Stereoselective synthesis of syn and anti 1,2-hydroxyalkyl moieties by Cu-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1039/c0cc05161f

A stereoselective synthesis of 1,2-hydroxyalkyl moieties is described herein. These valuable building blocks are obtained with complete regiocontrol and excellent stereocontrol both for the syn or the anti products, by choosing the appropriate enantiomer

Full text of DOI:10.1039/c0cc05161f

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COMMUNICATION
Stereoselective synthesis of syn and anti 1,2-hydroxyalkyl moieties by
Cu-catalyzed asymmetric allylic alkylationw
Martın Fananas-Mastral, Bjorn ter Horst, Adriaan J. Minnaard and Ben L. Feringa*
´ ˜
´
Received 24th November 2010, Accepted 1st April 2011
DOI: 10.1039/c0cc05161f
A stereoselective synthesis of 1,2-hydroxyalkyl moieties is
described herein. These valuable building blocks are obtained
with complete regiocontrol and excellent stereocontrol both for
the syn or the anti products, by choosing the appropriate
enantiomer of the ligand in a copper-catalyzed asymmetric
allylic alkylation of d-alkoxy-substituted allyl bromides.
1,2-Hydroxyalkyl moieties are key subunits in a diverse array
of natural products and pharmaceuticals, and their synthesis
has been a prime objective for synthetic organic chemists for
many years.1 A variety of methods has been reported for
the direct and enantioselective assembly of these important
moieties, the aldol reaction being the most important trans-
formation for their construction.2 Furthermore, alternative
strategies such as crotylations,3 allenylations,4 selective
radical processes5 and sequential substitutions6 are of high
importance. Despite their great versatility, most of these
methods need a chiral auxiliary or rely on substrate control
for stereoselectivity. Because of this, the development of
catalytic asymmetric reactions for the synthesis of these sub-
units with the stereochemistry under catalyst control continues
to be highly warranted.
Scheme 2 Preparation and reactivity of allyl bromides 2.
could give rise to the stereoselective formation of 1,2-
hydroxymethyl units.
We first prepared allyl bromides 2 by reacting the corres-
ponding benzoate- and benzyl-protected allyl alcohols 1 with
1,4-dibromo-2-butene in the presence of 10 mol% of the
Hoveyda–Grubbs second generation catalyst. However, the
subsequent copper-catalyzed reaction with MeMgBr only gave
rise to the undesired a-substituted product 3 (Scheme 2).
When alternative protecting groups, such as TBDPS or
MOM, were used no reaction was observed. Taking into
account that the alkoxy substituent may be too bulky,
we decided to use allyl bromide 4 (Scheme 3) which is
easily obtained in three steps from commercially available
1,2:5,6-di-O-isopropylidene-D-mannitol.9,10 In this case the
alkoxy substituent is part of a dioxolane ring which might
reduce the steric problem.
Recently, it has been reported by our group that copper-
catalyzed asymmetric allylic alkylation (AAA) with Grignard
reagents can be achieved with excellent regio- and enantio-
selectivities on C-substituted and ester-substituted allyl
bromides (Scheme 1).7,8 We envisioned that this AAA with
MeMgBr on d-alkoxy-substituted allyl bromides as substrates
To our delight, the reaction with MeMgBr using
CuBrꢀSMe2 and (R,R)-(+)-taniaphos L1 (Fig. 1) as a catalyst
at ꢁ75 1C gave rise to compound anti-5a as the major product
of the reaction together with a small amount of the linear
product 6 (Table 1, entry 1). The use of the other enantiomer
Scheme 1 Asymmetric Cu-catalyzed AAA and hetero-AAA (for the
ligand structure see Fig. 1).
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh
4, 9747 AG, Groningen, The Netherlands. E-mail: b.l.feringa@rug.nl;
Fax: +31 50 363 4296; Tel: +31 50 363 4235
w Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data. See DOI: 10.1039/c0cc05161f
Scheme 3 Cu-catalyzed AAA on 4.
c
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substitution reactions of allylic substrates with organo-
copper(I) reagents. In analogy with the proposed mechanism
by Goering and co-workers for the copper-catalyzed allylic
alkylation of allylic carboxylates with Grignard reagents,12
a
catalytic cycle which involves the formation of a CuIII
s-complex intermediate could be proposed for the mechanism
of the AAA with Grignard reagents catalyzed by Cu–taniaphos.
This CuIII s-complex (see ESIw for further details) would yield
the anti or syn product, depending on the configuration of the
catalyst, via reductive elimination at ꢁ80 1C (Table 1, entries 11
and 12). Upon raising the temperature to ꢁ75 1C (entries 1
and 2), conversion of the s-complex to the p-complex
can occur,11 resulting in a lower regioselectivity (see ESIw).
Fig. 1 Screened ligands.
Table 1 Screening of ligands and conditions with MeMgBr (Scheme 3)a
Entry
L
T/1C anti-5ab (%) syn-5ab (%) 6b (%)
1
(R,R)-(+)-L1 ꢁ75
92
33
0
0
28
0
1
4
8
0
27
0
4
8
39
100
60
34
33
27
40
49
47
0
Table 2 Cu-catalyzed stereoselective synthesis of 1,2-hydroxyalkyl
substrates (Scheme 3, L = L1)a
2
(S,S)-(ꢁ)-L1
ꢁ75
ꢁ75
ꢁ75
ꢁ75
ꢁ75
ꢁ75
ꢁ75
ꢁ75
ꢁ75
3c
4
—
PPh3
d
Entry L1
R
5
antib,c (%) synb,c (%)
39
62
59
73
33
51
49
100
10
5
6
7
8
(R,S)-L2
(S,R)-L2
(R,S)-L3
(S,R)-L3
(R)-L4
1
2
3
(R,R)-(+)-L1 Me
(S,S)-(ꢁ)-L1 Me
(R,R)-(+)-L1 Et
100 (91)
0
9
10
11
12
(S)-L4
(R,R)-(+)-L1 ꢁ80
0
90
(S,S)-(ꢁ)-L1
ꢁ80
0
10
90 (85)
a
Reagents and conditions: MeMgBr (1.5 eq.), CuBrꢀSMe2 (5 mol%), L
b
c
(6 mol%), CH2Cl2, 4 h. Based on GC analysis. 1 eq. CuBrꢀSMe2 +
d
2 eq. MeMgBr. 10 mol%.
100 (89)
0
of this ligand ((S,S)-(ꢁ)-taniaphos L1), under the same
conditions, led to a mismatch situation and afforded an almost
1 : 1 : 1 mixture of both the anti and syn isomers of 5a and the
linear product 6 (entry 2).
4
5
(S,S)-(ꢁ)-L1 Et
12
88 (80)
To investigate the role of the catalyst in this process we
studied a variety of conditions (Table 1).
When the reaction was carried out using a magnesium
cuprate without any ligand (entry 3) we only observed the
formation of the linear product 6. Also the use of PPh3 as the
ligand led preferentially to the formation of the linear product
(entry 4). Various chiral phosphines (Fig. 1) were also tested as
ligands, but in all cases (entries 5–10) lower selectivities were
obtained as those observed for taniaphos (entries 1 and 2).
Remarkably, when the temperature was decreased to ꢁ80 1C,
we observed complete selectivity towards the anti product
using (+)-taniaphos L1 as the ligand (entry 11). After
purification anti-5a was obtained in 91% yield. The use of
the same temperature (ꢁ80 1C) in the reaction with the
(ꢁ)-enantiomer of the ligand (entry 12) led to a more dramatic
change in the product ratio. In this case we could also direct
the reaction towards the syn isomer with high selectivity
(90 : 10). Noteworthily, the small amount of minor isomer
was readily removed by column chromatography to provide
pure syn-5a in 85% yield.
(R,R)-(+)-L1 PhCH2CH2
100 (84)
0
6
(S,S)-(ꢁ)-L1 PhCH2CH2
13
87 (72)
7
8
(R,R)-(+)-L1 n-Hex
(S,S)-(ꢁ)-L1 n-Hex
(R,R)-(+)-L1 c-C5H9
100 (87)
0
11
89 (79)
This dramatic change in the diastereoselectivity of this AAA
of allyl bromide 4 with MeMgBr catalyzed by Cu–taniaphos
can be explained on the basis of recent observations by Bertz,
Ogle and co-workers in the preparation and characterization
of the first examples of both s-allyl and p-allyl CuIII
complexes.11 It has been shown that temperature has a major
influence on the regioselectivity (SN2 or SN20 pathways) in the
9
100 (80)
0
a
Reagents and conditions: 4 (0.5 mmol, 1 eq.), RMgBr (1.5 eq.),
b
CuBrꢀSMe2 (2 mol%), L1 (2.4 mol%), CH2Cl2, ꢁ80 1C, 4 h. Based
c
on GC analysis. Isolated yield in parenthesis.
c
5844 Chem. Commun., 2011, 47, 5843–5845
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The diminished stereoselectivity is attributed to a change of
exclusive catalyst control to competing chiral substrate control.
In addition, the catalyst loading could be reduced to only
2 mol% without deterioration in the selectivity obtained
(Table 2, entries 1 and 2). Using these optimized conditions,
the allylic alkylation of 4 was performed using different
Grignard reagents with high selectivities in all cases
(Table 2). Again, when (+)-taniaphos was used as the ligand,
the anti isomers were obtained selectively (entries 1, 3, 5 and 7).
The (ꢁ)-enantiomer of the ligand was slightly less selective,
but led to the syn product with very high ratios (entries 2, 4, 6
and 8) and in all cases the minor isomer could be readily
removed by column chromatography. An important feature is
that the reaction is readily scalable to 5 mmol with similar
results as shown for entries 4 and 7. Noteworthily, the reaction
also provided the anti isomer with total selectivity when
a cyclic Grignard reagent was used in combination with
(+)-taniaphos (entry 9). However, when (ꢁ)-taniaphos was
used with this Grignard reagent, a strong mismatch effect was
observed and the products were obtained in a 20 : 20 : 60
syn : anti : linear ratio. PhMgBr was also used but in this case
no reaction was observed at ꢁ80 1C and the starting material
was recovered.
additional proof of the versatility of this methodology, we
applied this synthetic route to compound anti-5d and obtained
g-hexyl substituted a,b-unsaturated d-lactone 8b in a comparable
yield (Scheme 4b). These examples show that this new methodo-
logy gives access to cis and trans disubstituted d-lactones
with total stereocontrol and with the possibility of introducing
different alkyl groups at the g-position in a general fashion.
In summary, we have described a stereoselective synthesis of
syn and anti 1,2-hydroxyalkyl structures based on a copper-
catalyzed asymmetric allylic alkylation of d-alkoxy-substituted
allylic bromides with Grignard reagents. The use of a dioxolane-
containing allylic bromide is crucial for the regiochemistry
while the syn–anti stereochemistry of the product can be tuned
using the appropriate enantiomer of the chiral catalyst.
Financial support from The Netherlands Organization for
Scientific Research (NWO-CW) is acknowledged. M.F.-M. is
grateful to the Spanish Ministry of Science and Innovation
(MICINN) for a postdoctoral grant.
Notes and references
1 (a) K.-S. Yeung and I. Paterson, Chem. Rev., 2005, 105, 4237;
(b) B. Schetter and R. Mahrwald, Angew. Chem., Int. Ed., 2006, 45,
7506; (c) J. Li and D. Menche, Synthesis, 2009, 2293.
2 (a) Modern Aldol Reactions, ed. R. Mahrwald, Wiley-VCH,
Weinheim, 2004; (b) I. Paterson, in Asymmetric Synthesis—The
The optically active syn and anti 1,2-hydroxyalkyl moieties 5
obtained this way are versatile chiral building blocks for
natural products. The presence of a double bond13 in their
structure together with the presence of a protected primary
alcohol functionality opens a wide array of possible trans-
formations. An example of the synthetic potential of compounds
5 is shown in Scheme 4. A three-step deprotection–protection
sequence starting with compound syn-5b afforded diolefin 7a
in 80% combined yield. The latter was converted, by a ring-
closing metathesis,14 into g-ethyl substituted a,b-unsaturated
d-lactone 8a in 97% yield (Scheme 4a).
This type of g-ethyl substituted lactones is of great interest
because of its presence in a large number of natural products
that possess important biological activities including pironetin,15
phostalomycins14b,16 and bitungolides.17 This new methodo-
logy represents a catalytic alternative to the chiral boron-
mediated pentenylation14b which proceeds in the same fashion
as the chiral auxiliary-assisted asymmetric crotylation.3 As an
Essentials, ed. M. Christmann and S. Brase, Wiley-VCH,
¨
Weinheim, 2007, pp. 293–298; (c) B. M. Trost and C. S. Brindle,
Chem. Soc. Rev., 2010, 39, 1600.
3 R. W. Hoffmann, in Stereocontrolled Organic Synthesis,
ed. B. M. Trost, Blackwell Scientific Publications, Cambridge,
1994, 259–274.
4 J. A. Marshall, Chem. Rev., 2000, 100, 3163.
5 Y. Guindon, K. Houde, M. Pre
S. R. Landry, B. Daoust, M. Bencheqroun and B. Gue
J. Am. Chem. Soc., 2001, 123, 8496.
´
vost, B. Cardinal-David,
´
rin,
6 (a) S. Hanessian, J. Ma and W. Wang, J. Am. Chem. Soc., 2001,
123, 10200; (b) A. Whitehead, J. P. McParland and P. R. Hanson,
Org. Lett., 2006, 8, 5025.
´
7 (a) F. Lopez, A. W. van Zijl, A. J. Minnaard and B. L. Feringa,
Chem. Commun., 2006, 409; (b) K. Geurts, S. P. Fletcher and
B. L. Feringa, J. Am. Chem. Soc., 2006, 128, 15572.
8 For reviews on Cu-catalalyzed AAA, see: (a) S. Harutyunyan,
T. den Hartog, K. Geurts, A. J. Minnaard and B. L. Feringa,
Chem. Rev., 2008, 108, 2824; (b) A. Alexakis, J. E. Backvall,
N. Krause, O. Pamies and M. Die
2796.
¨
´
guez, Chem. Rev., 2008, 108,
9 (a) J. A. Marshall, J. D. Trometer and D. G. Cleary, Tetrahedron,
1989, 45, 391; (b) A. R. Ellwood, A. J. P. Mortimer, D. A. Tocher
and M. J. Porter, Synlett, 2008, 2199.
10 The (S)-enantiomer of allyl bromide 4 was chosen for our studies
but also the (R)-enantiomer is readily available from L-ascorbic
acid: C. Hubschwerlin, Synthesis, 1986, 962.
11 E. R. Bartholomew, S. H. Bertz, S. Cope, M. Murphy and
C. A. Ogle, J. Am. Chem. Soc., 2008, 130, 11244.
12 C. C. Tseng, S. D. Paisley and H. L. Goering, J. Org. Chem., 1986,
51, 2884.
13 For an example of versatile use of a terminal olefin, see: T. den
´
Hartog, B. Macia, A. J. Minnaard and B. L. Feringa, Adv. Synth.
Catal., 2010, 352, 999.
14 (a) A. Furstner and K. Langemann, J. Am. Chem. Soc., 1997, 119,
¨
9130; (b) S. Shibahara, M. Fujino, Y. Tashiro, K. Takahashi,
J. Ishihara and S. Hatakeyama, Org. Lett., 2008, 10, 2139.
15 S. Kobayashi, K. Tsuchiya, T. Harada, M. Nishide, T. Kurokawa,
T. Nakagawa, N. Shimada and K. Kobayashi, J. Antibiot., 1994,
47, 697.
16 S. Fushimi, S. Nishikawa, A. Shimazu and H. Seto, J. Antibiot.,
1989, 42, 1019.
17 S. Sirirath, J. Tanaka, I. I. Ohtani, T. Ichiba, R. Rachmat, K. Ueda,
T. Usui, H. Osada and T. Higa, J. Nat. Prod., 2002, 65, 1820.
Scheme 4 Reagents and conditions: (a) (i) AcOH, H2O, rt; (ii)
TBDPSCl (1.1 eq.), imidazole (1.1 eq.), DMAP (cat.), DMF, 0 1C to
rt; (iii) acryloyl chloride (1.5 eq.), iPr2EtN (2 eq.), CH2Cl2, 0 1C;
(b) Grubbs 2nd generation (5 mol%), CH2Cl2, 0.01 M, reflux, 12 h.
P = TBDPS.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5843–5845 5845