An approach toward homocalystegines and silyl-homocalystegines. acid-mediated migrations of acetates in seven-membered ring systems

Article abstract of DOI:10.1021/jo101945h

A short access to homocalystegine analogues silylated at C7 is described. The synthesis involves the desymmetrization of a (phenyldimethylsilyl) methylcycloheptatriene using osmium-mediated dihydroxylation, followed by the diol protection and a cycloaddition involving the remaining diene moiety and an acylnitroso reagent. Additions of the osmium and acylnitroso reagents were shown, through X-ray diffraction studies of the resulting major isomers, to occur anti and syn, respectively, relative to the SiCH₂ substituent.N-Obond cleavage on the resulting cycloadduct then produces the aminopolyol having a silylmethyl substituent. Oxidation of the C-Si bond also afforded an access to unusual amino-heptitols having five contiguous stereogenic centers. In the course of this work, we finally observed a unusual rearrangement taking place on cycloheptanone 18 substituted by two acetyl groups and a neighboring Boc-protected amine. A profound reorganization of the substituents on the seven-membered ring effectively took place under acidic conditions (TFA) leading to the thermodynamically more stable homocalystegine-type compound. DFT calculations of the conformational energy of isomeric silyl homocalystegines indicated that the product observed upon the acid-mediated rearrangement was the most stable of a series of analogues with various distributions of substituents along the seven-membered ring backbone. A tentative mechanism is proposed to rationalize the acetate migrations and inversions of the stereochemistry at various stereocenters.

Full text of DOI:10.1021/jo101945h

pubs.acs.org/joc
An Approach Toward Homocalystegines and Silyl-homocalystegines.
Acid-Mediated Migrations of Acetates in Seven-Membered Ring Systems
†
,†
‡
§
Redouane Beniazza, Val ꢀe rie Desvergnes,* Goverdhan Mehta, Nicolas Blanchard,
†
,†
Fr ꢀe d ꢀe ric Robert, and Yannick Landais*
†
Universit eꢀ de Bordeaux, Institut des Sciences Mol eꢀ culaires, UMR-CNRS 5255, 351, Cours de la Lib eꢀ ration,
F-33405 Talence cedex, France, Department of Organic Chemistry, Indian Institute of Science,
‡
§
Bangalore 560 012, India, and Organic, Bioorganic and Macromolecular Chemistry Department,
ENSCMu - CNRS - Universit eꢀ de Haute-Alsace, 3 rue Alfred Werner, 68093 Mulhouse Cedex, France
v.desvergnes@ism.u-bordeaux1.fr; y.landais@ism.u-bordeaux1.fr
Received October 1, 2010
A short access to homocalystegine analogues silylated at C7 is described. The synthesis involves the
desymmetrization of a (phenyldimethylsilyl)methylcycloheptatriene using osmium-mediated dihy-
droxylation, followed by the diol protection and a cycloaddition involving the remaining diene
moiety and an acylnitroso reagent. Additions of the osmium and acylnitroso reagents were shown,
through X-ray diffraction studies of the resulting major isomers, to occur anti and syn, respectively,
relative to the SiCH substituent. N-O bond cleavage on the resulting cycloadduct then produces the
2
aminopolyol having a silylmethyl substituent. Oxidation of the C-Si bond also afforded an access to
unusual amino-heptitols having five contiguous stereogenic centers. In the course of this work, we
finally observed a unusual rearrangement taking place on cycloheptanone 18 substituted by two
acetyl groups and a neighboring Boc-protected amine. A profound reorganization of the substit-
uents on the seven-membered ring effectively took place under acidic conditions (TFA) leading to the
thermodynamically more stable homocalystegine-type compound. DFT calculations of the con-
formational energy of isomeric silyl homocalystegines indicated that the product observed upon the
acid-mediated rearrangement was the most stable of a series of analogues with various distributions
of substituents along the seven-membered ring backbone. A tentative mechanism is proposed to
rationalize the acetate migrations and inversions of the stereochemistry at various stereocenters.
Introduction
such as castanospermine 1 and swainsonine 2 (Figure 1) have
been the subjects of numerous reports for their biological
Calystegines are secondary metabolites isolated for the
1
first time in 1988 from Calystegia sepium; 26 different
4
activities, calystegines have attracted much less attention.
However, these alkaloids enjoy an unusual polyhydroxy-
lated bicyclic skeleton, and interesting biological activities
probably lie hidden as shown by the recent report by Asano
et al., who showed that calystegines A (3), B (4), B (5), and
2
members of this class of alkaloids have been isolated so far.
They possess a polyhydroxylated nortropane skeleton and
exhibit specific glycosidase (glucosidase and galactosidase)
3
inhibitory activities. Interestingly, whereas other iminosugars
3
1
2
5
C (6) are potent lead compounds for Gaucher disease.
1
6
Various elegant approaches have been devised, starting
7
from sugar precursors, using for instance ring-closing me-
(
1) Tepfer, D.; Goldmann, Pamboukdjian, N.; Maille, M.; Lepingle, A.;
Chevalier, D.; Denarie, J.; Rosenberg, C. J. Bacteriol. 1988, 170, 1153–1161.
2) (a) Goldmann, A.; Milat, M. L.; Ducrot, P. H.; Lallemand, J. Y.;
Maille, M.; Lepingle, A.; Charpin, I.; Tepfer, D. Phytochemistry 1990, 29,
125–2127. (b) Dragger, B. Nat. Prod. Rep. 2004, 21, 211–223. (c) Watson,
A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry
001, 56, 265–295. (d) Biastoff, S.; Dr €a ger, B. Alkaloids 2007, 64, 49–102.
e) Asano, N. Glycoscience 2008, 1887–1911.
8
tathesis to generate the seven-membered ring. Other strate-
gies were based on the stereocontrolled introduction of the
(
9
required substituents on cycloheptane building blocks. As
2
shown previously, we have recently initiated a study on a
novel approach to calystegines and analogues relying on the
2
(
DOI: 10.1021/jo101945h
r 2011 American Chemical Society
Published on Web 01/11/2011
J. Org. Chem. 2011, 76, 791–799 791

Beniazza et al.
JOCArticle
1
2
faces of the triene framework and may be oxidized later
in the sequence to afford an additional hydroxyl group.
For biological activity screening purposes, it may also be
interesting to keep the silicon group in the final target as
this lipophilic group has been shown recently to enhance the
1
3
activity in certain cases. We report here the extension of the
above approach to the synthesis and desymmetrization of
7
-silylmethylcycloheptatrienes such as II and their subse-
quent elaboration. Compound II is available from the
tropylium salt I and can be functionalized into calystegine
analogue III using osmium-mediated dihydroxylation and
acyl-nitroso cycloaddition, these processes allowing the in-
corporation of the OH and NH substituents. In the course
2
of these investigations, we also observed an intriguing re-
arrangement that has not, to our knowledge, been described
so far. A complete description on the elaboration of II and
a tentative mechanism of the rearrangement is proposed
below.
FIGURE 1. Calystegines and analogues.
Results and Discussion
desymmetrization of silyl-cycloheptatrienes, starting from
0
1
commercially available tropylium salts. Various silyl-metal
complexes can be added that generate 7-silylcyclohepta-
The study started with the synthesis of (phenyldimethylsilyl)-
methylcycloheptatriene 7, obtained in a reasonable yield
through treatment of tropylium tetrafluoroborate with the
1
1
trienes in good yield. Interestingly, this approach offers an
entry to calystegines having hydroxyl substituents both on
the five- and six-membered rings, by the suitable functiona-
lization of the three double bonds of cycloheptatriene. The
silicon group both used is to differentiate the diastereotopic
1
1
suitable Grignard reagent (Scheme 1). Dihydroxylation of
7 using K OsO dihydrate as an osmium source and K Fe-
(CN) as a reoxidant led to a separable mixture of diol 8
2
4
3
1
4
6
and hydroxyketone 9. The latter is likely the result of an
overoxidation of the osmate intermediate in the medium,
a well-known reaction observed with other metals, includ-
(
3) (a) Simmonds, M. S. J.; Kite, G. C.; Porter, E. A. In Iminosugars as
Glycosidase inhibitors-Nojirimycin and Beyond; St u€ tz, A. E., Ed.; Wiley-
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G. W. Tetrahedron: Asymmetry 2000, 11, 1645–1680. (c) Asano, N.; Kato,
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Curr. Top. Med. Chem. 2003, 3, 471–484. (e) Asano, N. Glycobiology 2003,
15
ing Mn and Ru. The overall yield of the dihydroxyla-
tion was found to be less than that observed for the
SCHEME 1. Synthesis and Dihydroxylation of 7
1
3, 93R–104R. (f) Goldmann, A.; Message, B.; Tepfer, D.; Molyneux, R. J.;
Duclos, O.; Boyer, F.-D.; Pan, Y. T.; Elbein, A. D. J. Nat. Prod. 1996, 59,
137–1142. (g) Asano, N.; Kato, A.; Kizu, H.; Matsui, K.; Griffiths, R. C.;
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1
(
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J. M. F. G. J. Biol. Chem. 1998, 273, 26522.
(
4) Iminosugars: From Synthesis to Therapeutic Applications; Compain,
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73, 4082–4092.
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(
2
(
2
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7
92 J. Org. Chem. Vol. 76, No. 3, 2011

Beniazza et al.
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TABLE 1. Cycloaddition Reactions between 10 and 11 and Acylnitroso
Reagents
the solvent, and the oxidant. The results are summarized in
Table 1.
The reaction led in most cases to two regioisomers as single
diastereomers that could be separated through chromatog-
raphy. Moderate to good regiocontrol was observed, depending
on the nature of the protective groups, the benzylated precursor
leading to higher differentiation. The large amount of oxidant
and hydroxylamine generally required may be explained by
the low reactivity of dienes 10-11. The regio- and diaster-
eoselectivity of the cycloaddition on diacetate 10 was estab-
lished unambiguously through X-ray structure determination
of the regioisomer 13a. The same topicity was assumed for
the dibenzylated analogue 11. The formation of 13a-15a as
major regioisomers may be rationalized invoking steric
interactions between the bulky carbamate and the silylmethyl
a/b
product ratio
yield
g
(%)
e
entry diene
oxidant
solvent
Cl
a
4
c
f
1
2
3
4
5
10
10
10
11
11
n-Bu
4
NIO
CH
2
2
/MeOH3:1 13a/13b
2:1
3:2
5:4
52
73
66
56
57
b
4
c
d
c
c
NaIO
NaIO
NaIO
NaIO
MeOH/H
MeOH/H
MeOH/H
MeOH/H
2
O3:1
2
O3:1
2
O3:1
2
O3:1
13a/13b
13a/13b
b
4
10
groups. As observed in the silylcycloheptatrienes series, the
approach of the nitroso reagent occurred syn to the silylmethyl
substituent.
b
4
14a/14b 16:1
15a/15b 15:1
b
b
4
a
1
0 equiv of oxidant and hydroxylamine were used. 3 equiv of
Although benzylated diene 11 led to better regiocontrol,
the further elaboration of the cycloadduct was continued
with bis-acetate 13a more easily available on larger scale.
Cleavage of the N-O bond was thus performed using Mo-
(CO) in CH CN/H O mixture (use of SmI in THF gave
c d e
oxidant and hydroxylamine were used. T = 20 °C. T = 40 °C. Ratio
of isolated isomers. 10% of a third isomer was isolated, which structure
f
g
could not be determined. Combined isolated yields of both isomers.
1
6
silylcyclohexadiene analogue, probably due to some con-
formational effects. In contrast, the silylmethyl group was
found to be very efficient at differentiating the two diastereo-
topic faces, the osmium reagent approaching anti relative to
the silyl group (vide infra, X-ray diffraction studies on 13a).
The diastereocontrol was estimated to be complete by
6
3
2
2
similar results), leading to Boc-protected amino-alcohol 16
in good yield. The five-membered nitrogen ring found in
SCHEME 2. Elaboration of 13a and Synthesis of Silyl-calyste-
gine 20
1
H NMR studies. An enantioselective version of this reaction
was also performed using Sharpless chiral ligands. Diol 8
with up to 63% enantiomeric excess was thus obtained
using (DHQD) PYR as a chiral ligand. However, because of
2
this low enantiocontrol, the remaining part of the study was
carried out and described in racemic series using achiral
quinuclidine as a ligand. Protection of the diol as a bisacetate led
to 10 in good yield. It is important to notice that performing
the reaction via a three-step sequence without purification of
intermediates 7 and 8 led to exactly the same overall yield.
The hydroxyl groups were also protected as benzyl ethers,
but in this case, yields were modest, the reaction leaving a
large amount of monobenzylated product 12.
With cycloheptadienes 10 and 11 in hand, a cycloaddition,
involving the diene moiety of 10 and 11 and an acyl-nitroso
reagent generated in situ, was performed to introduce the
1
7
required amino and hydroxyl groups. The regio- and diaster-
eocontrol were studied varying the nature of the precursor,
(
13) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc.
007, 129, 1020–1021.
14) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
2
(
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M. J. Org.
Chem. 1992, 57, 2768–2771. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000;
pp 357-398.
(15) (a) Plietker, B. J. Org. Chem. 2003, 68, 7123–7125. (b) Plietker, B.
Org. Lett. 2004, 6, 289–291. (c) Plietker, B.; Niggemann, M.; Pollrich, A. Org.
Biomol. Chem. 2004, 2, 1116–1124. (d) Plietker, B.; Niggemann, M. Org.
Biomol. Chem. 2004, 2, 2403–2407.
(16) (a) Angelaud, R.; Landais, Y. J. Org. Chem. 1996, 61, 5202–5203. (b)
Angelaud, R.; Landais, Y. Tetrahedron Lett. 1997, 38, 8841–8844. (c)
Angelaud, R.; Landais, Y.; Parra-Rapado, L. Tetrahedron Lett. 1997, 38,
8
845–8848. (d) Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org.
Chem. 1999, 64, 9613–9624.
17) (a) Souli ꢀe , J.; Faitg, T.; Betzer, J. F.; Muller, B.; Lallemand, J. Y.
(
Tetrahedron Lett. 1996, 52, 9485–9488. (b) Souli ꢀe , J.; Faitg, T.; Betzer, J. F.;
Lallemand, J. Y. Tetrahedron 1996, 52, 15137–15146.
J. Org. Chem. Vol. 76, No. 3, 2011 793

Beniazza et al.
JOCArticle
12
calystegines was then elaborated through oxidation of the
unprotected alcohol with PCC, followed by hydrogenation
of the double bond, leading to ketone 18 in 81% over two
steps. Removal of the Boc group under acidic conditions
was supposed to provide the corresponding calystegine-type
structure A, but surprisingly, X-ray diffraction studies of
crystals issued from the Boc deprotection led to structure 19,
in which an acetate (at C2) and the amino group (at C1) had
migrated. Efforts were made to perform the deprotection of
the unexpected calystegine analogue 19. Mild basic condi-
tions last provided the acetamide 20 in quantitative yield.
Unfortunately and regardless of the conditions used, it was
impossible in our hands to cleave efficiently the acetamide
moiety to provide the free amine. The rearrangement observed
in the sequence depicted in Scheme 2 is puzzling, and it was
not clear in which step it occurred. Reasoning that the hydro-
genation step in the presence of palladium catalysts might be
at the origin of the rearrangement due to π-allyl-palladium
complexes formed during the reaction, it was decided to
repeat the whole sequence, changing the order of the steps.
The new sequence of reactions is depicted in Scheme 3 below.
Diacetate 13a was thus hydrogenated to provide the satu-
rated analogue 21 in nearly quantitative yield. N-O bond
the C-Si bond. Using standard Fleming conditions, oxida-
tion of 18 afforded the R-bromoketone 23, which structure
was unambiguously assigned through X-ray diffraction stud-
ies. Bromination occurs before or after the C-Si bond oxida-
tion, through reaction between the enol form of ketone 18
and bromine issued from the reaction of KBr and AcOOH
under acidic conditions. Finally, from the structure of 23, it
can be deduced that 18 has not been rearranged during the
sequence in Scheme 3, implying that the rearrangement does
take place during Boc deprotection under acidic conditions
(TFA).
The rather mild conditions used for the deprotection of
the Boc protecting group imply that a strong driving
force operates during the rearrangement. Seven-mem-
bered rings are known to be flexible, and acetates are
well-known to migrate from one position to another, for
instance in sugars. We therefore envisioned that a thermo-
dynamically driven pathway might lead to the rearranged
TABLE 2. DFT Calculations (B3LYP-6-31G(d)) of the Conforma-
tional Energy of Isomeric Silylcalystegines
cleavage with SmI led to the protected amino-alcohol 22,
2
which was then oxidized with PCC, affording the N-protected
aminoketone 18, identical in many respect with that
formed by the sequence depicted in Scheme 2. Boc de-
protection of 18 with TFA led as before to the rearranged
product 19 in 86% yield. In our efforts to reach homo-
calystegine analogues, we also attempted the oxidation of
SCHEME 3. Second Approach to the Synthesis of Silyl-calys-
tegine 19
7
94 J. Org. Chem. Vol. 76, No. 3, 2011

Beniazza et al.
JOCArticle
FIGURE 2. Mechanism of the rearrangement of Boc-protected amino-ketone 18.
structure 19 through a succession of acetate migrations and
aminal ring opening. DFT calculations (B3LYP-6-31G(d))
were thus carried out to estimate the ground state energy of
the various isomers of 19 and the expected product A
SCHEME 4. Synthesis of Protected Amino-heptitol 25
(Scheme 2). As the number of stereoisomers is very high,
considering the number of stereogenic centers, we considered
in the calculations only isomers in which the relative config-
uration between C3 and C4 is trans for steric reasons. The
results summarized in Table 2 indicate that the expected
product A (entry 1) exhibits a relatively high conformational
energy of 15.7 kcal/mol relative to the rearranged product
19 (entry 4), which is effectively the most stable isomer in
this series.
On the basis of these calculations, we propose below a
tentative mechanism for the rearrangement (Figure 2),
which should involve the removal of the Boc group and
then the protonation of the nitrogen of the aminal, followed
by the migration of the acetate from the C2 to the C1
center. This migration would then be followed by the
inversion of the configuration at C3 through an acid-mediated
diacetate 21, through the sequence depicted in Scheme 4.
This involves a C-Si bond oxidation, followed by the
protection of the hydroxyl group as an acetate, which
provided triacetate 24 in 68% overall yield. The N-O bond
18
retro-Michael-Michael process, leading to the more stable
silyl-calystegine 19. This mechanism thus involves two
important events: (1) the acetate migration from C1 to C2
and (2) the epimerization at C3 and C4. We could also
consider that these two events may be inverted, the epimer-
ization occurring first. This pathway was however ruled
cleavage using Mo(CO) (which is easier to handle than
6
SmI ) finally afforded the expected hydroxycarbamate 25.
2
Our efforts to oxidize the free alcohol function unfortunately
led to an inseparable mixture of the desired ketone and the
corresponding unsaturated ketone resulting from the β-elim-
ination of the exocyclic acetate. This last observation sup-
ports our hypothesis of a retro-Michael-Michael process
occurring during the transformation of 18 into 19 (Scheme 3
and Figure 2).
As discussed above, nitroso cycloaddition led, under some
conditions, to large amount of the regioisomeric cycloadducts
13b, 14b, and 15b (Table 1), which might also be valuable
intermediates en route for the synthesis of unusual calystegines.
Compound 13b was thus further functionalized following
the strategy described for the other regioisomer. N-O bond
cleavage of cycloadduct 13b led to the allylic alcohol 26,
oxidation of which using PCC provided a 4:1 mixture of the
unsaturated ketone 27 and the corresponding Boc-protected
aminal 28. Hydrogenation of the double bond in 27 and
removal of the Boc group with trifluoroacetic acid finally
afforded the silyl-calystegine 30 in 34% overall yield from 13b.
0
out by calculating the conformational energy of A (Table 2,
0
entry 2), an epimer of A (at C3 and C4). The energy of A was
found to be lower by nearly 4 kcal/mol relative to the other
isomers, implying that if epimerization at C3 and C4 from 18
0
occurred first, then A would likely be the only product of the
reaction. Allowing for the fact that only 3,4-trans product was
formed, 3,4-cis isomers energies were not calculated.
This rearrangement thus leads to an unusual type of calys-
tegines having a fully functionalized five-membered ring
starting from the readily available cycloheptane aminodiol
18. In parallel, we have developed a straightforward route to
the penta-substituted aminocycloheptitol 25 starting from
(
18) Retro-Michael processes have been observed during our studies on
closely related ketones, with the loss of the acetate and formation of the R,β-
unsaturated ketone.
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Beniazza et al.
SCHEME 6. Synthesis of Protected Calystegine 34
JOCArticle
SCHEME 5. Synthesis of Silyl-calystegine 30
salt. In the course of our investigations, we have encountered
an unexpected rearrangement, likely resulting from a ther-
modynamically driven intra- and intermolecular acetate group
migration.
Experimental Section
7-((Dimethyl(phenyl)silyl)methyl)cyclohepta-3,5-diene-1,2-diyl
Diacetate (10). To a solution of 8 (300 mg, 1.09 mmol, 1 equiv) in
CH Cl (7 mL) were added pyridine (345 mg, 4.36 mmol, 4
2
2
equiv), a small amount of DMAP, and acetic anhydride (670 mg,
.54 mmol, 6 equiv) at 20 °C. The resulting mixture was stirred
for 14 h at room temperature, poured into saturated NH Cl
6
4
aq
(
20 mL), and extracted with CH
organic layers were washed with brine (20 mL), dried over
Na SO , and concentrated in vacuum. The crude residue was
2
Cl
2
(3 ꢀ 10 mL). The combined
The structure of 30 exhibits all substituents on both rings in
equatorial position as shown by X-ray diffraction studies
2
4
purified by silica gel column chromatography (petroleum ether/
AcOEt: 90/10) to provide 10 as a colorless oil (360 mg, 92%).
(Scheme 5).
As above, the silyl group may also be oxidized to provide
R
f
= 0.4 (petroleum ether/EtOAc: 90/10). IR (film, NaCl): ν
417, 2955, 2899, 1745, 1732, 1427, 1371, 1229, 1113, 1027, 837,
3
7
the corresponding aminocycloheptitol, then the unnatural
calystegine. Hydrogenation of the double bond of regioisomer
13b prior to the oxidation of the C-Si bond provided, after
protection of the alcohol as an acetate, the bicyclic skeleton
-1 1
02 cm . H NMR (CDCl , 300 MHz): δ (ppm) 7.59-7.47 (m,
3
2H), 7.42-7.30 (m, 3H), 6.01-5.87 (m, 1H), 5.84-5.72 (m, 1H),
5.68-5.55 (m, 3H), 5.29-5.20 (m, 1H), 2.69-2.56 (m, 1H), 2.05
(
s, 3H), 2.01 (s, 3H), 1.07 (dd, J=14.7, 4.5 Hz, 1H), 0.92 (dd, J=
4.7, 10.2 Hz, 1H), 0.37 (s, 3H), 0.36 (s, 3H). C NMR (CDCl ,
3
5.5 MHz): δ (ppm) 170.4, 170.1, 138.6, 136.1, 133.6, 129.1, 128.8,
1
3
1
7
1
of 31, and reduction of the N-O bond with Mo(CO) led to
6
pentasubstituted heptitol 33 in reasonable yields (Scheme 6).
PCC oxidation of the free alcohol function finally provided
the unnatural protected calystegine 34, along with its open
ketone form 35 in 26% overall yield from 13b. Compounds
28.0, 125.3, 123.4, 77.7, 71.4, 38.3, 21.6, 21.1, 21.0, -2.1, -2.3.
þ
HRMS (ESI): [M þ Na] C H O SiNa calcd 381.1498, found
2
0
26
4
3
81.1506.
Acyl Nitroso Cycloaddition General Procedure. Method A.
2
n-Bu NIO (3-10 equiv), RNHOH (3-10 equiv), in CH Cl /
3
4 and 35 were obtained as an inseparable mixture, and their
1
4
4
2
MeOH (3/1). Silylcycloheptadienes 10 (1 mmol) and n-Bu4-
ratio was estimated from the H NMR spectra of the crude
product.
NIO
CH
4
(3-10 mmol) were dissolved in a 3/1 mixture of
/MeOH (0.1 M), and BocNHOH (3-10 mmol) in
2
Cl
2
In summary, we have disclosed here our recent studies on
the desymmetrization and functionalization of silylmethyl-
cycloheptatrienes as a route to silyl-homocalystegines and
homocalystegines. These compounds can be obtained in 7 and
CH Cl (10-20 mL) was added dropwise during 2 h. The
2
2
resulting solution was stirred for 12 h at 20 °C and then
quenched with a saturated aqueous solution of Na
2 2 3
S O .
The aqueous layer was extracted with EtOAc. The combined
organic layers were washed with saturated brine and dried
8
steps, respectively, from commercially available tropylium
7
96 J. Org. Chem. Vol. 76, No. 3, 2011

Beniazza et al.
JOCArticle
over anhydrous Na SO , and the solvents were concentrated
2
(ppm) 7.55-7.49 (m, 2H), 7.42-7.27 (m, 20H), 6.27 (t, J=7.6 Hz,
J=8.6 Hz, 1H), 6.12 (t, J=7.2 Hz, J=8.5 Hz, 1H), 5.25-5.14 (m,
2H), 5.06-4.95(m, 1H), 4.68-4.53 (m, 3H), 4.42 (d, JAB=11.6 Hz,
1H), 4.26 (d, J=6.6 Hz, 1H), 4.11 (dd, J=4.2, 6.6 Hz, 1H), 3.66
(dd, J=4.0, 8.4 Hz, 1H), 2.23-2.13 (m, 1H), 1.28-1.21 (m, 1H),
4
under reduced pressure. The crude reaction mixture was
purified by silica gel column chromatography (petroleum
ether/EtOAc: 95/15 to 80/20)) affording the cycloadducts
1
3a and 13b.
Method B. NaIO
1
3
4
(3 equiv), RNHOH (3 equiv), in MeOH/
O (3/1). Silylcycloheptadienes 10 (1 mmol) and NaIO
3
1.09-0.99 (m, 1H), 0.33 (s, 3H), 0.32 (s, 3H). C NMR (CDCl ,
H
2
4
100.75 MHz): δ (ppm) 155.9, 138.8, 138.5, 138.3, 136.0, 133.8,
131.0, 129.2, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.87,
127.84, 127.55, 127.5, 83.1, 78.2, 75.0, 72.7, 72.6, 68.0, 53.3, 40.7,
(
(
3 mmol) were dissolved in a 3/1 mixture of MeOH/H O
2
0.1 M), and BocNHOH (3 mmol) in MeOH was added
þ
dropwise. The resulting solution was stirred for 12 h at
0 °C and then quenched with a saturated aqueous solution
of Na S O . The aqueous layer was extracted with EtOAc.
17.3, -2.2, -2.4. MS (ESI) m/z (%): 620 [M þ H] (100), 452
þ
2
[M þ H - (CbzNHOH)] (39). HRMS (ESI): [M þ H] C H -
38
41
NO Si calcd 620.2826, found 620.2849.
5
2
2
3
The combined organic layers were washed with saturated
brine and dried over anhydrous Na SO , and the solvents
were concentrated under reduced pressure. The crude reac-
tion mixture was purified by silica gel column chromatogra-
phy (petroleum ether/EtOAc (95/15 to 80/20)) affording the
cycloadducts 13a and 13b.
Benzyl 3,4-Bis(benzyloxy)-2-((dimethyl(phenyl)silyl)methyl)-
6-oxa-7-azabicyclo[3.2.2]non-8-ene-7-carboxylate (15b). R =0.22
(petroleum ether/EtOAc: 85/15). IR (film, NaCl): ν 3373, 2970,
2
4
f
-1 1
3
1714, 1454, 1250, 1111, 1072, 1045, 831 cm . H NMR (CDCl ,
400 MHz): δ(ppm) 7.60-7.49 (m, 2H), 7.48-7.37 (m, 20H), 6.27-
6.25 (m, 2H), 5.28-5.27 (m, 2H), 4.81-4.77 (m, 3H), 4.74-4.57
(m, 3H), 4.23 (dd, J=7.0, 4.2 Hz, 1H), 3.90-3.85 (m, 1H), 2.28-
2.23 (m, 1H), 1.41-1.33 (m, 1H), 1.02-0.96 (m, 1H), 0.42 (s, 6H).
7
-(tert-Butoxycarbonyl)-4-((dimethyl(phenyl)silyl)methyl)-6-oxa-
-azabicyclo[3.2.2]non-8-ene-2,3-diyl Diacetate (13a). R =0.15
petroleum ether/EtOAc: 85/15). Mp=135-137 °C (EtOAc). IR
7
f
13
(
(
3
C NMR (CDCl , 100.75 MHz): δ (ppm) 158.0, 138.9, 138.7,
-
1
.
solid, KBr): ν 3584, 2955, 2360, 1747, 1371, 1368, 1242, 836 cm
138.6, 136.1, 134.0, 131.3, 129.3, 128.8, 128.7, 128.6, 128.4, 128.2,
128.1, 128.0, 127.9, 127.8, 83.6, 76.0, 73.5, 73.1, 72.8, 68.1, 57.1,
1
H NMR (CDCl
.33 (m, 3H), 6.22 (t, J=8.9 Hz, J=7.3 Hz, 1H), 6.11 (t, J=7 Hz,
J=8 Hz, 1H), 5.46-5.43 (m, 1H), 5.27-5.21 (m, 1H), 4.97 (t, J=
3
, 400 MHz): δ (ppm) 7.56-7.46 (m, 2H), 7.41-
þ
7
38.6, 17.2, -2.0, -2.4. MS (ESI) m/z (%): 620 [M þ H] (20), 452
þ
[M þ H - (CbzNHOH)] (55). HRMS (ESI): [M þ H] C38
41
H -
6
2
0
.7 Hz, J=6.3 Hz, 1H), 4.27 (d, J=6.7 Hz, 1H), 2.10-2.01(m, 1H),
NO Si calcd 620.2826, found 620.2834.
5
.05 (s, 3H), 1.99 (s, 3H), 1.47 (s, 9H), 1.20-1.09 (m, 1H),
3-(tert-Butoxycarbonylamino)-7-((dimethyl(phenyl)silyl)methyl)-
6-hydroxycyclohept-4-ene-1,2-diyl Diacetate (16). A mixture of
13a (480 mg, 0.981 mmol, 1 equiv), Mo(CO) (285 mg, 1.08
6
1
3
.96-0.87 (m, 1H), 0.35 (s, 3H), 0.33 (s, 3H). C NMR (CDCl
3
,
100.75 MHz): δ (ppm) 169.9, 155.5, 138.3, 133.7, 131.5, 129.3,
1
28.0, 127.6, 82.5, 76.8, 74.7, 69.7, 53.2, 39.9, 28.2, 20.9, 17.4, -2.4.
mmol, 1.1 equiv), 10.8 mL of acetonitrile, and 1.2 mL of water
was heated under reflux during 16 h and allowed to cool to room
temperature. Then 2 g of silica gel and EtOAc (10 mL) were then
added to the mixture, the solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography (petroleum ether/EtOAc: 70/30) affording 16
þ
HRMS (ESI): [M þ Na]
25 7
C H35NO SiNa calcd 512.2147,
found 512.2149.
7
-(tert-Butoxycarbonyl)-2-(dimethyl(phenyl)silyl)methyl)-6-oxa-
-azabicyclo[3.2.2]non-8-ene-3,4-diyl Diacetate (13b). R =0.13
petroleum ether/EtOAc: 85:15). Mp=146-148 °C (EtOAc). IR
7
f
(
(
-
1
.
solid, KBr): ν 3585, 2957, 2362, 1747, 1374, 1368, 1246, 838 cm
f
as a colorless oil (310 mg, 65%). R = 0.1 (petroleum ether/
1
H NMR (CDCl
3
, 300 MHz): δ (ppm) 7.56-7.48 (m, 2H),
.41-7.32 (m, 3H), 6.28 (t, J = 8.3 Hz, 1H), 6.11-6.03 (m,
H), 5.38-5.27 (m, 2H), 4.87 (t, J=6.4 Hz, 1H), 4.52 (d, J=7.5
EtOAc 70:30). IR (film, NaCl): ν 3556, 2975, 2360, 1745, 1697,
-
1 1
7
1
1367, 1249, 1166, 1034, 836 cm . H NMR (CDCl , 400 MHz):
3
δ (ppm) 7.56-7.48 (m, 2H), 7.38-7.30 (m, 3H), 5.61-5.52 (m,
1H), 5.49-5.39 (m, 1H), 5.22-5.14 (m, 1H), 4.94-4.85 (m, 1H),
4.82-4.63 (m, 3H), 2.14 (br s, 4H), 1.93 (s, 3H), 1.61-1.53 (m,
2H), 1.45 (s, 9H), 1.12 (dd, J=5.2, 15.1 Hz, 1H), 0.80 (dd, J=9.7,
Hz, 1H), 2.09-2.00 (m, 4H), 1.96 (s, 3H), 1.05 (AB system, JAB
=
1
0
1
3
0.7 Hz, 1H), 0.85 (AB system, JAB=14.8 Hz, 1H), 0.37 (s, 3H),
13
.33 (s, 3H). C NMR (CDCl , 75.5 MHz): δ (ppm) 170.0, 169.8,
3
1
3
57.0, 138.3, 133.8, 132.7, 129.3, 128.0, 126.6, 82.3, 75.0, 71.8, 57.2,
7.2, 28.3, 20.9, 20.8, -2.0, -2.6. MS (ESI) m/z (%): 512 [M þ
3
15.3 Hz, 1H), 0.36 (s, 3H), 0.34 (s, 3H). C NMR (CDCl ,
100 MHz): δ (ppm) 170.8, 170.1, 155.4, 138.8, 136.1, 133.8,
130.0, 129.2, 128.1, 79.8, 74.6, 68.5, 48.7, 44.3, 28.5, 21.3, 20.9,
þ
þ
þ
Na] (12), 456 [M þ Na - (C
4
H
8
)] (100), 412 [M þ Na - Boc]
þ
þ
(
found 512.2149.
5). HRMS (ESI): [M þ Na] C H NO SiNa calcd 512.2147,
12.3, -2.4, -2.5. MS (ESI) m/z (%): 514 [M þ Na] (100).
2
5
35
7
þ
HRMS (ESI): [M þ Na]
25 7
C H37NO SiNa calcd 514.2237,
Benzyl 2,3-Bis(benzyloxy)-4-((dimethyl(phenyl)silyl)methyl)-
-oxa-7-azabicyclo[3.2.2]non-8-ene-7-carboxylate (15a) and Benzyl
,4-Bis(benzyloxy)-2-((dimethyl(phenyl)silyl)methyl)-6-oxa-7-aza-
found 514.2237.
6
3
3-(tert-Butoxycarbonylamino)-7-((dimethyl(phenyl)silyl)methyl)-
6-oxocyclohept-4-ene-1,2-diyl Diacetate (17). To a stirred solu-
tion of 16 (300 mg, 0.61 mmol, 1 equiv) in dry dichloromethane
bicyclo[3.2.2]non-8-ene-7-carboxylate (15b). Silylcycloheptadiene
1 (374 mg, 0.823 mmol, 1 equiv) and NaIO (706 mg, 3.293
mmol, 4 equiv) were dissolved in a 2/1 mixture of MeOH/H O (6/
˚
1
4
(7 mL), under nitrogen at 20 °C, was added 4 A molecular sieves
(350 mg, crushed). PCC (0.262 g, 1.098 mmol, 1.8 equiv) was
then added, and the resulting suspension was stirred for 20 h.
Diethyl ether (10 mL) was added, and the slurry was filtered
through a pad of silica gel. The solvent was removed under
reduced pressure, and the crude residue was then purified by
silica gel column chromatography (petroleum ether/EtOAc: 80/
2
3), and CbzNHOH (412 mg, 2.469 mmol, 3 equiv) in MeOH was
added dropwise during 2 h. The resulting solution was
stirred for 12 h at 20 °C and then quenched with a saturated
aqueous solution of Na S O . (30 mL) The aqueous layer
2
2
3
was extracted with EtOAc (3 ꢀ 30 mL). The combined
organic layers were washed with saturated brine and dried
20) to provide 17 (246 mg, 82%) as a colorless oil. R
f
= 0.6
2 4
over anhydrous Na SO , and the solvents concentrated under
reduced pressure. The crude reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc:
(petroleum ether/EtOAc: 70/30). IR (film, NaCl): ν 3556, 2975,
-
1 1
2341, 1743, 1653, 1558, 1371, 1237, 680 cm . H NMR (CDCl3,
400 MHz): δ (ppm) 7.51-7.42 (m, 2H), 7.38-7.29 (m, 3H), 6.16
(d, J=12.9 Hz, 1H), 5.80 (d, J=13.1 Hz, 1H), 5.36 (d, J=9.1 Hz,
1H), 5.14 (d, J=5.5 Hz, 1H), 4.95-4.70 (m, 2H), 2.95-2.84 (m,
1H), 2.05 (s, 3H), 1.99 (s, 3H), 1.42 (s, 9H), 1.29-1.15 (m, 1H),
9
1
0/10) affording a 18/1 mixture of 15a/15b (273 mg of 15a (54%),
8 mg of 15b (3%)).
Benzyl 2,3-Bis(benzyloxy)-4-((dimethyl(phenyl)silyl)methyl)-
-oxa-7-azabicyclo[3.2.2]non-8-ene-7-carboxylate (15a). R =0.25
1
3
6
f
3
1.12-1.00 (m, 1H), 0.31 (s, 3H), 0.28 (s, 3H). C NMR (CDCl ,
(
1
petroleum ether/EtOAc: 85/15). IR (film, NaCl): ν 2952, 1703,
100 MHz): δ (ppm) 201.0, 170.4, 170.1, 155.2, 141.4, 137.7, 133.8,
129.7, 129.3, 128.0, 80.3, 74.2, 70.8, 51.8, 50.1, 28.4, 21.0, 20.9,
-
1 1
454, 1261, 1112, 1072, 834 cm . H NMR (CDCl , 400 MHz): δ
3
J. Org. Chem. Vol. 76, No. 3, 2011 797

Beniazza et al.
12.7, -3.6, -4.0. HRMS (ESI): [M þ Na] C H NO NaSi calcd
JOCArticle
þ
þ
1
6.9, -2.6, -3.0. HRMS (ESI):[M þ Na] C H NO SiNa calcd
2
5
35
7
18 27
4
5
12.2075, found 512.2070.
-(tert-Butoxycarbonylamino)-3-((dimethyl(phenyl)silyl)methyl)-
-oxocycloheptane-1,2-diyl Diacetate (18). Compound 17 (230 mg,
.47 mmol, 1 equiv) was dissolved in a mixture of methanol and
ethyl acetate (2:1, 6 mL), and Pd/C 10 mol % (50 mg, 0.047 mmol,
.1 equiv) was added. An inert atmosphere of H was installed, and
372.16071, found 372.1604.
7
3-Bromo-7-(tert-Butoxycarbonylamino)-3-(hydroxymethyl)-4-oxo-
cycloheptane-1,2-diyl Diacetate (23). Peracetic acid (36-40% in
AcOH, 0.8 mL) was added dropwise to a stirred mixture of 18
(120 mg, 0.24 mmol, 1 equiv) in acetic acid (0.5 mL) at 0 °C, and
then potassium bromide (57 mg, 0.48 mmol, 2 equiv) and
sodium acetate (79 mg, 0.96 mmol, 4 equiv) were also added.
The mixture was allowed to warm to room temperature, and the
mixture was stirred overnight. The mixture was quenched with
aqueous sodium thiosulfate solution (25% (15 mL) at 0 °C, and
the aqueous layer was saturated with NaCl. The mixture was
extracted with ethyl acetate (3 ꢀ 20 mL). The combined organic
layers were washed with saturated aqueous sodium carbonate
4
0
0
2
the reaction mixture was stirred at 20 °C for 24 h. The reaction
mixture was filtered through a Celite pad and washed with ethyl
acetate. The solvent was removed under reduced pressure, the crude
residue (98% yield) was clean enough to be used in the further step
without any purification. It was purified by silica gel column chro-
matography (petroleum ether/EtOAc: 80/20) to provide 18 (200mg,
87%) as a colorless oil, which was fully characterized. R = 0.2
f
2 4
and brine, dried (Na SO ), and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (petroleum ether/EtOAc: 65/35) to provide 23 (35 mg,
(petroleum ether/EtOAc 70:30). IR (film, NaCl): ν3556, 2360, 1743,
-
1 1
1
633, 1420, 1260, 1224, 1024, 799, 668 cm . H NMR (CDCl
MHz): δ (ppm) 7.56-7.42 (m, 2H), 7.41-7.29 (m, 3H), 5.17-4.98
m, 2H), 4.72(d, J=8.6 Hz, 1H), 4.09 (br s, 1H), 2.77-2.66 (m, 1H),
.60-2.37 (m, 2H), 2.07 (s, 4H), 1.98 (s, 3H), 1.83-1.65 (m, 1H),
.40 (s, 9H), 1.31-1.17 (m, 1H), 0.96 (dd, J=6.5, 14.6 Hz, 1H), 0.33
3
, 400
3
4
1
2%) as a yellow solid. R = 0.35 (petroleum ether/EtOAc: 60/
f
(
2
1
0). Mp = 153-154 °C (CHCl
691, 1530, 1213, 1165, 1050, 813 cm . H NMR (CDCl
3
). IR (film, NaCl): ν 1760, 1710,
1 1
-
3
, 400
13
MHz): δ (ppm) 5.69 (s, 1H), 5.17 (d, J = 10.3 Hz, 1H),
.80-4.70 (m, 1H), 4.32 (dd, J = 6.7, 12 Hz, 1H), 4.30-4.16
m, 1H), 4.02 (dd, J = 5.6, 12.1 Hz, 1H), 3.32 (brs, 1H), 3.13 (t,
(
s, 3H), 0.31 (s, 3H). C NMR (CDCl
3
, 100.75 MHz): δ (ppm)
4
(
210.8, 170.5, 169.8, 155.3, 138.0, 133.8, 129.3, 128.0, 79.9, 74.3, 73.0,
5
1.2, 50.0, 38.8, 28.4, 27.8, 21.1, 20.9, 16.3, -2.6, -2.9. MS (ESI) m/
þ
þ
8
)] (100), 414 [M
J = 12.7 Hz, 1H), 2.56 (t, J = 12.7 Hz, J = 12.3 Hz, 1H),
2.36-2.19 (m, 1H), 2.24 (s, 3H), 2.18-2.0 (m, 1H), 2.04 (s, 3H),
z (%): 514 [M þ Na] (7), 458 [M þ Na - (C
4
H
þ
þ
þ Na - (Boc)] (10). HRMS (ESI): [M þ Na] C H NO SiNa
25
37
7
13
.77 (br s, 1H), 1.65-1.35 (m, 1H), 1.41 (s, 9H). C NMR
1
calcd 514.2237, found 514.2234.
-((Dimethyl(phenyl)silyl)methyl)-5-hydroxy-8-azabicyclo[3.2.1]
(
CDCl , 100 MHz): δ (ppm) 203.3, 171.6, 169.3, 155.4, 80.0,
3
6
7
5.1, 73.3, 66.8, 66.4, 49.9, 37.6, 28.9, 28.4, 21.1, 21.0. MS (ESI)
octane-2,7-diyl Diacetate (19). At 0 °C, TFA (1.8 mL, 24.7 mmol,
þ
þ
m/z (%): 474 [M þ Na] (100), 418 [M þ Na - (C H )] (24).
4
8
1
1
35 equiv) was added to a solution of 18 (90 mg, 0.183 mmol,
equiv) in CH Cl (9 mL), and the reaction mixture was stirred at
þ
HRMS (ESI): [M þ Na]
17 8
C H25BrNO Na calcd 474.0733,
2
2
found 474.0756.
4-(tert-Butoxycarbonylamino)-3-((dimethyl(phenyl)silyl)methyl)-
-oxocycloheptane-1,2-diyl Diacetate (29). Compound 27 (90 mg,
this temperature for 30 min until reaction completion (TLC
control). A 3 M NaOH solution was added until the pH remained
basic (pH e 11). The reaction mixture was then stirred at room
temperature for 50 min. After separation of the two layers, the
aqueous one was extracted with CH Cl (2 ꢀ 20 mL).The com-
7
0.18 mmol, 1 equiv) was dissolved in a mixture of methanol and
ethyl acetate (2:1, 2.5 mL), and then Pd/C 10% (19 mg, 0.018 mmol,
.1 equiv) was added under N atmosphere. An atmosphere of H
2
2
2
0
2
4
bined organics were washed with brine (30 mL), dried over MgSO ,
was installed, and the reaction mixture was stirred at 20 °C for 12 h.
The reaction mixture was filtered through a pad of Celite and
washed with ethyl acetate. The solvent was removed under reduced
pressure, and the crude residue was then purified by silica gel
column chromatography (petroleum ether/EtOAc: 80/20) to pro-
filtered, and concentrated in vacuo to provide 19 (70 mg, 96%) as a
white solid. R =0.1 (petroleum ether/EtOAc 20:80). Mp=157-
f
1
59 °C (EtOAc). IR (film, NaCl): ν 3353, 2956, 2360, 1736, 1654,
-1 1
3
1540, 1248, 1155, 1025, 834, 667 cm . H NMR (CDCl , 400
MHz): δ (ppm) 7.54-7.46 (m, 2H), 7.39-7.30 (m, 3H), 6.59 (d,
J= 6.0 Hz, 1H), 4.34 (d, J= 5.8 Hz, 1H), 3.95-3.84 (m, 2H),
vide 29 (75 mg, 80%) as a colorless oil. R = 0.4 (petroleum
f
ether/EtOAc: 70/30). IR (film, NaCl): ν 3376, 2917, 1747, 1668,
-
1 1
2
1
1
.38-2.26 (m, 2H), 2.01-1.87 (m, 1H), 1.97 (s, 3H), 1.95 (s, 3H),
1
3
427, 1225, 1168, 910, 732 cm . H NMR (CDCl , 300 MHz):
.80-1.68 (m,1H), 1.32-1.19 (m,1H), 1.03 (dd, J=3.5, 14.6 Hz,
δ (ppm) = 7.59-7.49 (m, 2H), 7.40-7.30 (m, 3H), 5.44 (br s,
1H), 5.14-5.04 (m, 1H), 4.56-4.39 (m, 1H), 3.89-3.71 (m, 1H),
2.62-2.36 (m, 3H), 2.19-1.93 (m, 2H), 2.06 (s, 3H), 1.99 (s, 3H),
1
3
H), 0.97-0.86 (m, 1H), 0.34 (s, 3H), 0.29 (s, 3H). C NMR
(
CDCl , 100 MHz): δ (ppm) 172.6, 170.8, 138.4, 133.5, 129.4,
3
1
28.0, 106.8, 81.0, 80.2, 49.0, 47.1, 29.9, 25.1, 23.4, 21.1, 12.9, -2.1,
1.70-1.56 (m, 1H), 1.40 (s, 9H), 0.94-0.83 (m, 2H), 0.42 (s,
þ
13
-
found 414.1718. Anal. Calcd for C H NO Si (391.18): C 61.35,
3.4. HRMS (ESI): [M þ Na] C20
H
29NO
5
SiNa calcd 414.1712,
3H), 0.40-0.31 (m, 3H). C NMR (CDCl , 75.5 MHz): δ (ppm)
3
20
29
5
201.2, 169.9, 169.6, 154.7, 138.0, 133.6, 129.5, 128.2, 79.8, 75.5, 74.6,
50.9, 39.2, 38.6, 28.5, 23.4, 21.1, 20.7, 11.7, -2.7, -3.3. MS (ESI)
H 7.47, N 3.58. Found: C 61.55, H 7.44, N 3.56.
-(7-((Dimethyl(phenyl)silyl)methyl)-1,4,6-trihydroxy-8-azabi-
þ
þ
1
m/z (%): 514 [M þ Na] (7), 458 [M þ Na - (C
4
H
8
)] (21), 414
þ
þ
cyclo[3.2.1]octan-8-yl)ethanone (20). To a solution of the acetate
compound 19 (125 mg, 3.19 mmol) in methanol was added
[M þ Na - (Boc)] (14), 354 [M - H - (SiMe Ph)] (100).
2
þ
HRMS (ESI): [M þ Na] C25
7
H37NO SiNa calcd 514.2237, found
2
-
DOWEX CO
3
(2 spoons). The mixture was stirred overnight at
514.2228.
room temperature. It was then filtered, and the resin was rinsed
thoroughly with methanol. The crude material was obtained
after evaporation and purification by silica gel column chroma-
4-((Dimethyl(phenyl)silyl)methyl)-1-hydroxy-8-azabicyclo[3.2.1]
octane-2,3-diyl Diacetate (30). At 0 °C, TFA (1.12 mL, 15.12 mmol,
135 equiv) was added to a solution of 29 (55 mg, 0.11 mmol,
tography (CH
solid (112 mg, 97%). R =0.42 (CH Cl /MeOH: 90/10). Mp=
2
Cl
2
/MeOH: 90/10) provided 20 as a colorless
2 2
1 equiv) in CH Cl (5.5 mL), and the reaction mixture was stirred at
this temperature until completion. A 3 M NaOH solution was
added until pH remained basic (pH e 11). The reaction mixture
was then stirred at rt during 50 min. After separation of the two
f
2
2
5
1
8-60 °C (EtOAc). IR (neat ATR): ν 3277, 2951, 1642, 1547,
-1 1
3
426, 1248, 1111, 1003, 828 cm . H NMR (CD OD, 200 MHz):
δ (ppm) 7.65-7.49 (m, 2H), 7.38-7.23 (m, 3H), 4.00-3.72 (m,
layers, the aqueous one was extracted with CH
The combined organic layers were washed with brine, dried over
MgSO , filtered, and concentrated in vacuo. The crude reaction
2
Cl
2
(2 ꢀ 10 mL).
3
0
H), 2.15-1.20 (m, 6H), 1.93 (s, 3H), 0.94 (d, J=7.8 Hz, 2H),
13
.40 (s, 3H), 0.39 (s, 3H). C NMR (CD
3
OD, 75.5 MHz): (two
4
rotamers are visible and are noted R1 and R2) δ (ppm) 172.4
R1), 172.3 (R2), 133.3, 128.6, 127.6, 127.5, 106.7, 82.6, 76.4,
3.2, 46.6, 29.7, 23.3 (R1), 23.2 (R2), 21.4 (R1), 21.3 (R2),
mixture was purified by silica gel column chromatography
(petroleum ether/EtOAc: 20/80) to provide 30 (28 mg, 65%)
as a white solid. R = 0.1 (petroleum ether/EtOAc 20:80).
f
(
5
7
98 J. Org. Chem. Vol. 76, No. 3, 2011

Beniazza et al.
JOCArticle
Mp=154-156 °C (EtOAc). IR (Solid, KBr): ν 3353, 2955, 2360,
Acknowledgment. We thank the Cefipra program (no.
3605-E) for a Ph.D. grant to R.B. and the CNRS for the
financial support. We also thank Dr. B. Kauffmann (IECB
Bordeaux) for X-ray diffraction studies.
-1 1
1
737, 1653, 1540, 1227, 1248, 1155, 1025, 834 cm . H NMR
(
3
1
CDCl
3
, 300 MHz): δ (ppm) 7.53-7.46 (m, 2H), 7.38-7.31 (m,
H), 5.16-5.06 (m, 2H), 3.13 (d, J=7.5 Hz, 1H), 2. 46-2.31 (m,
H), 2.05 (s, 3H), 2.03 (s, 3H), 1.90-1.76 (m, 2H), 1.56-1.40 (m,
13
1
H), 0.97 (t, J=7.1 Hz, 2H), 0.32 (s, 6H). C NMR (CDCl
MHz): δ (ppm) 170.7, 170.0, 138.4, 133.7, 129.2, 128.0, 90.3, 74.2,
2.1, 59.3, 42.7, 30.6, 28.2, 21.1, 21.0, 19.3, -2.3, -2.6. HRMS
3
, 75.5
Supporting Information Available: Experimental proce-
dures and spectroscopic data for compounds 8, 9, 11, 12, 14,
21, 22, 24, 25, 26, 27, 28, 31, 32, and 33 not described in the
7
þ
1
13
(
ESI): [M þ H]
Anal. Calcd. for C20
Found: C 61.31, H 7.45, N 3.48.
20 5
C H29NO Si calcd 392.1893, found 392.1880.
Experimental Section; copies of H and C NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
5
H29NO Si (391.18): C 61.35, H 7.47, N 3.58.
J. Org. Chem. Vol. 76, No. 3, 2011 799