Acylzirconocene chloride as an 'unmasked' acyl anion: Enantioselective 1,2-addition to α,β-unsaturated ketone derivatives

Article abstract of DOI:10.1002/(SICI)1521-3773(19990816)38:16<2395::AID-ANIE2395>3.0.CO;2-W

The chiral monodentate phosphane ligand (R)-MOP facilitated the first enantioselective nucleophilic 1,2-addition of an 'unmasked' acyl anion to a carbonyl group in the Pd(II)-catalyzed reaction of α,β-unsaturated ketones with acylzirconocene chlorides [Eq

Full text of DOI:10.1002/(SICI)1521-3773(19990816)38:16<2395::AID-ANIE2395>3.0.CO;2-W

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Soc. 1994, 116, 811 ± 812; g) E. T. Kool, Chem. Rev. 1997, 97, 1473 ±
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since both processes involve the dissociation of a DNA duplex to
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Nakao, Nucleosides Nucleotides 1998, 17, 233 ± 242.
Acylzirconocene Chloride as an ªUnmaskedº
Acyl Anion: Enantioselective 1,2-Addition to
a,b-Unsaturated Ketone Derivatives**
Yuji Hanzawa,* Nobuhito Tabuchi, Kosuke Saito,
Satoshi Noguchi, and Takeo Taguchi*
Recently, we reported palladium-catalyzed regioselective
acylation reactions[1] of a,b-unsaturated ketone derivatives
with acylzirconocene chloride.[2] The acyl group of acylzircon-
ocene chloride reacted as a formal ªunmaskedº acyl anion.[3]
In particular, the regioselectivity of the reaction can be
controlled by modifying the palladium catalyst system. For
example, in the reaction of nonanoylzirconocene chloride (1)
with cyclohexenone (Scheme 1), the use of [PdCl2(PPh3)2]
O
[5] A Merck LiChrospher 100 RP-18(e) column; linear acetonitrile/H2O
gradient from 5/95 to 50/50 at 25 min.
[6] The pure trans isomer isolated by HPLC was partially (about 10%)
converted into the cis isomer by ambient light.
HO
n-C8H17
a
O
O
[7] In the determination of the Tm value of the cis isomer, UV light was
irradiated in the middle of the measurement to minimize the effect of
the thermal isomerization to the trans form. By this treatment, the
fraction of the cis isomer was kept almost constant at 70% throughout
the measurement, as confirmed by HPLC and UV/Vis spectroscopy.
[8] For the duplex between 5'-GGGXGGGG-3' and 5'-CCCCCCCC-3',
the trans !cis isomerization of the incorporated azobenzene moiety
resulted in a decrase in Tm from 32.2 to 23.08C ([oligonucleotide]0 ˆ
+
O
n-C8H17
ZrCp2Cl
b
1
n-C8H17
3
O
O
R
Scheme 1. Regioselective acylation of cyclohexenone with nonanoylzircon-
ocene chloride (1): a) 1,2-acylation, 5 mol% [PdCl2(PPh3)2] or 5 mol%
Pd(OAc)2/PPh3 (Pd/P ˆ 1/2); b) 1,4-acylation, 10 mol% Pd(OAc)2/BF3 ´
OEt2.
1
10mmolL at pH 7.1 (without NaCl)). Here the modified oligonu-
cleotide was used as a mixture of the two diastereomers since they
could not be separated by HPLC.
[9] The argument is substantiated by the fact that the trans-azobenzene
moiety of 1a exhibits a bathochromic shift upon formation of the 1a ±
2 duplex. In aqueous solutions, the absorption maximum of the
azobenzene appears at 353 nm. When 2 is added to the solutions (at a
temperature below the Tm of the duplex), however, the absorption
band shifts towards longer wavelength (e.g., the absorption maximum
is located at 359 nm under the conditions presented in the text). As
expected, the absorption spectrum is hardly affected by 2 when the
temperature is higher than the Tm.
(5 mol%) as catalyst in toluene gave the 1,2-addition product
2, whereas the use of 10 mol% [Pd(OAc)2]/BF3 ´ OEt2 in THF/
diethyl ether gave the 1,4-addition product 3 (Scheme 1).[4]
A
5 mol% Pd(OAc)2/PPh3 (Pd/P ˆ 1/2) system was also found to
be an effective catalyst for regioselective formation of the 1,2-
acylation product 2. Bidentate diphosphane ligands such as
1,2-bis(diphenylphosphanyl)ethane (dppe) and 1,3-bis(diphe-
nylphosphanyl)propane (dppp) gave lower regioselectivities.
In the palladium-catalyzed reactions of 1 with a,b-unsatu-
rated ketones, concomitant formation of diketone 4 (<10%)
was observed.[5] This suggests a transmetalation of 1 with PdII
and subsequent reductive elimination of Pd0 from the
resulting bis-acylpalladium complex to give 4 (Scheme 2).
Thus, electron transfer from Pd0 to cyclohexenone, formation
of the acylpalladium p-allylic complex 5, and reductive
elimination of Pd0 would give the 1,2- or 1,4-acylation product
(2 or 3) (Scheme 2).[6] The role of the triphenylphosphane
ligand in the regioselective formation of 2 could be explained
by preferred formation of the stereochemically less crowded
intermediate complex 5A rather than 5B and subsequent
reductive elimination of Pd0 from 5A.
[10] J. M. Robertson, J. Chem. Soc. 1939, 232 ± 236.
[*] Prof. Dr. Y. Hanzawa, Prof. Dr. T. Taguchi, N. Tabuchi, K. Saito,
S. Noguchi
School of Pharmacy, Tokyo University of Pharmacy & Life Science
1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
Fax: (‡81)426-76-3257
E-mail: hanzaway@ps.toyaku.ac.jp
[**] This work was supported by the Ministry of Education, Science, and
Culture, Japan (No.(C)(2)10672000).
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chiral induction into the product (R)-2 (entry 5; [a]D24
ˆ
42.1
O
PdII
O
O
(c ˆ 1.04 in CHCl3), 66% ee, 88% yield).[10] There is no
significant difference between (R)-MOP and its derivatives
(BnO-, iPrO-, and tBuMe2SiO-(R)-MOP)[9] in the chiral
induction and the reactivity of 1. The product yield and the
reaction rate were significantly increased by using (R)-MOP
as a ligand instead of triphenylphosphane.
O
n-C8H17
ZrCp2Cl
n-C8H17
Pd
n-C8H17
n-C8H17
n-C8H17
1
O
4
Pd0
O
2 or 3
The use of (R)-MOP enabled us to obtain a 1,2-acylation
product (67% ee, 36% yield)[10, 11] from cyclopentenone,
which gave a complex mixture of products with Pd(OAc)2/
PPh3.[1] The present enantioselective reaction is less efficient
for acyclic a,b-unsaturated ketones, but high yields and good
regioselectivity are obtained (Table 2). The absolute config-
OZrCp2Cl
CO-n-C8H17
Pd
L
5
Scheme 2. Generation of Pd0 and a catalytic cycle for the acylation of
cyclohexenone with 1.
Table 2. Pd(OAc)2/(R)-MOP-catalyzed reactions of 1 with a,b-unsatu-
rated ketones.
OZrCp2Cl
CO-n-C8H17
OZrCp2Cl
L
Pd
Pd
5 mol % PdꢀOAc†
2
!
L
CO-n-C8H17
1
‡
a,b-unsaturated ketone
1,2-adduct
10 mol % ꢀR†-MOP
5A
5B
5A > 5B (L = PPh3)
ketone
Yield [%]
ee [%]
O
These observations and considerations suggested that
enantioselective formation of 1,2-acylation products 2 would
be possible by treating cyclohexenone with 1 in the presence
of PdII and a chiral phosphane ligand. To our knowledge,
however, there is no precedent for the enantioselective
nucleophilic acylation of an ªunmaskedº acyl anion with
carbonyl compounds. The results of PdII-catalyzed reactions
of 1 with cyclohexenone in the presence of chiral phosphane
ligands in toluene are listed in Table 1.
36
92
67[a]
O
O
38[a]
17
6
91
84
O
All reactions were carried out with 5 mol% palladium
catalyst and chiral phosphane ligand (Pd/P ˆ 1/2). The reac-
tion is very slow and not regioselective with the bidentate
phosphane ligands (R)-BINAP and (R,R)-CHIRAPHOS
(entries 1 and 2).[7, 8] The (R)-MOP ligand, which was devel-
oped by Hayashi et al.,[9] shows a considerable efficiency of
[a] See ref. [11].
uration of (R)-2 obtained by using the (R)-MOP ligand was
confirmed by comparison of the sign of the specific rotation
[a]D with the independently prepared enantiomer (S)-2. The
synthesis of (S)-2 was carried out in seven steps from the
readily accessible allylic alcohol 6[12] (Scheme 3).[10]
Table 1. PdII-catalyzed reactions of 1 with cyclohexenone in the presence of
chiral phosphane ligands.[a]
O
O
HO
O
PdII catalyst
n-C8H17
+
n-C8H17
ZrCp2Cl
chiral phosphane
1
2
Entry Pd catalyst[b]
Phosphane[c]
±
Yield [%][d] ee [%][e]
[PdCl2{(R)-BINAP}]
Pd(OAc)2
Pd(OAc)2
[PdCl2(PPh3)2]
Pd(OAc)2
19[f]
±
±
1
2
3
4
5
6
7
(R,R)-CHIRAPHOS[g] 14[h]
(‡)-NMDP[i]
(R)-MOP[j]
(R)-MOP
(R)-MOP
(R)-MOP
81
90
88
89
92
±
12
66
61
62
[PdCl2(PhCN)2]
[Pd(acac)2]
Cl
Pd
Pd
8
(R)-MOP
48
56
Cl
9
[PdCl2(CH3CN)2]
[Pd2(dba)3] ´ CHCl3
(R)-MOP
(R)-MOP
86
70
64
64
10
Scheme 3. Alternative synthesis of (S)-2: a) tBuOOH, Ti(OiPr)4, (‡)-
DIPT; (R)-6: [a]2D3:0 ˆ 6.6 (c ˆ 0.50 in CHCl3), 45%, 90% ee; b) tBuOOH,
Ti(OiPr)4, ( )-DIPT; 8: [a]D26:0 ˆ 26.1 (c ˆ 1.38 in CHCl3), 90%, >95% ee;
c) (PhSe)2/NaBH4 in EtOH; 9: [a]2D6:0 ˆ 43.24 (c ˆ 0.60 in CHCl3), 95%,
m.p. 91 ± 92.58C; d) HC(OMe)3/PPTS in DMF; 10: quantitative; e) i.
NaIO4 in aqueous THF (53%), ii. DIBAL-H in CH2Cl2 (78%), iii. Swern
oxidation (75%). DIBAL-H ˆ diisobutylaluminum hydride, DIPTˆ diiso-
propyl tartrate, PPTS ˆ pyridinium p-toluenesulfonate.
[a] Reactions were carried out at ambient temperature in toluene. [b] 5 mol%
catalyst was used; acac ˆ acetylacetonate, dba ˆ dibenzylideneacetonate.
[c] Pd/P ˆ 1/2. [d] Yield of isolated product. [e] Determined by HPLC on a
chiracel AD column after conversion to the benzoyl ester. [f] Compound 3 was
formed in 17% yield. [g] (2R,3R)-Bis(diphenylphosphanyl)butane. [h] 3 was
formed in 11% yield. [i] (‡)-Neomenthyldiphenylphosphane. [j] (R)-2-(Diphe-
nylphosphanyl)-2'-methoxy-1,1'-binaphthyl.
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We exploited the Sharpless asymmetric epoxidation[13] and
kinetic resolution[14] of 6 to control the absolute configuration.
The kinetic resolution of allylic alcohol 6 with (‡)-DIPT,
Ti(OiPr)4, and tBuOOH gave the optically active allylic
alcohol (R)-6 (90% ee, 45% yield)[15] and epoxy alcohol 7. The
subsequent epoxidation of (R)-6 with Ti(OiPr)4 and tBuOOH
in the presence of ( )-DIPT gave epoxy alcohol 8 (90%,
>95% ee).[10, 16] Treatment of 8 with sodium phenylselenide
gave vic-diol 9,[10, 17] which was protected as cyclic orthofor-
mate 10.[10, 18] The oxidation of 10 with sodium periodate at
08C, deprotection of the vic-diol protecting group (DIBAL-
H), and Swern oxidation of the secondary alcohol gave (S)-2
[>95% ee, [a]2D6 ˆ 45.5 (c ˆ 0.57 in CHCl3)], which was
identical in every respect with the product (R)-2 derived
from the enantioselective acylation, except for the sign of
specific rotation.[19] Thus, the R configuration of the product
of the enantioselective palladium-catalyzed reactions of 1 in
the presence of (R)-MOP was confirmed. On the basis of the
hypothetical acylpalladium p-allylic complex 5A and the
X-ray structure of an (R)-MOP-ligated p-allylic palladium
complex,[8] we assume that the intermediate 5A' (L* ˆ (R)-
MOP) is responsible for the chiral induction in the present
reactions (Scheme 4). Therefore, the sense of the chiral
solution, the mixture was extracted with diethyl ether. The combined ether
extracts were washed with saturated aqueous NaCl solution, dried over
MgSO4, and filtered. Concentration of the filtrate and purification of the
residual oil by silica gel column chromatography (hexanes/ethyl acetate 50/
1 to 30/1) gave pure (R)-2 (105 mg, 88% yield). Colorless oil; [a]D24:0
ˆ
42.1 (c ˆ 1.04 in CHCl3); 1H NMR (400 MHz, CDCl3): d ˆ 0.87 (t, J ˆ
6.8 Hz, 3H), 1.26 ± 1.31 (m, 10H), 1.57 ± 1.66 (m, 3H), 1.77 ± 1.88 (m, 3H),
2.03 ± 2.21 (m, 2H), 2.50 (dt, J ˆ 1.3, 8.3 Hz, 2H), 4.03 (s, 1H), 5.47 (qd, J ˆ
1.3, 9.9 Hz, 3H), 6.12 ± 6.15 (m, 1H); 13C NMR (100.6 MHz, CDCl3): d ˆ
14.1, 18.1, 22.6, 24.0, 24.8, 29.1, 29.2, 29.3, 31.8, 33.3, 36.3, 76.0, 126.1, 133.6,
1
‡
213.8; IR (neat): nÄ ˆ 3467, 2927, 1709 cm
; EI-MS: m/z: 238 [M ];
elemental analysis calcd for C15H26O2: C 75.58, H 10.99; found: C 75.28,
H 10.92.
Received: March 5, 1999 [Z13111IE]
German version: Angew. Chem. 1999, 111, 2552 ± 2555
Keywords: acylations ´ asymmetric catalysis ´ P ligands ´
palladium ´ zirconium
[1] Y. Hanzawa, N. Tabuchi, T. Taguchi, Tetrahedron Lett. 1998, 39, 8141.
[2] Reviews: a) P. Wipf, H. Jahn, Tetrahedron 1996, 52, 12853; b) J. A.
Labinger in Comprehensive Organic Synthesis, Vol. 8 (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, 1991, p. 667; c) J. Schwartz, J. A.
Labinger, Angew. Chem. 1976, 88, 402; Angew. Chem. Int. Ed. Engl.
1976, 15, 333; d) C. A. Bertelo, J. Schwartz, J. Am. Chem. Soc. 1975, 97,
228.
[3] a) S. Harada, T. Taguchi, N. Tabuchi, K. Narita, Y. Hanzawa, Angew.
Chem. 1998, 110, 1769; Angew. Chem. Int. Ed. 1998, 37, 1696; b) Y.
Hanzawa, N. Tabuchi, T. Taguchi, Tetrahedron Lett. 1998, 39, 6249.
Concerning the ªunmaskedº acyl anion: ªAcyl Anionen und deren
Derivateº: R. W. Saalfrank in Methoden der organischen Chemie
(Houben-Weyl), 4th ed., Vol. E-19d, 1993, p. 567, and references
therein.
OMe
n-C8H17-CO
ClCp2ZrO
Pd
X
ClCp2ZrO
L*
Pd
P
[4] In these palladium-catalyzed reactions, the a,b-unsaturated ketone
framework was an essential factor in facilitating the reaction, since
b,g-unsaturated and saturated ketone derivatives were unreactive
toward the acylzirconocene chloride under otherwise identical con-
ditions.
5A' [L* = (R)-MOP]
X = CO-n-C8H17
Scheme 4. (R)-MOP-ligated acylpalladium p-allylic complex 5A'.
[5] The reaction of 1 with a stoichiometric amount of Pd(OAc)2 without
the addition of cyclohexenone also gave 4 in 15% yield.
induction under the present reaction conditions indicates the
reductive elimination of palladium metal in the (R)-MOP
ligated acylpalladium p-allylic complex 5A' (L* ˆ (R)-MOP).
In summary, we have demonstrated the first example of
enantioselective nucleophilic acylation with an ªunmaskedº
acyl anion. The present nucleophilic acylation of a,b-unsatu-
rated ketone with acylzirconocene chlorides in the presence of
the chiral monodentate phosphane ligand (R)-MOP opens
new possibilities for directly introducing an ªunmaskedº acyl
anion into the carbonyl group of a,b-unsaturated ketones in
an enantioselective manner. The stability and easy accessi-
bility of acylzirconocene chlorides favors their use as synthetic
reagents over other transition metal acyl complexes.[20]
[6] A similar electron-transfer mechanism was established in the low-
valent nickel- or palladium-catalyzed reactions of alkenylzirconocene
chloride derivatives with a,b-unsaturated carbonyl derivatives: a) J.
Schwartz, M. Loots, H. Kosugi, J. Am. Chem. Soc. 1980, 102, 1333;
b) F. M. Dayrit, J. Schwartz, J. Am. Chem. Soc. 1981, 103, 4466. In our
reaction, the use of [Ni(acac)2] also gave 2 and 3 in 14 and 41% yields,
respectively.
[7] (R)-BINAP: (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl: a) H.
Takaya, K. Mashima, K. Koyano, M. Yagi, H. Kumobayashi, T.
Taketomi, S. Akutagawa, R. Noyori, J. Org. Chem. 1986, 51, 629;
(R,R)-CHIRAPHOS: (2R,3R)-bis(diphenylphosphanyl)butane; Pd ±
CHIRAPHOS complex: b) Y. Yamaguchi, T. Shima, T. Yamagishi, M.
Hida, Tetrahedron Lett. 1990, 31, 5049.
[8] A similar observation was made by Hayashi et al. in an asymmetric
reduction of allylic esters with formic acid and a Pd/chiral phosphane
catalyst: T. Hayashi, H. Iwamura, M. Naito, Y. Matsumoto, Y.
Uozumi, J. Am. Chem. Soc. 1994, 116, 775.
[9] (R)-MOP: (R)-2-(diphenylphosphanyl)-2'-methoxy-1,1'-binaphthyl;
a) T. Hayashi, J. Synth. Org. Chem. Jpn 1994, 52, 900; b) Y. Uozumi,
T. Hayashi, Pure. Appl. Chem. 1992, 64, 1911; c) Y. Uozumi, N. Suzuki,
A. Ogiwara, T. Hayashi, Tetrahedron 1994, 50, 4293; d) Y. Uozumi, A.
Tanahashi, S.-Y. Lee, T. Hayashi, J. Org. Chem. 1993, 58, 1945.
[10] Optical purity was determined by HPLC on a chiralcel AD column.
All isolated new compounds showed appropriate spectroscopic data
(IR, NMR, MS) and correct elemental analyses or high-resolution
mass spectra.
Experimental Section
(R)-2: 1-Octene (0.32 mL, 2 mmol) was added to
a suspension of
[Cp2ZrHCl] (258 mg, 1 mmol) in CH2Cl2 (8 mL) at ambient temperature,
and the mixture was stirred for 0.5 h under an argon atmosphere. The argon
was replaced by CO (1 atm), and the mixture was stirred for a further 2 h at
ambient temperature. Concentration of the solution to dryness in vacuo
gave 1 as a pale yellow powder, which was dissolved in toluene (15 mL). To
the solution of
1 in toluene were added cyclohexenone (0.05 mL,
0.5 mmol), Pd(OAc)2 (5.5 mg, 0.025 mmol), and (R)-MOP (23 mg,
0.05 mmol) with ice cooling, and the mixture was then stirred at ambient
temperature for 20 min. After addition of saturated aqueous NaHCO3
[11] 1,2-addition product from cyclopentenone: [a]2D5 ˆ 36.32 (c ˆ 1.02 in
CHCl3). 1,2-addition product from cycloheptenone: [a]D25
ˆ
35.65
(c ˆ 0.92 in CHCl3). The absolute configurations were not determined.
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[12] Alcohol 6 was prepared by the Shapiro reaction of cyclohexanone p-
toluenesulfonylhydrazone with n-nonanal in 48% yield. R. H. Sha-
piro, Org. React. (N.Y.) 1976, 13, 405. See also: N. E. Schore, M. J.
Knudsen J. Org. Chem. 1997, 52, 569.
[13] T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974.
[14] V. S. Martin, S. S. Woodard, T. Katsuki, Y. Yamada, M. Ikeda, K. B.
Sharpless, J. Am. Chem. Soc. 1981, 103, 6237.
[15] A similar system to 6 was reported to give the resolved (R)-alcohol
efficiently by using l-(‡)-DIPTunder the Sharpless kinetic resolution
conditions.[14] The optical purity of (R)-6 was determined by Mosher
analysis.
R2
R2
*
O
O
catalyst
catalyst
H
H
R4
R3
+
+
R3
(1)
(2)
O
O
R1
R1 * O * R4
R3
R3
R5
R2
R4
R2
R4
*
*
R1O
R1O
O
R5
*
[16] Although the highly diastereoselective epoxidation of (R)-6 is possible
without adding chiral tartrate, we added ( )-tartrate, whose chirality
matches that of (R)-6, to improve the optical purity of epoxy alcohol 8.
[17] D. P. G. Hamon, R. A. Massy-Westropp, J. L. Newton, Tetrahedron:
Asymmetry 1990, 1, 771.
[18] The protection of the diol 9 is required for the subsequent oxidation of
the phenylselenide group; otherwise, the selenide 9 was reconverted
to the epoxy alcohol 8 under the oxidation conditions.
[19] Starting from epoxy alcohol 7 (49% ee), which is obtained by the first
kinetic resolution of 6 with (‡)-tartrate, gave (R)-2 (43% ee) on
applying the same synthetic sequence. Therefore, we believe that no
epimerization takes place at the quaternary alcohol carbon atom of 9
throughout the reactions.
[20] a) E. J. Corey, L. S. Hegedus, J. Am. Chem. Soc. 1969, 91, 4926; b) M. P.
Cook, Jr., R. M. Parlman, J. Am. Chem. Soc. 1977, 99, 5225; c) L. S.
Hegedus, R. J. Perry, J. Org. Chem. 1985, 50, 4955; d) J. Collin, J. L.
Namy, F. Dallemer, H. B. Kagan, J. Org. Chem. 1991, 56, 3118.
class of asymmetric HDA reaction would provide a direct
route to enantiomerically enriched dihydropyran derivatives
from simple achiral starting materials, setting up to three
stereocenters in the cyclization and allowing ultimate access
to tetrahydropyran derivatives with five defined stereocenters
by elaboration of the resultant double bond. Herein we
describe highly effective chiral catalysts for these types of
HDA reactions.[5]
Evaluation of tridentate Schiff base chromium(iii) com-
plexes of the type 1a and 1b revealed catalysis of the HDA
reaction between (2Z, 4E)-triethylsilyloxy-2,4-hexadiene (4b)
and aldehydes 5a and 5b, affording tetrahydropyranones 6a
and 6b after desilylation (Scheme 1). In both cases, nearly
O
OR
1) catalyst (3 mol%)
4Å sieves, RT
Me
Me
+
R1CHO
16-40 h
2) TBAF, AcOH, THF
Me
O
R1
Me
1
:
1
Highly Enantio- and Diastereoselective
Hetero-Diels ± Alder Reactions Catalyzed by
New Chiral Tridentate Chromium(iii)
Catalysts**
4a: R = SiMe3 (TMS)
b: R = SiEt3 (TES)
c: R = Si(tBu)Me2
(TBS)
5a: R1 = Ph
6a-h
b: R1 = CH2OTBS
c: R1 = CH2OBn
>95% de
(all cis)
d: R1 = n-C5H11
d: R = Si(iPr)3 (TIPS)
e: R1 = (CH2)4CH=CH2
f: R1 = CH2CH2Ph
g: R1 = CH2CH2NHBoc
h: R1 = 2-furyl
Alexander G. Dossetter, Timothy F. Jamison, and
Eric N. Jacobsen*
The formal hetero-Diels ± Alder reaction (HDA) between
dienes and carbonyl compounds[1] has emerged as an impor-
tant target for asymmetric catalysis. Successes reported in this
area have involved the reaction of electron-rich dienes such as
1-methoxy-3-(trimethylsilyloxy)butadiene (Danishefskyꢁs di-
ene) and/or electron-deficient dienophiles such as glyoxylate
derivatives.[2±4] As yet, however, there exists no effective
method for asymmetric HDA reactions between less nucle-
ophilic dienes bearing fewer than two oxygen substituents and
unactivated carbonyl compounds [Eq. (1) and (2)]. This new
R2
R2
=
=
tBu
H
R3
=
=
tBu
R2
(1R,2S)-1a,b
(1R,2S)-2a,b
R3
R3
R3
N
O
X
R2
=
Me
=
(1R,2S)-3a,b
Cr
O
a : X = Cl b : X = SbF6
Scheme 1. Hetero-Diels ± Alder reaction between substituted hexadienes
4 and aldehydes 5. Bn ˆ benzyl; Boc ˆ tert-butoxycarbonyl; MS ˆ molec-
ular sieve; TBAF ˆ tetrabutylammonium fluoride.
[*] Prof. E. N. Jacobsen, A. G. Dossetter, T. F. Jamison
Department of Chemistry and Chemical Biology
Harvard University
perfect selectivity for the endo cyclization product (all-cis
configuration) was observed, in 80% and 57% ee, respec-
tively (Table 1, entries 1 and 2).[6] Chromium(iii) complexes 2a
and 2b, bearing the larger 1-ethyl-1-methylpropyl group,
retained the high diastereoselectivity exhibited by 1a and 1b
and provided an increase in ee, particularly in the case of
aliphatic aldehydes such as 5b (85% ee with catalyst 2b;
Table 1, entry 3).
Cambridge, MA 02138 (USA)
Fax: (‡1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] We are indebted to W. Zhang and Z. Li for their preparation of some
of the catalysts and catalyst precursors that proved critical to this
study. This work was supported by the National Institutes of Health
(GM-59316), and by postdoctoral fellowships to A.G.D. from Glaxo-
Wellcome and to T.F.J. from the Cancer Research Fund of the Damon
Runyon-Walter Winchell Foundation (DRG-1431).
As part of this examination of the relationship of catalyst
structure to reaction enantioselectivity, adamantyl-substituted
chromium(iii) complex 3a was prepared from readily acces-
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the author.
2398
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Angew. Chem. Int. Ed. 1999, 38, No. 16