Highly selective reduction of acyclic β-alkoxy ketones to protected syn-1,3-diols

Article abstract of DOI:10.1021/ol048801k

(Chemical Equation Presented) The conversion of 1-(2-methoxyethoxy)ethyl- protected β-hydroxy ketones to syn-1,3-ethylidene acetals is effected by Et₃SiH and SnCl₄. This reaction is proposed to proceed via a cyclic oxocarbenium ion i

Full text of DOI:10.1021/ol048801k

ORGANIC
LETTERS
2
004
Vol. 6, No. 18
143-3145
Highly Selective Reduction of Acyclic
â-Alkoxy Ketones to Protected
syn-1,3-Diols
3
Aaron J. Cullen and Tarek Sammakia*
Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309-0215
sammakia@colorado.edu
Received June 23, 2004
ABSTRACT
3 4
The conversion of 1-(2-methoxyethoxy)ethyl-protected â-hydroxy ketones to syn-1,3-ethylidene acetals is effected by Et SiH and SnCl . This
reaction is proposed to proceed via a cyclic oxocarbenium ion intermediate and provides the products in yields that range from 69 to 94%
and with diastereoselectivities that are >200:1.
Some time ago, we described an asymmetric ionic Diels-
the acetal in a compound such as 6 would provide acyclic
oxocarbenium ion 7, which would undergo intramolecular
attack by the ketone to provide the cyclic oxocarbenium ion
8. Reduction of 8 by a reducing agent that is compatible
with the reaction conditions should proceed via axial delivery
Alder reaction that proceeds by way of a cyclic oxocarbe-
1
nium ion (Scheme 1). In this reaction, treatment of 1 with
4
HBF induces ionization of the acetal to generate the acyclic
oxocarbenium ion 2. This compound then undergoes in-
5
tramolecular attack by the proximal carbonyl to provide the
of hydride, and provide the all-syn-ethylidene acetal 9.
In our initial investigations, we studied the ethoxyethyl-
2
cyclic oxocarbenium ion 3, which then undergoes an ionic
Diels-Alder reaction with excellent diastereoselection due
to the structural rigidity of 3. We sought to expand this
method to include the stereoselective synthesis of 1,3-diols.
Extended 1,3-polyol units are found in many biologically
active oxo polyene macrolides, and for the construction of
protected ketone 10, which was prepared by aldol addition
Scheme 1. Asymmetric Diels-Alder Reaction via Cyclic
Oxocarbenium Ion
3
such polyol chains, we viewed the reduction of cyclic
oxocarbenium ions derived from â-alkoxy ketones as a
4
concise means of accessing protected 1,3-diol units. In this
Letter, we describe the implementation of this strategy.
In analogy with our Diels-Alder studies, we wished to
study the reaction sequence shown in Scheme 2. We
envisioned that Lewis or protic acid-catalyzed ionization of
(
1) Sammakia, T.; Berliner, M. A. J. Org. Chem. 1995, 60, 6652.
(2) For selected examples of chiral oxocarbenium ions in synthesis, see:
(
(
a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976.
b) Molander, G. A.; Cameron, K. O. J. Org. Chem. 1993, 58, 5931. (c)
Hashimoto, Y.; Saigo, K.; Machida, S.; Hasegawa, M. Tetrahedron Lett.
990, 31, 5625. (d) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel,
K. A. J. Am. Chem. Soc. 1999, 121, 12208.
1
1
0.1021/ol048801k CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/04/2004

Scheme 2. Proposed Reduction via Cyclic Oxocarbenium Ion
Scheme 5. Directed Ionization
6
of acetone to hydrocinnamaldehyde as shown in Scheme
3
3. We examined the reduction of this compound using Et -
SiH and a variety of Lewis acids in numerous solvents and
This simple modification proved fruitful. Conversion of
â-hydroxy ketone 18 to the 1-(2-methoxyethoxy)ethyl-
protected ketone 19 was accomplished in good yield by
Scheme 3. Initial Studies
8
treatment with 2-methoxyethyl vinyl ether and PPTS in
dichloromethane at room temperature. Treatment of a dichlo-
romethane solution of 19 with triethylsilane (1.05 equiv) and
tin(IV) chloride (1.0 equiv) at -78 °C for 5 min, followed
by warming to -25 °C for 90 min, provided the desired all-
syn-ethylidene acetal 20 in 90% yield and in >200:1
diastereoselectivity (Scheme 6).
Scheme 6. Reduction via Cyclic Oxocarbenium Ion
at different temperatures, and while we were able to observe
the desired acetal 11, the best yield we could consistently
obtain was about 55%. The reaction typically produced two
side products, 12, the product of hydrolysis of the acetal,
and 13, the product of elimination of the â-alkoxy group.
The generation of 12 likely stems from complexation of the
Lewis acid to the internal oxygen of the acetal (14, Scheme
4), and we, therefore, sought to direct complexation to the
We have examined the scope and utility of this reaction
as shown in Table 1. Steric and electronic modifications are
well tolerated R to the ketone, affording the all-syn product
with >200:1 selectivity and in excellent yield (entries 1-3
and 5). Reduction of t-butyl ketone-derived substrate 25,
although highly selective, suffered from diminished yields
Scheme 4. Undesired Pathway
(
69%, entry 4) due to significant amounts of elimination
(3) Reviews: (a) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021. (b)
Schneider, C. Angew. Chem., Int. Ed. 1998, 37, 1375. (c) Oishi, T.; Nakata,
T. Synthesis 1990, 635. Recent polyol synthesis strategies: (d) Paterson,
I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187. (e) Dreher, S. D.;
Leighton, J. L. J. Am. Chem. Soc. 2001, 123, 341. (f) Smith, A. B.; Pitram,
S. M. Org. Lett. 1999, 1, 2001. (g) Sinz, C. J.; Rychnovsky, S. D. Angew.
Chem., Int. Ed. 2001, 40, 3224. (h) Burova, S. A.; McDonald, F. E. J. Am.
Chem. Soc. 2002, 124, 8188.
desired oxygen of the acetal. Our strategy was to introduce
a coordinating heteroatom in the ethyl group of the acetal
and to then use a Lewis acid capable of chelation such that
binding to the desired oxygen of the acetal is preferred (16,
(4) For related allylation reactions, see: Rychnovsky, S. D.; Skalitzky,
D. J. Synlett 1995, 555. Boons, G.-J.; Eveson, R.; Smith, S.; Stauch, T.
Synlett 1996, 536. Rychnovsky, S. D.; Frysman, O.; Khire, U. R.
Tetrahedron Lett. 1999, 40, 41.
1
7, Scheme 5).7
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Org. Lett., Vol. 6, No. 18, 2004

Table 1. Selective Reduction of Acyclic
-(2-Methoxyethoxy)ethyl-Protected â-Hydroxy Ketonesa,b
1
Figure 1. Proposed model accounting for the observed all-syn
stereochemistry.
tion of the proximal ketone in preference to the distal one
(entry 8). Unfortunately, attempted reduction of R,â-unsatur-
ated ketone 29 provided a complex mixture of products under
all conditions examined (entry 6).
The stereochemical outcome of this reaction can be
rationalized by a model in which the reduction proceeds via
a half-chair conformation wherein the substituents occupy
pseudoequatorial positions (35, Figure 1). Stereoelectroni-
5
cally preferred axial delivery of hydride to the oxocarbenium
ion carbon would provide the syn-1,3-diol 9. This model is
analogous to that for the chelation-controlled reduction of
9
,10
â-alkoxy ketones.
In summary, we have described a direct and highly
selective synthesis of protected syn-1,3-diols from the
corresponding protected â-hydroxy ketones by way of a
cyclic oxocarbenium ion. Additional studies of the use of
oxocarbenium ions in synthesis are ongoing.
Acknowledgment. We wish to thank Dr. Mark Mitton-
Fry for insightful discussions and early experimental work
on this project and Dr. Richard Shoemaker for assistance in
obtaining NOE spectra. This work was supported by the
National Institutes of Health (GM48498) and Array Bio-
pharma. NMR instrumentation used in this work was
supported in part by the National Science Foundation CRIF
program (CHE-0131003).
Supporting Information Available: Characterization
data for all products, synthesis of 2-methoxyethyl vinyl ether,
and representative procedures for the reduction. This material
is available free of charge via the Internet at http://pubs.acs.org.
a
All starting ketones were prepared by a route analogous to that shown
b
for the synthesis of compound 10 (Scheme 3). For a representative
procedure, see Supporting Information. Stereochemistry determined by H
NOE. Determined by H NMR spectroscopy of the crude reaction mixture.
c
1
OL048801K
d
1
e
f
g
Isolated yield. Ketone readily rearranges to the cyclic dioxane. Elimi-
(6) For a general aldol procedure, see: Martin, V. A.; Murray, D. H.;
Pratt, N. E.; Zhao, Y.-b.; Albizati, K. F. J. Am. Chem. Soc. 1990, 112,
6965.
nation observed (∼15%). Complex mixture. i See Supporting Information
h
for a modified reduction procedure.
(
7) Itoh and Overman have reported the use of (2-methoxyethoxy)methyl
(
MEM) ether units as selective leaving groups in the Lewis acid-promoted
ionization of mixed acetals. See: (a) Nishiyama, H.; Itoh, K. J. Org. Chem.
1982, 47, 2496. (b) Castaneda, A.; Kucera, D. J.; Overman, L. E. J. Org.
Chem. 1989, 54, 5695. (c) Blumenkopf, T. A.; Bratz, M.; Castaneda, A.;
Look, G. C.; Overman, L. E.; Rodriguez, D.; Thompson, A. S. J. Am. Chem.
Soc. 1990, 112, 4386.
(
∼15%) of the â-alkoxy group. Ketones possessing additional
oxygen functionality, such as 30 and 32, are potential polyol
building blocks, and also furnished the desired products in
good yield and with high selectivities (entries 7 and 8).
Interestingly, unsymmetrical diketone 32 underwent reduc-
(8) For the synthesis of this compound, see Supporting Information.
(9) (a) Narasaka, K.; Pai, F. C. Tetrahedron 1984, 40, 2233. (b) Chen,
K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. Tetrahedron
Lett. 1987, 28, 155.
(
5) For a discussion, see: Deslongchamp, P. Stereoelectronic Effects in
(10) Greeves, N. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: New York, 1991; Vol. 8, pp 1-24.
Organic Chemistry; Pergamon Press: Oxford, 1983; Chapter 6.
Org. Lett., Vol. 6, No. 18, 2004
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