Alpha-amino silanes via metalated imines as an approach to the synthesis of silanediol protease inhibitors Dedicated to Paul A. Wender on the occasion of the award of the Tetrahedron Prize for Creativity in Organic Chemistry

Article abstract of DOI:10.1016/j.tet.2013.06.022

Metalation of benzophenone imines for elaboration of the alpha-amino silane component of silanediol-based protease inhibitors allows for rapid diversification of targets. Coupling this chemistry with recently developed asymmetric hydrosilylation chemistry

Full text of DOI:10.1016/j.tet.2013.06.022

Tetrahedron 69 (2013) 7779e7784
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Alpha-amino silanes via metalated imines as an approach to the
synthesis of silanediol protease inhibitors
*
Yingjian Bo, Paul B. Finn, Buddha B. Khatri, Scott McN. Sieburth
Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, PA 19122, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Metalation of benzophenone imines for elaboration of the alpha-amino silane component of silanediol-
based protease inhibitors allows for rapid diversification of targets. Coupling this chemistry with recently
developed asymmetric hydrosilylation chemistry for preparing beta-silyl acids results in a streamlined
process for drug design.
Received 2 March 2013
Received in revised form 2 June 2013
Accepted 6 June 2013
Available online 14 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated to Paul A. Wender on the occa-
sion of the award of the Tetrahedron Prize
for Creativity in Organic Chemistry
Keywords:
Organosilane
Aminomethylsilane
Metalation
Alkylation
Protease inhibitor
Imine
1. Introduction
toolbox, the silanediol, exemplified by structure 4, which has very
different structure and properties.9
Proteolytic enzymes mediate many biological processes. An
improper level of protease activity can cause disease and many
disease-causing organisms have proteases that play crucial roles in
their life cycle.1,2 Protease inhibitors are commercial pharmaceu-
ticals, important in the treatments for hypertension, AIDS, cancer,
and periodontal disease, to name a few.3e7
Design of protease inhibitors based on the protease substrate
often begins with a suitable mimic of the tetrahedral intermediate
2 formed during protease-mediated hydrolysis of peptide 1, Fig. 1.8
Silicon is the element most similar to carbon, and like carbon
has no intrinsic toxicity. Unlike carbon however, silicon only forms
double bonds under duress, and therefore silanediols can act as
stable tetrahedral gem-diol analogs of hydrated carbonyls.10
To prepare silanediols like 4 we initially developed the chem-
istry outlined in Fig. 2.11,12 At the outset of this endeavor, silande-
diols with acid or amino functional groups were unknown.
Effective replacements for the hydrated amide
2
inclu-
de hydroxyethylene 3, which is found in nearly all HIV protease
inhibitors. The choice of functional group to replace this tetrahedral
intermediate is often specific to the class of protease (aspartic,
metallo-, serine or cysteine) and the functional group carries with it
the physical properties of the selected analog, which in turn affects
the entire molecule and its pharmacokinetic properties. Our re-
search seeks to add a new analog of 2 to the medicinal chemist’s
* Corresponding author. Tel.: þ1 215 204 7916; fax: þ1 215 204 1532; e-mail
Fig. 1. Protease enzymes stabilize the hydrated amide hydrolysis intermediate.
A typical aspartic protease inhibitor structure 3 and silanediol inhibitor 4.9
address: scott.sieburth@temple.edu (S.McN. Sieburth).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.022

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Y. Bo et al. / Tetrahedron 69 (2013) 7779e7784
Similarly, stereochemistry was not present in known silanediols at
that time. Silanediol 5 has two different structural subunits: a beta-
silyl amide group and an alpha-amino silane, each carrying a ster-
eogenic center. In this first solution to the structure 5, the beta-silyl
amide was constructed with enantiomerically pure lithium reagent
10, with absolute stereochemistry derived from the commercially
available Roche ester.12 The alpha-amino silane component was
prepared via the silyl ketone 7. Overall the sequence was effective,
but it was lengthy and not particularly general.
Fig. 4. N-Trimethylsilylmethyl imines can desilylate under mild conditions.18
2. Results and discussion
Assembly of the protease inhibitor was envisioned to use the
sequence outlined retrosynthetically in Fig. 5. The protected in-
hibitor precursor 20 would come from the imine 22 after hydrolysis
of the imine and oxidation of the protected alcohol, or an equiva-
lent. Compound 22 would be prepared by alkylation of 23 after
deprotonation between the silicon and imine, and 23 would derive
from silylation of lithiated imine 24 and a suitable silane precursor
of the beta-silyl acid unit 25.
Fig. 2. The first preparation of a silanediol protease inhibitor.12
In the approach outlined in Fig. 2, installation of the alpha-
amino silane component required five steps, with introduction of
the benzyl substituent in the earliest stage (8). An intriguing al-
ternative to this approach is the late introduction of the substituent
between N and Si by metalationealkylation of the parent amino-
methylsilane, 12, Fig. 3. This approach has the potential benefit of
the well-known stabilization of carbanions alpha to silicon, as well
as the potential for asymmetric metalation to control the stereo-
chemistry. This approach has been investigated in the context of
Y¼Boc, but a suitably efficacious protocol did not emerge.13 Late
introduction of the aminomethylsilane substituent would lend
itself to diversification of protease inhibitor structures for study.
A different method for generating a primary aminomethyl anion
is the benzophenone N-methylimine 14.14 This readily available
imine is easily deprotonated to form a nucleophilic aminomethyl
anion. Indeed, metalation and alkylation of 14 has been reported
repeatedly over the last 43 years and silylation of this anion was
first performed 40 years ago.15,16 The resulting silylmethyl imines
have also been hydrolyzed to the free amine.17
Fig. 5. N-Diphenyl(alkyl)silylmethyl imine approach to the protease inhibitors.
Two beta-silyl acid precursors were used in this study, Fig. 6.
Fluorosilane 26 is generated by fragmentation of 27, prepared by
asymmetric hydroboration of 28, the latter
a product of
magnesium-mediated cyclization of isoprene with dichlor-
odiphenylsilane.19 Fluorosilane 29 is readily derived from 30 by
asymmetric hydrosilylation of 31.20
Fig. 3. Alpha-amino silane synthesis by metalationealkylation.
Fig. 6. Electrophilic fluorosilane precursors of beta-silyl acids.19,20
On the other hand, N-silylmethyl imines are also well known
precursors of azomethine ylides. Compound 17 has been found to
desilylate under a variety of conditions, including simply stirring
with watereacetic acid in a polar solvent at ambient temperature,
Fig. 4.18 Nevertheless, the anticipated simplicity of generating
structures, such as 15, and the precedent for hydrolysis to the free
amine, stimulated our interest in this approach.
In the event, coupling of the lithiated imine derived from 14
with 26 and 29 proceeded in very good yield. In the case of 26,
racemic fluorosilane was used (Fig. 7).
In contrast, hydrolysis of the imine of 33, using oxalic acid
conditions described by Silverman17 led to cleavage of the just-
formed CeSi bond and isolation of silanol 34 in 58% yield

Y. Bo et al. / Tetrahedron 69 (2013) 7779e7784
7781
Fig. 7. Silylation of lithiated imine.
(72% based on recovered starting material, Fig. 8). An alternative
Silverman procedure using basic conditions, hydrazine hydrate in
alcohol, was more successful.21 Stirring 33 in methanol with excess
hydrazine hydrate at reflux led to slow liberation of the amine and
after 48 h amine 35 was isolated in 83% yield. Subjecting imine 32
to similar conditions, 1 equiv of hydrazine hydrate in ethanol at
ambient temperature, after 4 days produced the amine in 57% yield.
This unsaturated amine was accompanied, however, with satd 37
resulting from simultaneous reduction of the alkene.
Fig. 9. Alkylation between nitrogen and silicon. Yields in parentheses are based on
recovered starting material. In all cases the diastereomeric ratio of products was 1:1.
Fig. 10. Hydrazinolysis and conversion to known diastereomers 44.
Fig. 8. Hydrolysis and hydrazinolysis of imine 32 and 33.
protease inhibitors. It intersects nicely with the recently developed
beta-silyl ester syntheses. The sequence would profit from a more
facile hydrolysis procedure and a diastereoselective alkylation. In
principle, the silylation, alkylation, and hydrolysis could be com-
bined into a single operation. Additional results will be reported in
due course.
We next turned our attention to alkylation of the silylated im-
ines 32 and 33. For this second deprotonation we found sec-
butyllithium to be the most suitable base, Fig. 9. Use of n-butyl-
lithium gave none of the anticipated alkylation product and largely
recovered starting material, whereas the use of LDA as base led to
alkylated product but only in low yield. Addition of a primary
bromide (or methyl iodide) gave the anticipated product in good
yield as a 1:1 mixture of diastereomers. Notably, these reactions
were very clean, with only product and starting material present in
the crude mixture, the two readily separated by chromatography.
Hydrazinolysis of the alkylated products focused on 39 as
a representative example, and these reactions were found to be
more difficult than for the less hindered 32 and 33. After some
experimentation it was found that amine 43 could be isolated in
moderate yield after nearly a week in refluxing methanol using
a large excess of hydrazine hydrate, Fig. 10. Subsequent depro-
tection of the alcohol and benzamide formation under Schot-
teneBaumann conditions gave amide-alcohol 44 in good yield as
a mixture of diastereomers. This mixture was identical to this
structure previously prepared en route to the ACE inhibitor 5.12
4. Experimental
4.1. General
Reagents and solvents were purchased from Gelest, Aldrich,
Fisher Scientific, Alfa Aesar, and Acros. Reaction solvents were pu-
rified using a ‘Grubbs-style’ Solvent Dispensing System purchased
from Glass Contour.
Chromatography was conducted over silica gel (170e400 mesh,
ꢀ
60 A) or basic alumina (activated 50e200 micron).
Analytical thin layer chromatography utilized Analtech Uniplate
Silica Gel GF (250 micron) pre-coated glass plates. TLC visualization
was conducted with UV light, iodine, and phosphomolybdic acid
solution.
Proton and carbon NMR spectra were recorded on Bruker
Avance 400 spectrometer and Bruker Avance III 500 spectrometers.
Chemical shifts were measured relative to the residual solvent
resonance. IR spectra were recorded on Mattson 4020 GALAXY
Series FT-IR. Mass spectra were obtained with an Agilent 6520B
3. Conclusion
This study has demonstrated the use of the benzophenone
N-methylimine as a viable method for preparation of silanediol

7782
Y. Bo et al. / Tetrahedron 69 (2013) 7779e7784
Accurate-Mass Q-TOF LC/MS and from the Mass Spectrometry
Facility of University of California at Riverside.
extracted with ethyl acetate (2ꢁ10 mL), the combined organics
were washed with satd NaCl (5 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash chroma-
tography using a gradient elution (10:1e8.5:1 hexanes/ethyl ace-
tate) to give 33 as a light yellow oil (0.86 g, 1.74 mmol, 87%). Rf¼0.45
4.2. (2S)-3-(Fluorodiphenylsilyl)-2-methyl-1-propyl methox-
ymethyl ether (29)
(4:1 hexanes/ethyl acetate). ½a D20
ꢂ
3.0 (c 1.09, CHCl3). IR: 3052, 2949,
To
a
0
ꢀC solution of (S)-4-methyl-2,2-diphenyl-1-oxa-2-
mixture of
2880, 1428, 1110, 1045 cmꢃ1. 1H NMR (500 MHz, CDCl3)
d 7.45e7.54
silacyclopentane 3020 (1.29 g, 5.07 mmol) in
a
(m, 6H), 7.23e7.40 (m, 12H), 6.55e6.59 (m, 2H), 4.50 (d, J¼6.5 Hz,
1H), 4.48 (d, J¼6.5 Hz, 1H), 3.82 (s, 2H), 3.31 (dd, J¼9.0, 5.5 Hz, 1H),
3.28 (s, 3H), 3.25 (dd, J¼9.0, 7.0 Hz, 1H), 1.98e2.08 (m, 1H), 1.42 (dd,
J¼15.0, 5.0 Hz, 1H), 1.07 (dd, J¼15.0, 9.0 Hz, 1H), 0.90 (d, J¼6.5 Hz,
dichloromethane/methanol (5:1, 10 mL) was added slowly 48% HF
(1.09 mL, 30.1 mmol). The mixture was allowed to warm to rt
overnight and then concentrated with a rotary evaporator. The
residue was partitioned between ethyl acetate (20 mL) and water
(40 mL). The aqueous phase was extracted with ethyl acetate
(2ꢁ10 mL). The combined organics were washed with water until
neutral, washed with satd NaCl (10 mL), dried over Na2SO4, filtered,
and concentrated in vacuo to give crude fluoro(3-hydroxy-2-
methylpropan-1-yl)diphenylsilane as a yellow oil (1.38 g), which
was used in next step without purification. The yellow oil was taken
up in dimethoxymethane (15 mL). Lithium bromide (0.44 g,
5.07 mmol) and p-toluenesulfonic acid monohydrate (0.30 g,
1.58 mmol) were added and the mixture was stirred at rt overnight.
The solvent was removed with a rotary evaporator, partitioned
between ethyl acetate (20 mL) and water (10 mL). The aqueous
phase was extracted with ethyl acetate (2ꢁ5 mL) and the combined
organics were washed with satd NaCl (10 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. Flash chromatography (9:1
hexanes/ethyl acetate) gave the title compound as a light yellow oil
3H). 13C NMR (125 MHz, CDCl3)
d 166.4, 140.5, 136.5, 135.6, 135.4,
135.3, 129.6, 129.4, 128.4, 128.3, 128.1, 128.0, 127.9, 96.6, 75.5, 55.3,
45.8, 29.9, 20.5, 16.9. Exact Mass for C32H36NO2Si [MþH]þ; calcd:
494.2510, found: 494.2520.
4.5. 1-[((2S)-Methyl)-3-methoxymethoxypropyl]diphenylsila-
nol (34)
A mixture of 33 (23.6 mg, 47.8
mmol) in ether (2 mL), ethanol
(0.3 mL), and oxalic acid dihydrate (3.0 mg, 23.9
mmol) was stirred
at rt for 2 d. Satd NaHCO3 was added until the solution was neutral.
The aqueous phase was extracted with ethyl acetate (3ꢁ2 mL), the
combined organics were dried over Na2SO4, filtered, and concen-
trated. Purification by flash chromatography using a gradient elu-
tion (30:1e5:1e3:2 hexanes/ethyl acetate) gave silanol 34 as a clear
oil (8.7 mg, 27.5
m
mol, 58%, 72% based on recovered 33). Rf¼0.34
(1.34 g, 4.21 mmol, 83%). Rf¼0.68 (4:1 hexanes/ethyl acetate). ½a D20
ꢂ
(4:1 hexanes/ethyl acetate). ½a D20
ꢂ
1.6 (c 0.58 CHCl3). IR: 3413 (br),
ꢃ0.64 (c 1.28, CHCl3). IR: 3071, 2951, 2884, 1591, 1461, 1429, 1386,
3069, 2951, 1428, 1113, 1042 cmꢃ1 1H NMR (500 MHz, CDCl3)
.
1216 cmꢃ1
.
1H NMR (500 MHz, CDCl3)
d
7.59e7.68 (m, 4H),
d 7.54e7.70 (m, 4H), 7.30e7.44 (m, 6H), 4.46e4.58 (m, 2H), 3.75 (s,
7.37e7.50 (m, 6H), 4.55 (d, J¼6.5 Hz, 1H), 4.54 (d, J¼6.5 Hz, 1H), 3.32
(s, 3H), 3.29e3.39 (m, 2H), 2.04e2.14 (m, 1H), 1.43e1.52 (m, 1H),
1.09e1.18 (m, 1H), 1.01 (d, J¼6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3)
1H, disappearance after adding D2O), 3.48 (dd, J¼9.5, 4.5 Hz, 1H),
3.31 (s, 3H), 3.29 (dd, J¼9.5, 5.5 Hz, 1H), 2.02e2.15 (m, 1H), 1.24 (dd,
J¼15.0, 8.0 Hz, 1H), 1.17 (dd, J¼15.0, 5.0 Hz, 1H), 0.97 (d, J¼7.0 Hz,
d
134.3, 134.2, 134.1, 133.9, 133.8, 130.6, 128.2, 96.5, 74.9, 55.2, 29.4,
3H). 13C NMR (125 MHz, CDCl3)
d 137.4, 137.2, 134.3, 134.2, 129.84,
20.0, 19.1 (d, JCF¼14.5 Hz). Exact Mass for C18H23FNaO2Si [MþNa]þ;
129.81, 128.1, 128.0, 96.6, 75.5, 55.6, 29.7, 21.8, 21.5. Exact Mass for
calcd: 341.1344, found: 341.1343.
C18H24NaO3Si [MþNa]þ; calcd: 339.1387, found: 339.1377.
4.3. N-(Diphenylmethylene)-1-[(4-(3-methyl)-1-butenyl)di-
4.6. a-[[(2S)-2-Methyl-3-(methoxymethoxy)propyl]diphe-
phenyl silyl]methanamine (32)
nylsilyl]methanamine (35)
Following the procedure for 33 using benzophenone N-methyl-
imine (150 mg, 0.77 mmol) and fluorosilane 2619 (0.14 g, 0.52 mmol)
gave 32 as a light yellow oil (0.19 g, 0.43 mmol, 84%). Rf¼0.89 (1:1
Following the procedure for 43, using 33 (230.0 mg, 0.47 mmol)
and hydrazine hydrate (0.11 mL, 2.26 mmol) in methanol (1 mL) for
2 d gave 35 as a colorless oil (127.8 mg, 0.39 mmol, 83%). Rf¼0.24
hexanes/ethyl acetate). 1H NMR (400 MHz, CDCl3)
d
7.33e7.49 (m,
(ethyl acetate). ½a D20
ꢂ
1.1 (c 0.58 CHCl3). IR: 3776, 3068, 2950, 2906,
6H), 7.31e7.52 (m,12H), 6.72 (dt, J¼6.4,1.6 Hz, 2H), 5.91 (ddd, J¼17.2,
10.4, 7.2 Hz, 1H), 4.95 (dt, J¼17.2, 1.6 Hz, 1H), 4.87 (ddd, J¼10.0, 2.0,
0.8 Hz,1H), 3.98 (d, J¼12.0 Hz,1H), 3.95 (d, J¼12.0 Hz,1H), 2.52e2.64
(m,1H),1.52 (dd, J¼15.2, 6.8 Hz,1H),1.40 (dd, J¼14.8, 7.2 Hz,1H),1.11
2883, 2822, 1428, 1110, 1045 cmꢃ1 1H NMR (500 MHz, CDCl3)
.
d
7.54e7.60 (m, 4H), 7.33e7.42 (m, 6H), 4.52 (d, J¼6.5 Hz,1H), 4.51 (d,
J¼6.5 Hz,1H), 3.30 (s, 3H), 3.29 (dd, J¼8.0, 5.5 Hz,1H), 3.26 (dd, J¼9.5,
6.0 Hz,1H), 2.81 (d, J¼15.0 Hz,1H), 2.77 (d, J¼15.0 Hz,1H),1.91e2.01
(m, 1H), 1.38 (dd, J¼15.0, 4.5 Hz, 1H), 1.26 (br, 2H), 1.01 (dd, J¼15.0,
(d, J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 166.3, 146.7, 140.5,
136.5, 135.6, 135.4, 135.3, 129.5, 129.4, 128.4, 128.3, 128.1, 128.0,
127.9, 127.8, 111.5, 45.7, 33.9, 24.0, 20.3. Exact Mass for C31H31NNaSi
[MþNa]þ; calcd: 468.2118, found: 468.2098.
8.5Hz,1H), 0.89 (d, J¼6.5Hz, 3H).13C NMR(125MHz, CDCl3)
d 135.24,
135.23,135.1,129.7,128.2, 96.6, 75.5, 55.3, 29.9, 28.7, 20.5,16.4. Exact
Mass for C19H28NO2Si [MþH]þ; calcd: 330.1884, found: 330.1886.
4.4. N-(Diphenylmethylene)-1-[(1-((2S)-methyl)-3-
4.7. a-[4-[2-Methyl-1-propenyl]diphenylsilyl]methanamine (36)
methoxymethoxypropyl)diphenylsilyl]methanamine (33)
Following the procedure for 43, using 32 (260.0 mg, 0.58 mmol)
and hydrazine hydrate (0.02 mL, 0.49 mmol) in ethanol (5.5 mL) at
rt for 4 d gave an 85:15 mixture of 36 and 37 as a clear, colorless oil
(93 mg, 0.33 mmol, 57%). Rf¼0.24 (1:1 hexanes/ethyl acetate). IR:
LDA (5.44 mmol) was prepared by adding 3.39 mL n-butyl-
lithium (1.6
M in hexanes) to diisopropylamine (0.76 mL,
5.44 mmol) in THF (6 mL) and stirring for 0.5 h at ꢃ78 ꢀC. This
was added dropwise to benzophenone N-methylimine (0.59 g,
3.02 mmol) in THF (6 mL) at ꢃ78 ꢀC. The mixture was stirred for
1.5 h to give a dark red solution that was added to fluorosilane 29
(0.64 g, 2.00 mmol) in THF (4 mL) and this mixture was stirred at
ꢃ78 ꢀC for 1.5 h. After addition of satd NH4Cl (2 mL) at ꢃ78 ꢀC the
solvent was evaporated and the residue was partitioned between
ethyl acetate (15 mL) and water (10 mL). The aqueous phase was
3436, 3373, 3068, 2958, 2902, 2872,1428,1333,1114, 998, 911 cmꢃ1
.
1H NMR (500 MHz, CDCl3)
d 7.51e7.66 (m, 4H), 7.30e7.49 (m, 6H),
5.78 (ddd, J¼17.5, 10.0, 7.5 Hz, 1H), 4.91 (d, J¼17.0 Hz, 1H), 4.83 (d,
J¼10.0 Hz, 1H), 2.81 (s, 2H), 2.35e2.48 (m, 1H), 1.36 (dd, J¼15.0,
7.5 Hz, 1H), 1.25 (dd, J¼15.0, 7.0 Hz, 1H), 1.03 (d, J¼7.0 Hz, 3H). 13C
NMR (125 MHz, CDCl3)
d 146.5, 135.25, 135.23, 129.6, 129.5, 128.1,
111.7, 34.0, 28.6, 24.1, 19.9.

Y. Bo et al. / Tetrahedron 69 (2013) 7779e7784
7783
4.8. N-(Diphenylmethylene)-1-[(4-(3-methyl)-1-butenyl)di-
phenylsilyl]-2-phenylethanamine (38)
0.79 (d, J¼6.6 Hz, 3H).13C NMR (125 MHz, CDCl3)
d
165.7,140.7,137.0,
136.2, 134.9, 134.7, 134.5, 134.4, 129.53, 129.46, 128.5, 128.4, 128.3,
128.2, 127.9, 127.84, 127.82, 127.78, 96.59, 96.55, 75.6, 75.5, 55.24,
55.20, 51.21, 51.18, 29.9, 29.8, 20.6, 20.5,18.2,15.65,15.59. Exact Mass
for C33H38NO2Si [MþH]þ; calcd: 508.2666, found: 508.2669.
Following the procedure for 39, using 32 (40 mg, 90
benzyl bromide (21.2 L, 180 mol) gave 38 as a clear, colorless oil,
a 1:1 mixture of diastereomers (34 mg, 63.5
mol, 71%). 1H NMR
(500 MHz, CDCl3)
7.67 (ddd, J¼9.3, 5.4, 1.5 Hz, 4H), 7.60 (dd, J¼8.0,
mmol) and
m
m
m
d
4.11. N-(Diphenylmethylene)-1-[(1-((2S)-methyl)-3-
methoxymethoxypropyl)diphenylsilyl]-4-methyl-1-
pentanamine (41)
1.4 Hz, 4H), 7.54 (dt, J¼8.2,1.2 Hz, 4H), 7.47e7.28 (m,18H), 7.20e7.11
(m, 8H), 7.02 (td, J¼8.2, 2.3 Hz, 4H), 6.93e6.87 (m, 4H), 5.78 (dtd,
J¼17.1, 10.1, 7.1 Hz, 2H), 5.70 (s, 3H), 4.82 (dt, J¼17.1, 1.5 Hz, 1H),
4.77e4.67 (m, 3H), 3.71 (ddd, J¼11.4, 9.8, 1.8 Hz, 2H), 3.16 (dd,
J¼13.2, 11.3 Hz, 2H), 2.95 (ddd, J¼13.2, 3.0, 1.8 Hz, 2H), 2.48e2.33
(m, 2H), 1.45 (ddd, J¼15.0, 6.2, 4.3 Hz, 2H), 1.37e1.29 (m, 3H), 0.98
(d, J¼6.7 Hz, 3H), 0.95 (d, J¼6.7 Hz, 3H). 13C NMR (125 MHz, CDCl3)
Following the procedure for 39, using 33 (38.0 mg, 77.0
and 1-bromo-3-methylbutane (18.5 L, 154 mol) gave 41 as a clear
oil, a 1:1 mixture of diastereomers (17 mg, 30.9 mol, 40%, 95%
based on recovered starting material). Rf¼0.83 (4:1 hexanes/ethyl
acetate). IR: 3068, 2952, 2927, 1428 cmꢃ1 1H NMR (500 MHz,
CDCl3)
7.58 (d, J¼7.4 Hz, 8H), 7.52 (dd, J¼7.0, 0.9 Hz, 4H), 7.25e7.38
mmol)
m
m
m
d
165.4, 146.7, 146.6, 141.5, 140.4, 136.5, 136.5, 136.2, 136.1, 134.6,
.
134.3, 134.2, 134.0, 129.6, 129.3, 129.2, 129.0, 128.1, 127.9, 127.9,
127.8, 127.7, 127.5, 127.3, 125.6, 111.1, 110.9, 58.9, 58.8, 38.58, 38.55,
33.5, 33.3, 23.7, 23.4, 19.1, 19.0. Exact Mass for C38H37NNaSi
[MþNa]þ; calcd: 558.2587, found: 558.2577.
d
(m, 24H), 6.59 (d, J¼3.6 Hz, 4H), 4.51 (q, J¼6.4 Hz, 2H), 4.48 (d,
J¼0.8 Hz, 2H), 3.59 (dd, J¼4.5, 2.2 Hz, 1H), 3.57 (dd, J¼4.5, 2.2 Hz,
1H), 3.28 (s, 3H), 3.24 (s, 3H), 3.16e3.33 (m, 4H), 1.85e2.02 (m, 4H),
1.65 (ddd, J¼13.2, 6.7, 4.0 Hz, 2H), 1.42 (ddd, J¼14.9, 10.0, 4.9 Hz,
2H), 1.31 (ddd, J¼13.2, 8.3, 5.0 Hz, 2H), 1.13e1.24 (m, 2H), 1.05 (ddd,
J¼14.8, 8.8, 1.0 Hz, 2H), 0.86e0.91 (m, 2H), 0.85 (d, J¼6.6 Hz, 3H),
0.82 (d, J¼6.6 Hz, 3H), 0.75 (d, J¼2.6 Hz, 3H), 0.74 (d, J¼2.6 Hz, 3H),
0.72 (d, J¼2.8 Hz, 3H), 0.71 (d, J¼2.8 Hz, 3H). 13C NMR (125 MHz,
4.9. N-(Diphenylmethylene)-1-[(1-((2S)-methyl)-3-methoxy-
methoxypropyl)diphenylsilyl]-2-phenylethanamine (39)
sec-Butyllithium (0.29 mL of a 1.1 M solution in cyclohexanes,
0.32 mmol) was added to a ꢃ78 ꢀC solution of 33 (104 mg,
CDCl3) d 164.9, 140.7, 137.2, 136.3, 136.2, 136.1, 135.1, 134.7, 134.6,
0.21 mmol) in THF (5 mL). After 1.5 h benzyl bromide (50.1
m
L,
134.4, 129.45, 129.39, 129.36, 129.3, 128.5, 128.31, 128.26, 128.1,
127.89, 127.85, 127.74, 127.71, 96.61, 96.56, 75.6, 75.5, 56.75, 56.69,
55.3, 55.2, 38.52, 38.48, 30.06, 30.00, 29.89, 29.85, 28.0, 22.9, 22.6,
20.6, 15.6, 15.4. Exact Mass for C37H46NO2Si [MþH]þ; calcd:
564.3292, found: 564.3368.
0.42 mmol) in THF (1 mL) was added to the dark red solution and
then stirred for 5 h. To the resulting light yellow solution was added
satd NH4Cl (0.5 mL) at ꢃ78 ꢀC and the mixture was concentrated.
The residue was partitioned between ethyl acetate (3 mL) and
water (1 mL). The aqueous phase was extracted with ethyl acetate
(2ꢁ3 mL), the combined organics were washed with satd NaCl
(1 mL), dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography using gradient elution
(12:1e9:1 hexanes/ethyl acetate) gave the 39 as a light yellow oil,
a 1:1 mixture of diastereomers (70 mg, 0.12 mmol, 57%). Compound
33 (40 mg, 0.08 mmol) was recovered (92% yield of 39). Rf¼0.12
4.12. N-(Diphenylmethylene)-4-[(1-((2S)-methyl)-3-
methoxymethoxypropyl)diphenylsilyl]-1-buten-4-amine (42)
Following the procedure for 39, using 33 (32 mg, 64.8
allyl bromide (11.2 L,130 mol) gave 42 as a clear oil, a 1:1 mixture
of diastereomers (15 mg, 28.1 mol, 43%, 63% based on recovered
mmol) and
m
m
m
(30:1 hexanes/ethyl acetate) IR: 3058, 2924, 2882, 1428, 1280 cmꢃ1
.
starting material). Rf¼0.71 (4:1 hexanes/ethyl acetate). IR: 3069,
1H NMR (500 MHz, CDCl3)
d
7.71 (d, J¼6.4 Hz, 4H), 7.60 (d, J¼7.0 Hz,
2949, 2925, 2883, 1428, 1109, 911 cmꢃ1. 1H NMR (500 MHz, CDCl3)
8H), 7.55 (d, J¼7.2 Hz, 4H), 7.27e7.48 (m, 21H), 7.10e7.23 (m, 9H),
7.03 (t, J¼7.5 Hz, 4H), 6.92 (d, J¼3.6 Hz, 4H), 5.74 (br s, 4H), 4.55
(ABq, J¼8.4 Hz, 2H), 4.52 (s, 2H), 3.72 (d, J¼11.0 Hz, 2H), 3.32e3.39
(m, 2H), 3.31 (s, 3H), 3.28 (s, 3H), 3.18 (dd, J¼25.5, 13.5 Hz, 2H), 2.98
(dd, J¼12.8, 8.9 Hz, 2H), 2.01 (dt, J¼14.2, 7.7 Hz, 2H),1.51 (dd, J¼15.0,
4.7 Hz, 2H), 1.09e1.18 (m, 2H), 0.90 (d, J¼6.5 Hz, 3H), 0.89 (d,
d 7.51e7.66 (m, 12H), 7.20e7.37 (m, 24H), 6.61e6.74 (m, 4H), 5.61
(ddt, J¼13.3, 7.4, 6.8 Hz, 2H), 4.88 (d, J¼12.2 Hz, 4H), 4.48 (dd, J¼4.6,
2.1 Hz, 4H), 3.71 (dt, J¼10.9, 2.1 Hz, 2H), 3.28 (s, 3H), 3.24 (s, 3H),
3.16e3.33 (m, 4H), 2.64e2.75 (m, 2H), 2.35e2.45 (m, 2H), 1.85e1.96
(m, 2H), 1.41 (ddd, J¼15.0, 4.4, 3.7 Hz, 2H), 1.06 (dd, J¼9.0, 5.0 Hz,
1H), 1.03 (dd, J¼9.0, 5.0 Hz, 1H), 0.83 (d, J¼7.0 Hz, 3H), 0.81 (d,
J¼6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d
165.7, 141.73, 141.71,
J¼6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 165.5, 140.7, 138.4, 136.9,
140.5, 136.6, 136.3, 136.22, 136.18, 134.7, 134.3, 134.0, 129.8, 129.6,
129.55, 129.52, 129.3, 128.25, 128.20, 128.1, 128.01, 127.99,
127.9, 127.8, 127.5, 125.8, 96.61, 96.57, 75.6, 75.5, 59.19, 59.16, 55.3,
55.2, 38.66, 38.62, 29.93, 29.87, 20.64, 20.62, 15.7, 15.5. Exact Mass
for C39H42NO2Si [MþH]þ; calcd: 584.2979, found: 584.2992.
136.3, 136.21, 136.17, 134.7, 134.3, 134.2, 134.0, 129.6, 129.52, 129.50,
129.4,128.6,128.4,128.2,128.1,127.99,127.94,127.91,127.84,127.79,
115.7, 96.60, 96.56, 75.50, 75.49, 56.51, 56.46, 55.3, 55.2, 36.85,
36.81, 29.88, 29.83, 20.59, 20.57, 15.7, 15.5. Exact Mass for
C35H40NO2Si [MþH]þ; calcd: 534.2823, found: 534.2829.
4.10. N-(Diphenylmethylene)-1-[(1-((2S)-methyl)-3-
4.13. 1-[(1-((2S)-Methyl)-3-methoxymethoxypropyl)diphe-
methoxymethoxypropyl)diphenylsilyl]-1-ethanamine (40)
nylsilyl]-2-phenyl-1-ethanamine (43)
Following the procedure for 39, compound 33 (38.2 mg,
Hydrazine monohydrate (0.26 mL, 5.35 mmol) was added to
a solution of 39 (63.5 mg, 0.11 mmol) in methanol (2 mL) and the
solution was heated to reflux for 6 d. The mixture was concentrated
and then partitioned between ethyl acetate (5 mL) and water
(1 mL). The aqueous phase was extracted with ethyl acetate
(2ꢁ5 mL) and the combined organics were washed with satd NaCl
(1 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography using a gradient
elution (12:1e2:1 hexanes/ethyl acetate) to give 43 as a clear oil
(18.4 mg, 0.044 mmol, 40%). Compound 39 (22 mg, 0.038 mmol)
was recovered (62% yield based on recovered starting material).
77.4
m
mol) and methyl iodide (9.6
mL,155
mmol) gave 40 as a clear oil,
a 1:1 mixture of diastereomers (23 mg, 45.3
m
mol, 59%, 92% based on
recovered starting material). Rf¼0.71 (4:1 hexanes/ethyl acetate).
IR: 3067, 2949, 2924, 2884, 1428 cmꢃ1. 1H NMR (500 MHz, CDCl3)
d
7.61 (dd, J¼6.5, 5.5 Hz, 4H), 7.57 (dd, J¼6.5, 5.0 Hz, 4H), 7.54 (dd,
J¼5.5, 4.5 Hz, 4H), 7.27e7.44 (m, 24H), 6.85 (br s, 4H), 4.49 (dd,
J¼10.2, 6.3 Hz, 2H), 4.46 (dd, J¼8.6, 6.2 Hz, 2H), 3.74 (q, J¼7.1 Hz, 2H),
3.27 (s, 3H), 3.24 (s, 3H), 3.15e3.29 (ddd, J¼14.5, 9.2, 6.9 Hz, 4H),
1.85e2.00 (m, 2H), 1.38 (d, J¼5.0 Hz, 3H), 1.38 (d, J¼5.0 Hz, 3H),
1.33e1.42 (m, 2H),1.02 (dt, J¼15.1, 8.6 Hz, 2H), 0.83 (d, J¼6.6 Hz, 3H),

7784
Y. Bo et al. / Tetrahedron 69 (2013) 7779e7784
The same reaction (67 mg of 39, 0.08 M in ethanol) with hy-
Supplementary data
drazine hydrate (30 equiv) under reflux for 1 d gave 15% yield (24%
based on recovered starting material).
1H and 13C NMR spectra of new compounds is available as
Supplementary data. Supplementary data related to this article can
be found at http://dx.doi.org/10.1016/j.tet.2013.06.022.
Rf¼0.75 (1:1 hexanes/ethyl acetate). IR: 3364, 3297, 3069, 3024,
2925, 1428, 1109 cmꢃ1. 1H NMR (500 MHz, CDCl3)
d 7.62e7.71 (m,
7H), 7.34e7.47 (m, 12H), 7.24e7.32 (m, 5H), 7.17e7.22 (m, 2H),
7.12e7.17 (m, 4H), 4.48e4.54 (m, 4H), 3.292 (s, 3H), 3.288 (s, 3H),
3.21e3.28 (m, 4H), 3.04e3.13 (m, 4H), 2.28e2.36 (m, 2H), 1.87e1.97
(m, 2H), 1.39 (br, 4H), 1.34e1.49 (m, 2H), 1.06 (dd, J¼15.0, 8.5 Hz,
2H), 0.87 (d, J¼6.5 Hz, 3H), 0.83 (dd, J¼6.5 Hz, 3H). 13C NMR
References and notes
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(125 MHz, CDCl3) d 140.74,140.72,135.9,134.3,134.2,134.14,134.09,
129.8, 129.3, 128.7, 128.2, 126.4, 96.6, 75.5, 75.4, 55.3, 41.6, 40.6,
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calcd: 420.2353, found: 420.2357.
4.14. N-[1-[[(2S)-3-Hydroxy-2-methylpropyl]diphenylsilyl]-2-
phenylethyl]-benzamide (44)12
A methanolic solution of HCl (17.5
mL, 4 M) was added to 43
(4.9 mg, 11.7
m
mol) at 0 ꢀC and stirred at rt overnight. The solvent
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We gratefully acknowledge support from the National Institutes
of Health (GM076471).