Palladium-catalyzed asymmetric synthesis of allylic alcohols from unsymmetrical and symmetrical racemic allylic carbonates featuring C-O-bond formation and dynamic kinetic resolution

Article abstract of DOI:10.1016/j.tetlet.2005.07.044

Described is the asymmetric synthesis of the allylic alcohols 11 (85% ee), 15 (99% ee), 17 (93% ee), 19 (61% ee), and 21 (69% ee) through a Pd-catalyzed reaction of the unsymmetrical carbonates rac-10, rac-12, rac-14, rac-16, rac-18, and rac-20, respectively, with KHCO₃ and H₂O in the presence of bisphosphane 6. Similarly the allylic alcohols 23 (99% ee) and 25 (97% ee) have been obtained from the symmetrical carbonates rac-22 and rac-24, respectively. Reaction of the meso-biscarbonate 26 with H₂O and Pd(0)/6 afforded alcohol 27 (96% ee), which was converted to the PG building block 32. The unsaturated bisphosphane 33 showed in the synthesis of alcohols 36, 37, and 39 a similar high selectivity as 6. The formation of alcohols 11, 15, and 17 involves an efficient dynamic kinetic resolution.

Full text of DOI:10.1016/j.tetlet.2005.07.044

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6279–6283
Palladium-catalyzed asymmetric synthesis of allylic
alcohols from unsymmetrical and symmetrical
racemic allylic carbonates featuring C–O-bond formation
and dynamic kinetic resolution
Hans-Joachim Gais,* Oleg Bondarev and Ralf Hetzer
Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen, Technischen Hochschule (RWTH) Aachen,
Landoltweg 1, 52056 Aachen, Germany
Received 30 June 2005;accepted 12 July 2005
Abstract—Described is the asymmetric synthesis of the allylic alcohols 11 (85% ee), 15 (99% ee), 17 (93% ee), 19 (61% ee), and 21
(69% ee) through a Pd-catalyzed reaction of the unsymmetrical carbonates rac-10, rac-12, rac-14, rac-16, rac-18, and rac-20, respec-
tively, with KHCO3 and H2O in the presence of bisphosphane 6. Similarly the allylic alcohols 23 (99% ee) and 25 (97% ee) have been
obtained from the symmetrical carbonates rac-22 and rac-24, respectively. Reaction of the meso-biscarbonate 26 with H2O and
Pd(0)/6 afforded alcohol 27 (96% ee), which was converted to the PG building block 32. The unsaturated bisphosphane 33 showed
in the synthesis of alcohols 36, 37, and 39 a similar high selectivity as 6. The formation of alcohols 11, 15, and 17 involves an efficient
dynamic kinetic resolution.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Chiral allylic alcohols are important intermediates in the
synthesis of natural and non-natural compounds.1 Sev-
eral methods have been developed for their asymmetric
synthesis including kinetic resolution2 and those based
on C–H-1c,3 and C–C-bond4 formation. Particularly
interesting are alternative approaches featuring C–O
bond formation.5 We have recently described a Pd-cata-
lyzed asymmetric synthesis of allylic alcohols, 5, through
reaction of the corresponding symmetrical racemic car-
bonates, rac-1, with the chiral catalyst Pd(0)/66 and
water7a (Scheme 17b).
The important steps of this synthesis are (1) the in situ
anion exchange of the p-allyl-Pd complex through
hydrolysis, 2!3, and (2) the enantioselective substitu-
tion of the latter complex by the hydrogen carbonate
ion with formation of an allylic hydrogen carbonate,
4, the decomposition of which gives the allylic alcohol,
Scheme 1.
Keywords: Asymmetric synthesis;Palladium catalysis;Allylic alcohols.
*
5. Key to the attainment of a high efficiency is the con-
version of both enantiomers of the allylic carbonate, 1
Corresponding author. Tel.: +49 241 8094686;fax: +49 241
8092665;e-mail: Gais@RWTH-Aachen.de
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.044

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H.-J. Gais et al. / Tetrahedron Letters 46 (2005) 6279–6283
Scheme 4.
Scheme 2.
and ent-1, to one p-allyl-Pd complex, 2, by the catalyst
because of the symmetrical carbon skeleton of the sub-
strate and the C2-symmetry of the ligand 6.
It was now of interest to see whether racemic unsymmet-
rical allylic carbonates are also capable to undergo a
highly efficient catalytic transformation to the corre-
sponding allylic alcohols with Pd(0)/6 and water. Here
the situation is much more complex since both enantio-
mers of the substrate, 7 and ent-7, react with the catalyst
with formation of two diastereomeric p-allyl-Pd com-
plexes, 8 and 9, respectively (Scheme 2).8 Only if there
is (1) a different reactivity of the complexes, (2) a fast
interconversion of both complexes or racemization of
the substrate, (3) a high stereoselectivity induced by
the ligand, and (4) a high regioselectivity caused by the
substituents can the racemic substrate be completely
converted to the chiral alcohol with high enantio- and
regioselectivity. An interconversion and racemization
could in principle be caused either by an anti substitu-
tion of the allyl complexes by the Pd(0) catalyst (e.g.,
8!9) and/or by a Pd-centered syn substitution of the al-
lyl complex by the anion (e.g., 8!ent-7), respec-
tively.2f,8–10 However, examples for a Pd-catalyzed
allylic substitution of unsymmetrical racemic substrates
of type rac-7 that proceed with high yield and enantiose-
lectivity (dynamic kinetic resolution2h) are very rare.11
Scheme 5.
vide for a high regioselectivity of the substitution2f,g,12
and the importance of the corresponding allylic alcohols
as starting material for the synthesis of chiral
compounds.
2. Results and discussion
Treatment of the carbonate rac-10 with 4 mol % of
Pd(0)/6 and 1.4 equiv of KHCO3 in the two-phase sol-
vent system composed of CH2Cl2 and H2O at room tem-
perature for 36 h gave alcohol 1113 with 85% ee in
85% yield (Scheme 3). Formation of the isomeric alcohol
was not observed (P98%). A reduction of the amount of
the catalyst to 2 mol % saw a decrease of the ee-value of
11 to 78%. Interestingly, at the same catalyst concentra-
tion but in the single-phase solvent system THF/H2O
the ee-value of 11 dropped to 35%. Similarly, the omis-
sion of KHCO3 in the reaction of rac-10 with the cata-
lyst in CH2Cl2/H2O resulted in the isolation of 11 with
only 41% ee. Finally the isomeric carbonate rac-12 was
submitted to the reaction with 4 mol % of Pd(0)/6 and
1.4 equiv of KHCO3 in CH2Cl2/H2O at room tempera-
ture for 36 h, which afforded exclusively alcohol 11
(P98%) with 84% ee in 83% yield.
2.1. Unsymmetrical substrates
We selected the racemic allylic carbonates shown in
Schemes 3–5 because of their electronically and steri-
cally different substituents, which are expected to pro-
With the less reactive acetate rac-13 a highly selective
kinetic resolution took place (Scheme 4).10 Treatment
Scheme 3.

H.-J. Gais et al. / Tetrahedron Letters 46 (2005) 6279–6283
6281
of rac-13 with 4 mol % of Pd(0)/6 and 1.4 equiv of
KHCO3 in CH2Cl2/H2O gave alcohol 11 with 88% ee
in 45% yield and acetate ent-1313 with 98% ee in 42%
yield. A non-linear regression of a series of ee- and con-
version-values gave a selectivity factor of S = 73 32.
88% ee in 89% yield. Gratifyingly, lowering the temper-
ature to 3 °C allowed the isolation of alcohol 23 with
99% ee in 83% yield after a reaction time of 72 h under
otherwise identical reaction conditions. Similarly, reac-
tion of the racemic carbonate rac-24 with 2 mol % of
Pd(0)/6 and 1.4 equiv of KHCO3 in CH2Cl2/H2O at
room temperature for 24 h gave indenol 25 with 97%
ee in 88% yield.
Next the synthetically more attractive functionalized
racemic carbonates rac-14, rac-16, rac-18, and rac-20
were investigated (Scheme 5). Treatment of the ester
rac-14 with 8 mol % of Pd(0)/6 and 1.4 equiv of KHCO3
in CH2Cl2/H2O at room temperature for 96 h gave
alcohol 1514a,b with 99% ee in 87% yield. The sulfone
rac-16 afforded under similar conditions with half
amount of the catalyst alcohol 1714b,15 with 93% ee in
87% yield. The utilization of THF/H2O instead of
CH2Cl2/H2O resulted also in this case in a decrease of
the ee-value of 17 to 60% (89% yield). The substitutions
of the nitrile rac-18 and the phosphonate rac-20 pro-
ceeded less selectively. Reaction of rac-18 and rac-20
with 4 mol % of Pd(0)/6 and 1.4 equiv of KHCO3 in
CH2Cl2/H2O at room temperature for 96 h furnished
alcohol 1916 with 61% ee in 87% yield and alcohol 2117
with 69% ee in 83% yield, respectively. All of the substi-
tutions of rac-14, rac-16, rac-18, and rac-20 were highly
regioselective (P98%).
2.3. Synthesis of a prostaglandin building block
As a final example, the substitution of the meso-config-
ured biscarbonate 26 was studied (Scheme 7).
Treatment of 26 with 4 mol % of Pd(0)/6 in CH2Cl2/
H2O at 0 °C and a concentration of 0.1 M of the sub-
strate for 48 h afforded alcohol 27 with 96% ee in
87% yield. At room temperature, the ee-value of 27 fell
to 53%. Interestingly, the same reaction of 26 at a con-
centration of 1 M gave 27 with 94% ee in 17% yield
and carbonate 2921 with 66% ee in 67% yield. Carbonate
29 is most likely formed by a competing Pd/6-catalyzed
intra-molecular substitution of the hydrogen carbonate
28.
The synthetic utility of alcohol 27 is demonstrated by its
conversion to ketone 32 (Scheme 8), the enantiomer of
which is a key starting material in the asymmetric
synthesis of prostaglandins.22 Silyl protection of the
2.2. Symmetrical substrates
The cyclic allylic alcohols 2318 and 2519 (Scheme 6) are
valuable starting materials for the synthesis of chiral li-
gands and biologically active compounds. Therefore the
substitutions of the acetate rac-22 and carbonate rac-24
were studied.
We had previously observed that the Pd-catalyzed reac-
tion of the carbonate derived from alcohol rac-23 with
water in CH2Cl2 afforded 23 with only 43% ee in 91%
yield.7a The carbonate of rac-23 shows a strong memory
effect in Pd-catalyzed allylic substitution in the presence
of 6, that is, both enantiomers not only react with a dif-
ferent rate with the chiral catalyst but also with a differ-
ent enantioselectivity with the nucleophile.12,20 Most
importantly, the catalyst Pd(0)/6 also causes a partial
racemication of the slower reacting enantiomer of the
carbonate. This suggested the use of the less reactive
acetate rac-22. Treatment of rac-22 with 4 mol % of
Pd(0)/6 and 1.4 equiv of KHCO3 in CH2Cl2/H2O at
room temperature for 18 h afforded alcohol 23 with
Scheme 7.
Scheme 6.
Scheme 8.

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H.-J. Gais et al. / Tetrahedron Letters 46 (2005) 6279–6283
asymmetric synthesis of a number of synthetically inter-
esting unsymmetrical and symmetrical allylic alcohols.
The high enantioselectivity observed with some of the
unsymmetrical racemic carbonates points to the opera-
tion of an efficient dynamic kinetic resolution featuring
either an interconversion of the intermediate diastereo-
meric p-allyl-Pd complexes and/or a racemization of
the substrate, which are faster than the highly selective
substitution of the more reactive p-allyl-Pd complex.28
Experiments with the unsaturated bisphosphane 33
showed it to have a similar selectivity and activity in
Pd-catalyzed allylic substitution as its saturated analog
6.
Acknowledgments
Financial support of this work by the Deutsche
Forschungsgemeinschaft (SFB 380) is gratefully
acknowledged.
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26. Representative experimental procedure. A Schlenk flask
was successively charged with argon, Pd2dba3/CHCl3
(104 mg, 0.10 mmol), 6 (138 mg, 0.20 mmol) and degassed
CH2Cl2 (45 mL). The solution was stirred at room
temperature for 15 min and then degassed water (5 mL)
and carbonate 26 (1.08 g, 5 mmol) were added. After
the mixture was stirred at 4 °C for 48 h, it was poured in
hexane/EtOAc, 1:1 (100 mL). The mixture was filtered
through silica gel and the filtrate was dried (MgSO4) and
concentrated in vacuo. Purification of the residue by
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ded alcohol 27 (687 mg, 87%) with 96% ee (GC, Hydro-
21
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