Silylacetic Esters: Enolate Reactions and Polyol Preparation

Full text of DOI:10.1021/jo9721960

J . Org. Chem. 1998, 63, 2761-2764
2761
be used in situations in which an alcohol is not desired.10
The Tamao oxidation employs a fluoride source and
hydrogen peroxide and requires at least one alkoxy
substituent on the silane. Fleming oxidations are con-
ducted under acidic conditions (AcOH/AcO2H or HBF4),
and the silane must have an aryl substituent at the
outset. Basic conditions (KH, tert-butylhydroperoxide,
and TBAF) have been elucidated recently which are
compatible with a wide range of alkyl and aryl substit-
uents on silicon.11
Silyla cetic Ester s: En ola te Rea ction s a n d
P olyol P r ep a r a tion
Mary M. Mader* and J onathan C. Edel
Department of Chemistry, Grinnell College,
Grinnell, Iowa 50112
Received December 3, 1997
In tr od u ction
By exploiting the versatility of the silyl moiety, we
report aldol condensation/silyl oxidation and condensa-
tion/protodesilylation sequences which complement exist-
ing methods for the preparation of polyhydroxylated
natural products. Diols can be prepared in an anti
fashion by aldol reactions of R-hydroxycarbonyl com-
pounds12 and in a syn relationship by dihydroxylation
reactions.13 Secondary alcohols can be prepared by
various methods,14 including aldol reaction/reduction of
an R-thioether.15 However, no single precursor yields
both mono- and dihydroxylated materials with ease. We
detail reliable conditions for the synthesis of â-hydroxy-
R-silyl esters and their subsequent conversion to R,â-
dihydroxy esters, â-hydroxy esters, and bis-protected
triols. Such a sequence of condensation and, ultimately,
oxidation or protodesilylation requires that the silyl
moiety be disposed toward oxidation, and thus ethyl
(dimethylphenylsilyl)acetate (1)16 was utilized as starting
material, with the aim of employing one of Fleming’s
reported one-pot methods for oxidation of the arylsilane
as a key step in the sequence.
Organosilanes are increasingly employed in organic
synthesis, as precursors to alkenes via the Peterson
olefination1 and as precursors to alcohols via the Tamao2
and Fleming oxidations.3 Recently, Landais demon-
strated that R-silyl ester enolates can be readily alkylated
and that 1,2-diols can be obtained following reduction of
the ester and oxidation of the alkoxysilyl substituent.4
R-Silyl ester and R-silyl ketone enolates5 have been
employed more commonly as starting materials in the
Peterson olefination, via aldol reactions which eliminate
silanol to yield R,â-unsaturated esters.6 Larcheveˆque, for
example, isolated a series of â-hydroxy-R-trimethylsilyl
esters in the stereoselective syntheses of R,â-unsaturated
esters, but no characterization data were reported for
these potentially sensitive compounds. In general, how-
ever, workers have not isolated the â-hydroxy-R-silyl
compounds but have directly converted the aldol products
to R,â-unsaturated esters by treatment with base. In
these instances, the silyl substituent was trimethylsilyl,
which is not easily oxidized. Although Larson reported
difficulty in isolating alcohols via an aldol route with a
diphenylmethylsilyl substituent,7 Kita obtained â-hy-
droxy-R-silyl esters by reaction of (tert-butyldimethylsi-
lyl)ketene with alkoxystannanes followed by condensa-
tion with aldehydes.8 The Peterson olefination via
R-silylcarbanions has been applied to imines as well, but
there has been little attempt to isolate the â-amino-R-
silyl compounds.9
A systematic study of reaction conditions reveals that
the preparation of â-hydroxy-R-silyl esters can be per-
formed cleanly by reaction of 1 with lithium diisopropyl-
amide (LDA) to form the ester enolate at -78 °C, followed
by exchange of the counterion with MgBr2‚OEt2.17 After
allowing 60 min for the Li-Mg exchange to take place,
the aldehyde is added. Under these conditions, the
â-hydroxy-R-silyl condensation product is isolated with
minimal formation of the alkene (Scheme 1). Apparently,
the more covalent Mg-O bond suppresses tendency
toward elimination.6 Three sources of magnesium were
investigated (MgBr2‚OEt2, anhydrous MgBr2 (both ob-
tained from Aldrich), and MgBr2 generated in situ from
The oxidation chemistry of silanes has been exploited
more frequently in natural product syntheses, as silicon’s
ability to act as a “masked” hydroxyl group allows it to
* Corresponding author. Phone: (515) 269-3010. Fax: (515) 269-
4285. E-mail: mader@ac.grin.edu.
(1) For an extensive review of the Peterson olefination, see: Ager,
D. J . In Organic Reactions; Paquette, L. A., Ed.; J ohn Wiley and
Sons: New York, 1990; Vol. 38, Chapter 1.
(2) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694-1696.
(10) (a) In the synthesis of phorbol C-ring: Magar, S. S.; Desai, R.
C.; Fuchs, P. L. J . Org. Chem. 1992, 57, 5360-5369. (b) In the synthesis
of methyl (+)-nonactate: Ahmar, M.; Duyck, C.; Fleming, I. Pure Appl.
Chem. 1994, 66, 2049-2052.
(11) Smitrovich, J . H.; Woerpel, K. A. J . Org. Chem. 1996, 61, 6044-
6046.
(12) For representative examples in natural product synthesis,
see: (a) Mukai, C.; Kim, I. J .; Furu, E.; Hanaoka, M. Tetrahedron 1993,
49, 8323-8336. (b) Paterson, I.; Nowak, T. Tetrahedron Lett. 1996,
37, 8243-8246.
(13) For a review of asymmetric dihydroxylation of alkenes, see:
Lohray, B. B. Tetrahedron Asymmetry 1992, 3, 1317-1349.
(14) For reviews of the preparation of optically active alcohols, see:
(a) Knochel, P. Angew. Chem., Int. Ed. Engl. 1992, 31, 1459-1461. (b)
Singh, V. K. Synthesis 1992, 607-617. (c) Davis, F. A.; Kumar, A. J .
Org. Chem. 1992, 57, 3337-3339 and references therein.
(15) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127-2129.
(3) For recent reviews of the oxidation of organosilanes, see: (a)
J ones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7662. (b)
Fleming, I. Chemtracts - Org. Chem. 1996, 9, 1-64. (c) Fleming, I.;
Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J . J . Chem.
Soc., Perkin Trans. I 1995, 317-336.
(4) Andrey, O.; Landais, Y.; Planchenault, D.; Weber, V. Tetrahedron
1995, 51, 12083-12096.
(5) For a review of the chemistry of R-silylcarbonyl compounds,
see: Larson, G. L. Advances in Silicon Chemistry; J AI Press: Green-
wich, CT, 1996; Vol. 3, pp 105-271.
(6) Larcheveˆque, M.; Debal, A. J . Chem. Soc., Chem. Commun. 1981,
877-878.
(7) Larson, G. L.; de Kaifer, C. F.; Seda, R.; Torres, L. E.; Ramirez,
J . R. J . Org. Chem. 1984, 49, 3385-3386.
(8) (a) Akai, S.; Tsuzuki, Y.; Matsuda, S.; Kitagaki, S.; Kita, Y.
Synlett 1991, 911-912. (b) Akai, S.; Tsuzuki, Y.; Matsuda, S.; Kitagaki,
S.; Kita, Y. J . Chem. Soc., Perkin Trans. 1 1992, 2813-2820.
(9) Konakahara, T.; Takagi, Y. Tetrahedron Lett. 1980, 21, 2073-
2076.
(16) Bagheri, V.; Doyle, M. P.; Taunton, J .; Claxton, E. E. J . Org.
Chem. 1988, 53, 6158-6160.
(17) Swiss, K. A.; Choi, W.-B.; Liotta, D. C.; Abdel-Magid, A. F.;
Maryanoff, C. A. J . Org. Chem. 1991, 56, 5978-5980.
S0022-3263(97)02196-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/24/1998

2762 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
Ta ble 2. Oxid a tion a n d P r otod esilyla tion of
Con d en sa tion P r od u cts
Sch em e 1
yield
(%)
yield
(%)
entry
R’
X
product
product
1
2
CH(CH3)2
Ph
O
3b
3g
63
72
4b
4g
48
99
NCOPh
Ph2, -SiMe2(O-Pr-i), and -SiMe(OEt)2. The bulk of two
phenyl groups greatly hindered the aldol reaction,7 and
the alkoxy groups enhanced the elimination, despite the
presence of magnesium. Commercially available ethyl
(trimethylsilyl)acetate also showed a greater propensity
toward elimination than the dimethylphenyl analogue.
The condensation gives only the anti diastereomer,
with the syn diastereomer undetectable by 1H NMR and
GC analysis of the crude materials. The anti assignment
can be made on the basis of the R-methine proton
coupling to the â-methine proton (J ) ∼3.5 Hz), prece-
dent from earlier work that found that use of Mg2+ in
aldol condensations yields only the anti diastereomer,17
Ta ble 1. Rea ction of Eth yl Dim eth ylp h en ylsilyl a ceta te
1 w ith Ald eh yd es a n d Im in es
entry
R’
X
product
yield (%)
1
1
2
3
4
5
6
7
Ph
i-Pr
Bu
PhCHdCH
t-Bu
Ph
O
O
O
O
O
2a
2b
2c
2d
2e
2f
76
64
72
70
(alkene)
43
60
and comparison of the H NMR spectrum of compound
3g that has been confirmed to be the anti diastereomer.20
Molecular modeling21 of the enolate and Zimmerman-
Traxler transition state support the experimental results.
Experimentally, the Z enolate of ethyl (dimethylphenyl-
silyl)acetate should be formed under kinetic conditions
by treatment with LDA due to the bulk of the -SiMe2Ph
and -OEt groups, and modeling confirms that the Z
enolate is thermodynamically preferred as well. Com-
parison of the chair conformations of the aldol transition
state involving the Z enolate indicates that anti addition
is favored.
NBoc
NCOPh
Ph
2g
Mg and 1,2-dibromoethane18), and the stable dietherate
gave consistently superior results. Variation of the Mg2+
stoichiometry confirmed that it plays a critical role in
suppressing the Peterson olefination: use of 0.5 equiv
gave predominantly the alkene product, and greater than
1.25 equiv did not improve the yield of alcohol. Other
bases (LHMDS, magnesium bromide diisopropylamide)
as well as Lewis acids (Bu2BOTf and TiCl4) were studied,
but these reagents yielded crude materials which were
contaminated with many other reaction byproducts.
A variety of aldehydes and imines were reacted with
the ester enolate in good yield, as shown in Table 1.
Peterson olefination byproducts were observed in the
crude mixtures, but in very low yield (<10%). In reaction
with cinnamaldehyde, the â-hydroxy-R-silyl product is
isolated, and none of the diene is observed in the crude
product. In only one instance (2e) did the alkene
predominate, presumably because the steric bulk of the
tert-butyl and dimethylphenyl substituents causes the
elimination pathway to be favored. Although the yields
of reaction of the enolate with imines are low, the imines
for entries 6 and 7 are hydrolytically unstable and were
used in the condensation immediately after preparation
without purification. Treatment of the enolate with a
less electrophilic imine (N-phenylbenzylidene)19 yielded
unreacted starting materials.
The utility of these condensations lies in the subse-
quent chemistry of the silyl moiety to obtain polyfunc-
tionalized compounds by oxidation and reduction (Scheme
1). The results of these studies are found in Table 2.
First, we investigated a variety of one-pot oxidation
methods3c,11 on â-hydroxy ester 2b and â-amino ester 2g.
Treatment of these condensation products with 1.0 M Br2
in AcOH/AcO2H at 0 °C as described by Fleming3c yielded
R,â-dihydroxy ester 3b and â-amino-R-hydroxy ester 3g.
The anti configuration at the R-center was retained as
determined by 1H NMR coupling constants for the R- and
â-protons and is precedented for these arylsilane oxida-
tions. Other one-pot methods (Hg(OAc)2/AcO2H and KBr/
AcO2H/NaOAc/AcOH) were less successful with these
substrates and, in the case of buffered KBr, did not go to
completion. The oxidation was potentially problematic,
as the retroaldol reaction could become competitive
without protection of the extant hydroxyl group, but no
1
evidence of the retroaldol was observed in the H NMR
of the crude materials. However, both products decom-
posed to a minor extent during purification by column
chromatography, diminishing the yields somewhat. None-
theless, this condensation/oxidation sequence provides
highly functionalized compounds diastereoselectively and
concisely. Note that 3g is an analogue of the unnatural
amino acid phenylisoserine, and the route should be
applicable to the synthesis of other natural products. The
sequence has advantages over earlier, lengthier synthe-
The substituents on silicon also influence the aldol
reaction toward elimination, and the dimethylphenylsi-
lane was found to have less of this tendency. Bearing in
mind that we ultimately wished to oxidize the silicon, it
had to bear at least one alkoxy or aryl substituent that
would allow oxidation by Tamao’s or Fleming’s method,
respectively. Four R-silylacetates were prepared from
ethyl diazoacetate by the methods of Doyle16 and Lan-
dais.4 The silyl substituents included -SiMe2Ph, -SiMe-
(20) Patel, R. N.; Banerjee, A.; Howell, J . M.; McNamee, C. G.;
Brozozowski, D.; Mirfakhrae, D.; Nanduri, V.; Thottathil, J . K.; Szarka,
L. J . Tetrahedron Asymmetry 1993, 4, 2069-2084.
(21) Molecular modeling was performed using the PM3 parameter
set with Spartan, version 4.1; Wavefunction, Inc., 18401 Von Karman
Ave., #370, Irvine, CA 92715.
(18) Vedejs, E.; Daugulis, O. J . Org. Chem. 1996, 61, 5702-5703
(supplemental information).
(19) Li, A.-H.; Dai, L.-X.; Hou, X.-L.; Chen, M.-N. J . Org. Chem.
1996, 61, 4641-4648.

Notes
J . Org. Chem., Vol. 63, No. 8, 1998 2763
Sch em e 2
provides direct access to three substitution patterns: R,â-
disubstituted and â-monosubstituted esters and R,â,γ-
triols.
Exp er im en ta l Section
Gen er a l Exp er im en ta l Meth od s. All reactions were con-
ducted in oven-dried glassware, needles, syringes, and stir bars
that were cooled in a desiccator over CaSO4. All reactions were
conducted under an atmosphere of N2. THF was dried and
distilled from potassium under an atmosphere of N2. Amines
(triethylamine (Et3N) and diisopropylamine (i-Pr2NH) were
distilled from KOH under N2 prior to use. All aldehydes were
distilled from anhydrous CaSO4 powder under N2 immediately
prior to use. Peracetic acid was obtained from Aldrich as a 32
wt % solution in dilute acetic acid and was used at this
concentration. Other chemical reagents were used as received
from Aldrich without further purification. “Drying” of extracts
refers to drying with MgSO4. NMR was obtained on a Bruker
A300 at 300 MHz (1H) and 75 MHz (13C). Shifts are recorded
in ppm and were obtained in and referenced to CDCl3 at δ 7.24
for 1H NMR and δ 77.00 for 13C NMR. High-resolution mass
spectra (HRMS) were obtained at the University of Iowa.
Elemental analyses (C, H) were performed by MHW Laborato-
ries of Phoenix, AZ, and agree within (0.4% of the calculated
values.
Rep r esen ta tive P r oced u r e for Ald ol Con d en sa tion . In
a typical procedure, diisopropylamine (1.10 mmol) was added
to THF (5 mL) at -78 °C followed by n-BuLi (1.10 mmol, 1.1 M
in hexane). After 5 min, the silyl ester 116 (1.00 mmol) was
added neat, dropwise by syringe. After 30 min, a suspension of
MgBr2‚OEt2 (1.25 mmol) in THF (5 mL) was added, and the
mixture was stirred for another 60 min. Neat, freshly distilled
aldehyde (1.20 mmol) was added, and the reaction mixture was
maintained at -78 °C. After the reaction was quenched with 5
mL of satd aq NH4Cl, the bath was removed and the heteroge-
neous mixture was stirred at room temperature for at least 15
min, until the phases melted and separated. The organic phase
was decanted; the heterogeneous aqueous phase was diluted
with 3 mL of water and extracted with Et2O (3 × 5 mL). The
combined organic phases were dried, filtered, and concentrated
by rotary evaporation to yield the crude â-hydroxy-R-silyl ester.
The crude alcohol was purified by flash column chromatography
on silica gel.
ses of 1,2-amino alcohols via silyl oxidation which re-
quired protection of the amine and employed a two-step
silyl oxidation protocol.8
Next, we investigated the protodesilylation chemistry
of the condensation products. Treatment with 1.2 equiv
each of Hg(OAc)2 and 1.0 M TBAF in 1:1 THF-MeOH
at 0 °C cleanly and quickly effected the protodesilylation
within 15 min. The starting materials did not need to
be protected prior to this reaction, and again, no retroal-
dol was observed. The reaction appears to be facilitated
by the presence of the ester, perhaps via an incipient
enolate, as attempts to perform protodesilylation on
(dimethylphenylsilyl)octane resulted in no reaction. The
isolated yield was higher for 4g which possesses chro-
mophores that facilitated its detection by UV during
column chromatography. The use of this combination of
reagents to effect protodesilylation has not been reported
and is notable in that other one-pot protodesilylation
methods require either the presence of an alkoxy group
on silicon22 or strongly basic conditions.23 Ongoing efforts
in our lab are directed at investigating the scope of this
reaction.
Last, bis-protected triol 6 can be obtained via the aldol
condensation/oxidation sequence if the intermediate al-
dolate is reduced in situ with diisobutylaluminum hy-
dride (Scheme 2). The reduction takes advantage of the
“protection” of the alcohol afforded by the magnesium
counterion, and little or no elimination and retroaldol are
observed. An alternative route of isolation of the â-hy-
droxy ester, protection, and reduction was complicated
by the tendency of the hydroxy ester to undergo a
retroaldol reaction during the protection attempt; thus
in situ reduction is more efficient. Oxidation of silane 5
is effected by Hg(OAc)2 in peracetic acid in this case,
yielding the bis-protected triol 6.
2-(Dim eth ylph en ylsilyl)-3-h ydr oxyph en ylpr opan oic acid,
1
eth yl ester (2a ): H NMR (300 MHz, CDCl3) δ 7.22-7.51 (m,
10 H), 4.90 (d, 1 H, J ) 5.5 Hz), 3.95 (q, 2 H, J ) 7.3 Hz), 2.83
(d, 1 H, J ) 5.5 Hz), 1.04 (t, 3 H, J ) 7.3 Hz), 0.46 (s, 6 H); 13C
NMR (75 MHz, CDCl3) δ 174.6, 143.8, 134.0, 129.6, 128.2, 127.8,
127.3, 127.1, 125.9, 72.5, 60.2, 46.0, 14.0,-3.30, -3.40; FTIR
(neat) cm-1 3451 (br, OH), 1717 (s, CdO). Anal. Calcd for
C
19H24O3Si: C, 69.47; H, 7.36. Found: C, 69.64; H, 7.09.
2-(Dim et h ylp h en ylsilyl)-3-h yd r oxy-4-m et h ylp en t a n oic
a cid , eth yl ester (2b): 1H NMR (300 MHz, CDCl3) δ 7.30-
7.56 (m, 5 H), 4.00 (q, 2 H, J ) 7.3 Hz), 3.26 (dd, 1 H, J ) 3.0,
8.1 Hz), 2.54 (d, 1 H, J ) 3.0 Hz), 1.60 (m, 1 H), 1.14 (t, 3 H, J
) 7.3 Hz), 0.90 (d, 3 H, J ) 6.8 Hz), 0.80 (d, 3 H, J ) 6.8 Hz),
0.46 (s, 3 H), 0.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.5,
136.5, 134.1, 129.6, 127.9, 60.1, 41.0, 34.7, 19.7, 18.9, 14.2, -3.00,
-3.30; FTIR (neat) cm-1 3501 (br, OH), 1693 (s, CdO). Anal.
Calcd for C16H26O3Si: C, 65.26; H, 8.90. Found: C, 65.06; H,
8.61.
In conclusion, enolate reactions of ethyl(dimethylphen-
ylsilyl)acetate with aldehydes and imines provide access
to polyfunctionalized alcohols and amines by suppression
of the Peterson olefination. The use of MgBr2‚OEt2
stabilizes the aldolate intermediate and results in anti
diastereoselectivity. One-pot oxidation of the â-hydroxy-
and â-aminosilyl esters can be performed without protec-
tion of the â-substituent, offering an efficient route to
substitution patterns found in many natural products.
Last, a bis-protected triol was prepared from the aldol
intermediate by ester reduction, diol protection, and,
finally, silane oxidation. Thus the condensation product
2-(Dim eth ylp h en ylsilyl)-3-h yd r oxyh ep ta n oic a cid , eth yl
ester (2c): 1H NMR (300 MHz, CDCl3) δ 7.30-7.57 (m, 5 H),
4.03 (q, 3 H, J ) 7.0 Hz), 3.67 (m, 1 H), 2.37 (d, 1 H, J ) 3.5
Hz), 1.52 (m, 1 H), 1.25 (m, 6 H), 1.13 (t, 3 H, J ) 7.0 Hz), 0.82
(t, 3 H), 0.45 (s, 3 H), 0.42 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 175.3, 136.2, 134.0, 129.5, 127.8, 70.6, 60.0, 43.6, 37.4, 28.3,
22.4, 14.1, 13.9, -3.10, -3.40; FTIR (neat) cm-1 3487 (br, OH),
1696 (s, CdO). Anal. Calcd for C17H28O3Si: C, 66.19; H, 9.15.
Found: C, 66.00; H, 8.82.
(E)-2-(Dim eth ylp h en ylsilyl)-3-h yd r oxy-5-p h en yl-4-p en -
ten oic a cid , eth yl ester (2d ): 1H NMR (300 MHz, CDCl3) δ
7.22-7.56 (m, 10 H), 6.45 (d, 1 H, J ) 15.8 Hz), 6.12 (dd, 1 H,
J ) 6.6, 15.8 Hz), 4.46 (dd, 1 H, J ) 5.3, 6.6 Hz), 4.06 (q, 2 H,
J ) 7.0 Hz), 2.58 (d, 1 H, J ) 5.3 Hz), 1.16 (t, 3 H, J ) 7.0 Hz),
0.49 (s, 3 H), 0.46 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 174.6,
(22) Hale, M. R.; Hoveyda, A. H. J . Org. Chem. 1992, 57, 1643-
1645.
(23) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. J . Am. Chem.
Soc. 1982, 104, 6809-6811.

2764 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
136.5, 135.9, 134.1, 131.3, 130.4, 129.6, 128.4, 127.8, 127.6, 126.5,
71.4, 60.3, 44.6, 14.2, -3.1, -3.5; FTIR (neat) cm-1 3460 (br,
OH), 1716 (s, CdO), 1631 (s, CdC). Anal. Calcd for C21H26O3-
Si: C, 71.15; H, 7.39. Found: C, 71.30; H, 7.20.
MHz, CDCl3) δ 173.5, 72.7, 60.7, 38.4, 33.1, 18.3, 17.7, 14.2. Anal.
Calcd for C8H16O3: C, 59.97; H, 10.06. Found: C, 59.95; H, 9.88.
â-(Ben zoyla m in o)b en zen ep r op a n oic a cid , et h yl est er
(4g): white solid, mp 83-86 °C; 1H NMR (300 MHz, CDCl3)
7.90-7.20 (m, 10 H), 5.62 (dd, 1 H, J ) 5.3, 5.7 Hz), 4.06 (q, 2
H, J ) 7.0 Hz), 2.96 (dd, 1 H, J ) 15.8, 5.3 Hz), 2.89 (dd, 1 H,
J ) 15.8, 5.7 Hz), 1.15 (t, 3 H, J ) 7.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 171.6, 166.5, 140.5, 134.2, 131.7, 128.6, 127.6, 127.0,
126.2, 60.9, 49.8, 39.9, 14.0; MS (EI) 297, 252, 192, 105, 77.
3-[(ter t-Bu t oxyca r b on yl)a m in o]-2-(d im et h ylp h en ylsi-
lyl)p h en ylp r op a n oic a cid , eth yl ester (2f): 1H NMR (300
MHz, CDCl3) δ 7.20-7.50 (m, 10 H), 6.46 (br d, 1 H), 4.95 (br d,
1 H, J ) 3.4 Hz), 3.85 (q, 2 H, J ) 6.8 Hz), 2.75 (d, 1 H, J ) 3.4
Hz), 1.43 (s, 9 H), 0.97 (t, 3 H, J ) 6.8 Hz), 0.46 (s, 3 H), 0.45 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 173.8, 154.9, 145.5, 135.9,
134.0, 129.6, 128.3, 127.9, 126.8, 125.9, 79.2, 60.1, 44.4, 28.4,
14.0, -3.40, -3.60; FTIR (neat) cm-1 3427 (br, OH), 1706 (s,
CdO). Anal. Calcd for C24H33NO4Si: C, 67.41; H, 7.78; N, 3.28.
Found: C, 67.47; H, 7.83; N, 3.18.
1,3-Dia ce t oxy-2-(d im e t h ylp h e n ylsilyl)-4-m e t h ylp e n -
ta n e (5). Following addition of the aldehyde and stirring for
60 min at -78 °C, the reaction mixture of the aldol condensation
prepared as described above was treated with DIBALH (1.0 M
in toluene; 5.0 mL, 5.0 mmol), and immediately warmed to 0
°C, and stirred for another 60 min. The reaction was quenched
with saturated aq NH4Cl (5 mL), and the mixture stirred 30
min and was further treated with saturated aq K‚Na tartrate
(5 mL). After stirring for 1.5 h, the phases were separated and
the milky, heterogeneous aqueous phase was extracted with
Et2O (3 × 5 mL). The combined organic phases were dried,
filtered, and concentrated by rotary evaporation to yield 300 mg
of crude, clear oil. A portion of this crude mixture (0.1943 g,
0.77 mmol; assuming 100% conversion for the previous reaction)
was added to a stirred solution of Et3N (214 µL, 1.54 mmol),
DMAP (0.0188 g, 0.154 mmol), and acetic anhydride (145 µL,
1.54 mmol) in CH2Cl2 at -10 °C. This reaction mixture was
concentrated by rotary evaporation after 60 min without workup
and purified by flash column chromatography (10:1 hexanes-
EtOAc). The diacetate (0.1351 g, 0.400 mmol, 52%) was isolated
as a clear, colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.27-
7.51 (5 H, m), 4.97 (1 H, AMX, J ) 5.7, 6.1 Hz), 4.28 (1 H, dd,
J ) 4.0, 11.4 Hz), 4.16 (1 H, dd, J ) 6.2, 11.4 Hz), 1.94 (3 H, s),
1.86 (3 H, s), 1.83 (1 H, m), 1.64 (1 H, m), 0.83 (3 H, d, J ) 6.6
Hz), 0.70 (3 H, d, J ) 6.60 Hz), 0.35 (6 H, s); 13C NMR (75 MHz,
CDCl3) δ 171.0, 170.5, 137.2, 133.7, 129.2, 127.8, 76.7, 62.5, 31.8,
29.0, 21.0, 20.89, 19.7, 17.5, -3.0, -3.7. Anal. Calcd for
C18H28O4Si: C, 64.25; H, 8.39. Found: C, 64.06; H, 8.54.
3-(Ben zoyla m in o)-2-(d im et h ylp h en ylsilyl)p h en ylp r o-
1
p a n oic a cid , eth yl ester (2g): mp 98-102 °C; H NMR (300
MHz, CDCl3) δ 8.65 (d, 1 H, J ) 8.8 Hz), 7.18-7.78 (m, 15 H),
5.60 (d, 1 H, J ) 8.8 Hz), 4.10 (q, 2 H, J ) 7.0 Hz), 2.93 (d, 1 H,
J ) 2.6 Hz), 1.09 (t, 3 H, J ) 7.0 Hz), 0.56 (s, 3 H), 0.54 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 174.8, 165.4, 142.9, 133.7, 131.3,
129.5, 128.6, 128.3, 127.8, 126.9, 125.6, 60.3, 50.8, 43.6, 14.3,
-3.40, -3.60; FTIR (KBr) cm-1 3408 (br, -NH), 1703 (s, CdO),
1670 (s, CdO). Anal. Calcd for C26H29NO3Si: C, 72.35; H, 6.77;
N, 3.24. Found: C, 72.37; H, 6.83; N, 3.06.
Rep r esen ta tive F lem in g Oxid a tion P r oced u r e. A solu-
tion of hydroxysilane 2b (0.0782 g, 0.265 mmol) in peracetic acid
(32 wt % solution; 2.6 mL) at 0 °C was treated dropwise with
Br2 (0.50 mL; 1 M in acetic acid). The mixture was warmed to
room temperature slowly over 3.5 h as the ice-water bath
melted and then stirred for an additional 1.5 h. The reaction
mixture was diluted with EtOAc (10 mL), and 2 mL of satd aq
Na2S2O3 was added slowly, dropwise, until the pale- orange color
dispersed. The phases were separated, and the organic phase
was carefully washed with H2O (3 mL) and satd aq NaHCO3 (4
× 3 mL). The combined aqueous phases were back-extracted
with EtOAc (10 mL). After drying, the combined organic phases
were filtered and concentrated by rotary evaporation. The crude
oil was purified by flash column chromatography (Florisil, 10:1
hexanes-ethyl acetate) to yield diol 3b (0.0295 g, 0.167 mmol,
63%).
1,3-Dia cetoxy-4-m eth yl-2-p en ta n ol (6). Mercuric acetate
(0.0350 g, 0.110 mmol) was added to silane 5 (0.0342 g, 0.102
mmol) in peracetic acid (1.0 mL; 32 wt % solution), and the
mixture was stirred at 20 °C for 40 min. Ether (15 mL) was
added to the solution, and the mixture was treated dropwise
with 5 mL of satd aq Na2S2O3 (ca u tion - vigorous reaction!).
The layers were separated, and the organic phase was extracted
with 5 mL each of H2O, satd aq Na2CO3, and brine. Following
drying, the organic phase was concentrated in vacuo to yield
alcohol 6 (0.016 g, 0.074 mmol, 74%) which required no purifica-
tion: 1H NMR (300 MHz, CDCl3) δ 4.81 (t, 1 H, J ) 6.15 Hz),
4.20 (dd, 1 H, J ) 2.2, 11.9 Hz), 4.05 (dd, 1 H, J ) 6.6, 11.9 Hz),
3.95 (dt, 1 H, J ) 2.2, 6.6 Hz), 2.08 (s, 3 H), 2.07 (s, 3 H), 2.02
2,3-Dih yd r oxy-4-m eth ylp en ta n oic a cid , eth yl ester (3b):
mp 31-33 °C; 1H NMR (300 MHz, CDCl3) δ 4.26 (2 H, ABX3, J
) 7.0, 7.5 Hz), 4.24 (1 H, d, J ) 3.5 Hz), 3.46 (1 H, dd, J ) 3.5,
7.5 Hz), 2.08 (1 H, br s), 1.86 (1 H, m), 1.30 (3 H, ABX3, J ) 7.0,
7.5 Hz), 0.99 (3 H, d, J ) 7.0 Hz), 0.96 (3 H, d, J ) 6.6 Hz); 13
C
NMR (75 MHz, CDCl3) δ 173.2, 78.7, 72.3, 62.0, 30.0, 19.2, 18.5,
14.2; FTIR (KBr) cm-1 3440 (br, OH), 1742 (s, CdO); MS (EI)
133 (M - CH(CH3)2), 104, 76, 72, 43. Anal. Calcd for C8H16O4:
C, 54.53; H, 9.15. Found: C, 54.33; H, 8.94.
â-(Ben zoylam in o)-r-h ydr oxyben zen epr opan oic acid, eth -
yl ester (3g): mp 138-140 °C (lit.20 mp 161-163 °C); 1H NMR
(300 MHz, CDCl3) δ 7.79 (1 H, d, J ) 8.8 Hz), 7.24-7.49 (10 H,
m), 5.60 (1 H, dd, J ) 3.5, 8.8 Hz), 4.66 (1 H, d, J ) 3.5 Hz),
4.13 (2 H, ABX3, J ) 7.0, 7.5 Hz), 1.23 (3 H, t, J ) 7.0 Hz); 13C
NMR (75 MHz, CDCl3) δ 171.7, 166.6, 136.4, 134.0, 131.7, 128.5,
128.2, 127.6, 127.0, 72.3, 62.2, 55.4, 14.3; FTIR (KBr) cm-1 3345
(s, -NH, -OH), 1718 (s, CdO), 1645 (s, CdO). Anal. Calcd for
C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C, 68.87; H, 6.01;
N, 4.19.
Gen er a l P r oced u r e for th e P r otod esilyla tion . A solution
of the silyl alcohol 2b (0.0686 g, 0.209 mmol) in 1:1 THF-MeOH
(2.0 mL) at 0 °C was treated with Hg(OAc)2 (0.0795 g, 0.250
mmol) followed by 1.0 M TBAF (250 µL, 0.250 mmol). The
yellow homogeneous solution was stirred for 15 min and then
diluted with EtOAc (10 mL). The mixture was washed with 3
mL each of satd NH4Cl, H2O, and brine. A yellow precipitate
which formed upon addition of EtOAc dissolved upon addition
of the NH4Cl solution. The organic phase was dried and
concentrated by rotary evaporation to yield an oil which was
purified by flash column chromatography (eluted with 5:1
hexanes-EtOAc).
(m, 1 H), 0.94 (d, 3 H, J ) 7.0 Hz), 0.90 (d, 3 H, J ) 6.6 Hz); 13
C
NMR (75 MHz, CDCl3) δ 171.4, 171.1, 77.97, 69.49, 65.6, 28.7,
20.8, 19.3, 17.0; HRMS (EI) m/z calcd for C10H17O4 (M - OH)+
201.2446, found 201.1133.
Ack n ow led gm en t. Support of this work by the
American Chemical Society-Petroleum Research Fund
(ACS-PRF 28447-GB1), NSF Research Planning Grant
(CHE-9510292), Research Corporation (CC3865), and
Grinnell College (Harris Faculty Fellowship) is grate-
fully acknowledged. We thank Prof. David Hart and
Yannick Landais for helpful discussions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 3g and 4g (4 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
3-Hyd r oxy-4-m eth ylp en ta n oic a cid , eth yl ester (4 b): 1H
NMR (300 MHz, CDCl3) δ 4.14 (q, 2 H, J ) 7.0 Hz), 3.74 (br m,
1 H), 2.90 (br s, 1 H), 2.47 (dd, 1 H, J ) 2.6, 16.3 Hz), 2.34 (dd,
1 H, J ) 9.7, 16.3 Hz), 1.67 (m, 1 H), 1.25 (t, 3 H, J ) 7.0 Hz),
0.92 (d, 3 H, J ) 6.6 Hz), 0.90 (d, 3 H, J ) 7.0 Hz); 13C NMR (75
J O9721960