Directed regio- and stereoselective hydroformylation of mono- and 1,3-disubstituted allylic alcohols: A catalytic approach to the anti-aldol-retron

Article abstract of DOI:10.1039/b311378g

Regioselective and diastereoselective hydroformylation of mono- and 1,3-disubstituted allylic alcohol o-DPPB esters is described. The products represent synthetically important anti-aldol retrons.

Full text of DOI:10.1039/b311378g

Directed regio- and stereoselective hydroformylation of mono- and
1,3-disubstituted allylic alcohols: a catalytic approach to the
anti-aldol-retron†
Bernhard Breit,* Peter Demel and Antje Gebert
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104
Freiburg, Germany. E-mail: bernhard.breit@organik.chemie.uni-freiburg.de; Fax: 0049-761-2038715;
Tel: 0049-761-2036051
Received (in Cambridge, UK) 18th September 2003, Accepted 24th October 2003
First published as an Advance Article on the web 11th November 2003
Table 1 Dependence of chemo-, regio- and diastereoselectivity of the o-
DPPB-directed hydroformylation of allylic ester 5 (R = Bn) on reaction
conditions
Regioselective and diastereoselective hydroformylation of
mono- and 1,3-disubstituted allylic alcohol o-DPPB esters is
described. The products represent synthetically important anti-
aldol retrons.
[Rh]a
Entry (mol%) bar
pCO/H2
/
Conv.b,c
T/°C Time (%)
dr (6)b
8b (%) rsb (6 : 7) (anti : syn)
Hydroformylation of alkenes belongs to the most important
industrially applied processes relying on homogenous catalysis.1
However, control of stereochemistry in the course of this reaction
is still a challenge.2 We3 and others4 recently introduced a solution
to this problem which employs substrate bound catalyst-directing
groups. For instance, with the ortho-diphenylphosphanylbenzoate
function (o-DPPB) as the catalyst-directing group we were able to
achieve efficient acyclic stereocontrol upon hydroformylation of
1,2-disubstituted allylic alcohol derivatives 1 to give the syn-
aldehydes 2.5 These are interesting building blocks for polyketide
synthesis.6 However, to become a synthetically flexible method a
similar approach to an anti-stereochemical relation between
controlling and newly formed stereogenic center was certainly in
demand.
1
2
3
4
5
6
7
0.7
1.2
1.2
2.0
1.8
2.0
2.0
20
20
30
30
40
40
40
30 13 d 83
5
7
< 2
< 2
< 2
10
87 : 13 89 : 11
90 : 10 93 : 7
90 : 10 98 : 2
89 : 11 94 : 6
90 : 10 98 : 2
89 : 11 90 : 10
90 : 10 98 : 2
30
30
7 d 90
4 d 89
30 47 h 92
30 44 h 90
40 46 h 90
20 48 h 88
< 2
a [Rh] = [Rh(CO)2acac]/1.67 P(OPh)3. b Determined from NMR analysis
of the crude reaction product. c Chemoselectivity towards aldehyde
formation was 100% in all cases.
resulted in a significantly reduced diastereoselectivity (entry 6) and
gave a significant amount of the undesired elimination product 8.
Hence, best results were achieved employing 1.8 mol% catalyst
loading, 40 bar syngas and 30 °C in toluene for about 44 h (Table
1, entry 5). These conditions allowed a 90% conversion of o-DPPB
ester 5 to furnish anti-aldehyde 6 in a regioselectivity (6 : 7) of 90
: 10 and a diastereomer ratio (anti-6 : syn-6) of 98 : 2.
We herein report on the first regio- and diastereoselective
hydroformylation of 1,3-disubstituted allylic alcohol derivatives 3
(RA = Me) with the aid of the catalyst-directing o-DPPB group.
Extension of this methodology towards hydroformylation of mono-
substituted allylic alcohols 3 (RA = H) is also described.
With these optimized conditions in hand we looked at the
dependence of the selectivity parameters as a function of the nature
of the substituent R at the controlling stereogenic center. Thus,
excellent diastereoselectivity was obtained for primary alkyl
substituents (Table 2, entries 1, 2, 4). Somewhat reduced diaster-
eoselectivities were noted for secondary alkyl substituents (entries
5, 6), whereas regioselectivity stays in most cases in the order of 9
: 1. However, for an isopropyl-substituted derivative the best
regioselectivity (98 : 2, entry 5) was observed.
In order to learn about the influence of double bond geometry on
the regio- and stereochemical outcome of the title reaction we
studied hydroformylation of cis-configured allylic-o-DPPB ester 5
(R = Bn). Surprisingly, chemo-, regio- and diastereoselectivity
were significantly lower compared to the trans-alkenic system 5
(see Table 2, entries 2 and 3).
In the course of the hydroformylation of an allylic alcohol
derivative 3 two selectivity issues appear, regio- and diaster-
eoselectivity, which have to be controlled simultanously.
We were pleased to find that hydroformylation of allylic o-DPPB
ester 5 (R = Bn) proceeded smoothly at 30 °C and 20 bar syngas
pressure with a rhodium catalyst loading of 0.7 mol% to give the
anti-aldehyde 6 as the major product in good regio- and
diastereoselectivity‡ (Table 1, entry 1). However, the reaction rate
was too low. Increasing the catalyst loading to 1.2 mol% reduced
the reaction time to 7 d (entry 2). Further improvement was
achieved when the pressure was increased to 30 and finally 40 bars
(entries 3–5). However, going to higher reaction temperatures
Interestingly, when monosubstituted allylic o-DPPB esters were
used a similar regio- and stereodirecting effect of the catalyst-
directing o-DPPB group was observed (Scheme 1, Table 3). Thus,
regioselectivities up to 86 : 14 (10 : 11) and diastereoselectivities‡
up to 95 : 5 (anti-10 : syn-10) were found (Table 3) with formation
† Electronic supplementary information (ESI) available: experimental. See
http://www.rsc.org/suppdata/cc/b3/b311378g/
114
C h e m . C o m m u n . , 2 0 0 4 , 1 1 4 – 1 1 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

View Article Online
Table 2 Dependence of chemo-, regio- and diastereoselectivity of the o-
DPPB-directed hydroformylation of allylic esters 5 on substrate structure
Table 3 Regio- and diastereoselectivity for o-DPPB-directed hydro-
formylation of mono-substituted allylic esters 9
Conv.a,b
(%)
dr (6)a
Conv.a,b
(%)
dr (10)a
12a (%) rsa (10 : 11) (anti : syn)
Entry Major product
1
8a (%) rsa (6 : 7) (anti : syn)
Entry Major product
1
> 97
5
64 : 36
91 : 9
90
90
3
91 : 9
95 : 5
2
3
90
90
3
8
86 : 14
83 : 17
95 : 5
2
< 2
39
5
90 : 10
61 : 39
92 : 8
98 : 2
58 : 42
92 : 8
3
4
from cis-5 (R = Bn) 40
86 : 14
90
91
95
4
92
19
84 : 16
88 : 12
a See footnotes a, b in Table 2. b See footnotes a, b in Table 2.
5
6
3
7
98 : 2
87 : 13
91 : 9
Notes and references
90 : 10
‡ The anti-stereochemical relation of 6 (R = Bn) and 10 (R = i-Pr) could
be determined upon chemical transformation into the benzylidene acetals 13
and 14, respectively, employing the following reaction sequence: i LiAlH4,
ether, 0 °C; ii PhCH(OMe)2, TsOH cat., CH2Cl2, rt. Inspection of coupling
constants as well as NOESY data allowed assignment of relative
configuration.
a Determined from NMR analysis of the crude reaction product. b Chemose-
lectivity towards aldehyde formation was 100% in all cases.
1 C. D. Frohning and C. W. Kohlpaintner, in Applied Homogeneous
Catalysis with Organometallic Compounds, ed. B. Cornils and W. A.
Herrmann, Wiley-VCH, Weinheim, 2000, ch. 2.1.
2 B. Breit and W. Seiche, Synthesis, 2001, 1.
3 B. Breit, Chem. Eur. J., 2000, 6, 1519.
4 I. J. Krauss, C. C.-Y. Wang and J. L. Leighton, J. Am. Chem. Soc., 2001,
123, 11514; R. W. Jackson, P. Perlmutter and E. E. Tasdelen, J. Chem.
Soc., Chem. Commun., 1990, 763; S. D. Burke and J. E. Cobb,
Tetrahedron Lett., 1986, 27, 4237.
5 B. Breit, G. Heckmann and S. K. Zahn, Chem. Eur. J., 2003, 9, 425; B.
Breit, Liebigs Ann., 1997, 1841; B. Breit, Angew. Chem., 1996, 108,
3021; B. Breit, Angew. Chem., Int. Ed. Engl., 1996, 35, 2835.
6 B. Breit and S. K. Zahn, J. Org. Chem., 2001, 66, 4870; B. Breit, M.
Dauber and K. Harms, Chem. Eur. J., 1999, 5, 1819.
7 E. M. Carreira, Aldol Reaction: Methodology and Stereochemistry in
Modern Carbonyl Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000,
ch. 8; M. Braun, J. S. McCallum and L. S. Liebeskind, in Methods of
Organic Chemistry (Houben-Weyl) – Stereoselective Synthesis, E 21, ed.
G. Helmchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Thieme,
Stuttgart, 1996, pp. 1603–1735.
8 D. Hoppe, W. R. Roush and E. J. Thomas, in Methods of Organic
Chemistry (Houben-Weyl) – Stereoselective Synthesis, E 21, ed. G.
Helmchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Thieme,
Stuttgart, 1996, ch. 1.3.3; S. R. Chemler and W. R. Roush, Recent
Applications of the Allylation Reaction to the Synthesis of Natural
Products in Modern Carbonyl Chemistry, ed. J. Otera, Wiley-VCH,
Weinheim, 2000, ch. 11.
Scheme 1 Conditions: (i) 1.8 mol% [Rh(CO)2acac], 3 mol% P(OPh)3, H2/
CO (1 : 1) 40 bar, toluene, 30 °C, 46 h.
of the anti-aldol retron 10 as the major product. Interestingly,
aldehyde 10 represents a potentially valuable building block for the
synthesis of polypropionates.
In conclusion, o-DPPB-directed regio- and diastereoselective
hydroformylation of 1,3-disubstituted and mono-substituted allylic
o-DPPB esters 3 could be achieved. This methodology gives access
to the anti-aldol retron which is difficult to reach through aldol
chemistry directly. Thus, directed hydroformylation may become a
synthetically attractive alternative to established aldol7 or allylme-
tal8 chemistry for the construction of anti-aldol retron type
products.
We thank DFG, the Fonds of the Chemical Industry and the
Krupp Foundation (Krupp Award for young university teachers to
BB) for financial support.
C h e m . C o m m u n . , 2 0 0 4 , 1 1 4 – 1 1 5
115