Simple, stable, and versatile double-allylation reagents for the stereoselective preparation of skeletally diverse compounds

Article abstract of DOI:10.1021/ja068985t

A new and efficient class of double-allylation reagents, α-trimethylsilylmethyl allylboronate 1 and the crotylboronates 12, is reported. These stable bimetallicreagents are prepared easily in enantiomerically pure form and add under BF₃ catalysis onto a wide range of aldehydes to afford a direct access to hydroxyl-functionalized allylic silanes in very high E/Z selectivity and excellent enantioselectivity (up to 98% ee). The useful hydroxyl-functionalized allylsilane intermediates can be exploited in chemodivergent syntheses of various compound classes such as acyclic propionate units, polysubstituted furans, vinylcyclopropanes, and larger carbocycles. Copyright

Full text of DOI:10.1021/ja068985t

Published on Web 02/22/2007
Simple, Stable, and Versatile Double-Allylation Reagents for the
Stereoselective Preparation of Skeletally Diverse Compounds
Feng Peng and Dennis G. Hall*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada
Received December 15, 2006; E-mail: dennis.hall@ualberta.ca
Multifunctional reagents that display chemodivergent reactivity
are of great interest for the preparation of novel organic compounds
using diversity-oriented and target-oriented synthesis. There are still
very few multifunctional reagents that provide high diastereo- and
enantiocontrol in a variety of bimolecular and multicomponent reac-
tions, and that are stable, safe, and easy to prepare. In this respect, a
few examples were reported of chiral double-allylation reagents of
type I1 and type II2 based on boron and silicon (Figure 1). Addition
of such reagents onto a carbonyl substrate unveils an intermediate
that features a second allylmetal unit. Even beyond the need for
providing high stereocontrol, there are major chemoselectivity issues
in the design of double-allylation reagents. Indeed, the second allyl-
metal intermediate could compete with the initial reagent and react
indiscriminately with the electrophile to give mixtures of products.
There is no general approach to the preparation and use of
nonracemic R-functionalized reagents of type III.3 Here, we describe
the first optically active R-trialkylsilylmethyl allylboronates of type
III, and we report that their chemodivergent reactivity can be
controlled with ease to generate a broad range of useful and diverse
products such as propionate units, polysubstituted furans, vinylcy-
clopropanes, and larger carbocycles.
Figure 1. General types of bimetallic double-allylation reagents.
Scheme 1. One-Step Preparation of Optically Active Reagent 1
Table 1. Scope of Aldehyde in Additions with Reagent 1a
entry
R1
product
yield (%)b
E:Zc
ee (%)d
In our design of a reagent of type III, we anticipated that boron
and silicon could be judiciously positioned to react independently
with a variety of electrophiles. We first targeted R-trialkylsilyl-
methyl allylboronate reagents such as 1 (Scheme 1). Their allylic
boron unit should add chemoselectively to a first electrophile, such
as an aldehyde, without interference from the allylsilane of the
addition product. Indeed, additions of 3-substituted allylic trialkyl-
silanes to carbonyl compounds require activation from strong Lewis
acids at relatively high temperatures.4 Furthermore, the resulting
allylic silanes are known to display a broad reactivity that would
confer a wide applicability to reagent 1.5 A straightforward method
for the preparation of optically pure 1 was achieved using a simple
Matteson homologation of pinanedioxy ethyleneboronic ester,6
followed by in situ addition of trimethylsilylmethyl-MgBr (Scheme
1). This “one-pot” preparation provided a 70% yield of reagent 1,
which is robust enough for chromatographic purification and long-
term storage. It is noteworthy that pinanediol is available in both
enantiomeric forms at a reasonable price.
We found that reagent 1 adds onto aldehydes under uncatalyzed
conditions to give the expected homoallylic alcohols, however, with a
disappointingly low E/Z selectivity.7 In contrast, the low-temperature
Lewis acid-catalyzed allylboration manifold8 provided the products 3
in very high E/Z selectivity and excellent enantioselectivities (Table
1).7 Since most products are obtained in over 95% ee and R-sub-
stituted allylic boronates are known to transfer chirality with near
perfection,9 the optical purity of reagent 1 is inferred to be >98%.
The outstanding E selectivity is of crucial importance because the Z
isomer of 3 is epimeric at the carbinol9 and would require a sepa-
ration in the event of a lower selectivity. This issue is avoided with
the Lewis acid-promoted conditions, and remarkably, no double-
1
2
3
4
5
6
7
8
Ph(CH2)2
n-C7H15
i-Pr
BnOCH2
Ph
(E)-PhCHdCH
(E)-MeCHdCH
(n-C5H11)CC
3a
3b
3c
3d
3e
3f
77
70
63
70
72
75
81
85
>30:1
>30:1
>30:1
>25:1
>30:1
>30:1
>30:1
>30:1
95
98
96
91
95
79
96
95
3g
3h
a Time: 12 h. Typical scale: 0.2-1.0 mmol at 0.2 M. See Supporting
Information for more details. b Isolated yields. c Measured by 1H NMR
analysis of crude products. d Measured by chiral HPLC of free alcohol,
except entries 2, 3, 7, and 8, where an isocyanate derivative was employed.
allylation products from further reaction of the allylic silane 3 were
observed. A wide range of aliphatic and unsaturated aldehydes are
suitable substrates. As depicted in transition structure model 2, the
enantiofacial selectivity is controlled by the configuration of the
reagent’s R-carbon center and the preference for a pseudo-equatorial
orientation of the substituent. The influence of the pinanedioxy unit
is likely negligible.8d The high degree of E/Z selectivity can be
tentatively explained by a late transition state10 involving coordina-
tion of the Lewis acid to a boronate oxygen.11
This new preparation of intermediates 3 is direct and more E/Z
selective compared to previous methods, which involve a cross-
metathesis of allylTMS on terminal homoallylic alcohols.12 The
potential versatility of reagent 1 is linked to the rich chemistry of
allylic silanes 3.5 For example, a condensation with aldehydes
afforded the all-cis trisubstituted furans 5-7 in very high diastereo-
and enantioselectivity (eq 1). The diastereoselectivity is explained
by the pseudo-diequatorial arrangement of R1 and R2 in transition
state model 4.13 Remarkably, the unprecedented use of ketones in
9
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10.1021/ja068985t CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
this reaction provides 1,1,2,4-tetrasubstituted furans in high yields
and acceptable diastereoselectivities (eq 2). Preliminary results also
indicate that a sequential one-pot three-component reaction between
1 and two aldehydes is possible.14
allylboronate 1 and the crotylboronates 12. These stable bimetallic
reagents add onto a wide range of aldehydes to afford a direct access
to hydroxyl-functionalized allylic silanes in very high E/Z selectivity
and excellent enantioselectivity. The use of the Lewis acid-catalyzed
allylboration manifold was key to the overall selectivity of this
process. Through the hydroxyl-functionalized allylsilane products,
reagents 1 and 12 can be exploited in chemodivergent syntheses
of various compound classes such as propionate units, polysubsti-
tuted furans, vinylcyclopropanes, and larger carbocycles. Other
transformations of allylic silanes such as oxidations5b and Pd-
catalyzed reactions16 can be envisaged. Thus, reagents 1 and 12
are expected to find multiple applications in natural product
synthesis and diversity-oriented synthesis.
Transformation of the hydroxyl group of products 3 into a triflate
triggers, upon warming, the formation of vinylcyclopropanes in high
enantio- and diastereoselectivity (eq 3).12 These vinylcyclopropanes
are highly valued synthetic intermediates.15
Acknowledgment. This work was funded by the Natural
Sciences and Engineering Research Council (NSERC) of Canada,
and the University of Alberta. F.P. thanks the Alberta Ingenuity
Foundation for a Graduate Scholarship. We thank Eric Pelletier
for help with HPLC analyses, and Dr. Robert McDonald for the
X-ray crystallographic analysis of compound 20.14
Supporting Information Available: Full experimental details, a
proof of absolute stereochemistry (on compound 18), additional
examples, and NMR spectral reproductions for new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
The Z and E crotyl reagents 12 were prepared in high yields
from the corresponding 2-propenylboronic esters.14 Their addition
onto aldehydes afforded the syn propionate products 13-15 and
anti diastereomers 16-18 in high yields and high selectivity (eqs
4 and 5). These adducts undergo the same reactions as allylsilanes
3 to form the corresponding methylated furans and cyclopropanes.14
References
(1) For examples, see: (a) Roush, W. R.; Grover, P. T. Tetrahedron Lett.
1990, 31, 7567-7570. (b) Barrett, A. G. M.; Malecha, J. W. J. Org. Chem.
1991, 56, 5243-5245. (c) Roush, W. R.; Grover, P. T. Tetrahedron 1992,
48, 1981-1998. (d) Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62,
1112-1124. (e) Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C.
Tetrahedron Lett. 2000, 41, 9413-9417. (f) Flamme, E. M.; Roush, W.
R. J. Am. Chem. Soc. 2002, 124, 13644-13645.
(2) Barrett, A. G. M.; Braddock, D. C.; de Koning, P. D.; White, A. J. P.;
Williams, D. J. J. Org. Chem. 2000, 65, 375-380.
(3) For racemic Si/Si reagents of type III, see: (a) Smitrovich, J. H.; Woerpel,
K. A. Synthesis 2002, 2778-2785. (b) Sarkar, T. K.; Haque, S. A.;
Basak, A. Angew. Chem., Int. Ed. 2004, 43, 1417-1419. For two ex-
amples of optically pure reagents, which were prepared in several steps,
see: (c) Fleming, I.; Ghosh, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
2733-2738. (d) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675-
678.
(4) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry;
Otera,J.,Ed.;Wiley-VCH: Weinheim,Germany,2000;Chapter10,pp299-402.
(5) (a) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. (b)
Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063-2192.
(6) Matteson, D. S. Tetrahedron 1998, 54, 10555-10606.
(7) The uncatalyzed reaction at 25 °C gives a ca. 3:1 ratio favoring the Z
isomer. The use of stoichiometric BF3 was necessary for a high E/Z ratio.
(8) (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586-
11587. (b) Ishiyama, T.; Ahiko, T.-a.; Miyaura, N. J. Am. Chem. Soc.
2002, 124, 12414-12415. (c) Lachance, H.; Lu, X.; Gravel, M.; Hall, D.
G. J. Am. Chem. Soc. 2003, 125, 10160-10161. (d) Gravel, M.; Lachance,
H.; Lu, X.; Hall, D. G. Synthesis 2004, 1290-1302.
The use of dicarbonyl substrates can provide several opportunities
for accessing carbocycles and other ring systems. For example,
reagents 1 and (Z)-12 add onto ketoaldehydes to give the oxabicyclic
products 19 and 20 via a double-allylation cascade (eqs 6 and 7).
(9) (a) Hoffmann, R. W. Pure Appl. Chem. 1988, 60, 123-130. (b) Hoffmann,
R. W.; Neil, G.; Schlapbach, A. Pure Appl. Chem. 1990, 62, 1993-1998.
(10) Carosi, L.; Lachance, H.; Hall, D. G. Tetrahedron Lett. 2005, 46, 8981-
8985.
(11) Rauniyar, V.; Hall, D. G. J. Am. Chem. Soc. 2004, 126, 4518-4519.
(12) Taylor, R. E.; Engelhardt, F. C.; Schmitt, M. J.; Yuan, H. J. Am. Chem.
Soc. 2001, 123, 2964-2969.
(13) (a) Mohr, P. Tetrahedron Lett. 1993, 34, 6251-6254. (b) Cassidy, J. H.;
Marsden, S. P.; Stemp, G. Synlett 1997, 1411-1413. (c) Meyer, C.; Cossy,
J. Tetrahedron Lett. 1997, 38, 7861-7864.
(14) See Supporting Information for details and additional examples.
(15) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151-1196.
(16) Macsa´ri, I.; Szabo´, K. Tetrahedron Lett. 2000, 41, 1119-1122.
In summary, we have disclosed a new family of simple and
efficient double-allylation reagents: the R-trimethylsilylmethyl
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