Diastereoselective construction of syn-1,3-dioxanes via a bismuth-mediated two-component hemiacetal/oxa-conjugate addition reaction

Article abstract of DOI:10.1021/ja208668u

The bismuth-mediated two-component hemiacetal/oxa-conjugate addition of δ-trialkylsilyloxy and δ-hydroxy α,β-unsaturated aldehydes and ketones with alkyl aldehydes provides the syn-1,3-dioxanes in a highly efficient and stereoselective manner. The key advantages of this protocol are its operational simplicity and its ability to directly access electron-withdrawing groups without recourse to oxidation state adjustments.

Full text of DOI:10.1021/ja208668u

Communication
pubs.acs.org/JACS
Diastereoselective Construction of syn-1,3-Dioxanes via a
Bismuth-Mediated Two-Component Hemiacetal/Oxa-Conjugate
Addition Reaction
P. Andrew Evans,*,† Aleksandr Grisin,† and Michael J. Lawler‡
†Department of Chemistry, The University of Liverpool, Crown Street, Liverpool L69 7ZD, United Kingdom
‡Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
S
* Supporting Information
Table 1. Optimization and Aldehyde (R2CHO) Scope for the
ABSTRACT: The bismuth-mediated two-component
hemiacetal/oxa-conjugate addition of δ-trialkylsilyloxy
and δ-hydroxy α,β-unsaturated aldehydes and ketones
with alkyl aldehydes provides the syn-1,3-dioxanes in a
highly efficient and stereoselective manner. The key
advantages of this protocol are its operational simplicity
and its ability to directly access electron-withdrawing
groups without recourse to oxidation state adjustments.
Diastereoselective Two-Component Hemiacetal/
Oxa-Conjugate Addition Reaction [eq 1; R1 = Ph(CH2)2]
a
homoallylic alcohol
rac-1
aldehyde
R2
b
c
entry
P
EWG
yield (%)
ds rac-2/3
1
2
3
H
H
COMe
COMe
CO2Me
COMe
COMe
COMe
COMe
CHO
Me
Ph
Ph
Me
iPr
99
−
−
34
98
90
98
68
33
83
≥19:1
−
−
≥19:1
≥19:1
≥19:1
≥19:1
17:1
H
d
4
H
5
H
he stereoselective construction of syn-1,3-diols remains
6
H
tBu
T
the focus of considerable attention due to the ubiquity of
this motif in pharmacologically important molecules.1−4 In this
context, the base-mediated combination of an aryl aldehyde with
a δ-hydroxy α,β-unsaturated carboxylic acid derivative pro-
vides one of the most direct and convenient methods developed
to date.4−6 Nevertheless, the analogous process with α,β-
unsaturated aldehydes and ketones has not been forthcoming,
despite the fact that this would circumvent the necessity for
oxidation state adjustments.7−9 Additionally, the base-mediated
process is limited to non-enolizable aromatic aldehydes, which
requires multiple additions of the aryl aldehyde and base to
minimize the effect of a competing Cannizarro reaction.6,10 We
envisioned that the acid-catalyzed version of this transformation
would permit α,β-unsaturated aldehydes and ketones to be
employed directly by using more electrophilic aliphatic
aldehydes.11 In a program directed toward the exploration of
bismuth-mediated reactions, we have demonstrated that bismuth-
(III) salts facilitate a number of acid-catalyzed reactions with
unique reactivity and selectivity because of their ability to
modulate the acid concentration and thereby buffer the
reaction.12,13 Herein, we now disclose the diastereoselective
construction of syn-1,3-dioxanes 2 via a two-component hemi-
acetal/oxa-conjugate addition of δ-triorganosilyloxy and δ-hydroxy
α,β-unsaturated aldehydes and ketones 1 with alkyl aldehydes
(eq 1).
7
H
H
8
TES
H
Me
Me
9
CHO
17:1
e
10
TES
CHO
Me
≥19:1
a
All reactions were carried out on a 0.5 mmol reaction scale utilizing
10 mol % bismuth(III) nitrate and the requisite aldehyde (5 equiv) in
b
c
dichloromethane at ambient temperature. Isolated yields. Ratios of
diastereoisomers were determined by 500 MHz H NMR analysis of
the crude reaction mixtures. Reaction was conducted with 20 mol %
nitric acid. 20 equiv.
1
d
e
Treatment of the δ-hydroxy α,β-unsaturated ketone rac-1a
(P = H, EWG = COMe) with acetaldehyde and catalytic Bi-
(NO3)3·5H2O furnished the syn-1,3-dioxane rac-2a in 99%
yield with ≥19:1 diastereoselectivity (entry 1). In contrast, the
corresponding aryl aldehydes failed to react with either the α,β-
unsaturated ketone or ester (entries 2 and 3), which is in full
accord with our hypothesis.11 Interestingly, the analogous process
with nitric acid provided the 1,3-dioxane rac-2a in signi-
ficantly lower yield, again illustrating the superiority of bismuth
salts (entry 4). Further studies demonstrated that the reaction is
applicable to a variety of aliphatic aldehydes (entries 5 and 6),
in which even formaldehyde provided the syn-1,3-dioxane rac-2
(R2 = H) in excellent yield (entry 7). Although the ability to
form the syn-1,3-dioxane rac-2a from α,β-unsaturated methyl
ketones circumvents the necessity to functionalize an ester or
amide, the ability to employ an aldehyde directly would circumvent
unnecessary oxidation state adjustments and thereby dramatically
improve the synthetic utility of this process.7 Treatment of the
Table 1 outlines the development of the bismuth-mediated
two-component hemiacetal/oxa-conjugate addition reaction.
Received: August 16, 2011
Published: February 1, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
δ-triethylsilyloxy α,β-unsaturated aldehyde rac-1k (P = TES,
EWG = CHO) under the optimized reaction conditions furnished
the 1,3-dioxanes rac-2k/3k in 68% yield, favoring the syn
diastereoisomer rac-2k (entry 8). Interestingly, the δ-hydroxy α,β-
unsaturated aldehyde rac-1k (P = H) provided the 1,3-dioxanes
rac-2k/3k in significantly lower yield (entry 9). The marked
difference in the efficiency is presumably the result of the
triorganosilyl ether controlling the concentration of the secondary
alcohol through the rate of protodesilylation.14 Finally, the effi-
ciency and selectivity of this remarkable process was further
improved by increasing the concentration of acetaldehyde to reduce
competitive self-condensation (entry 10).
RK-397 (Figure 1)19−22 using the iterative sequence outlined in
Scheme 1. The enantiomerically enriched homoallylic alcohol
(R)-4 was converted to the δ-triethylsilyloxy α,β-unsaturated
Figure 1. Mapping of syn-1,3-dioxanes 2 onto the polyene macrolide
RK-397 using the bismuth-mediated two-component hemiacetal/oxa-
conjugate reaction.
Table 2. Scope of the Diastereoselective Bismuth-Mediated
a
Oxa-Conjugate Addition Reaction (eq 1; R2 = Me)
homoallylic alcohol rac-1
Scheme 1. Iterative Bismuth-Mediated Two-Component
Hemiacetal/Oxa-Conjugate Reaction to syn-1,3-Dioxanes
yield
b
c
entry
R1
P
EWG
COMe
(%)
ds rac-2/3
1
Ph(CH2)2
PhCH2
H
H
a
b
c
d
e
f
99
97
92
99
92
96
98
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
2
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COMe
CHO
3
Me
H
4
Br(CH2)5
iPr
H
5
H
6
(CH3)2CHCH2
(CH3)2CH(CH2)2
BnOCH2
TBDPSO(CH2)2
Ph
H
7
H
g
h
i
d
8
H
96
95
97
83
64
56
74
72
75
72
72
72
70
9
H
10
11
12
13
14
15
16
17
18
19
20
H
j
Ph(CH2)2
PhCH2
TES
TES
TES
TES
TES
TES
TES
TES
TES
TES
k
l
CHO
Me
CHO
m
n
o
p
q
r
Br(CH2)5
iPr
CHO
CHO
(CH3)2CHCH2
(CH3)2CH(CH2)2
BnOCH2
TBDPSO(CH2)2
Ph
CHO
CHO
CHO
aldehyde 1r in 98% overall yield via cross-metathesis23 with
acrolein using the Hoveyda−Grubbs second-generation catalyst
(HG-II),24 followed by in situ protection of the secondary
alcohol at low temperature to suppress the formation of the
extended triethylsilyl enol ether. Treatment of 1r under the
optimized reaction conditions for the bismuth-mediated two-
component hemiacetal/oxa-conjugate addition furnished the
protected syn-1,3-dioxane 2r in 71% yield with excellent
CHO
s
CHO
t
a
All reactions were carried out on a 0.5 mmol reaction scale utilizing
10 mol % bismuth(III) nitrate in dichloromethane at ambient
b
c
temperature for 16−160 h. Isolated yields. Ratios of diastereo-
isomers were determined by 500 MHz 1H NMR analysis of the crude
reaction mixtures.16,17 95% on a 50 mmol scale.
d
1
diastereocontrol (ds ≥19:1 by H NMR). Enantioselective
Table 2 summarizes the application of the optimized reaction
conditions (Table 1, entries 1 and 10) to a variety of δ-hydroxy
and δ-triethylsilyloxy α,β-unsaturated ketones and aldehydes,
respectively (vide supra). This study probed the effect of various
substituents on the efficiency and selectivity of the process.
For example, linear and branched alkyl derivatives, including
benzyl and triorganosilyl15 protected hydroxyalkyl derivatives,
provided excellent selectivity, albeit the aldehydes were generally
less efficient because of competing side reactions (cf. entries
11−20 vs 1−10). Nevertheless, this work represents a direct
and synthetically useful method for the stereoselective
construction of syn-1,3-dioxanes.16−18 The overall process is
operationally simple since it does not require the exclusion of
air and moisture and can be conducted on a large scale with
similar efficiency (entry 8).
allylation of aldehyde 2r (ds = 98:2 by HPLC), using
Muruoka’s protocol,25 provided the homoallylic alcohol
required to demonstrate the iterative process. Cross-meta-
thesis with methyl vinyl ketone provided α,β-unsaturated
ketone 6 (E/Z ≥19:1 by 1H NMR), which was treated under
conditions analogous to those outlined for the δ-hydroxy α,β-
unsaturated ketones to afford bis-protected syn-1,3-diol 7 in
1
91% yield with excellent diastereocontrol (ds ≥19:1 by H
NMR). The advantage of this approach is the experimental
simplicity coupled with the ability to directly utilize α,β-
unsaturated aldehydes and ketones, which makes this an
extremely attractive approach to syn-1,3-dioxanes.8h
In conclusion, we have developed a highly diastereoselective
bismuth-mediated two-component hemiacetal/oxa-conjugate
addition reaction that provides syn-1,3-dioxanes under ex-
tremely mild conditions. This operationally simple protocol
To highlight the synthetic utility of this process, we elected
to prepare the C18−C28 fragment of the polyene macrolide
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Journal of the American Chemical Society
Communication
Lett. 2007, 48, 4683. (h) Guo, H.; Mortensen, M. S.; O’Doherty, G. A.
Org. Lett. 2008, 10, 3149. (i) Yadav, J. S.; Rajendar, G.; Ganganna, B.;
Srihari, P. Tetrahedron Lett. 2010, 51, 2154.
provides the electron-withdrawing group in the aldehyde/
ketone oxidation state, which alleviates the necessity for redox
adjustments. The synthetic utility of this approach was
highlighted in a five-step synthesis of the C18−C28 fragment
of the polyene macrolide RK-397 in 48% overall yield. Finally,
we envision that this approach will find favor in a number of
synthetic applications that require either the aldehyde or ketone
oxidation state.8,9
(9) For the conversion of syn-1,3-dioxanes containing esters and
amides to the aldehydes, see: (a) Hung, D. T.; Nerenberg, J. B.;
Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054. (b) Hayes, C. J.;
Heathcock, C. H. J. Org. Chem. 1997, 62, 2678. (c) Hayakawa, H.;
Miyashita, M. Tetrahedron Lett. 2000, 41, 707. (d) Hunter, T. J.;
O’Doherty, G. A. Org. Lett. 2001, 3, 2777. (e) Garaas, S. D.; Hunter,
T. J.; O’Doherty, G. A. J. Org. Chem. 2002, 67, 2682. (f) Smith, C. M.;
O’Doherty, G. A. Org. Lett. 2003, 5, 1959. (g) Dineen, T. A.; Roush,
W. R. Org. Lett. 2004, 6, 2043. (h) Chandrasekhar, S.; Shyamsunder,
T.; Prakash, S. J.; Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2006,
47, 47. (i) Vincent, A.; Prunet, J. Synlett 2006, 2269. (j) Krishna, P. R.;
Srinivas, R. Tetrahedron: Asymmetry 2007, 18, 2197. (k) Yadav, J. S.;
Kumar, N. N.; Prasad, A. R. Synthesis 2007, 1175. (l) Chandrasekhar,
S.; Rambabu, C.; Reddy, A. S. Tetrahedron Lett. 2008, 49, 4476. (m) de
Lemos, E.; Poree, F. H.; Bourin, A.; Barbion, J.; Agouridas, E.; Lannon,
M. I.; Commercon, A.; Betzer, J. F.; Pancrazi, A.; Ardisson, J. Chem.
Eur. J. 2008, 14, 11092. (n) Sabitha, G.; Bhaskar, V.; Reddy, S. S. S.;
Yadav, J. S. Tetrahedron 2008, 64, 10207. (o) Yadav, J. S.; Sunitha, V.;
Reddy, B. V. S.; Gyanchander, E. Synthesis 2008, 2933. (p) Dittoo, A.;
Bellosta, V.; Cossy, J. Synlett 2008, 2459. (q) Palimkar, S. S.; Uenishi,
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectral data (including NOE data)
for all new compounds, and a CIF file for rac-2v. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Andrew.Evans@liverpool.ac.uk
■
ACKNOWLEDGMENTS
■
We sincerely thank the National Institutes of Health (GM54623)
for generous financial support. We also thank the Royal Society
for a Wolfson Research Merit Award (P.A.E.). We acknowledge
Jean-Philippe Ebram for some preliminary studies with different
electron-withdrawing groups. We are also grateful to the EPSRC
National Mass Spectrometry Service Centre (Swansea, UK) for
high-resolution mass spectrometry.
(10) Geissman, T. A. Org. React. 1944, 2, 94.
(11) For quantification of the electrophilic reactivity of aldehydes,
see: Appel, R.; Mayr, H. J. Am. Chem. Soc. 2011, 133, 8240.
(12) For selected reviews of bismuth(III)-mediated transformations,
see: (a) Matano, Y.; Ikegami, T. In Organobismuth Chemistry; Suzuki,
H., Matano, Y., Eds.; Elsevier: New York, 2001; Chapter 5, pp 371−440.
(b) Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58,
8373. (c) Roux, C. L.; Dubac, J. Synlett 2002, 181. (d) Gaspard-
Iloughmane, H.; Roux, C. L. Eur. J. Org. Chem. 2004, 2517.
(e) Bothwell, J. M.; Krabbe, S. W.; Mohan, R. S. Chem. Soc. Rev.
2011, 40, 4649.
(13) For a discussion of the mechanism of bismuth-mediated
etherification reactions and applications in synthesis, see: (a) Evans,
P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J. Am. Chem. Soc. 2003, 125,
11456. (b) Evans, P. A.; Cui, J.; Gharpure, S. Org. Lett. 2003, 5, 3883.
(c) Evans, P. A.; Andrews, W. J. Tetrahedron Lett. 2005, 46, 5625.
(d) Evans, P. A.; Andrews, W. J. Angew. Chem., Int. Ed. 2008, 47, 5426.
(14) The oxocarbenium ion intermediate is additionally stabilized by
the triorganosilyl group.13
(15) Although silyl migration/cyclization is a major side reaction in
the base-catalyzed version using the tert-butyldimethylsilyl-protected
hydroxymethyl derivative (R1 = TBSOCH2, EWG = CO2Et), we
observed only a trace amount (≤5%) of triisopropylsilyl migration
(R1 = TIPSOCH2, EWG = COMe, 2u, 96%, ds ≥19:1) with the new
method. For more details, see: Hunter, T. J.; O’Doherty, G. A. Org.
Lett. 2001, 3, 1049.
(16) The stereochemistry of the syn-1,3-dioxanes rac-2a−v was
confirmed using nuclear Overhauser effect (NOE) experiments and
further supported by the X-ray crystal structure of rac-2v (see the
Supporting Information).
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