Catalytic asymmetric acyl halide-aldehyde cyclocondensations. A strategy for enantioselective catalyzed cross aldol reactions [11]

Full text of DOI:10.1021/ja992369y

9742
J. Am. Chem. Soc. 1999, 121, 9742-9743
formation with ensuing enantioselective aldehyde addition had
not been reported.9 During preliminary development of the
Al(III)-catalyzed AAC reactions, the optically active Al(III)-
triamine complex 1 (10 mol %) was found to catalyze the
cyclocondensation of acetyl bromide (AcBr) and benzyloxy-
acetaldehyde (2a), employing di(isopropyl)ethylamine (DIEA) as
the base, to afford the optically active â-lactone 3a as a 71:19
[4(R):4(S)] mixture of enantiomers (eq 2).
Catalytic Asymmetric Acyl Halide-Aldehyde
Cyclocondensations. A Strategy for Enantioselective
Catalyzed Cross Aldol Reactions
Scott G. Nelson,* Timothy J. Peelen, and Zhonghui Wan
Department of Chemistry, UniVersity of Pittsburgh
Pittsburgh, PennsylVania 15260
ReceiVed July 8, 1999
Considerable interest currently exists in developing catalyzed
asymmetric variants of aldol addition reactions. Despite elegant
solutions to this problem, examples of asymmetric catalyzed cross
aldol reactions that require no pre-enolization1 or special substrate
derivatization are relatively rare.2,3 The considerable homology
existing between traditional aldol addition reactions and ketene-
aldehyde cycloadditions implicates these transformations as
alternative platforms for developing catalyzed asymmetric variants
of cross aldol bond constructions.4,5 Catalyzed asymmetric acyl
halide-aldehyde cyclocondensation (AAC) reactions presented
herein successfully integrate in situ ketene formation and aldehyde
cycloaddition in realizing catalyzed aldol-type bond constructions
employing commercially available reaction partners (eq 1).
The success of this initial Al(III)[triamine]-catalyzed AAC
reaction implicated optically active triamine ligands as platforms
for further refinement of the Al(III)-derived cyclocondensation
catalysts. Evaluating catalyst efficiency as a function of the
triamine ligand’s terminal amine functionality and alkyl group
structure led to the L-valine-derived ligand 4 being identified as
providing catalyst complexes exhibiting optimum enantioselection
and turnover numbers in the catalyzed AAC reactions.10 Catalyst
systems were generated by reacting triamine 4 with AlMe3 or
Me2AlCl to afford Al(III) complexes 5a and 5b, respectively (eq
3); these two catalyst systems function nearly equivalently in the
We have recently described Al(III)-catalyzed cyclocondensa-
tions of acyl halides and enolizable aldehydes as a strategy for
effecting catalyzed cross aldol reactions.6 These investigations
identified the reactive Lewis acid-aldehyde complex responsible
for mediating the operative [2 + 2] ketene-aldehyde cycload-
dition as the strategic construct for inducing asymmetry during
C-C bond formation.7,8 In designing asymmetric variants of these
reactions, we were aware that cycloaddition reaction variants and
accompanying catalyst systems that merged in situ ketene
AAC reactions.11 Substoichiometric quantities of the Al(III)
complex 5a (or 5b) (10 mol %), in concert with DIEA (1. 7
equiv), catalyze the cyclocondensation of acetyl bromide (1.9
equiv) and benzyloxyacetaldehyde (2a) to afford the â-lactone
“cross aldol” adduct 3a as the exclusive reaction product with an
enantiomer ratio of 4(R):4(S) ) 96:4 (91% yield) (eq 2). No
background reaction of acetyl bromide and the aldehyde was
observed in the absence of the Al(III)-triamine catalyst. Remark-
ably, the trialkylammonium‚HBr salt generated during the cy-
clocodensation process has no deleterious effect on reaction
(1) For recent asymmetric catalyzed additions of latent enolates, see: (a)
Kru¨ger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838. (b)
Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032-10039. (c) Evans, D. A.;
Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B.
T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685 and references therein.
(d) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W.
J. Am. Chem. Soc. 1999, 121, 686-699 and references therein. For a review,
see: (e) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
(2) For highly enantioselective catalyzed aldol addition reactions involving
commercially available reagents, see: Carreira, E. M.; Lee, W.; Singer, R.
A. J. Am. Chem. Soc. 1995, 117, 3649-3650.
(3) For a recent example of catalyzed asymmetric intermolecular aldol
reactions, see: (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178. For other examples
of catalytic aldol-type reactions, see: (b) Shibasaki, M.; Sasi, H.; Arai, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256 and references therein.
(c) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405-
6406.
(8) Asymmetric catalyzed ketene additions to chloral and related alde-
hydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166-
168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979.
Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fuku-
moto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d)
Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem.
Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions
using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M.
J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison,
P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.;
Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein.
(g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h)
Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661.
For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org.
Chem. 1996, 61, 8006-8007.
(4) Optically active 4-methylene-2-oxetanones have been developed as
propionate aldol synthons, see: Calter, M. A.; Guo, X. J. Org. Chem. 1998,
63, 5308-5309.
(5) For the utility of aldol adducts as precursors to â-lactones, see: (a)
Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176-1185. (b)
Yang, H. W.; Romo, D. J. Org. Chem. 1997, 62, 4-5. (c) Wedler, C.; Ludwig,
R.; Schick, H. Pure Appl. Chem. 1997, 69, 605-608. (d) Yang, H. W.; Romo,
D. J. Org. Chem. 1998, 63, 1344-1345.
(9) For a comprehensive review of syntheses of optically active â-lactones,
see: Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403-6434.
(10) Triamine 4 was prepared according to the published procedure:
Cernerud, M.; Skrinning, A.; Be´rge`re, I.; Moberg, C. Tetrahedron: Asymmetry
1997, 8, 3437-3441.
(11) For structural investigations of related Al(III)-triamine complexes,
see: (a) Emig, N.; Re´au, R.; Krautscheid, H.; Fenske, D.; Bertrand, G. J.
Am. Chem. Soc. 1996, 118, 5822-5823. (b) Jegire, J. A.; Atwood, D. A.
Inorg. Chem. 1997, 36, 2034-2039.
(6) Nelson, S. G.; Wan, Z.; Peelen, T. J.; Spencer, K. L. Tetrahedron Lett.
1999, 40, 6535-6539.
(7) Nelson, S. G.; Peelen, T. J.; Wan, Z. Tetrahedron Lett. 1999, 40, 6541-
6543.
10.1021/ja992369y CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/04/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 41, 1999 9743
Table 1. Asymmetric Acetyl Bromide-Aldehyde
ethers afforded significant quantities of desilylated aldehyde and
correspondingly low reaction yields. Incorporating the less acid-
sensitive tert-butyldiphenylsilyl (TBDPS) protecting group in the
R-alkoxyaldehyde 2f alleviated silyl ether cleavage, affording the
â-lactone 3f in high yield and enantiomeric excess (entry f).
Conjugated ynals are also very reactive electrophiles in the
asymmetric AAC reactions, delivering the corresponding â-lac-
tones with enantiomeric purities and chemical yields consistent
with those obtained for aliphatic aldehydes (entries g and h).
Conjugated aldehydes are not, however, generally effective
electrophiles in the catalyzed AAC reactions; conjugated enals
afford little to no â-lactone product under the optimized reaction
conditions. Aldehydes possessing branching at the R-carbon,
represented by cyclohexanecarboxaldehyde (entry i), presently are
also not functional electrophiles in the asymmetric cycloconden-
sation reactions.
Cyclocondensationsa
The preparative utility of the asymmetric AAC reactions was
documented in a reaction using 10 mmol (1.5 g) of benzyloxy-
acetaldehyde (2a). Using the typical experimental procedure, 10
mol % of the enantiomeric form of the preformed Al(III) catalyst
5a afforded â-lactone ent-3a in 89% isolated yield and 92% ee,
values that are nearly identical for those obtained on 1 mmol
reaction scale.14
a Reactions were carried out using the conditions given in ref 12.
b Reported values are for chromatographically purified materials.
c Isolated yield is reflective of product volatility. d Enantiomer ratios
for entries a, b, e and g were determined by HPLC (chiral Chiralcel
OD-H column); enantiomer ratios for entries c, d, h, and i were
determined by capillary GC (chiral Chiraldex G-TA column).
Ring-opening alcoholysis reveals the optically active â-lactone
adducts derived from the asymmetric AAC reactions as direct
progenitors of prototypical acetate aldol adducts. We have
previously disclosed that 4-substituted 2-oxetanones undergo rapid
lanthanum alkoxide-catalyzed ring-opening with alcohols to afford
the corresponding â-hydroxy esters.6 The La(Ot-Bu)3-catalyzed
(5 mol %) ring-opening of the enantiomerically enriched â-lac-
tones 3c-f,i with benzyl alcohol affords the optically active
benzyl acetate aldols 6c-f,i in nearly quantitative yield (eq 5).
efficiency or enantioselectivity. The catalyzed addition of pre-
formed ketene to benzyloxyacetaldehyde using 10 mol % 5b, a
process that is free of any ammonium halide salts, afforded the
â-lactone 3a with chemical yield and enantioselection directly
paralleling those values obtained from the cyclocondensation
reaction (89% yield, 92% ee).
Catalyst complexes 5a and 5b render a variety of structurally
diverse, enolizable aldehydes as effective electrophiles for the
catalyzed asymmetric AAC reactions.12 Straight-chain, â-branched,
and alkoxy-substituted aldehydes afford the derived â-lactone
adducts 3a-f with uniformly high enantioselection (89-95% ee)
and chemical yields using 10 mol % 5a/b at -40 to -50 °C (eq
4; Table 1).13 Further enhanced â-lactone enantiomer ratios are
Catalyzed asymmetric AAC reactions provide an effective
strategy for executing enantioselective C-C bond constructions
that constitute surrogates for typical cross aldol addition reactions.
These catalyzed aldol variants are characterized by their opera-
tional simplicity and their use of inexpensive, commercially
available reaction components. The access to enantiomerically
enriched â-lactones afforded by this methodology is expected to
accelerate the exploitation of these intermediates both as masked
aldol adducts and as versatile intermediates for asymmetric
organic synthesis.
obtained at lower reaction temperatures at the expense of extended
reaction times (entry b). Catalyzed AAC reactions are also
compatible with certain silyl ether protecting groups encountered
widely in organic synthesis. Attempted cyclocondensation of
aldehydes incorporating primary tert-butyldimethylsilyl (TBS)
(12) Typical experimental procedure: Under a N2 atm, a solution of 54
mg of triamine ligand 4 (0.10 mmol) in 8 mL of CH2Cl2 is treated with 100
µL of a 1 M hexanes solution of dimethylaluminum chloride (0.10 mmol) at
ambient temperature. The resulting homogeneous, colorless solution was stirred
at room temperature for 1 h, whereupon 300 µL of di(isopropyl)ethylamine
(1.7 mmol) was added via syringe. The reaction was cooled to -50 °C, and
140 µL of acetyl bromide (1.9 mmol) and the aldehyde (1.0 mmol) were added
via syringe. The reaction was stirred until complete as monitored by TLC
(∼8-72 h). The reaction mixture was eluted through a silica gel pad with
CH2Cl2, and the filtrate was concentrated in Vacuo. If necessary, crude reaction
mixtures were purified by flash chromatography (hexanes:ethyl acetate). For
an experimental procedure using preformed Al(III) complex 5a, see the
Supporting Information.
Acknowledgment. The National Science Foundation (CHE-9875735)
and the University of Pittsburgh are gratefully acknowledged for support
of this work. The authors thank Dr. Beon-Kyu Kim for characterizing
the catalyst complexes and Mark A. Hilfiker for the results of the large-
scale reaction.
Supporting Information Available: Experimental procedures, details
of compound characterization, and copies of representative 1H/13C spectra
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) The absolute configuration of â-lactones 3a,b,i was established by
reduction to the corresponding 1,3-diol derivatives (LiAlH4, Et2O, 0 °C) and
correlation of their optical rotation to those of authentic samples of known
configuration; see the Supporting Information for full procedural details. The
configuration of the remaining â-lactones (3c-h) was assigned by analogy
to these determinations.
JA992369Y
(14) As part of synthesis studies underway in our laboratories, the
enantiomeric form of lactone 3a was required. Thus, this large-scale reaction
was conducted with the enantiomer of catalyst 5a.