Diastereoselective construction of anti-4,5-disubstituted-1,3-dioxolanes via a bismuth-mediated two-component hemiacetal oxa-conjugate addition of γ-hydroxy-α,β-unsaturated ketones with paraformaldehyde

Article abstract of DOI:10.1039/c5cc01949d

The bismuth-mediated two-component hemiacetal oxa-conjugate addition of γ-hydroxy-α,β-unsaturated ketones with paraformaldehyde affords anti-4,5-disubstituted-1,3-dioxolanes in an efficient and stereoselective manner. The reaction provides a practical, inexpensive and atom-economical approach to these types of heterocycles, which represent useful intermediates for target-directed synthesis and precursors to syn-1,2-diols.

Full text of DOI:10.1039/c5cc01949d

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Diastereoselective construction of anti-4,5-
disubstituted-1,3-dioxolanes via a bismuth-mediated
two-component hemiacetal oxa-conjugate addition
of c-hydroxy-a,b-unsaturated ketones with
paraformaldehyde†
Cite this:DOI: 10.1039/c5cc01949d
Received 7th March 2015,
Accepted 21st May 2015
DOI: 10.1039/c5cc01949d
Aleksandr Grisin,a Samuel Oliver,b Michael D. Ganton,b John Bacsab and
P. Andrew Evans*a
www.rsc.org/chemcomm
The bismuth-mediated two-component hemiacetal oxa-conjugate
addition of c-hydroxy-a,b-unsaturated ketones with paraformaldehyde
affords anti-4,5-disubstituted-1,3-dioxolanes in an efficient and
stereoselective manner. The reaction provides a practical, inexpensive
and atom-economical approach to these types of heterocycles, which
represent useful intermediates for target-directed synthesis and
precursors to syn-1,2-diols.
Chiral 1,2-diols are extremely ubiquitous structural motifs found in
a plethora of biologically active natural products, pharmaceuticals,1
chiral ligands and chiral auxiliaries.2 As a result, powerful synthetic
methodologies for accessing this moiety with high levels of enantio-
and diastereocontrol3 are continually being reported.4 Furthermore,
the direct preparation of semi- and fully-protected 1,2-diols is of
great importance since it alleviates the necessity for additional
Scheme 1 Bismuth-mediated two-component hemiacetal oxa-conjugate
addition for the construction of syn-1,3-dioxanes and anti-1,3-dioxolanes.
functional group manipulations, which is critical for increasing advantage of this approach over the more classical strategy is
efficiency in multi-step target-directed synthesis. the ability to directly prepare the protected 1,2-diol in a single
In a program directed towards the examination of bismuth- operation from an allylic alcohol derivative, which is particu-
mediated hetero-conjugation reactions,5–7 we recently reported larly attractive given the ubiquity of protected syn-1,2-diols in
a highly stereoselective construction of syn-1,3-dioxanes via a two- important synthetic intermediates.1,2
component hemiacetal oxa-conjugate addition promoted by
Herein, we now describe the diastereoselective construction of
bismuth(III) nitrate pentahydrate, which provides a Brønsted acid anti-4,5-disubstituted-1,3-dioxolanes 2 via the bismuth-mediated
surrogate (Scheme 1A).8,9 Although the application of this strategy hemiacetal oxa-conjugate addition reaction of g-hydroxy-a,b-
to g-hydroxy-a,b-unsaturated ketones would provide the corres- unsaturated ketones 1 with paraformaldehyde in a practical,
ponding 1,3-dioxolanes, the use of alkyl aldehydes as coupling inexpensive and atom-economical manner (Scheme 1B). Further-
components results in mixtures of diastereoisomers whereas more, the dioxolane 2 can be readily reduced and deprotected
symmetrical ketones are unreactive in this type of process.10 To to afford the corresponding syn,syn- or syn,anti-1,2,4-triols in a
this end, we envisioned that paraformaldehyde would circumvent stereoselective manner, which represent important motifs in an
the formation of diastereosiomers and provide the necessary array of biologically active natural products.11
reactivity to afford the requisite 1,3-dioxolane. An additional
Table 1 summarizes the optimization of the bismuth-mediated
two-component hemiacetal oxa-conjugate addition reaction of the
g-hydroxy-a,b-unsaturated methyl ketone 1a with paraformaldehyde
to afford the anti-4,5-disubstituted-1,3-dioxolane 2a (Table 1).
Preliminary studies focused on the effect of the bismuth salts,
which have a dramatic impact on the outcome of this transfor-
mation.7–9 Interestingly, bismuth(III) chloride and bromide
promote the desired hemiacetal oxa-conjugate addition to
a Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, ON,
K7L 3N6, Canada. E-mail: Andrew.Evans@chem.queensu.ca
b Department of Chemistry, University of Liverpool, Crown Street, Liverpool,
L69 7ZD, UK
† Electronic supplementary information (ESI) available: Experimental procedures,
spectral data and copies of spectra. CCDC 1050168 (5). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c5cc01949d
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Table 1 Optimization of the two-component bismuth-mediated hemiacetal oxa-conjugate addition g-hydroxy-a,b-unsaturated methyl ketone 1a with
paraformaldehyde (R = Ph(CH2)2)a
Yieldb (%)
Ratioc (2a/3a) : 4
dsc 2a : 3a
BiX3
Entry
Mol%
Conc. (M)
1
2
3
4
5
6
7
BiCl3
BiBr3
BiI3
10
10
10
10
10
5
0.1
0.1
0.1
0.1
0.1
0.1
0.25
18
13
—
16
78
75
83
1 : 1
1 : 4
—
Z19 : 1
Z19 : 1
Z19 : 1
Z19 : 1
6 : 1
5 : 1
—
6 : 1
13 : 1
13 : 1
13 : 1
Bi(OTf)3
Bi(NO3)3Á5H2O
Bi(NO3)3Á5H2O
Bi(NO3)3Á5H2O
10
a
All reaction were carried out on a 0.5 mmol scale using paraformaldehyde (5 equiv.) in reagent grade dichloromethane at room temperature for
ca. 36 hours. Isolated yield of 2a/3a. The ratio of products and diastereoisomers were determined by 500 MHz 1H NMR on the crude reaction mixtures.
b
c
afford 2a in poor yield and with modest diastereocontrol, in a Table 2 Scope of the diastereoselective two-component hemiacetal
oxa-conjugate addition of substituted g-hydroxy-a,b-unsaturated methyl
process that is further complicated by the competitive dehy-
drative cyclization of 1a to afford the 2,5-disubstituted furan 4
ketones 1 with paraformaldehydea,b,c,d
(entries 1 and 2).12 In contrast, bismuth(III) iodide is ineffective
for either process (entry 3), whereas bismuth(III) triflate favors
the chemoselective formation of the 1,3-dioxolanes 2a/3a, albeit
with similar efficiency and selectivity (entry 4 vs. entries 1
and 2). Further studies demonstrated that bismuth(III) nitrate
pentahydrate provides the optimal catalyst for this process,
both in terms of the efficiency and selectivity (entry 5). Attempts to
reduce the amount of catalyst led to a reduction in the yield, while
maintaining similar chemo- and diastereocontrol (entry 6). Finally,
increasing the concentration afforded the anti-4,5-substituted-1,3-
dioxolane 2a in an improved 83% yield with similar selectivity
(entry 7). Overall, this process provides an operationally simple
procedure for the diastereoselective preparation of anti-4,5-
disubstituted-1,3-dioxolanes using environmentally benign
reagents in an atom-economical process, which does not
require the exclusion of air and moisture. The relative stereo-
chemistry of the 1,3-dioxolane 2a was unambiguously deter-
mined by the X-ray analysis of the dinitrophenylhydrazone
derivative 5, which clearly indicates anti-configuration of the
alkyl substituents on the five-membered heterocycle (Fig. 1).‡§
Table 2 outlines the application of the optimized reaction
conditions (Table 1, entry 7)¶ to an array of g-hydroxy-a,b-
unsaturated methyl ketones 1. Interestingly, the allylic substituent
impacts both the level of stereocontrol and overall efficiency of
this process. For example, simple straight chain alkyl groups
provide modest selectivity (entries 1–3), whereas a-branched
a
All reaction were carried out on a 0.5 mmol scale using paraformalde-
hyde (5 equiv.) in reagent grade dichloromethane at room temperature
b
c
for ca. 36–72 hours. Isolated yield of 2/3. Ratios of diastereoisomers
were determined by 500 MHz 1H NMR on the crude reaction mixtures.
d
Trace amounts of the 2,5-disubstituted furan products 4 (5%) were
also detected.
alkyl derivatives afford improved diastereocontrol (entries 4–6).
Moreover, b- and g-branching also provides synthetically useful
levels of diastereocontrol (entries 7 and 8). In addition, protected
hydroxymethyl groups serve as useful substrates, in which the
relative size of the protecting group directly impacts the level of
stereocontrol (entry 9 vs. 10). The ability to utilize primary silyl
ethers as protecting groups is particularly important, given that
they have the propensity to undergo protodesilylation. Finally,
aryl substituents also proceed with excellent diastereocontrol,
Fig. 1 ORTEP structure of hydrazone
disubstituted 1,3-dioxolane 2a.
5 derived from the anti-4,5-
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which further serves to demonstrate the scope of this approach reaction that provides anti-4,5-disubstituted 1,3-dioxolanes using
(entries 11 and 12). Overall, this method provides a very mild and operationally simple conditions. For instance, the trans-
convenient, inexpensive and atom economical approach to formation can be conducted without exclusion of air and moisture
the construction of anti-4,5-disubstituted-1,3-dioxolanes with using 10 mol% catalyst loading, with broad substrate scope and
good to excellent levels of stereoinduction.
functional group compatibility. In addition, the products can be
Fig. 2 details a plausible explanation for the origin of stereo- subjected to stereodivergent reduction and deprotected under
control in this type of cyclization reaction. We envision that the mild conditions to convert the 1,3-dioxolane to the syn,syn- and
addition occurs though the kinetic cyclization13 of the protonated syn,anti-1,2,4-triols. We envision that this approach will find its
a,b-unsaturated ketone, which adopts an s-trans conformation,14 niche in the area of target-directed synthesis, especially for the
to form an allyl type cation15 I that is irreversibly trapped in the construction of complex polyketide natural products.
pseudo-equatorial orientation to afford the favoured diastereo-
We sincerely thank the National Sciences and Engineering
isomer.16 The minor diastereoisomer can either result from the Research Council (NSERC) for a Discovery Grant and Queen’s
cyclization of the opposite rotamer II or the transition state with University for generous financial support. NSERC is also thanked
the pseudo-axial orientation of the allylic substituent III, which for supporting a Canada Research Chair (PAE). Additionally,
are presumably disfavored due to the presence of a 1,3-steric we acknowledge the Royal Society for a Wolfson Research Merit
interaction with the allylic substituent (R).
Award (PAE).
In order to illustrate the utility of this approach, we inves-
tigated the divergent reduction of the methyl ketone and
removal of the 1,3-dioxolane to provide 1,2,4-triols found in a
plethora of natural products (Scheme 2).11 Treatment of 2j with
lithium aluminum hydride in the presence of lithium iodide
in diethyl ether at –100 1C provided the Cram-chelate alcohol 6
in 95% yield with Z19 : 1 diastereocontrol (Scheme 2A).17
Alternatively, the samarium diiodide-mediated reduction of 2j
furnished the anti-product 7 in 73% yield with modest stereo-
control (ds = 7 : 1).18 To further showcase the benefits of this
approach, the 1,3-dioxolane was cleaved to liberate the triol
(Scheme 2B). Reduction of the ketone 2a (ds = 13 : 1), followed
by acetal cleavage using BF3ÁEt2O and 1,3-propanedithiol
afforded the triol 8 in 96% overall yield (two steps).19,20
In conclusion, we have developed a diastereoselective bismuth-
mediated two-component hemiacetal oxa-conjugate addition
Notes and references
‡ Crystal structure data for 5: C20H22N4O6, M = 414.41, colorless needle,
0.5 Â 0.07 Â 0.03 mm3, monoclinic, space group P21/n (No. 14),
a = 18.938(6) Å, b = 5.2580(17) Å, c = 20.517(7) Å, b = 108.760(5)1,
V = 1934.4(11) Å3, Z = 4, T = 100(2) K, Dcalc = 1.423 g cmÀ3, MoKa
radiation, l = 0.71073 Å, T = 100(2) K, 2ymax = 50.71, 9510 reflections
collected, 3543 unique (Rint = 0.0600). Final GooF = 1.022, R1 = 0.0510,
wR2 = 0.1117, R indices based on 2158 reflections with I 4 2s(I) (refinement
on F2), 272 parameters and 114 restraints.
§ Correspondence regarding the X-ray crystallography should be
addressed to: J. Bacsa, Department of Chemistry, Emory University,
Atlanta, GA 30322, USA.
¶ Representative experimental procedure for the diastereoselective
bismuth-mediated two-component hemiacetal oxa-conjugate addition
reaction of g-hydroxy-a,b-unsaturated ketones with paraformaldehyde:
Bismuth(III) nitrate pentahydrate (24 mg, 0.05 mmol, 0.1 equiv.) was
added to a stirred solution of the g-hydroxy-a,b-unsaturated ketone 1a
(102 mg, 0.5 mmol, 1 equiv.) and paraformaldehyde (76 mg, 2.5 mmol,
5 equiv.) in DCM (2 ml) at room temperature. The reaction mixture
was then stirred at this temperature for ca. 36 hours (t.l.c. control),
filtered through a pad of silica gel with diethyl ether and concentrated
in vacuo to afford the crude product. Purification by flash chromato-
graphy (silica gel, 25–30% diethyl ether/petroleum ether gradient)
furnished the dioxolanes 2a/3a (97.2 mg, 83%) as a colorless oil (ds = 13:1
by 500 MHz 1H NMR).
1 (a) J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro and M. R.
Prinsep, Nat. Prod. Rep., 2014, 31, 160; (b) J. W. Blunt, B. R. Copp,
R. A. Keyzers, M. H. G. Munro and M. R. Prinsep, Nat. Prod. Rep., 2013,
30, 237; (c) A. M. S. Mayer, A. D. Rodriguez, O. Taglialatela-Scafati and
N. Fusetani, Mar. Drugs, 2013, 11, 2510.
Fig. 2 Origin of stereocontrol in the oxa-conjugate addition reaction.
2 (a) Chiral Auxiliaries and Ligands in Asymmetric Synthesis, ed.
J. Seyden-Penn, Wiley-VCH, New York, 1995; (b) Privileged Chiral
Ligands and Catalysts, ed. Q.-L. Zhou, Wiley-VCH, Weinheim, 2011.
3 For a recent review of classical 1,2-diol syntheses, see: C. Nativi and
S. Roelens, in Science of Synthesis, ed. J. Clayden, Thieme, Stuttgart,
Germany, 2008, vol. 36, p. 757.
4 For selected novel methods for the formation of 1,2-diols, see:
(a) D. Kim, J. S. Lee, S. B. Kong and H. Han, Angew. Chem., Int.
Ed., 2013, 52, 4203; (b) L. Raffier, G. R. Stanton and P. J. Walsh, Org.
Lett., 2013, 15, 6174; (c) J. K. Park and D. T. McQuade, Angew. Chem.,
Int. Ed., 2012, 51, 2717; (d) P. E. Gormisky and M. C. White, J. Am.
Chem. Soc., 2011, 133, 12584; (e) D. Cartigny, K. Pu¨ntener, T. Ayad,
M. Scalone and V. Ratovelomanana-Vidal, Org. Lett., 2010, 12, 3788;
( f ) E. Vedrenne, O. A. Wallner, M. Vitale, F. Schmidt and V. K. Aggarwal,
Org. Lett., 2009, 11, 165.
5 For recent reviews of bismuth(III)-mediated transformations, see:
(a) J. M. Bothwell, S. W. Krabbe and R. S. Mohan, Chem. Soc. Rev.,
2011, 40, 4649; (b) T. Ollevier, Org. Biomol. Chem., 2013, 11, 2740;
(c) Bismuth-Mediated Organic Reactions, ed. T. Ollevier, Springer-
Verlag, Berlin, 2012.
Scheme 2 Stereodivergent 1,3-reduction and deprotection of 1,3-
dioxolanes 2j and 2a.
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6 For a recent review of the oxa-Michael addition reaction, see: C. F.
H. Murata, I. Ohama, K.-I. Harada, M. Suzuki, T. Ikemoto, T. Shibuya,
T. Haneishi, A. Torikata, Y. Itezono and N. Nakayama, J. Antibiot.,
1995, 48, 850; (e) Bryostatins: K. J. Hale and S. Manaviazar, Chem. –
Asian J., 2010, 5, 704; ( f ) Paenilamicins: S. Mu¨eller, E. Garcia-
¨
Nising and S. Brase, Chem. Soc. Rev., 2012, 41, 988 and pertinent
references cited within.
7 For examples of bismuth-mediated oxa-conjugate addition reactions,
see: (a) P. A. Evans and W. J. Andrews, Tetrahedron Lett., 2005,
46, 5625; (b) P. A. Evans and W. J. Andrews, Angew. Chem., Int. Ed.,
2008, 47, 5426.
¨
Gonzalez, A. Mainz, G. Hertlein, N. C. Heid, E. Moesker, H. van
den Elst, H. S. Overkleeft, E. Genersch and R. D. Su¨essmuth, Angew.
Chem., Int. Ed., 2014, 53, 10821.
8 P. A. Evans, A. Grisin and M. J. Lawler, J. Am. Chem. Soc., 2012, 12 For Brønsted acid-mediated dehydrative cyclisation of g-hydroxy-
134, 2856.
a,b-unsaturated ketones, see: T. J. Donohoe and J. F. Bower, Proc.
Natl. Acad. Sci. U. S. A., 2010, 107, 3373.
9 For a discussion of the mechanism of bismuth-mediated etherifica-
tion reactions and applications in synthesis, see: (a) P. A. Evans and 13 Equilibration of the cis- and trans-4,5-disubstituted-1,3-dioxolanes
D. K. Leahy, J. Am. Chem. Soc., 2003, 125, 8974; (b) P. A. Evans, J. Cui,
S. J. Gharpure and R. J. Hinkle, J. Am. Chem. Soc., 2003, 125, 11456;
(c) P. A. Evans, J. Cui and S. J. Gharpure, Org. Lett., 2003, 5, 3883;
(d) P. A. Evans, J. Cui, S. J. Gharpure, A. Polosukhin and H.-R. Zhang,
J. Am. Chem. Soc., 2003, 125, 14702.
2a/3a (ds = 13 : 1) with catalytic 1,8-diazabicycloundec-7-ene (DBU) at
both room and elevated temperatures (80 1C, PhMe) furnished the
acetals 2a/2b with slightly lower diastereoselectivity (ds = 7.8 : 1),
which implies the initial addition occurs under kinetic control.
14 A. Bienvenu¨e, J. Am. Chem. Soc., 1973, 95, 7345.
10 For enantioselective examples of the organocatalytic oxa-Michael 15 K. N. Houk and R. W. Strozier, J. Am. Chem. Soc., 1973, 95, 4094.
addition reactions using g-hydroxy a,b-unsaturated carbonyl deriva- 16 For similar mechanistic proposal for the intramolecular oxa-conjugate
tives, see: (a) T. Okamura, K. Asano and S. Matsubara, Chem.
Commun., 2012, 48, 5076; (b) K. Asano and S. Matsubara, Org. Lett.,
2012, 14, 1620; (c) N. Yoneda, A. Hotta, K. Asano and S. Matsubara,
Org. Lett., 2014, 16, 6264.
cyclization of a,b-unsaturated ester surrogates for the construction of
tetrahydropyrans, see: H. Fuwa, N. Ichinokawa, K. Noto and M. Sasaki,
J. Org. Chem., 2012, 77, 2588.
17 Y. Mori, M. Kuhara, A. Takeuchi and M. Suzuki, Tetrahedron Lett.,
1988, 29, 5419.
11 For examples of natural products that contain syn,syn- or
syn,anti-1,2,4-triols, see: (a) Mycolactone A/B: S. Fidanze, F. Song, 18 G. E. Keck and C. A. Wager, Org. Lett., 2000, 2, 2307.
M. Szlosek-Pinaud, P. L. C. Small and Y. Kishi, J. Am. Chem. Soc., 19 Although the deprotection of a 1,3-dioxolane is generally quite
2001, 123, 10117; (b) Aflastatin A: H. Ikeda, N. Matsumori, M. Ono,
A. Suzuki, A. Isogai, H. Nagasawa and S. Sakuda, J. Org. Chem., 2000,
challenging, we have developed remarkably mild reaction condi-
tions that make this process very attractive and practical.20
65, 438; (c) Amphotericin B: W. Mechlinski, C. P. Schaffner, P. Ganis 20 Protective Groups in Organic Synthesis, ed. T. W. Greene and P. G. M. Wuts,
and G. Avitabile, Tetrahedron Lett., 1970, 11, 3873; (d) Aculeximycin:
John Wiley & Sons, Inc., Hoboken, New Jersey, 4th edn, 2007, p. 300.
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