More than a protective group: Synthesis and applications of a new chiral silane

Article abstract of DOI:10.1021/ol071382h

Enantiomerically pure (-)-(R)- and (+)-(S)-(1-methoxy-2,2,2-triphenylethyl) dimethylsilanes (MOTES-H) were synthesized from triphenylacetaldehyde in five synthetic steps and with 60% overall yield. MOTES-protected α- and β-hydroxycarbonyl compounds were used in Grignard and Diels Alder reactions in the presence of MgBr₂ to afford addition products with 87-98% yield and selectivities of up to >120:1 dr. With this method, the pine beetle pheromone (-)-frontalin (67%, 98.5% ee) and naturally occurring (-)-(R)-octane-1,3-diol (90%, >99% ee) were synthesized.

Full text of DOI:10.1021/ol071382h

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3793-3796
More than a Protective Group:
Synthesis and Applications of a New
Chiral Silane
Maurizio Campagna, Michael Trzoss, and Stefan Bienz*
Institute of Organic Chemistry, UniVersity of Zurich, Winterthurerstrasse 190,
8057 Zurich, Switzerland
sbienz@oci.uzh.ch
Received July 6, 2007
ABSTRACT
Enantiomerically pure (
in five synthetic steps and with 60% overall yield. MOTES-protected
Alder reactions in the presence of MgBr2 to afford addition products with 87
the pine beetle pheromone ( )-frontalin (67%, 98.5% ee) and naturally occurring (
−
)-(R)- and (
+
)-(S)-(1-methoxy-2,2,2-triphenylethyl)dimethylsilanes (MOTES-H) were synthesized from triphenylacetaldehyde
- and -hydroxycarbonyl compounds were used in Grignard and Diels
98% yield and selectivities of up to >120:1 dr. With this method,
)-(R)-octane-1,3-diol (90%, >99% ee) were synthesized.
r
â
−
−
−
−
Silyl groups have been extensively used in organic chemistrys
mainly as protecting or activating moieties1 but also as
auxiliaries for stereoselective synthesis.2 We have introduced
a number of chiral silicon groups that were applied in
diastereoselective transformations.3,4 Here we present a new
silicon group that is more readily synthesized, not prone to
racemization, and that can be used as a protective group,
highly efficient chiral auxiliary, and chiral derivatizing agent.
Enantiomerically pure silanes (-)-(R)-3 and (+)-(S)-3 ((1-
methoxy-2,2,2-triphenylethyl)dimethylsilane, MOTES-H) were
synthesized from triphenylacetaldehyde5 (1) (Scheme 1).
Reaction with Me2PhSiLi6 and Me2SO4 formed phenylsilane
(()-2, and treatment with Br2/Fe followed by reduction with
LAH afforded racemic product (()-3 (overall 82%). Resolu-
tion of the enantiomers was effected by chromatographic
separation of the silyl ethers obtained with (S)-1,1,2-
triphenylethane-1,2-diol, followed by reduction with LAH,
and the absolute configuration of the enantiomers was
determined by X-ray analysis of a crystalline derivative. The
(1) For some important reviews: (a) Sommer, L. H. Stereochemistry,
Mechanism and Silicon; McGraw-Hill: New York, 1965. (b) The Chemistry
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Oshima, K. Main Group Metals in Organic Synthesis; Wiley-VCH:
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Georg Thieme: Stuttgart, Germany, 1994. (e) Nelson, T. D.; Crouch, R.
D. Synthesis 1996, 1031.
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L. G.; Jensen, B. L. Tetrahedron: Asymmetry 1994, 5, 797. (f) Denmark,
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1849.
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391. (b) Trzoss, M.; Shao, J.; Bienz, S. Tetrahedron 2002, 58, 5885.
(5) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555.
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S. C. Tetrahedron Lett. 1996, 37, 9395.
10.1021/ol071382h CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/22/2007

The versatility of the MOTES group is demonstrated with
the highly stereoselective chelate-controlled 1,2-addition of
organometallics to the R- and â-silyloxycarbonyl compounds
4 and 57 and the Lewis-acid-mediated Diels-Alder addition
of cyclopentadiene to the enones 6 and 78 (Table 1).9 In the
reactions of the Grignard reagents we focused our attention
on the 1,2-additions to R- and â-silyloxyaldehydes since they
have been reported to show lower selectivities in these types
of reactions as compared to their corresponding ketones.4,10
Diastereomeric ratios (dr) of up to >120:1 were observed
in the transformations; the dr values of up to 16:1 for the
reactions with 5 are among the best found for chiral 1,6-
Scheme 1. Synthesis of MOTES-H ((-)-(R)- and (+)-(S)-3)
1
inductions so far.11 Selectivities were determined by H
NMR, and the absolute configurations were deduced by
chemical correlation. The enantiomerically pure auxiliary can
be recovered almost quantitatively as (R)- or (S)-MOTES-H
((-)-(R)- or (+)-(S)-3) through reductive deprotection of the
addition products.
The stereochemical outcome of the reactions is consistent
with the formation of intermediary tridentate chelate com-
plexes, where the π-facial attack is sterically controlled
(Figure 1). It was experienced that the Lewis acid plays a
hydrosilanes MOTES-H are stable compounds that can be
stored at 23 °C for several months without decomposition.
Table 1. Results of MOTES-Directed Addition Reactionsa
Figure 1. Proposed transition structures for the MOTES-directed
stereoselective reactions.
entry educt
reagent
product
R
yieldd
dr
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4
4
4
4
4
4
5
5
5
5
5
5
6
7
MeMgBr
EtMgBr
i-PrMgBr
PhMgBr
allylMgBr
vinylMgBr
MeMgBr
EtMgBr
i-PrMgBr
PhMgBr
allylMgBr
vinylMgBr
C5H6
8a
9a
Me
Et
i-Pr
Ph
allyl
vinyl
Me
Et
i-Pr
Ph
97
95
93
96
88
91
96
95
96
91
98
93
91
87
70:1
80:1
70:1
70:1
80:1
70:1
14:1
15:1
11:1
pivotal role with regard to the extent of the selectivitiess
without pre-complexation of the substrates, distinctively
lower selectivities were observed for all transformations.
MgBr2 was used as the Lewis acid since this additive
proved advantageous over other metal salts in previous
related investigations.3,4 The scope of possible alternative
Lewis acids and other additives, however, has not been fully
explored yet and could give rise to interesting effects.12
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
12:1
16:1
16:1
allyl
vinyl
H
(7) (a) Chen, X.; Hortelano, E. R.; Frye, S. V. J. J. Am. Chem. Soc.
1992, 114, 1778. (b) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441.
(8) (a) Boeckman, R. K., Jr.; Barta, T. E. J. Org. Chem. 1985, 50, 3421.
(b) Coelho, P. J.; Blanco, L. Tetrahedron Lett. 1998, 39, 4261. (c) Coelho,
P. J.; Blanco, L. Tetrahedron 2003, 59, 2451. (d) Shirakawa, S.; Lombardi,
P. J.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 9974.
(9) The enantioselective preparation of 1,2-diols was recently reported
by auxiliary-controlled nucleophilic 1,2-addition to a carbonyl compound:
Vargas-D´ıaz, M. E.; Joseph-Nathan, P.; Tamariz, J.; Zepeda, L. G. Org.
Lett. 2007, 9, 13.
(10) (a) Charette, B. B.; Benslimane, A. F.; Mellon, C. Tetrahedron Lett.
1995, 36, 8557. (b) Charette, B. B.; Benslimane, A. F.; Mellon, C.
Tetrahedron Lett. 1995, 36, 8561.
(11) Stanway, S. J.; Thomas, E. J. Tetrahedron Lett. 1995, 36, 3417.
(12) Sibi, M. P.; Liu, M. Curr. Org. Chem. 2001, 7, 719.
>120:1
>120:1
C5H6
Me
a Only major isomers shown. b To a solution of 4 or 5 (1.0 mmol) in
CH2Cl2 (10.0 mL) was added subsequently a solution of MgBr2 (4.0 mL,
1.0 M in Et2O) and dropwise, at -78 °C, a solution of the Grignard reagent
(3.0 mL, 1.0 M in Et2O). After 20 min, the reaction was quenched with
saturated aqueous NH4Cl solution. c To a solution of 6 or 7 (0.46 mmol) in
CH2Cl2 (7.0 mL) was added a solution of Mg(OTf)2 (1.4 mL, 1.0 M in
Et2O), followed by cyclopentadiene (0.57 mL, 7.0 mmol) at -78 °C. After
20 min, the reaction was quenched with H2O. d Combined yields of the
two isomers in %.
3794
Org. Lett., Vol. 9, No. 19, 2007

Due to its rather simple structure and its bioactivity,
frontalin has attracted the interest of the chemical community,
which has led to more than 40 syntheses of the natural
product so far.15 Our enantioselective preparation of (-)-
frontalin is rather simple: silylation of R-hydroxyacetone
with (R)-MOTES-Br afforded R-silyloxyketone (R)-22,
which was treated with MgBr2 and Grignard reagent 2316 to
deliver directly the natural product in 67% overall yield and
98.5% ee after acidic workup (Scheme 2). When the addition
product 24 was isolated first (96%) and subsequently reduced
with LAH, diol 25 was formed in 95% yield together with
the auxiliary, recovered as (R)-MOTES-H in almost quantita-
tive yield. Treatment of 24 with TBAF in THF resulted in
cleavage of the silyl ether under mild conditions and
delivered diol 25 in 96% yield. Transacetalization of 25 to
(-)-frontalin was effected in 98% yield by treatment with a
catalytic amount of p-TsOH.
Scheme 2. Syntheses of (-)-Frontalin and
(-)-(R)-Octane-1,3-diol
(-)-(R)-Octane-1,3-diol ((R)-27) was prepared by addition
of pentylmagnesium bromide to aldehyde (R)-5, followed
by reductive cleavage of silyl ether 26. The addition product
26 arose with a dr of 16:1 and was further enriched by
chromatography to a dr of >99:1. Thus, the final 1,3-diol
(R)-27 was obtained in essentially enantiomerically pure
form.
As described above, the diastereomeric ratios observed in
1
our transformations were easily determined by H NMR.
Even though different chemical shifts for diastereomeric
compounds are common, the MOTES group shows distinct
and in most cases baseline resolved signals (singlets at ca.
5, ca. 3.5, ca. 0.3, and ca. -0.1 ppm) in different areas of
the spectra. This observation along with the ease of the
formation of MOTES ethers prompted us to investigate the
application of the MOTES group as a silicon-based chiral
derivatizing agent (CDA).17,18 Thus, a number of diastereo-
Applications of the MOTES group are shown with the
enantioselective syntheses of naturally occurring (-)-fron-
talin13 and (-)-(R)-octane-1,3-diol (26)14 (Scheme 2).
Table 2. MOTES as a Chiral Derivatizing Group
b
b
entry
educt
R1
Et
i-Pr
Ph
Ph
Nph
CO2Me
R2
products
yielda
∆δa
∆δb
1
2
3
4
5
6
7
28
29
30
31
32
33
34
Me
Me
Me
Et
Me
Me
35a/35b
36a/36b
37a/37b
38a/38b
39a/39b
40a/40b
41a/41b
95
93
96
97
97
93
82
0.312
0.339
0.132
0.144
0.208
0.121
0.084
0.324
0.332
0.527
0.531
0.541
0.372
0.258
a Combined yields in % of the two isomers. b ∆δa and ∆δb: chemical shift differences in ppm of the signals of the diastereotopic Me2Si of 35a-41a and
35b-41b, respectively.
Org. Lett., Vol. 9, No. 19, 2007
3795

Figure 2. 1H NMR (300 MHz, CDCl3) spectrum of 39a/39b (2.8:1).
meric pairs of silylated ethers and an amine were prepared
and studied by 1H NMR. The derivatives of the R-aryl/alkyl-
and alkoxycarbonyl/alkyl-substituted alcohols/amines, com-
pounds 37a-41a/37b-41b, in particular showed highly
distinctive spectra, which allows for unambiguous identifica-
tion and quantification of the compounds (Table 2).
As an example, a typical 1H NMR spectrum of a mixture
of (S,S)- and (R,S)-39 (ratio 2.8:1) is shown in Figure 2.
Interestingly, the effect of the CDA on the NMR is
particularly pronounced at the signals of Si-bound groups
rather than those of the original chiral alcohols. Above all,
the signals of the two pairs of diastereotopic MeSi groups
are typically well separated (see Table 2), which is beneficial
since they are registered in an otherwise signal-free region
of the spectrum.
The NMR results also suggest a potential application of
the MOTES group as a CDA for the direct determination of
absolute configurations. Except for the derivatives of the
alkyl/alkyl-substituted alcohols, where the diastereomeric
silyl ethers are not sufficiently differentiated (entries 1 and
2, Table 2), the relative shifting of the several signals due
to the CDA is consistently related to the relative configura-
tions of the two chiral moieties contained in the molecules:
the chemical shift differences of the two MeSi signals of
the silylated (R*,R*)-derivatives (∆δa) are always smaller
than those of the two MeSi signals of the (R*,S*)-derivatives
(∆δb), and in all cases the MeSi signals of the (R*,R*)-
derivatives are enframed by those of the (R*,S*)-counterparts.
Whether this pattern proves reliable over a larger range of
compounds is presently under investigation.
In conclusion, the MOTES group was shown to act
efficiently as a protective and stereodirecting group as well
as a potential CDA to differentiate enantiomeric alcohols
and to determine their absolute configurations. Diastereo-
selectivities of up to 98.8% and 94.2% respectivel, were
obtained by 1,5- and 1,6-chiral inductions with MOTES-
derivatized hydroxyaldehydes, -ketones, and -enones, and a
synthetic application of the group was shown with the
enantiospecific two-step preparation of (-)-frontalin. We
believe that the MOTES group can be multifunctionally
applied to any substrate that is able to chelate in derivatized
form, and thus it can be used as a universal tool in
enantioselective synthesis.
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Acknowledgment. We thank the Swiss National Science
Foundation for financial support and Ms. Lora Hristova,
Institute of Organic Chemistry, University of Zurich, for
preliminary experiments.
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Supporting Information Available: All experimental
procedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 9, No. 19, 2007