PDC) leads to products of identical
configuration.
(TMSOTf)and subsequent addition of water
(Scheme 6).
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Communications
The (À)-sparteine-mediated g-deprotonation of 1-alkenyl
carbamates is an efficient and expandable approach to
enantiomerically enriched homoenolate reagents starting
[
20]
from achiral precursors.
These react with the standard
electrophiles investigated with high regio- and stereospeci-
ficity. From a mechanistic point of view, the highly stereo-
selective removal of a remote proton deserves particular
attention.
Experimental Section
Scheme 5. Reaction of titanium compound (S)-9a with different alde-
Synthesis of the homoaldol products anti-ent-8ah–8ap: To a solution
of (À)-sparteine (0.353 g, 1.50 mmol) in dry toluene (2 mL) was
added at À788C ca. 1.6m butyllithium (1.4 mmol, 0.89 mL)in hexane.
After the reaction mixture had been stirred for 10 min at À788C, a
solution of carbamate 4a (1.0 mmol)in toluene (1 mL)was added
slowly. Stirring was continued for 1.5 h before a solution of
hydes to form highly enantioenriched homoaldol products. See Table 2
for R .
1
[
ClTi(NEt ) ] (3.0 mmol)in toluene (2 mL)was added dropwise.
2 3
After a transmetalation time of 2 h, the aldehyde 7 (3.0 mmol)was
added at À788C, and stirring was continued for further 2 h. For
workup, 2n aq HCl (10 mL)was introduced to the flask. The aqueous
phase was separated, and the aqueous solution was extracted with
diethyl ether (3 ” 25 mL, each). The combined organic extracts were
Scheme 6. Decarbamoylation of 4a and 4e by means of TMSOTf.
Table 2: Diastereo- and enantioselective homoaldol reaction, starting from 4a.
[
a]
[a]
20[b]
Entry
Aldehyde
Product
Yield [%]
66
d.r.
ee [%]
[a]D
1
95:5
98:2
97:3
97
À135
À133
À145
2
3
71
49
95
93
4
5
82
75
97:3
99:1
95
96
À148
À73
6
7
8
78
79
81
99:1
99:1
99:1
94
93
95
À91
À95
À100
9
77
99:1
95
À85
[a] Determined by HPLC (column Chira Grom-2, solvent: hexane/2-propanol). [b] c=0.5–1.25, CHCl3.
1
426
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Angewandte
Chemie
dried over MgSO , and the solvents evaporated in vacuo. The crude
lection EXPRESS (Nonius B.V., 1994)and COLLECT (Nonius
4
product anti-ent-8 was purified by flash chromatography on silica gel
B.V., 1998), data reduction MolEN (K. Fair, Enraf-Nonius B.V.,
1990)and Denzo-SMN (Z. Otwinowski, W. Minor, Methods
Enzymol. 1997, 276, 307), absorption corrections for CCD data
SORTAV (R. H. Blessing, Acta Crystallogr. Sect. A 1995, 51, 33;
R. H. Blessing, J. Appl. Crystallogr. 1997, 30, 421), structure
solution SHELXS-97 (G. M. Sheldrick, Acta Crystallogr. Sect. A
(diethyl ether/petroleum ether 1:1). For the yields and stereochemical
purity see Table 2.
Received: September 29, 2003 [Z52966]
1
990, 46, 467), structure refinement SHELXL-97 (G. M. Shel-
Keywords: asymmetric synthesis · homoaldol reaction · lithium ·
sparteine · titanium
.
drick, Universität Göttingen, 1997, E. Keller, Graphik SCHA-
KAL, Universität Freiburg, 1997). CCDC-219962 and CCDC-
219961 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[
[
[
1] Reviews: a)D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2282; b)D. Hoppe, F.
Marr, M. Brüggemann, Top. Organomet. Chem. 2003, 5, 61; c) P.
Beak, T. A. Johnson, D. D. Kim, S. H. Lim, Top. Organomet.
Chem. 2003, 5, 134; d)H. Ahlbrecht, U. Beyer, Synthesis 1999,
[
[
13] H. Paulsen, C. Graeve, D. Hoppe, Synthesis 1996, 141.
14] a)A. Carstens, D. Hoppe, Tetrahedron 1994, 50, 6697; b)C.
Derwing, D. Hoppe, Synthesis 1996, 149; c)C. Derwing, H.
Frank, D. Hoppe, Eur. J. Org. Chem. 1999, 3511; d)F. Ham-
merschmidt, A. Hanninger, P. Perric, H. Völlenkle, H. Werner,
Eur. J. Org. Chem. 1999, 3511; e)N. C. Faibish, Y. S. Park, S. Lee,
P. Beak, J. Am. Chem. Soc. 1997, 119, 11561.
15] Reviews on titanation: a)M. T. Reetz, Organotitanium Reagents
in Organic Synthesis, Springer, Berlin, 1986; b)B. Weidmann, D.
Seebach, Angew. Chem. 1983, 95, 12; Angew. Chem. Int. Ed.
Engl. 1983, 22, 32; c)“Organotitanium Chemistry”: M. T. Reetz
in Organometallics in Synthesis (Ed.: M. Schlosser), Wiley,
Chichester, 2002, p. 817.
3
65.
2] a)T. Krämer, J.-R. Schwark, D. Hoppe, Tetrahedron Lett. 1989,
0, 7037; b)D. Hoppe, O. Zschage, Angew. Chem. 1989, 101, 67;
3
Angew. Chem. Int. Ed. Engl. 1989, 28, 69; c)D. Hoppe, O.
Zschage, Tetrahedron 1992, 48, 5657; d)T. Krämer, D. Hoppe,
Tetrahedron Lett. 1987, 28, 5149; e)M. C. Whisler, L. V.
Vaillancourt, P. Beak, Org. Lett. 2000, 2, 2655.
[
3] The direction of chirality transfer is reversed if 1 reacts from the
1-exo-conformation rather than the 1-endo configuration (as
shown in Scheme 1).
[
[
[
[
[
4] D. Hoppe, T. Krämer, Angew. Chem. 1986, 98, 171; Angew.
Chem. Int. Ed. Engl. 1986, 25, 160.
5] At least half of the racemic starting material is lost during this
process.
[
16] Previously, only syn-S ’ additions of aldehydes have been
E
[1]
reported.
6] O. Zschage, J.-R. Schwark, D. Hoppe, Angew. Chem. 1990, 102,
[
17] The decreased enantioselectivity of 86% ee for the addition of
the lithium compound 6a to 2,2-dimethylpropanal (7l, Table 1,
entry 9)indicates a tendency for anti addition. The tendency
increases for branched alkanals and n-alkanals and causes the
predominant formation of addition products ent-8.
336; Angew. Chem. Int. Ed. Engl. 1990, 29, 296.
7] M. Özlügedik, J. Kristensen, B. Wibbeling, R. Fröhlich, D.
Hoppe, Eur. J. Org. Chem. 2002, 414.
8] a)H. Roder, G. Helmchen, E.-M. Peters, K. Peters, H.-G.
von Schnering, Angew. Chem. 1984, 96, 895; Angew. Chem. Int.
Ed. Engl. 1984, 23, 898; b)D. Heimbach, D. Hoppe, Synlett 2000,
[
18] a)V. E. Williams, R. P. Lemieux, G. R. J. Thatcher, J. Org. Chem.
1
996, 61, 1927; b)R. J. Wehmschulte, P. P. Power, J. Am. Chem.
950; c)M. Reggelin, C. Zurr, Synthesis 2000, 1.
Soc. 1997, 119, 2847.
[
9] For the asymmetric g-deprotonation of enamines see the ref. [1d]
[
[
19] H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79,
and, in particular, the contributions of the author cited therein.
1
920.
[
10] J. G. Peters, M. Seppi, R. Fröhlich, D. Hoppe, Synthesis 2002,
81.
20] J. Reubner, R. Fröhlich, D. Hoppe, Org. Lett. 2004, 6, in press.
3
[
[
11] M. Seppi, Dissertation, Universität Münster, 2001.
12] X-ray crystal structure analysis of ent-8ac: C H NO Sn, M =
3
5
39
2
w
6
1
24.36, colorless crystal 0.35 ” 0.15 ” 0.10 mm, a = 10.625(1), b =
3
4.474(1), c = 11.047(1)Š, b = 109.22(1)8, V= 1604.2(2)Š ,
À3
À1
1calcd = 1.293 gcm , m = 65.52 cm , empirical absorption correc-
tion by y-scan data (0.208 ꢀ Tꢀ 0.341), Z = 2, monoclinic, space
group P21 (no. 4), l = 1.54178 Š, T= 223 K, w/2q scans, 3591
À1
reflections collected (+ h, + k, Æ l), (sinq)/l = 0.62 Š , 3407
independent (R = 0.025)and 3162 observed reflections [ I ꢁ
int
2
2s(I)], 3507 refined parameters, R = 0.036, wR = 0.097, max.
À3
residual electron density 0.75 (À1.17)eŠ , Flack parameter
À0.003(9), hydrogen atoms calculated and refined as riding
atoms. X-ray crystal structure analysis of ent-8af: C H BrNO ,
2
4
28
3
M = 458.38, colorless crystal 0.35 ” 0.20 ” 0.20 mm, a = 9.272(1),
w
3
b = 12.938(1), c = 10.388(1)Š, b = 112.00(1)8, V= 1155.4(2)Š ,
À3
À1
1calcd = 1.318 gcm , m = 26.07 cm , empirical absorption correc-
tion via SORTAV (0.462 ꢀ Tꢀ 0.624), Z = 2, monoclinic, space
group P2 (no. 4), l = 1.54178 Š, T= 223 K, w?and f scans, 7530
1
À1
reflections collected (Æ h, Æ k, Æ l), [(sinq)/l] = 0.59 Š , 3077
independent (R = 0.028)and 2886 observed reflections [ I ꢁ
int
2
2
s(I)], 268 refined parameters, R = 0.029, wR = 0.077, max.
À3
residual electron density 0.22(À0.27)eŠ , Flack parameter
À0.030(18), hydrogens calculated and refined as riding atoms.
Data sets were collected with an Enraf-Nonius CAD4 and
Nonius KappaCCD diffractometers. Programs used: data col-
Angew. Chem. Int. Ed. 2004, 43, 1423 –1427
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