Catalytic enantioselective and catalyst-controlled diastereofacial- selective additions of allyl- and crotylboronates to aldehydes using chiral Bronsted acids

Article abstract of DOI:10.1002/anie.200504432

(Chemical Equation Presented) Towards the ideal: A chiral diol-SnCl ₄ complex is applied to the allylboration of aldehydes (see scheme). This approach highlights the use of chiral Bronsted acid catalysis in the development of an ideal method for the allylation of aldehydes which would display high diastereo- and enantioselectivity, wide substrate scope, and high practicality (ease of use, low cost, and low environmental impact).

Full text of DOI:10.1002/anie.200504432

Communications
aldehyde substrate), high levels of diastereo- and enantiose-
lectivity, and high practicality (ease of use, low cost, non-
toxicity, and low environmental impact).[1] Very importantly,
the ideal enantioselective allylation methodology would
circumvent the use of a chiral auxiliary through a simple
and efficient chiral catalyst.[2] The recent discovery of Lewis
and Brønsted acid catalyzed allylboration manifolds[3] has
opened doors towards an ideal methodology for the allylation
of carbonyl compounds. Indeed, pinacol allylboronates are
air- and water-stable nontoxic reagents whose additions to
aldehydes are characterized by very high levels of chemo-,
regio-, and diastereoselectivity. Efforts by us and others[3b] to
develop catalytic enantioselective additions with chiral Lewis
acids have led only to low levels of enantioselectivity in model
allylborations of aldehydes. Herein, following our recent
report of Brønsted acid catalyzed allylborations,[3e] we
demonstrate that the use of the Yamamoto chiral diol–SnCl4
complexes[4] (Scheme 1) provides
a significant advance
towards a general catalytic enantioselective allylboration
process. The current conditions are particularly advantageous
in promoting efficient diastereofacial control in additions to
a-chiral aldehydes.
Allylation
DOI: 10.1002/anie.200504432
Catalytic Enantioselective and Catalyst-
Controlled Diastereofacial-Selective Additions of
Allyl- and Crotylboronates to Aldehydes Using
Chiral Brønsted Acids**
Scheme 1. Left: diol–SnCl4 chiral Brønsted acid complex 1.[4] Right:
Proposed transition state in the Lewis acid (LA) catalyzed allylbor-
ation.[5]
Mechanistic studies of the Lewis acid catalyzed allylbor-
ation point to a cyclic bimolecular transition state with
boronate activation through coordination of an oxygen atom
of the hindered pinacolate to the metal center (Scheme 1).[5]
In this perspective, the use of a smaller activator, a proton,
seemed ideal and prompted us to investigate a number of
chiral Brønsted acid catalysts.[6] Among several systems tested
for the model reaction between hydrocinnamaldehyde and
pinacol allylboronate at À788C, the concept of “Lewis acid
assisted Brønsted acidity” with diol–SnCl4 complexes, devel-
oped by Yamamoto and co-workers,[4] was found to be the
most promising (Scheme 2).
As shown in Table 1, basic 1,2-diphenyl-1,2-ethanediol
(1a) provided product 4a with 37% ee (entry 1). Further
optimization of the diol, catalyst stoichiometry, and additives
led to the current optimal conditions shown in entry 12 with
commercially available (R,R)-(+)-1,2-di(1-naphthyl)-1,2-
ethanediol (1j). No other diol derivatives, including electroni-
cally modulated diaryl glycols (1e,f and 1i) and various
mono-O-alkylated diols (1b,c), led to higher enantioselectiv-
ities.[7] In all cases, the ee values were slightly higher in
anhydrous toluene than in dichloromethane. Interestingly,
SnCl4 alone promotes an allylboration at a comparable rate,
although in a non-enantioselective fashion. Thus, the use of a
slight excess of diol was found to be desirable (compare
Vivek Rauniyar and Dennis G. Hall*
Despite the extensive efforts of numerous research groups
over the course of more than two decades, there is still no
methodology for the allylation of aldehydes that possesses all
of the following attributes: mildness and chemoselectivity,
substrate generality (for both the allyl–metal reagent and
[*] V. Rauniyar, Prof. D. G. Hall
Department of Chemistry
Gunning-Lemieux Chemistry Centre
University of Alberta
Edmonton, Alberta, T6G2G2 (Canada)
Fax: (+1)780-492-8231
E-mail: dennis.hall@ualberta.ca
[**] Acknowledgment for financial support is given to the Natural
Sciences and Engineering Research Council (NSERC) of Canada
(Discovery Grant to D.G.H.), the Donors of the American Chemical
Society PetroleumResearch Funds (PRF-AC Grant to D.G.H.), and
the University of Alberta. V.R. thanks the Alberta Ingenuity
Foundation for a Graduate Scholarship. The authors are grateful to
Glen Bigamand Mark Miskolzie for help in the variable-temperature
NMR studies.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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Chemie
Table 2: Enantioselective additions of allyl- and crotylboronates.[a]
Scheme 2. Chiral R,R diols evaluated in the enantioselective allylbor-
ation catalyzed by diol–SnCl4 complexes.
Entry Aldehyde (R)
Boronate Product Yield [%][b] e.r.[c]
Table 1: Optimization of the diol–SnCl4 catalyst system.[a]
1
2
3
2a PhCH2CH2
2b CH3(CH2)8
2c C6H11
3
3
3
3
3
3
3
5
5
7
7
4a
4b
4c
4d
4e
4 f
4g
6a
6b
8a
8b
85
76
90
90
99
72
99
99
70
87
70
89:11
90:10
85:15
83:17
55:45
60:40
56:44
86:14
86:14
70:30
73:27
4
5
2d TBDPSO(CH2)2
2e Ph
=
6
2 f PhCH CH
7
8
9
10
11
2g CH3(CH2)4CC
2a PhCH2CH2
2b CH3(CH2)8
2a PhCH2CH2
2b CH3(CH2)8
Entry
Diol [mol%]
SnCl4 [mol%]
Additive
ee [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a (11)
1b (11)
1c (11)
1c (10)
1d (11)
1e (11)
1 f (11)
1g (11)
1h (11)
1i (11)
1j (11)
1j (11)
1j (11)
1j (11)
(10)
(10)
(10)
(20)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
Na2CO3
none
37
34
62
0
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
none
[a] Reaction conditions: all entries were performed with aldehyde
(0.25 mmol), allylboronate (0.275 mmol), 1j (0.0275 mmol), SnCl4
(0.025 mmol), Na2CO3 (0.05 mmol), and 4-Š molecular sieves (50 mg)
in toluene (1 mL) at À788C for 12 h (entries 1–7) or 24 h (entries 8–11).
[b] The yields are for the isolated product and are an average of two runs.
[c] All the e.r. values were measured by chiral HPLC (Chiralcel OD),
except for entries 3, 7, 9, and 11, which were measured through the
formation of Mosher esters and 19F NMR spectroscopic analysis.[7]
TBDPS=tert-butyldiphenylsilyl.
38
34
45
69
33
74
70
78
75
74
Na2CO3
Ag2CO3
K2CO3
[a] Conditions: all reactions were performed with aldehyde 2a
(0.25 mmol), allylboronate 3 (0.275 mmol), R,R diol 1 (0.0275 mmol),
SnCl4 (0.025 mmol), Na2CO3 (0.05 mmol), and 4-Š molecular sieves
(50 mg) in toluene (1 mL) at À788C for 12 h. [b] The absolute
configuration was determined by comparison with known compounds;[7]
all ee values were measured through the formation of Mosher esters and
19F NMR spectroscopic analysis.[7]
modest selectivities (entries 5–7), the enantiomeric ratio in
allylations of aliphatic aldehydes rose to 90:10 (80% ee;
entry 2). The e.r. values of prototypic crotylborations
(entries 8–11) were slightly lower than those obtained in the
simple allylborations, with trans-crotyl reagent 5 giving higher
selectivities. The diastereoselectivities of the crotylations are
very high (> 98:2 d.r.) and consistent with the corresponding
uncatalyzed allylborations.
entries 3 and 4). Because of worries that adventitious HCl
(e.g., residual HCl in commercial SnCl4) could lead to an
erosion of the stereoselectivity, mildly basic additives were
tested as precautionary HCl scavengers (entries 11–14). The
use of Na2CO3, insoluble in toluene, afforded the highest
enantioselectivity.[8] Other allylboronic esters, such as those
made from 1,2-cyclohexanediol, 1,2-cyclopentanediol, and
tetraphenylethanediol, provided much lower enantioselectiv-
ities, even with the optimal diol 1j (results not shown[7]).
The substrate scope of the catalytic enantioselective
allylborations was studied with a panel of model aldehydes
under the optimal conditions of Table 1[7] (the results are
summarized in Table 2). In contrast with several other
reported catalytic allylation systems,[1] aliphatic aldehydes
give higher enantioselectivities in the current allylboration
process. Whereas aromatic and unsaturated aldehydes gave
Uncatalyzed additions of pinacol allylboronates are
known to proceed very slowly at À788C. Nonetheless, we
carried out control experiments with hydrocinnamaldehyde
(2a), which confirmed the lack of a background reaction
(namely, < 2% conversion) in the absence of the diol–SnCl4
catalyst. The addition of allylboronate 3 to aldehyde 2a in the
presence of 100 mol% of [SnCl4(1j)] led only to a modest
improvement, from 78 (10 mol% [SnCl4(1j)]) to 83% ee.
These observations suggest that in the case of aliphatic
aldehydes the current level of enantioselectivity is not limited
by a competitive racemic background reaction, thus superior
diols could possibly be found. Satisfactorily, the current
conditions were found to be effective for the diastereocon-
trolled additions of allyl- and crotylboronates to chiral a-
methyl aldehyde 9, thus providing the very useful propionate
units of 10 and 11 and dipropionate “triads” of types 12 and 13
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Communications
[Eqs. (1) and (2)]. There has been huge interest in the
effect of the catalyst. These observations are consistent with a
passive role in which the basic additive Na2CO3 simply acts as
a scavenger of adventitious HCl, which is likely a strong but
non-enantioselective activator of this reaction.
This novel chiral Brønsted acid catalyzed enantioselective
allylation system constitutes the most efficient catalytic
enantioselective allylboration reported thus far. It represents
a significant advance that demonstrates the great potential of
chiral Brønsted acid catalysis towards the development of an
ideal methodology for the allylation of carbonyl compounds.
The current diol–SnCl4 catalyst system is readily applicable to
catalyst-controlled double diastereoselective allylations to
access, with improved selectivities, poly-
construction of these units for applications in the total
synthesis of bioactive polypropionate natural products.[9]
Current methods, however, require chiral allylation reagents
to effect a high diastereofacial selective addition (namely,
double diastereoselection).[10] Herein, we have demonstrated
that diol–SnCl4 catalysis of allylations and cis-crotylations of
chiral aldehydes can be successfully employed with conven-
ient, stable achiral pinacolate esters. The catalyst was found to
exert a strong influence on the diastereofacial selectivity. In
both the allylation [Eq. (1)] and cis-crotylation with 9
[Eq. (2)], the [SnCl4(1j)] catalyst system improved the
propionate units of the type found in a
large number of bioactive natural prod-
ucts.
Received: December 13, 2005
Published online: March 9, 2006
Keywords: allylation · asymmetric
.
synthesis · Brønsted acids ·
enantioselective catalysis · stereoselectivity
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N. Miyaura, J. Am. Chem. Soc. 2002, 124, 12414 – 12415; c) H.
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[4] a) K. Ishihara, M. Kaneeda, H. Yamamoto, J. Am. Chem. Soc.
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intrinsic selectivity preference of the SnCl4-catalyzed reac-
tions in the matched combination, and even improved the
selectivity of the disfavored diastereomer when using the
antipode of diol 1j. For example, selectivity in favor of the
anti–syn unit 12 was improved from a modest 2:1ratio to 19:1
using [SnCl4{(R,R)-1j}] [Eq. (2)]. For reasons not yet under-
stood, the trans crotylations with 5 were less successful, thus
giving low conversions, even after 24 h. The [SnCl4(1j)]-
catalyzed additions of 3 and 7, however, are particularly
impressive considering that pinacol allyl- and crotylboronates
react very slowly and unselectively in the absence of a
catalyst.[10] Combined with the commercial availability of diol
1j, this new system is operationally simple and could find
immediate use in the diastereoselective construction of
several types of propionate units found in bioactive natural
products.
The unusual conditions of this allylation system using an
insoluble basic additive (Na2CO3) warrant a brief mechanistic
discussion. We believe that catalysis is due to Brønsted acid
activation and not through a Lewis acid activation mecha-
nism, which could possibly occur by the base-promoted
formation of tin alkoxides.[11] Indeed, structural studies of the
[SnCl4(1a)] and [SnCl4(1j)] complexes by variable temper-
ature (VT) NMR spectroscopic analysis reveal the same
species at À788C with or without added Na2CO3.[7] This
tin(iv) complex does show the presence of activated hydroxy
protons and, according to 119Sn NMR shift data, is unambig-
uously hexacoordinated. The enantioselectivities in the
absence of Na2CO3 tend to be lower and irreproducible. A
soluble base, such as Et3N, however, shuts down the activating
[5] V. Rauniyar, D. G. Hall, J. Am. Chem. Soc. 2004, 126, 4518 –
4519.
[6] a) P. M. Pihko, Angew. Chem. 2004, 116, 2110 – 2113; Angew.
Chem. Int. Ed. 2004, 43, 2062 – 2064; b) C. Bolm, T. Rantanen, I.
Schiffers, L. Zani, Angew. Chem. 2005, 117, 1788 – 1793; Angew.
Chem. Int. Ed. 2005, 44, 1758 – 1763.
[7] See the Supporting Information for the full experimental details
and spectroscopic data.
[8] The use of several other additives, such as Ag(SbF6), AgBF4,
Cs2CO3, NaHCO3, phenol, 2,6-dimethylphenol, and 2,6-diphe-
nylphenol, was attempted but provided a lower selectivity.
[9] I. Paterson, Pure Appl. Chem. 1992, 64, 1821 – 1830.
[10] W. R. Roush, A. D. Palkowitz, M. A. Palmer, J. Org. Chem.
1987, 52, 316 – 318.
[11] F. Iwasaki, T. Maki, W. Nakashima, O. Onomura, Y. Matsumura,
Org. Lett. 1999, 1, 969 – 972.
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