Diastereoselective additions of nucleophiles to α-acetoxy ethers using the α-(trimethylsilyl)benzyl auxiliary

Article abstract of DOI:10.1021/ol0347904

(Matrix presented) We report the diastereoselective addition of a variety of nucleophiles to α-(trimethylsilyl)benzyl-substituted oxocarbenium ions. The oxocarbenium ions are generated from α-acetoxy ethers, which are easily prepared via reductive acetyla

Full text of DOI:10.1021/ol0347904

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2367-2370
Diastereoselective Additions of
Nucleophiles to r-Acetoxy Ethers Using
the r-(Trimethylsilyl)benzyl Auxiliary
Scott D. Rychnovsky* and Jennifer Cossrow
Department of Chemistry, 516 Rowland Hall, UniVersity of California-IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
Received May 8, 2003
ABSTRACT
We report the diastereoselective addition of a variety of nucleophiles to r-(trimethylsilyl)benzyl-substituted oxocarbenium ions. The oxocarbenium
ions are generated from r-acetoxy ethers, which are easily prepared via reductive acetylation of esters. The r-(trimethylsilyl)benzyl auxiliary
produces good to excellent facial selectivity with a variety of nucleophiles, including silyl enol ethers, silyl ketene acetals, allylsilanes, and
crotylsilanes. The utility of this auxiliary is further demonstrated in a complex ketone aldol coupling reaction.
Oxocarbenium ions are important intermediates in various
reactions, including Prins cyclizations, cation-olefin cy-
clizations, and addition reactions. Efforts to impart high
diastereofacial control in these reactions have led to the
development of a number of chiral auxiliaries.1 We recently
reported the synthesis of a new oxocarbenium ion chiral
auxiliary, R-(trimethylsilyl)benzyl alcohol (4).2 This auxiliary
offers several desirable features, including facile preparation
of both enantiomers, high diastereofacial selectivity in
addition reactions, and direct deprotection or conversion to
a benzyl ether. In a preliminary demonstration of the
auxiliary’s utility, we found that allylations of auxiliary-based
oxocarbenium ions, generated in situ according to Marko’s
protocol, proceeded with high diastereoselectivity (Scheme
1).1h,2 The facial selectivity could be rationalized by Lin-
derman’s model, in which R-silyl oxocarbenium ions adopt
a rigid conformation due to a stereoelectronic effect similar
Scheme 1. Diastereoselective Allylation of an in
Situ-Generated Oxocarbenium Ion
(1) (a) For a review of chiral acetals, see: Alexakis, A.; Mangeney, P.
Tetrahedron: Asymmetry 1990, 1, 477-511. (b) Tietze, L. F.; Dolle, A.;
Schiemann, K. Angew. Chem., Int. Ed. Engl. 1992, 31, 1372-1373. (c)
Tietze, L. F.; Schiemann, K.; Wegner, C. J. Am. Chem. Soc. 1995, 117,
5851-5852. (d) Tietze, L. F.; Schiemann, K.; Wegner, C.; Wulff, C. Chem.
Eur. J. 1996, 2, 1164-1172. (e) Tietze, L. F.; Volkel, L.; Wulff, C.;
Weigand, B.; Bittner, C.; McGrath, P.; Johnson, K.; Schafer, M. Chem.
Eur. J. 2001, 7, 1304-1308. (f) Imwinkelried, R.; Seebach, D. Angew.
Chem., Int. Ed. Engl. 1985, 24, 765-766. (g) Mukaiyama, T.; Ohshima,
M.; Miyoshi, N. Chem. Lett. 1987, 1121-1124. (h) Mekhalfia, A.; Marko,
I. E. Tetrahedron Lett. 1991, 32, 4779-4782. (i) Molander, G. A.; Haar, J.
P. J. Am. Chem. Soc. 1993, 115, 40-49.
(2) Cossrow, J.; Rychnovsky, S. D. Org. Lett. 2002, 4, 147-150.
10.1021/ol0347904 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/05/2003

to the â-silyl effect.3 While Marko’s procedure is operation-
ally convenient, it is limited to nucleophiles with reactivity
sufficiently low to permit the formation of oxocarbenium
ions in situ. We wished to expand the scope of the
R-(trimethylsilyl)benzyl auxiliary by exploring the addition
of a range of nucleophiles to oxocarbenium ion precursors.
To this end, auxiliary-modified R-acetoxy ethers were
prepared by reductive acetylation of esters.4 These stable
oxocarbenium ion precursors were then coupled with a
variety of nucleophiles.
Table 1. Allylation of R-Acetoxy Ether 6
entrya
Lewis acid (equiv)
yield (%)b
drc
1
TMSOTf (0.2)
TMSOTf (1.1)
TMSOTf (0.2)
TfOH (0.2)
87
93
83
97
93
67
76
47:1
44:1
65:1
28:1
13:1
8:1
To investigate the efficacy of auxiliary 4 in directing
various nucleophiles, R-acetoxy ether 6 was selected as the
test substrate (Scheme 2). Both racemic and optically pure
2d
3e
4
5
SnCl4 (1.1)
6
7
BF3‚OEt2 (1.3)
TiCl4 (1.3)
5:1
Scheme 2. Preparation of R-Acetoxy Ether 6a
a With 1.1 equiv of nucleophile used. b Yield of purified product.
c Determined by GC analysis of unpurified product. d Result for (S)-6 in
toluene. e With 2 equiv of 2,6-di-tert-butyl-4-methylpyridine (DBMP) added.
To expand the scope of the auxiliary couplings, we turned
to the investigation of other nucleophiles. The aldol-type
reaction between a silyl enol ether and R-acetoxy ether 6
was explored (Table 2). A Lewis acid screen revealed that
a Reaction conditions: (a) hexanoyl chloride, pyridine, CH2Cl2.
(b) (i) DIBAL-H, CH2Cl2, -78 °C; (ii) pyridine, DMAP, Ac2O.
alcohols 4 were acylated using hexanoyl chloride. Reductive
acetylation of ester 5 generated the R-acetoxy ether 6 in good
yield as a mixture of diastereomers at the acetal center.
Exploratory reactions were conducted with racemic 6, and
several couplings were performed with the optically pure
substrate.
Table 2. Addition of 2-(Trimethylsilyloxy)propene to 6
The first nucleophile systematically investigated was
allyltrimethylsilane. Use of this nucleophile in the in situ
protocol with hexanal afforded adduct 2 in 86% yield with
37:1 diastereoselectivity (Scheme 1). The same product was
accessed by Lewis acid-promoted allylation of R-acetoxy
ether 6 (Table 1). Of the Lewis acids examined, TMSOTf
was found to produce superior diastereoselectivity (entries
1-3). TMSOTf promotion in toluene provided the best
combination of high yield and selectivity (entry 2). However,
use of catalytic TMSOTf and excess 2,6-di-tert-butyl-4-
methylpyridine (DBMP) resulted in the highest selectivity
(65:1), suggesting that the selectivity may be lowered by
adventitious triflic acid (entry 3). Triflic acid alone proved
to be an effective catalyst, resulting in excellent yield and
28:1 selectivity (entry 4). Tin and titanium Lewis acids, as
well as BF3‚OEt2, produced notably inferior selectivities
(entries 5-7). Though allylation of R-acetoxy ether 6 was
highly selective, Marko’s one-pot procedure remains a
comparably efficient and more convenient route to the
desired homoallylic ether.
entrya
Lewis acid (equiv)
yield (%)b
drc
1
2
3d
4e
5
6
7
8
TMSOTf (0.1)
TMSOTf (1.1)
TMSOTf (1.1)
TMSOTf (0.2)
TfOH (0.2)
SnCl4 (1.1)
BF3‚OEt2 (1.1)
TiCl4 (1.1)
98
93
69
95
61
100
64
90
30:1
28:1
67:1
40:1
23:1
13:1
8:1
4:1
a With 1.1 equiv of nucleophile used. b Yield of purified product.
c Determined by GC analysis of unpurified product. d Result for (S)-6 in
toluene. e With 2 equiv of DBMP added.
TMSOTf again yielded superior selectivities. TMSOTf
promotion in dichloromethane produced the expected adduct
7 in excellent yield as a 30:1 mixture of diastereomers
(entries 1, 2).5 Replacing the solvent with toluene resulted
in improved selectivity (67:1) but was accompanied by a
reduction in yield (entry 3). Addition of the hindered base
DBMP to the TMSOTf-catalyzed reaction in dichloro-
(3) (a) Linderman, R. J.; Anklekar, T. V. J. Org. Chem. 1992, 57, 5078-
5080. (b) Linderman, R. J.; Chen, K. J. Org. Chem. 1996, 61, 2441-2453.
(c) Linderman, R. J.; Chen, S. Tetrahedron Lett. 1995, 43, 7799-7802. (d)
Linderman, R. J.; Chen, S. Tetrahedron Lett. 1996, 37, 3819-3822.
(4) (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,
8317-8320. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000,
65, 191-198.
(5) Configuration of adducts 7-9 were assigned by analogy to the
allyltrimethylsilane addition and to the configuration of adduct 18.
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Org. Lett., Vol. 5, No. 13, 2003

methane provided an optimal combination of high yield and
diastereoselectivity (entry 4). Triflic acid catalysis led to
slightly lower selectivity and significantly reduced yield
(entry 5). Titanium tetrachloride, tin tetrachloride, and
BF3‚OEt2 again gave modest selectivities (entries 6-8).
Attempts to carry out this type of coupling by in situ
formation of the oxocarbenium ion (by analogy to the
Marko’s protocol, Scheme 1) led instead to direct addition
of the nucleophile to the aldehyde. The R-acetoxy ether-
based aldol reaction represents a practical addition to existing
asymmetric aldol methodology.
Table 4. Addition of a Silyl Ketene Acetal to 6
entrya
Lewis acid (equiv)
solvent
yield (%)b
drc
Another efficient coupling partner with the R-acetoxy ether
6 was R-(trimethylsilyloxy)styrene (Table 3). Catalysis of
1
2
3
4
TiCl4 (1.1)
CH2Cl2
CH2Cl2
PhCH3
PhCH3
P h CH3
69
73
74
61
87
2:1
14:1
44:1
50:1
80:1
TMSOTf (1.1)
TMSOTf (0.2)
TMSOTf (1.1)
TMSOTf (2.5)
5d
Table 3. Addition of R-(Trimethylsilyloxy)styrene to 6
a With 1.1 equiv of nucleophile used. b Yield of purified product.
c Deteremined by GC analysis of unpurified product. d With 1.5 equiv of
nucleophile used. Subjecting (S)-6 to these reaction conditions afforded 73%
yield, 78:1 dr.
add to oxocarbenium ions to produce two diastereomers with
the syn product usually predominating.7 Lewis acid-mediated
solvolysis of R-acetoxy ether 6 in the presence of (E)-
crotyltrimethylsilane afforded mixtures of four different
diastereomers. The two major products, syn- and anti-10,
result from Linderman-type facial selectivity in the addition
to the oxocarbenium ion (Table 5). The minor isomers, syn-
entrya
Lewis acid
solvent
yield (%)b
drc
1d
2e
3
TMSOTf
TMSOTf
SnCl4
CH2Cl2
PhCH3
PhCH3
CH2Cl2
98
61
97
71
>20:1
>20:1
>20:1
2:1
4
TiCl4
a With 1.1 equiv of nucleophile used and 1.1 equiv of Lewis acid used.
b Yield of purified product. c Determined by 1H NMR analysis of unpurified
product; diastereomers inseparable by GC. d With 0.2 equiv TMSOTf and
2 equiv of DBMP used. e Result for (S)-6 in toluene.
Table 5. Addition of (E)-Crotyltrimethylsilane to 6
the reaction by TMSOTf in the presence of excess DBMP
provided the desired adduct in excellent yield and high
selectivity (entry 1).5 TMSOTf promotion in toluene resulted
in lower yield (entry 2), while use of tin tetrachloride gave
excellent results comparable to the best case (entry 3). As
previously observed, TiCl4 promotion resulted in significant
erosion of diastereoselectivity (entry 4).
In addition to silyl enol ethers, we found that a silyl ketene
acetal couples to 6 with surprisingly high diastereoselectivity.
Because silyl ketene acetals often give inferior selectivities
compared with silyl enol ethers in diastereoselective additions
to 2-acetoxy tetrahydropyrans,6 we were concerned that the
same might be true with our auxiliary. Gratifyingly, promo-
tion of the coupling reaction with TMSOTf in toluene
produced good yields and high selectivities (Table 4, entries
3-5).5 Exceptional selectivity (80:1) was observed when
excess TMSOTf and nucleophile were used (entry 5).
Promotion by TMSOTf in dichloromethane gave markedly
lower selectivity, while use of titanium tetrachloride afforded
only a 2:1 mixture of diastereomers (entries 1, 2).
diastereomer ratioc of
yield (%)b syn-10:anti-10:syn-11
entrya
conditions
1
2d
3
4e
5f
SnCl4, PhCH3
92
68
72
92
82
41:8:1
TMSOTf, PhCH3
TMSOTf, PhCH3
SnCl4, CH2Cl2
128:38:1
109:32:1
7:1:1.1
TMSOTf, CH2Cl2
27:2.4:1
a With 1.1 equiv of silane and 1.1 equiv of Lewis acid used. b Yield of
purified product. c Determined by GC analysis of unpurified product; anti-
11 was not detected. d With 0.2 equiv TMSOTf used. e A minor impurity
(potentially anti-11) was inseparable from syn-10 by GC. f Subjecting (S)-6
to these reaction conditions gave 78% yield, 22:2:1 syn-10:anti-10:syn-11.
11 and anti-11 (not shown, undetected by GC), arise from
addition to the opposite face of the oxocarbenium ion.
Excellent Linderman-type facial selectivity was observed in
toluene with TMSOTf, although the syn to anti ratio was
only 3:1 in these cases (entries 2, 3). An optimal balance
between the two modes of selectivity was found with
Extending this study to include crotylsilanes allowed for
the generation of two adjacent stereocenters. Crotylsilanes
(6) For example, see: Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron
1995, 51, 9413-9436.
(7) (a) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57, 5790-
5792. (b) Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999-1002.
Org. Lett., Vol. 5, No. 13, 2003
2369

TMSOTf promotion in dichloromethane (entry 5). Under
these conditions, an 11:1 syn/anti ratio was found for the
major products 10, with a 29:1 selectivity for the Linderman/
non-Linderman mode of addition (10:11). A similar trend
was observed with catalysis by tin tetrachloride (entries 1,
4). Higher Linderman-type selectivity was observed in
toluene, while slightly better syn/anti selectivity was achieved
in dichloromethane.
Scheme 4. Application to a Complex Aldol Coupling
All of the nucleophiles examined so far possess nucleo-
philic sp2 carbon atoms. The final two nucleophiles in our
survey have sp and sp3 nucleophilic carbon atoms, respec-
tively. Addition of TMSCN to R-acetoxy ether 6 afforded
the expected adduct 12 in excellent yield but with a modest
5:1 diastereoselectivity (Scheme 3). Similarly, addition of
reported to promote the diastereoselective Mukaiyama reac-
tion failed to improve the selectivity. The analogous auxiliary-
controlled coupling between R-acetoxy ether 17 and silyl
enol ether 15 gave the expected product 18 in good yield in
a 12:1 ratio with a minor diastereomer.9 In this case, our
oxocarbenium ion auxiliary was more effective than any of
the Mukaiyama aldol variants, including several chiral Lewis
acids.
Scheme 3. Addition of TMSCN and Diethylzinc to 6a
The auxiliary-substituted oxocarbenium ion precursor 6
leads to high facial selectivity with a variety of carbon
nucleophiles. Coupling complex nucleophiles to auxiliary-
derived R-acetoxy ethers provides access to various optically
active protected alcohols. We expect that this strategy for
introducing new stereogenic centers will have many synthetic
applications.
a Reaction conditions: (a) TMSCN (8 equiv), TMSOTf (2.5
equiv), PhCH3, -78 °C; (b) Et2Zn (2 equiv), TMSOTf (1.1 equiv),
PhCH3, -78 °C.
diethylzinc to 6 produced the ether 13 in good yield with a
4:1 selectivity. These selectivities are significantly lower than
those observed under similar reaction conditions with the
sp2 nucleophiles. These results may represent a limitation
of the auxiliary, although the cause for the erosion in
selectivity is unclear.
The final example, depicted in Scheme 4, shows the
application of our auxiliary to a problematic coupling
encountered in our recently reported synthesis of dermostatin
A.8 In the synthesis, Mukaiyama aldol coupling of aldehyde
14 and silyl enol ether 15 afforded adduct 16 in an optimized
3.2:1 anti/syn diastereomeric ratio. Several Lewis acids
Acknowledgment. The donors of the Petroleum Research
Fund, administered by the American Chemical Society
(37325-AC), provided financial support.
Supporting Information Available: Representative cou-
pling reactions and the preparation and characterization of
aldol adduct 18. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0347904
(9) Diastereomer ratio was estimated by 1H NMR analysis of purified
products. The minor diastereomer may be an artifact of the optical purity
of R-acetoxy ether 17 (88% ee at TBS-protected alcohol, 98% ee at the
R-TMS benzyloxy position) and silyl enol ether 15 (91% ee). These optical
purities would lead to a diastereomeric mixture containing ca. 90% 18 with
perfect selectivity in the coupling reaction. For proof of the stereochemistry,
see Supporting Information.
(8) (a) Sinz, C. J.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2001, 40,
3224-3227. (b) Sinz, C. J.; Rychnovsky, S. D. Tetrahedron 2002, 58,
6561-6576. (c) Sinz, C. J., Ph.D. Thesis, University of California-Irvine,
Irvine, 2001.
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