Mixed crossed aldol condensation between conjugated esters and aldehydes using aluminum tris(2,6-diphenylphenoxide)

Article abstract of DOI:10.1002/(SICI)1521-3773(19990614)38:12<1769::AID-ANIE1769>3.0.CO;2-0

The combined use of aluminum tris(2,6-diphenylphenoxide) (ATPH) and lithium 2,2,6,6-tetramethylpiperidide (LTMP) has proven to be effective for the mixed crossed aldol condensation between conjugated esters and various aldehydes. An example is shown in Eq

Full text of DOI:10.1002/(SICI)1521-3773(19990614)38:12<1769::AID-ANIE1769>3.0.CO;2-0

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Table 1. In vitro antitumor activity[a] of complex 6.
[7] Compound 2 was prepared from 1,3-dibromo-2-propanol by reaction
with NaN3 in DMF.
Cell line
Tumor of origin
MED[b] [mm]
Cisplatin
[8] 6: 1H NMR (500 MHz, D2O): d ˆ 4.39 (d, J(H1,H2) ˆ 8.0 Hz, 1H;
H1), 4.23 (m, 1H; CH(CH2NH2)2), 3.70 (dd, J(H6a,H6b) ˆ 12.5,
J(H5,H6a) ˆ 2.0 Hz, 1H; H6a), 3.55 (dd, J(H6a,H6b) ˆ 12.5,
J(H5,H6b) ˆ 5.0 Hz, 1H; H6b), 3.34 ± 3.23 (m, 3H; H3, H4, H5),
3.17 (dd, J(H2,H3) ˆ 9.5, J(H1,H2) ˆ 8.0 Hz, 1H; H2), 2.89 ± 2.84,
2.72 ± 2.65 (2m, 2 Â 2H; CH(CH2NH2)2); 13C NMR (125 MHz, D2O):
d ˆ 102.2 (C1), 76.5, 76.2 (C3, C5), 74.1 (CH(CH2NH2)2), 73.7 (C2),
70.1 (C4), 61.2 (C6), 46.2, 45.1 (CH(CH2NH2)2).
6
A2780S[c]
A2780cP[c]
MeWo[d]
ovarian
ovarian
melanoma
2.5
112
11.2
3.3
36
8
[a] Cytotoxicity was assessed by clonogenic survival assay as described.[12]
[b] Median effect dose. [c] A2780S and its cisplatin-resistant variant,
A2780cP, were obtained from Dr. Marshal Sklar (University of Miami)
and maintained in Paul G. Braunschweigerꢀs laboratory. [d] Obtained from
Dr. Jorgen Fogh and maintained in Paul G. Braunschweigerꢀs laboratory.
[9] Crystal structure data (Bruker P4/CCD diffractometer) for 6 ´ 1.5H2O:
C9H23Cl2N2O7.5Pt, Mr ˆ 545.28, crystal dimensions 0.32 0.22Â
0.06 mm3, Tˆ 295(2) K, monoclinic, space group P21, a ˆ 690.390(10),
b ˆ 3174.58(6), c ˆ 809.74(2) pm, b ˆ 115.0650(10)8, Z ˆ 4, Vˆ
1.60758(6) nm3, 1calcd ˆ 2.253 gcm 3, MoKa radiation (l0 ˆ 0.71073 Š),
m ˆ 9.096 mm 1, 2q ˆ 2.56 ± 56.688; of 9952 reflections collected, 6498
were independent (R(int)ˆ 0.031); refinement method: full-matrix least
squares on F 2, 397 refined parameters, empirical absorption correction
(SADABS software, Tmin and Tmax undefined), GOF ˆ 1.008 (based on
F 2), R1 ˆ 0.0383, wR2ˆ 0.0915 (s> 2s(I)), absolute structure parameter
0.007(8), residual electron density 2.559/3.782 eŠ 3. The structure
was solved and refined with the programs SHELXS-93 and SHELXTL.
The hydrogen atoms were placed in their geometric positions (riding
model), except that no hydrogen atoms were placed in the solvent
molecules. Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Center as supplementary publication no.
CCDC-113805. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
should open new avenues to explore this important area of
cancer chemotherapy.
Moreover, complex 6 is, to the best of our knowledge, the
first example of a carbohydrate-containing transition metal
complex in which the carbohydrate moiety is not only
unprotected, but also unbound to the metal center.[6, 14] Such
complexes should be obtainable as single crystals, which can
then be used to determine the solid-state structure of intact
and unprotected carbohydrates.
Experimental Section
6: A mixture of 1 (2.2 g, 5.36 mmol), 2 (1.14 g, 8.0 mmol), and 4-Š
molecular sieves (3.5 g) was stirred under Ar for 1 h at RT in CH2Cl2
(50 mL), and HgBr2 (0.39 g, 1.07 mmol) and HgO (1.16 g, 5.36 mmol) were
added. After being stirred in the dark for 2 d, the mixture was filtered
through a layer of Celite. The filtrate was washed with aqueous NaHCO3
solution, dried, and concentrated. Chromatography of the residue in
[10] For examples, see reference [6].
[11] J. Wang, Y. L. Bennani, F. Belanger-Gariepy, S. Hanessian, Acta
Crystallogr. Sect. C 1991, 47, 1067 ± 1069, and references therein; see
also reference [6].
hexanes/ethyl acetate (1/1) on silica gel afforded
Compound 3 (0.78 g, 2.56 mmol) and a catalytic amount of NaOMe were
3 (1.59 g, 63%).
[12] P. G. Braunschweiger, V. S. Basrur, O. Santos, J. P. Perras, A. M.
Markoe, P. Houdek, J. G. Schwade, Biotherapy 1997, 10, 129 ± 137.
stirred in MeOH (30 mL) for 6 h at RT. The mixture was neutralized by
1
[13] Solubility of 6 in water: >20 mgmL at 258C.
‡
addition of Dowex H ion-exchange resin and filtered, and Pd/C (60 mg)
[14] Crystal structures of platinum(ii) complexes of unprotected carbohy-
drate diolates have been reported, but there the carbohydrates are
directly bound to platinum, and the complexes are not used in
biological study. For examples, see a) A. Appelt, A. C. Willis, S. B.
Wild, J. Chem. Soc. Chem. Commun. 1988, 938 ± 940; b) M. A.
Andrews, G. L. Gould, Organometallics 1991, 10, 387 ± 389; c) M. A.
Andrews, E. J. Voss, G. L. Gould, W. T. Klooster, T. F. Koetzle, J. Am.
Chem. Soc. 1994, 116, 5730 ± 5740.
was added. After being stirred under H2 (35 psi) for 8 h, the mixture was
filtered through a layer of Celite, and the filtrate concentrated. The residue
was redissolved in H2O and lyophilized to give 4 (0.4 g, 96%). Compound 4
(0.18 g, 0.71 mmol) and 5 (0.3 g, 0.71 mmol) were stirred in H2O (10 mL)
for 2 d at RT, and concentrated. Chromatography of the residue on a gel
filtration column with Bio-gel P2 resin afforded 6 (0.28 g, 75%).
Received: January 13, 1999 [Z12900IE]
German version: Angew. Chem. 1999, 111, 1882 ± 1884
Keywords: antitumor agents
´ bioinorganic chemistry ´
carbohydrates ´ N ligands ´ platinum
[1] B. Rosenberg, L. VanCamp, J. E. Trosko, V. H. Mansour, Nature
(London) 1969, 222, 385 ± 386.
Mixed Crossed Aldol Condensation between
Conjugated Esters and Aldehydes Using
Aluminum Tris(2,6-diphenylphenoxide)
[2] a) Metal Complexes in Cancer Chemotherapy (Ed.: B. K. Keppler),
VCH, Weinheim, 1993; b) Molecular Aspects of Anticancer DrugÐ
DNA Interactions, Vol. 1 (Eds.: S. Neidle, M. Waring), Macmillian,
Basingstoke, 1993; c) J. Reedijk, Chem. Commun. 1996, 801 ± 806.
[3] Reviews: a) A. Pasini; F. Zunino, Angew. Chem. 1987, 99, 632 ± 642;
Angew. Chem. Int. Ed. Engl. 1987, 26, 615 ± 624; b) R. B. Weiss, M. C.
Christian, Drugs 1993, 46, 360 ± 377.
Susumu Saito, Masahito Shiozawa, and
Hisashi Yamamoto*
Crossed aldol condensation between two different carbonyl
compounds is one of the earliest and synthetically most
significant reactions for carbon ± carbon bond formation.[1]
[4] a) J. Reedijk, Inorg. Chim. Acta 1992, 198±200, 873±881, and references
therein; b) A. Iakovidis, N. Hadjiliadis, Coord. Chem. Rev. 1994, 135/
136, 17 ± 63, and references therein; c) K. F. Morris, L. E. Erickson,
B. V. Panajotova, D. W. Jiang, F. Ding, Inorg. Chem. 1997, 36, 601 ± 607.
[5] a) S. Hakamori, Annu. Rev. Biochem. 1981, 50, 733 ± 764; b) Y.-T. Li,
S.-C. Li, Adv. Carbohydr. Chem. Biochem. 1982, 40, 235.
[6] For examples of platinum(ii) complexes of diamino-dideoxy carbohy-
drates (coordination through the amino groups) as cisplatin analogues,
see a) T. Tsubomura, M. Ogawa, S. Yano, K. Kobayashi, T. Sakurai, S.
Yoshikawa, Inorg. Chem. 1990, 29, 2622 ± 2626; b) S. Hanessian, J. Y.
Gauthier, K. Okamoto, A. L. Beauchamp, T. Theophanides, Can. J.
Chem. 1993, 71, 880 ± 885; c) S. Hanessian, J.-G. Wang, Can. J. Chem.
1993, 71, 886 ± 895.
[*] Prof. Dr. H. Yamamoto, Dr. S. Saito, M. Shiozawa
Graduate School of Engineering, Nagoya University
CREST, Japan Science
and
Technology Corporation (JST)
Furo-cho, Chikusa
Nagoya 464-8603 (Japan)
Fax : (‡ 81)52-789-3222
E-mail: j45988a@nucc.cc.nagoya-u.ac.jp
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Our recent discovery[2] that aluminum tris(2,6-diphenylphen-
oxide)[3, 4] (ATPH, Figure 1) and lithium diisopropylamide
(LDA) trigger mixed crossed aldol condensation of conju-
gated aldehydes or ketones with aldehydes encouraged us to
tion was obtained with similar ineffectiveness (recovery of 2
90%, yield of 3 10%).
We thus chose to focus on the use of LTMP, and various
examples of ester± aldehyde combinations are listed in
Tables 1 and 2. Benzaldehyde (2) and pivalaldehyde (22)
were particularly well suited to this process. In contrast,
valeraldehyde (24) might suffer from competitive deprotona-
tion at the a-carbon atom. This difficulty was easily circum-
vented when cyclohexanecarboxaldehyde (23) branched at
the a-carbon atom was used to provide 28 (90%) and 29
(87%) with equal effectiveness. Aldolization at the g-
positions of lactones proceeded with similar success, despite
low diastereoselectivities (Table 1, entries 4 and 5). Highly
conjugated esters including dienoate 8, trienoate 9, tetra-
enoate 10, and even pentaenoate 11 participated in this
transformation; however, the reaction proceeded less
readily with 11 to give 20 in moderate yield (Table 1,
entries 9 ± 12).[6]
Figure 1. The molecular structure (left) and space-filling model of ATPH
(right).
improve this reaction to a more synthetically useful level.
Reported herein is the mixed aldol condensation between
conjugated esters and aldehydes[5] in the presence of ATPH;
lithium 2,2,6,6-tetramethylpiperidide (LTMP) instead of LDA
has proven to be an effective reagent.
Precomplexation of methyl crotonate (1, 2.0 equiv) and
benzaldehyde (2, 1.0 equiv) with ATPH (3.3 equiv) was
followed by treatment with a solution of LTMP (2.3 equiv)
in THF at 788C under an argon atmosphere (Scheme 1).
After stirring of the mixture at this temperature for 30 min,
quenching with aq NH4Cl, and purification by column
chromatography on silica gel, aldol adduct 3 was obtained in
One area where this system could be applied with particular
benefit is the rapid elaboration of elongated conjugated
esters, which have been demonstrated to be of great synthetic
potential.[7] For example, tosylation of aldol adduct 34, which
was obtained in 93% yield by the standard procedure (see
Table 1. Mixed aldol condensation of unsaturated esters with benzaldehyde
(2).
Entry[a] Ester
Product
Yield [%][b]
97
CO2Me
CO2Me
Ph
ATPH
ATPH
1
2
3
O
CO2Me
+
HO
O
1
CHO
ATPH
+
OMe
(3.3 equiv)
CO2Me
CO2Me
Ph
toluene
–78 °C
90
2
1
13
HO
4
(2.0 equiv) (1.0 equiv)
H
CO2Me
THF
LTMP
CO2Me
Ph
deprotonation
–78 °C (2.3 equiv)
3
72[c]
14
Cl
O
HO
5
HO
Cl
CO2Me
O
Ph
O
88[d]
70[e]
O
3
4
5
OH
15
16
6
Scheme 1. Crossed-aldol condensation of methyl crotonate (1) with
benzaldehyde (2) using ATPH and LTMP.
O
O
Ph
O
O
OH
7
97% yield with retention of the E configuration at the olefin
moiety (see entry 1 of Table 1). None of the Z isomer was
detected by H NMR spectroscopy or GC-MS analysis.
Ph
CO2Me
2 CO2Me
6
7
8
9
97
OH
8
17
1
Ph
Ph
3 CO2Et
CO2Et
Similar to the case of the conjugated aldehyde ± aldehyde
aldol system,[2] deprotonation and subsequent alkylation
occurred exclusively at the allylic terminus of the unsaturated
ester, and not at the a-carbon atom. The use of a smaller
amount of the ester, ATPH, and LTMP (1.0:2.2:1.2) proved
disappointing (yield of 3 57%). Under otherwise identical
conditions, the reaction with other lithium amides such as
LDA, lithium hexamethyldisilazide (LHMDS), and lithium
dicyclohexylamide proceeded less efficiently than with LTMP,
producing 3 with consistently lower yields of 33, 23, and 42%,
respectively. It should be emphasized that the ester and
aldehyde must be precomplexed with ATPH: when benzal-
dehyde (2) was exposed to the ATPH complex ( 788C,
5 min) prior to treatment with LTMP, the desirable aldoliza-
88
18
OH
OH
9
4 CO2Et
CO2Et
80
19
10
5 CO2Et
Ph
CO2Et
40[f]
20
CO2Me
21
OH
Ph
11
10
86
HO
CO2Me
12
[a] The reaction was performed using aldehyde (1 equiv), ester (2 equiv), ATPH
(3.3 equiv), and LTMP (2.3 equiv) in toluene/THF (1/1) at 788C for 30 min.
[b] Yield of isolated, purified products. [c] Diastereomeric ratio ˆ 76:24.
[d] Diastereomeric ratio ˆ 70:30. [e] Diastreomeric ratio ˆ 66:33. [f] An un-
identified isomer was also obtained (23%).
1770
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Angew. Chem. Int. Ed. 1999, 38, No. 12

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Table 2. Mixed aldol condensation of various aldehydes with conjugated
esters.[a, b]
concentrated, and the residue was purified by column chromatography on
silica gel (diethyl ether/hexane 1/2 !1/1 !5/1) to give 3 (99.2 mg, yield
97%) as a colorless liquid. 2,6-Diphenylphenol could be isolated in more
than 90% yield before the aldol product came off the column. The obtained
aldol adduct 3 showed identical spectral and analytical data with those
reported in the literature.[9]
CO2Me
ester
CO2Me
1
4
aldehyde
CO2Me
CO2Me
tBu
tBu
CHO
Received: December 29, 1998 [Z12839IE]
German version: Angew. Chem. 1999, 111, 1884 ± 1886
HO
(90%)
(87%)
HO
27
22
26
CO2Me
CO2Me
cHex
cHex
Keywords: aldol reactions ´ C C coupling ´ cross-coupling ´
enols
HO
(87%)
CHO
CHO
(90%)
CO2Me
(22%)
HO
29
23
24
28
CO2Me
nBu
nBu
[1] a) O. H. House in Modern Synthetic Reactions (Ed.: R. Breslow),
Benjamin, Menlo Park, NJ, USA, 1972, chap. 10, and references
therein; b) C. H. Heathcock in Comprehensive Organic Synthesis,
Vol. 2 (Eds.: B. M. Trost, I. Fleming, C. H. Heathcock), Pergamon,
Oxford, 1991, chap. 1.5, and references therein; c) C. H. Heathcock in
Modern Synthetic Methods 1992, Vol. 6 (Ed.: R. Scheffold), VHCA,
Basel, 1992, chap. 1, and references therein.
HO
Ph
(42%)
HO
Ph
31
30
CO2Me
(50%)
CO2Me
(71%)
CHO
25
HO
HO
32
33
[2] S. Saito, M. Shiozawa, M. Ito, H. Yamamoto, J. Am. Chem. Soc. 1998,
120, 813.
[a] The reaction was performed using aldehyde (1 equiv), ester (2 equiv),
ATPH (3.3 equiv) and LTMP (2.3 equiv) in toluene/THF (1/1) at 788C for
30 min. [b] The yields in parentheses are of isolated, purified products.
[3] For a general review of bulky aluminum reagents, including ATPH, see:
S.Saito, H. Yamamoto, Chem. Commun. 1997, 1585.
[4] ATPH was prepared as follows: To a solution of 2,6-diphenylphenol
(3 equiv) in toluene was added a 1m solution of Me3Al (1 equiv) in
hexane at room temperature under argon. The resulting pale yellow
solution was stirred at this temperature for 30 min and used without
further purification. a) S. Saito, M.Ito, H. Yamamoto, J. Am. Chem. Soc.
1997, 119, 611; b) T. Ooi, K. Hokke, K. Maruoka, Angew. Chem. 1997,
109, 1230; Angew. Chem. Int. Ed. Engl. 1997, 36, 1181; c) K. Maruoka,
M. Ito, H. Yamamoto, J. Am. Chem. Soc. 1995, 117, 9091; d) K.
Maruoka, S. Saito, H. Yamamoto, J. Am. Chem. Soc. 1995, 117, 1165;
e) K. Maruoka, H. Imoto, H. Yamamoto, J. Am. Chem. Soc. 1994, 116,
12115; f) K. Maruoka, H. Imoto, S. Saito, H. Yamamoto, J. Am. Chem.
Soc. 1994, 116, 4131.
Experimental Section), followed by elimination with DBU at
908C gave (2E,4E,6)-trienoate 35, one of the synthetic
intermediates for asukamycin,[7a] in 90% yield (6E:6Z ˆ
97:3, Scheme 2).
a
CO2Me
CO2Me
OH
34
35
[5] With the exception of our case, the extended dienolates of esters are
invariably prone to a-functionalization: a) D. Caine in Comprehensive
Organic Synthesis, Vol. 3 (Eds.: B. M. Trost, I. Fleming, G. Pattenden),
Pergamon, Oxford, 1991, chap. 1.1, and references therein; b) S. Saito,
H. Yamamoto, Chem. Eur. J., in press.
[6] Preparation of 5: a) H. O. House, V. K. Jones, G. A. Frank, J. Org.
Chem. 1964, 29, 3327. Highly conjugated esters 8 ± 11 were prepared as
described in the literature, through a Horner ± Emmons olefination
with diethyl phosphonoacetic acid ethyl ester (methyl ester for 8): b) M.
Bellassoued, A. Majidi, J. Org. Chem. 1993, 58, 2517.
Scheme 2. A rapid route to 35, the synthetic intermediate of asukamycin.
Reagents and conditions: a) 4-methylbenzenesulfonyl chloride (TsCl,
2.0 equiv), 4-(dimethylamino)pyridine (DMAP, 5.0 equiv), CH2Cl2, 258C,
18 h, 90%; 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 5 equiv), toluene,
908C, 5 h, >99%.
In summary, a directed access to d-hydroxy-a,b-unsaturat-
ed esters and their derivatives using two different ATPH ±
carbonyl complexes in place of carbonyl compounds them-
selves has been demonstrated. Such a strategy has proven to
be quite general with respect to both the aldehyde component
and the unsaturated esters. Moreover, this method should be
of practical value as a straightforward route to important
classes of synthetic intermediates such as highly polyenic
esters, and thus potentially useful for a short-step convergent
approach to complex natural products.[8]
[7] a) P. Wipf, P. D. G. Coish, Tetrahedron Lett. 1997, 38, 5073; b) B. H.
Lipshutz, C. Lindsley, J. Am. Chem. Soc. 1997, 119, 4555; c) J.
Ã
Thibonnet, M. Abarbi, J. L. Parrain, A. Duchene, Synlett 1997, 771; d) D.
Boschelli, T. Takemasa, Y. Nishitani, S. Masamune, Tetrahedron Lett.
1985, 26, 5239.
[8] There are many examples of d-hydroxy-a,b-unsaturated esters and
their related units involved in the synthesis of important natural
products: a) X. Fan, G. R. Flentke, D. H. Rich, J. Am. Chem. Soc. 1998,
120, 8893; b) T. I. Richardson, S. D. Rychnovsky, J. Am. Chem. Soc.
1997, 119, 12360; c) A. B. Smith III, G. R. Ott, J. Am. Chem. Soc. 1996,
118, 13095; d) C. S. Poss, S. D. Rychnovsky, S. L. Schreiber, J. Am.
Chem. Soc. 1993, 115, 3360; e) G. E. Keck, J. A. Murry, J. Org. Chem.
1991, 56, 6606; f) K. C. Nicolaou, T. K. Chakraborty, Y. Ogawa, R. A.
Daines, N. S. Simpkins, G. T. Furst, J. Am. Chem. Soc. 1988, 110, 4660;
g) K. C. Nicolaou, R. A. Daines, T. K. Chakraborty, Y. Ogawa, J. Am.
Chem. Soc. 1988, 110, 4685.
Experimental Section
The reaction of methyl crotonate (1) with benzaldehyde (2) is representa-
tive. To a solution of ATPH (1.65 mmol) in toluene (6.0 mL) was added 1
(106 mL, 1.0 mmol) and 2 (51 mL, 0.50 mmol) at 788C under argon. After
the mixture was stirred for 20 min, LTMPÐgenerated by treatment of a
solution of 2,2,6,6-tetramethylpiperidine (194 mL, 1.15 mmol) in THF
(6.0 mL) with a 1.60m solution of nBuLi (0.72 mL, 1.15 mmol) in hexane
at 788C for 30 minÐwas transferred by a steel cannula to the solution of
[9] P. R. Johnson, J. D. White, J. Org. Chem. 1984, 49, 4424.
ATPH-1 and ATPH-2 in toluene at
788C. The reaction mixture was
stirred at this temperature for 30 min and quenched with aq NH4Cl, and the
resulting suspension was filtered through a celite pad. The filtrate was
extracted with diethyl ether. The organic layer was dried over Na2SO4 and
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