I. Ibrahem, A. Cꢀrdova et al.
uene/EtOAc 3:1) to afford alcohols 4. Aldehydes 3 can also be isolated if
the reduction step is avoided.
high enantiomeric ratios (up to 98:2 e.r.). Despite the chal-
lenges of racemization and epimerization high stereocontrol
was achieved and maintained at the a-stereocenter of the
enolizable 2-allylaldehyde products. The co-catalytic direct
catalytic asymmetric allylic alkylation of linear aldehydes is
also a direct entry to valuable optically active 2-alkylhemi-
Large-scale procedure: An oven-dried Schlenk flask (25 mL) containing
a magnetic stir bar was charged with [Pd
5 mol%), sealed, and put under N2, followed by addition of DMSO
(2.0 mL) and 3a (586.8 mg, 3.33 mmol). solution of catalyst 1a
ACHTUNGTREN(NNUG PPh3)4] (196.4 mg, 0.17 mmol,
A
(217.0 mg, 0.67 mmol, 20 mol%) and aldehyde 2d (1.00 g, 10.0 mmol) in
DMF (2.0 mL) was added to this reaction. The resulting mixture was al-
lowed to stir at À208C for 48 h. Next, the reaction temperature was in-
creased to À158C, followed by addition of MeOH (11 mL) and slow ad-
dition of sodium borohydride (3.78 g, 99.9 mmol, 30.0 equiv). The mix-
ture was allowed to stir for 30 min at À158C. Next, it was transferred to
ACHTUNGTRENNUNGacetals and 2-alkyl-butane-1,4-diols as was demonstrated by
the formal total synthesis of (R)-3-methyl-N-(2-phenethyl)-
pyrrolidine. The total synthesis of (S)-Arundic acid was also
accomplished. Further mechanistic studies, applications in
total synthesis, and developments based on this concept are
ongoing in our laboratories and will be published in due
course.
a
flask containing a cold mixture of NH4Cl (sat. aq) and EtOAc
(100:15 mL) at 08C. The mixture was stirred for 5 min followed by ex-
traction. The organic phase was dried over Na2SO4 and filtered. The vola-
tiles were removed in vacuo and the residue purified by silica gel column
chromatography (3:1 toluene/EtOAc) to afford 4d (659.3 mg, 91% yield)
as yellow oil.
Experimental Section
Acknowledgements
General: IR spectra were recorded on a Termo Fisher Nicolet 6700 FTIR
spectrometer, nmax in cmÀ1. Bands are characterized as broad (br), strong
(s), medium (m), or weak (w). 1H NMR spectra were recorded on a
Bruker Avance 500 (500 MHz) spectrometer. Chemical shifts are report-
ed in ppm from tetramethylsilane with the solvent resonance resulting
from incomplete deuterium incorporation as the internal standard
(CDCl3: d=7.26 ppm). Data are reported as follows: chemical shift, mul-
tiplicity (s=singlet, d=doublet, q=quartet, br=broad, m=multiplet),
coupling constants (Hz), integration. 13C NMR spectra were recorded on
a Bruker Avance 500 (125.8 MHz) spectrometer with complete proton
decoupling. Chemical shifts are reported in ppm from tetramethylsilane
with the solvent resonance as the internal standard (CDCl3: d=
77.16 ppm). HRMS was performed on a Agilent 6520 -TOF ESIMS (pos-
itive mode). Enantiomeric ratios were determined by HPLC (Chiral
Technologies Chiralpak AS or OD column (4.6ꢂ250 mm)) in comparison
with authentic racemic materials. Optical rotations were measured on a
Perkin–Elmer 341 Polarimeter at 208C and 589 nm, in a 100 cm cell in
stated solvent. TLC was performed on silica gel/TLC-cards, with detec-
tion by UV light 254 nm or stained with Cerium-ammonium-molybdate
(CAM) reagent followed by heating. Unless otherwise noted, all reac-
tions were performed under an atmosphere of N2 in oven-dried (1358C)
glassware with standard vacuum-line techniques. All chemicals were pur-
chased from Aldrich and used as received without further purification.
DMSO (A.C.S Reagent) and DMF (anhydrous ꢀ99.8%) were degassed
with N2 for 10 min before use. The water content of these commercial
solvents was measured by Karl Fischer titration.
We are grateful for financial support by Mid Sweden University, Carl
Trygger foundation, European Union, and Hꢃkan Norberg for help in
setting up the lab.
[1] a) D. Caine in Comprehensive Organic Synthesis Vol 3 (Eds.: B. M.
Trost J. Fleming), Pergamon, Oxford, 1991, pp. 1–63; b) S. Carrettin,
c) Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH, Wein-
3102; b) G. Stork, A. Brizzolara, H. Landesman, J. Szmuskovicz, R.
6759; c) M. Braun, F. Laicher, T. Meier, Angew. Chem. 2000, 112,
3637; Angew. Chem. Int. Ed. 2000, 39, 3494; d) B. M. Trost, G. M.
tions of ketone enolates see: g) J. M. Fox, X. Huang, A. Chieffi,
121, 1473; i) T. Satoh, Y. Kametani, Y. Terao, M. Miura, M.
ylation using Cu–bis(oxazoline) catalysts, see: k) A. Bigot, A. E.
Harvey, S. P. Simonovich, C. R. Jamison, D. W. C. MacMillan, J. Am.
Typical experimental procedure: An oven-dried vial (8 mL) containing a
magnetic stir bar was charged with [PdACTHNUTRGNEUNG(PPh3)4] (17.3 mg, 0.015 mmol,
5 mol%), fitted with a septum, sealed, and flushed with a stream of N2
for 5 min, followed by addition of degassed DMSO (300 mL). After 3 min
of stirring at room temperature, allyl acetate 2 (0.3 mmol, 1.0 equiv) was
added and the mixture was stirred for another 3 min. In parallel to the
above procedure, an oven-dried vial (8 mL) was subsequently charged
with catalyst 5a (19.5 mg, 0.06 mmol, 20 mol%), aldehyde 1 (0.9 mmol,
3.0 equiv), fitted with a septum, sealed and flushed with a stream of N2
for 5 min, followed by addition of degassed DMF (300 mL). After 3 min.
of stirring, this mixture was transferred by a syringe to the vial containing
the mixture of [PdACHTUNGTRENNUNG(PPh3)4] and 2 in DMSO (300 mL) (final substrate con-
centration=0.50m). The temperature of the resulting mixture was de-
creased to À208C and stirred at this temperature for the time shown in
Table 2. Next, the temperature was increased to À158C, followed by ad-
dition of MeOH (1 mL) and NaBH4 (340.5 mg, 9.0 mmol, 30.0 equiv.)
and the resulting mixture was allowed to stir for 15 min. The mixture was
then transferred to a flask containing a cold mixture of NH4Cl (sat. aq)
and EtOAc (3:15 mL) at 08C. The resulting mixture was stirred for
5 min, dried over Na2SO4, and filtered. The volatiles were removed in
vacuo and the residue purified by silica gel column chromatography (tol-
1775, and references therein.
[7] a) M. Kimura, Y. Horino, R. Mukai, S. Tanaka, Y. Tamaru, J. Am.
2976
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2972 – 2977