O-Methoxycarbonyl cyanohydrin as a new protective group for carbonyls

Article abstract of DOI:10.1016/S0040-4020(00)00535-4

O-Methoxycarbonyl cyanohydrin, a new protective group of carbonyls, was prepared in high yields by an efficient one-step procedure using methyl cyanoformate and a secondary alkylamine at room temperature. Herein, we report efficient methods for the formation and cleavage of the protective group. Also, the ability of different types of carbonyls to be protected and the protective group's behavior under different chemical conditions were studied. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00535-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5995±6003
O-Methoxycarbonyl Cyanohydrin as a New Protective Group
for Carbonyls
*
David Berthiaume and Donald Poirier
Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL),
2705 Laurier Boulevard, Quebec G1V 4G2, Canada
Received 12 November 1999; accepted 6 June 2000
AbstractÐO-Methoxycarbonyl cyanohydrin, a new protective group of carbonyls, was prepared in high yields by an ef®cient one-step
procedure using methyl cyanoformate and a secondary alkylamine at room temperature. Herein, we report ef®cient methods for the formation
and cleavage of the protective group. Also, the ability of different types of carbonyls to be protected and the protective group's behavior
under different chemical conditions were studied. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Protective Group Formation
Equivalents of amine needed
The protection and deprotection of carbonyl groups are
common and necessary processes in organic synthesis, so
a large variety of protective groups have been developed for
this purpose.1 Among them, the O-substituted cyanohydrin
family counts four derivatives: acetyl,2,3 silyl,4±7 ethoxy-
ethyl,8 and tetrahydropyranyl.9 During the course of our
studies on the synthesis of C18-steroid derivatives as
inhibitors of 17b-hydroxysteroid dehydrogenase and steroid
sulfatase,10±17 we found that O-methoxycarbonyl cyano-
hydrin 2 can be easily obtained from a C17-steroid ketone
1 by a one-step procedure (Scheme 1).
The steroid ketone 1 was selected for the ®rst part of our
study. We started by determining the number of diiso-
propylamine (DIPA) equivalents that were necessary to
produce the desired cyanohydrin carbonate 2 (Table 1).
The conditions used were 10 equiv. of methyl cyanoformate
in THF at room temperature. We noted that the presence of
amine was crucial as the reaction did not take place without
DIPA (entry 1). Yields and reaction rates increased with the
addition of DIPA from 0 to 20 equiv. (entries 1±4), but at
50 equiv. yields dropped (entry 5). We kept 20 equiv. of
DIPA as a standard condition for the next tests.
To date, synthesis of O-methoxycarbonyl cyanohydrins has
been reported in moderate yields for aldehydes and aromatic
ketones solely.18±20 This fact led us to optimize the reactive
conditions of this one-step formation of 2. A preliminary
account of this unexpected formation of substituted cyano-
hydrins from ketones has recently been reported by our
group.21 We now report a full account of the formation
and cleavage of the O-methoxycarbonyl cyanohydrin
group on carbonyls and the characteristics of this new
protective group.
Effect of water, air and temperature on the reaction
We tested whether the presence of water or air could be
interfering with the reaction (Table 2). As illustrated, the
addition of one drop of water completely blocked the
reaction (entry 6). The reaction proceeded under both
argon and air atmospheres with no signi®cant differences
(entries 7 and 8). Since ambient air humidity did not
Scheme 1. Protective group formation.
Keywords: protecting groups; aldehydes; ketones; cyanohydrins; carbonates.
* Corresponding author. Tel.: 11-418-654-2296; fax: 11-418-654-2761; e-mail: donald.poirier@crchul.ulaval.ca
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00535-4

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D. Berthiaume, D. Poirier / Tetrahedron 56 (2000) 5995±6003
Table 1. Formation of derivative 2 from steroid ketone 1: effect of reaction
time and diisopropylamine (DIPA) equivalents
Table 4. Formation of derivative 2 from steroid ketone 1: effect of solvent
Entry
Solvent
Yields (%)a
Entry
DIPA (equiv.)
Yields (%)a
8 h 12 h
2 h
4 h
8 h
24 h
4 h
24 h
13
14
15
16
17
18
DMF
40
23
8
15
25
42
55
38
25
38
34
60
61
67
66
77
49
72
61
71
97
95
73
83
1
2
3
4
5
0
5
10
20
50
0
0
0
0
MeCN
EtOAc
THF
CH2Cl2
Toluene
18
21
31
61
54
52
67
72
75
75
85
77
86
95
91
75
1
a Yields were determined by 1H NMR.
a Yields were determined by H NMR.
Table 2. Formation of derivative 2 from steroid ketone 1: effect of water
presence
Entry
Conditionsa
Yields (%)b
24 h
4 h
48 h
6
7
8
a
b
c
0
44
43
0
92
96
0
91
96
a Conditions: (a) air atmosphere1water drop; (b) dry THF and argon
atmosphere; (c) air atmosphere.
b Yields were determined by 1H NMR.
Figure 1. Yields obtained for the formation of derivative 2 from steroid
ketone 1 with different solvents in function of reaction time.
Effect of the solvent on the reaction
Table 3. Formation of derivative 2 from steroid ketone 1: effect of tempera-
ture
We tried experimenting with different solvents (Table 4 and
Fig. 1) and used dimethylformamide (DMF), acetonitrile
(MeCN), ethyl acetate (EtOAc), tetrahydrofuran (THF),
dichloromethane (CH2Cl2), and toluene. Both EtOAc and
THF gave higher than 95% yields (entries 15 and 16).
Surprisingly, solvents that were slow to start the reaction
gave better yields than fast start solvents; so apparently two
steps are involved in the formation of the cyanohydrin
derivative. Our hypothesis is that solvent favoring the ®rst
step would impede the second one, thus preventing its
completion. On the other hand, solvent favoring the second
step would make the ®rst step more dif®cult, explaining the
Entry
Temperature (8C)
Yields (%)a
8 h
4 h
24 h
9
278
0
20
65
0
2
±
±
91
71
10
11
12
35
31
70
65
67
70
a Yields were determined by 1H NMR.
interfere with the reactions, all other experiments were
performed in air. The way the reaction behaved under differ-
ent temperatures was then studied (Table 3). The protective
group was not obtained at 2788C (entry 9). At 658C, the
reaction rate accelerated and we rapidly obtained 70%
yields after just 4 h, but the reaction did not run to comple-
tion (entry 12). The yields obtained at 0 and 208C (entries 10
and 11) were the same so the next experiments were
performed at room temperature. We also repeated this
experiment on a conjugated ketone (17b-(t-butyldimethyl-
silyl)testosterone) keeping the same temperatures to see if it
had an effect on the reactivity of conjugated ketones. The
effect of the temperature on the reaction was the same as on
the unconjugated ketones and did not give better yields than
at room temperature. The fact that a higher temperature
accelerates the reaction but causes the maximum yields to
drop indicates that an equilibrium is probably involved in
the reaction mechanism. At low temperatures, equilibrium
would enable a near quantitative yield of the desired cyano-
hydrin derivative, but at high temperature, the equilibrium
would shift a bit toward the ketone substrate.
Table 5. Formation of derivative 2 from steroid ketone 1 in THF: effect of
different amines
Entry
Amine
Yields (%)a
2 h
4 h
8 h
24 h
19
20
21
22
23
24
25
26
27
28
29
30
31
N-Butylamine
Diphenylamine
Diallylamine
Dipropylamine
±
±
±
±
0
0
4
30
8
9
0
±
±
0
0
0
0
0
0
0
0
±
±
0
Pyrrolidine
N-Ethylisopropylamine
Triethylamineb
0
3
6
10
44
56
96
95
92
93
99
24
48
22
23
43
70
71
36
58
58
60
70
96
96
Dimethylaminopyridineb
Diisopropylamine
N-Isopropylcyclohexylamine
2,2,6,6-Tetramethylpiperidine
N-t-Butylethylamine
cis-2,6-Dimethylpiperidine
22
45
31
1
a Yields were determined by H NMR.
b Yellow tar formed instead of dark red solution.

D. Berthiaume, D. Poirier / Tetrahedron 56 (2000) 5995±6003
5997
Figure 2. Structures of the amines used.
slow start in these cases. We kept THF as solvent for our
next experiments but EtOAc is also a good solvent for the
reaction.
diisopropylamine, N-isopropylcyclohexylamine and 2,2,6,
6-tetramethylpiperidine with 96, 95 and 92% yields of 2
respectively (entries 27±29). These yields were obtained
after 24 h of reaction though. Even better results were
obtained with N-t-butylethylamine and cis-2,6-dimethyl-
piperidine with yields of 96% in only 8 h (entries 30 and
31). It seems that only very hindered and rami®ed secondary
amines are able to produce the wanted reaction in good
yields. For the sake of uniformity, low cost and because
yields obtained were good, we kept diisopropylamine in
our next experiments.
Effect of the type of the amine
We tried to determine the most appropriate amine by doing
the reaction with a wide range of different amines (Table 5
and Figs. 2 and 3). Clearly, a primary amine (entry 19) is not
suitable to perform the protection. The type of amine was
also important since no protection occurred with diphenyl-
amine and diallylamine (entries 20 and 21). In the dialkyl-
amine series, dipropylamine and pyrrolidine were not better
with no protective group detected (entries 22 and 23).
N-Ethylisopropylamine gave some protected ketone in
10% yields (entry 24). Reactions with triethylamine and
dimethylaminopyridine produced some protective group
but the yields obtained never went above 44 and 58%,
respectively (entries 25 and 26). In these two cases, yellow
tar appeared in the ¯ask instead of the red color solution like
other effective amines. Better results were obtained with
Concentration and equivalents of methyl cyanoformate
needed
We attempted the reaction using DIPA as the only solvent
but the substrates were not soluble in neat amine, so we
repeated the reaction with a mixture of DIPA/THF (1:1)
instead. The quantity of the solvent mixture used to dissolve
the ketone substrate was calculated to get the required
20 equiv. of amine. In these conditions, we were able to
Figure 3. Yields obtained for the formation of derivative 2 from steroid ketone 1 in THF with different amines versus reaction time.

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D. Berthiaume, D. Poirier / Tetrahedron 56 (2000) 5995±6003
Table 6. Formation of derivative 2 from steroid ketone 1 in THF: effect of
reaction time and methyl cyanoformate (MCF) equivalents
obtain the cyanohydrin carbonate in 93% yield in only 5 h
(Table 6, entry 35). Having achieved the formation of the
protecting group in a short time, we tried to reduce the
number of equivalents of methyl cyanoformate to 1 or
2 equiv., but this was not enough to give good yields (entries
32 and 33). At 5 and 10 equiv., comparable yields resulted
after 5 h (entries 34 and 35), so 5 equiv. of methyl cyano-
formate was retained as a standard condition for the forma-
tion of the protecting group.
Entry
MCF (equiv.)
Yields (%)a
3 h
1 h
2 h
4 h
5 h
32
33
34
35
1
2
5
10
0
7
31
20
1
1
2
1
13
36
61
25
65
83
33
80
89
39
92
93
a Yields were determined by 1H NMR.
Carbonyls Reactivity
The ability of a series of different types of carbonyl groups
to be protected was also studied, and we determined the
isolated yields (Scheme 2 and Table 7). Diisopropylamine
(DIPA) was selected for these assays. Two different con-
ditions are reported: those for the ®rst experiments
(1.00 mmol of substrate, 10 equiv. of methyl cyanoformate
Scheme 2. Standard conditions for the formation of O-methoxycarbonyl
cyanohydrins 4 from carbonyls 3.
Table 7. Formation of O-methoxycarbonyl cyanohydrin derivatives 4 from carbonyl substrates 3
a Conditions: (a) 1.00 mmol of 3 and 5 equiv. of methyl cyanoformate in a DIPA (20 equiv.)/THF (1:1) mixture for 5±8 h. (b) 1 mmol of 3, 10 equiv. of methyl
cyanoformate and 20 equiv. of DIPA in 5 mL of THF for 24 h.
b
Isolated yields after chromatography.
Yields for each product: a (C-17 protected), b and c (two C-3 isomers of C-17 and C-3 diprotected).
For 0.60 mmol of substrate.
The protective group was not observed, we rather isolated the product of a double bond reduction.
c
d
e

D. Berthiaume, D. Poirier / Tetrahedron 56 (2000) 5995±6003
5999
and 20 equiv. of DIPA in 5 mL of THF, 24 h), and others
used for the last ones (1.00 mmol of substrate and 5 equiv.
of methyl cyanoformate in a DIPA (20 equiv.)/THF (1:1)
mixture, 5±8 h). The yields obtained with these two con-
ditions are very similar. The only difference was the
reaction time.
good yields by a number of conditions (Scheme 3 and Table
8). By dissolving the substrate in MeOH and treating that
solution with a K2CO3 (1%) in MeOH/H2O (3:1) solution,
the cleavage of the methoxycarbonyl cyanohydrin group of
compound 2 was done in 18 h and 92% yield (entry 52).
Since hydrolysis of carbonate groups occurs under these
conditions,24,25 the methoxycarbonyloxy moiety of 2 was
probably ®rst hydrolyzed, followed by elimination of
cyanide, and resulted with the formation of the carbonyl
group of 1. Other conditions where acetone was used as
the substrate solvent gave a better result with 97% yield in
18 h (entry 53). The removal of the protective group was
also accomplished by adding 4 equiv. of sodium methoxyde
in MeOH (25% w/v) to the substrate dissolved in dry THF
with 96% yield in only 15 min (entry 54). These later con-
ditions were preferred because of the better solubility of
studied substrates in THF and the improved rate of reaction.
The deprotection of a conjugated ketone, 17b-(t-butyl-
dimethylsilyl)-3-cyano-3-(methoxycarbonyloxy)-4-androstene,
was also obtained under these conditions in higher than 90%
yield on TLC. In opposition to ketones, aldehydes cannot be
restored from the protective group in these conditions.
Indeed, the basic or nucleophilic conditions used to cleave
the methoxycarbonyl cyanohydrin group induce the aldol
condensation of the regenerated aldehydes and limits its
use as a protective group of aldehydes.
Under standard conditions, cyclic and aliphatic ketones
(entries 36±39) reacted very well giving high isolated yields
(85±95%). For cyclooctanone, however, the yield dropped
to 50±57% (entry 40). Ketones in large rings are known to
be less reactive, especially the 8 to 11-membered rings.22,23
The reactivity of conjugated ketones was also studied and
we found that they were much less reactive than aliphatic
ones. Indeed, a,b-unsaturated cyclohexanone derivatives
(entries 41 and 42) gave the cyanohydrin derivative 4 in
only 18 and 28% yields. We tried the standard protective
conditions on a substrate containing both ketone types,
androstenedione (entry 43). Protection at the C-17 position
was obtained in 97% yield while protection at the C-3 posi-
tion was made in 37% yield. Aromatic ketones such as
desoxyanisoin and 6-methoxy-1-tetralone (entries 44 and
45) are less reactive and we obtained 19 and 15% of cyano-
hydrin derivative, respectively. In all cases, the starting
ketone was the only other compound detected. As demon-
strated with the two tetralones (entries 38 and 45) and the
three androstane derivatives (entries 37, 41 and 43), conju-
gated ketones are less reactive than unconjugated ones
regarding the formation of cyanohydrin carbonate. By a
judicious choice of the reaction times, this difference of
reactivity could be exploited to selectively protect an uncon-
jugated ketone in the presence of conjugated ones. The
protection of aliphatic aldehydes was obtained in 72±95%
yields (entries 46±49) while the protection of a benzylic
aldehyde was obtained in 64% yields (entry 50). As
observed with ketones, a conjugated aldehyde is less
reactive than an aliphatic one. To complete the aldehyde
series, cinnamaldehyde (entry 51) was treated under the
protective conditions, but the formation of the cyanohydrin
derivative was not observed. We rather isolated the product
of a double bond reduction.
Stability of the Protective Group
The stability of O-substituted cyanohydrin derivatives is
dependent on the cyano group and the O-R counter part.
Thus, the O-methoxycarbonyl cyanohydrin derivative 2
reacts in the presence of aqueous bases, nucleophiles and
some hydrides. Although it is reactive to LiAlH4, the protec-
tive group can resist reduction under DIBAL-H (2 equiv.)
and NaBH4 (2 equiv., 2.5 h). Acid conditions such as
aqueous HCl, AcOH, TfOH, and TsOH do not cleave the
O-methoxycarbonyl cyanohydrin protective group. Results
obtained also showed a very good stability with Lewis acids
(AlCl3, BBr3, BF3´OEt2) and oxidants (NaClO4, CrO3,
KMnO4, PCC, t-BuOOH, m-CPBA, and NaBiO3). Few
ketone protective groups combine stability under acid and
oxidizing conditions, so the addition of a new protective
group that is stable to both of these conditions should
prove handy. Also, the protection and deprotection reactions
Deprotection
Ketones can be easily restored from the protective group in
Scheme 3. Protective group cleavage model.
Table 8. Deprotection of the ketone 1 from the methoxycarbonyl cyanohydrin 2
Entry
Solvent
Conditions
Reaction time
Yieldsa (%)
52
53
54
MeOH
Acetone
THF
K2CO3 (1%) in MeOH/H2O (3:1)
K2CO3 (1%) in MeOH/H2O (3:1)
NaOMe (4 equiv.)/MeOH (25% w/v)
18 h
18 h
15 min
92
97
96
a Isolated yields after chromatography.

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D. Berthiaume, D. Poirier / Tetrahedron 56 (2000) 5995±6003
Table 9. Stability of the O-methoxycarbonyl cyanohydrin group of 2 under
usual reacting conditions
(25% w/v) solution. However, the deprotection of aldehydes
is not possible under these conditions. The protective group
can resist cleavage under strong acidic and oxidizing con-
ditions. Also, it can resist reduction by DIBAL-H and
NaBH4 (2.5 h).
Conditions
Stabilitya
pH
,1 (HCl/MeOH/H2O)
3 (HCl/MeOH/H2O)
5 (HCl/MeOH/H2O)
,1 (CF3COOH/CH2Cl2)
1 (CF3COOH/CH2Cl2)
3 (CH3COOH/MeOH)
10 (NaOH/MeOH/H2O)
13 (NaOH/MeOH/H2O)
S (20 h)
S
S
S
S
S
D
D
Experimental
General methods
Chemical reagents were purchased from Aldrich Chemical
Company (Milwaukee, WI) except t-butylethylamine which
was purchased from TCI America (Portland, OR). The
aldehyde 3-[30,170b-bis (t-butyldimethylsilyloxy)-10,30,
50(100)-estratrien-160a-yl]propanal (entry 48) was synthe-
sized as reported previously.26 Solvents were obtained from
Bases
1% K2CO3/MeOH/H2O
NaH (4 equiv.)/THF
D
S
Nucleophiles
NaOMe (4 equiv.)/THF
t-BuOK (4 equiv.)/THF
LDA (4 equiv.)/THF
D (,15 min)
D (,1 h)
D (,1 h)
Â
BDH Chemical (Montreal, Canada) or Fischer Chemicals
(Montreal, Canada). Glassware used in anhydrous con-
Â
ditions was ¯ame dried under argon current. Standard
inert atmosphere techniques were used for solvent transfers
by syringe. Flash-column chromatographies were
performed using 230±400 mesh ASTM silica gel 60 (E.
Merck, Darmstadt, Germany). Infrared spectra (IR) were
recorded on a Perkin±Elmer Series 1600 FT-IR spectro-
meter and are reported in cm21. For some compounds, the
nitrile band was too weak to be observed. The NMR spectra
were recorded at 300 MHz for 1H and 75 MHz for 13C on a
BruÈker AC/F300 spectrometer. The chemical shifts (d in
ppm) were referenced to CHCl3 (d 7.26 and 77.0 ppm for
1H and 13C, respectively). In the characterization of dia-
stereoisomeric mixtures, carbon peaks reported between
parenthesis are carbons that were duplicated due to the
Organometallics
n-BuLi/THF
BuMgCl/THF
R
R
Hydrides
NaBH4 (2 equiv.)/MeOH
DIBAL-H (2 equiv.)/benzene
LiAlH4/THF
S (2.5 h)
S
R
Oxidants
KMnO4/THF
CrO3/pyridine/acetone
NaClO4/acetonitrile
PCC (10 equiv.)/benzene, D
t-BuOOH (7 equiv.), PDC (cat.)/CH2Cl2
NaBiO3/AcOH/H2O/acetone
m-CPBA/CHCl3
S
S
S
S
S
S
S
1
presence of a new chiral center. H NMR evaluated yields
Others
NBS/THF
p-Toluenesulfonic acid/benzene
AlCl3/Benzene
BF3´OEt2/THF
S
S
S
S
S
were based on the integration of CH3-18 (0.91 and 0.96 ppm
for 1 and 2) and OCH3 (3.78 and 3.85 ppm for Ph-OCH3 and
±OCOOCH3) peaks on the crude products. The low resolu-
tion mass spectra (LRMS) were obtained with an API-150ex
apparatus with a turbo ionspray source while the high
resolution mass spectra (HRMS) were provided by the
BBr3 (3 equiv.)/CH2Cl2, 08C
a Stability: Sˆstable, Dˆdeprotected and Rˆreacted. Times in paren-
theses correspond to the appearance of unprotected ketone.
Â
Centre Regional de Spectrometrie de Masse (Universite de
Montreal, Montreal, Canada).
Â
Â
Â
Â
General procedure for the formation of the O-methoxy-
carbonyl cyanohydrin from carbonyls (Table 7)
for this new protective group are very mild. In some cases,
its mild basic or nucleophilic removal will surely be prefer-
able to the necessary acid hydrolysis of ketals. This new
protective group could be very useful for compounds that
can not withstand acidic conditions (Table 9).
The carbonyls were dissolved in a mixture of DIPA
(20 equiv.) and THF (1:1, v/v). The methyl cyanoformate
(5 equiv.) was added to the solution which was stirred
during 5±8 h. Then, the reaction was quenched by addition
of water and the crude product was extracted twice with
diethylether. The combined organic layers were thoroughly
washed with HCl 10% and saturated aqueous NaCl. The
organic phase was then dried over MgSO4 and evaporated
in vacuo. Puri®cation of the crude products was performed
by ¯ash column chromatography with an appropriate
mixture of ethyl acetate and hexanes as eluent.
Conclusion
The O-methoxycarbonyl cyanohydrin group was easily
formed at room temperature under mild conditions. To get
the protective group, the carbonyl substrate and methyl
cyanoformate (5 equiv.) were solubilized in a secondary
alkylamine (20 equiv.)/THF mixture (1:1, v/v). Conjugated
carbonyls are converted partially to the protective group, a
reactivity that permits selective protection of aliphatic
carbonyls vs. conjugated ones. Ketones, conjugated or not,
are easily restored in good yields (.95%) by treatment with
a K2CO3 (1%) in MeOH/H2O solution or NaOMe in MeOH
17a-Cyano-3-methoxy-17b-(methoxycarbonyloxy)estra-
1,3,5(10)-triene (entry 36). White solid; IR (KBr) n 2253
(CuN), 1754 (CvO, carbonate); 1H NMR (CDCl3) d 0.96
(s, 3H, CH3-18), 1.00±2.50 (m, 13H), 2.88 (m, 2H, CH2-6),
3.78 (s, 3H, CH3O), 3.85 (s, 3H, CH3O), 6.64 (d, Jˆ2.6 Hz,

D. Berthiaume, D. Poirier / Tetrahedron 56 (2000) 5995±6003
6001
1H, CH-4), 6.73 (dd, J1ˆ2.6 Hz and J2ˆ8.6 Hz, 1H, CH-2),
7.20 (d, Jˆ8.6 Hz, 1H, CH-1); 13C NMR (CDCl3) d 12.9,
23.1, 26.0, 27.1, 30.0, 33.6, 35.6, 38.8, 43.0, 48.1, 48.5, 55.1
(CH3O), 55.3 (CH3O), 85.0 (C-17), 111.6, 113.8, 118.4
(CuN), 126.3, 131.6, 137.6, 153.9 (OCOO), 157.6;
HRMS m/z calculated for C22H27O4N [M1] 369.1940,
found 369.1929.
LRMS m/z 505.0 [M1NH4]1, 488.0 [M1H]1; HRMS m/z
calculated for C27H42O4NSi [M2CH3]1 472.2883, found
472.2903.
1-Cyano-1-(methoxycarbonyloxy)-2-cyclohexene (entry
42). Colorless oil; IR (®lm) n 2242 (CuN), 1759 (CvO,
1
carbonate); H NMR (CDCl3) d 1.80 (m, 2H, CH2-5), 2.11
(m, 2H, CH2-6), 2.21 (m, 2H, CH2-4), 3.79 (s, 3H, CH3O),
6.03 (d, Jˆ10.1 Hz, 1H, CH-2), 6.13 (m, 1H, CH-3); 13C
NMR (CDCl3) d 17.4, 24.1, 33.0, 55.1 (CH3O), 70.2 (C-1),
118.2 (CuN), 122.1 (C-3), 136.4 (C-2), 153.2 (OCOO);
HRMS m/z calculated for C9H11O3N [M1] 181.0739,
found 181.0736.
17b-(t-Butyldimethylsilyloxy)-3-cyano-3-(methoxycarbonyl-
oxy)-5a-androstane (entry 37). White solid; IR (®lm) n
2255 (CuN), 1762 (CvO, carbonate); 1H NMR (CDCl3) d
0.001 and 0.005 (2 s, 6H, (CH3)2Si), 0.68 (s, 3H, CH3-19),
0.83 (s, 3H, CH3-18), 0.87 (s, 9H, (CH3)3C±Si), 0.90±2.50
(m, 22H), 3.54 (t, Jˆ8.2 Hz, 1H, CH-17), 3.83 (s, 3H,
CH3O); 13C NMR (CDCl3) d 24.8, 24.5, 11.4, 12.1,
18.1, 20.8, 23.5, 25.8 (3£), 27.8, 30.9, 31.2 (2£), 35.1,
35.4, 35.5, 36.8, 37.0, 43.0, 43.3, 50.4, 53.9, 55.2 (CH3O),
76.5 (C-3), 81.7, 118.3 (CuN), 153.1 (OCOO); HRMS m/z
calculated for C28H46O4NSi [M2H]1 488.3196, found
488.3192.
17a-Cyano-17b-(methoxycarbonyloxy)-4-androstene-3-
one (entry 43a). White solid; IR (®lm) n 2248 (CuN),
1761 (CvO, carbonate), 1674 (CvO, a,b-unsaturated
1
ketone); H NMR (CDCl3) d 0.96 (s, 3H, CH3-18), 1.18
(s, 3H, CH3-19), 1.00±3.00 (m, 19H), 3.82 (s, 3H, CH3O),
5.72 (s, 1H, CH-4); 13C NMR (CDCl3) d 12.9, 17.3, 20.5,
23.3, 31.2, 32.4, 33.3, 33.8, 35.4, 35.6, 35.7, 38.4, 47.6,
48.9, 52.8, 55.4 (CH3O), 84.7 (C-17), 118.2 (CuN), 124.2
(C-4), 153.8 (OCOO), 169.8 (C-5), 199.1 (C-3); HRMS m/z
calculated for C22H29O4N [M1] 371.2097, found 371.2093.
2-Cyano-6-methoxy-2-(methoxycarbonyloxy)-1,2,3,4-
tetrahydronaphthalene (entry 38). White solid; IR (®lm)
n 2241 (CuN), 1759 (CvO, carbonate); 1H NMR (CDCl3)
d 2.44 (m, 2H, CH2-3), 3.02 (m, 2H, CH2-4), 3.30 and 3.52
(2 d, Jˆ16.3 Hz, 2H, CH2-1), 3.77 (s, 3H, CH3O), 3.84 (s,
3H, CH3O), 6.65 (d, Jˆ2.3 Hz, 1H, CH-5), 6.74 (dd,
J1ˆ8.3 Hz and J2ˆ2.3 Hz, 1H, CH-7), 6.99 (d, Jˆ8.5 Hz,
1H, CH-8); 13C NMR (CDCl3) d 25.6, 31.6, 38.0, 55.2
(CH3O), 55.3 (CH3O), 73.0 (C-2), 113.1 (2£), 117.9
(CuN), 121.7, 130.1, 134.4, 153.2 (OCOO), 158.6;
HRMS m/z calculated for C14H15O4N [M1] 261.1001,
found 261.0999.
3,17a-Dicyano-3,17b-bis(methoxycarbonyloxy)-4-andro-
stene (entry 43b). White solid; IR (®lm) n 2254 (CuN),
1760 (CvO, carbonates); 1H NMR (CDCl3) d 0.93 (s, 3H,
CH3-18), 1.05 (s, 3H, CH3-19), 1.00±3.00(m, 19H), 3.82
and 3.83 (2s, 6H, 2£CH3O), 5.85 (s, 1H, CH-4); 13C NMR
(CDCl3) d 12.9, 17.8, 20.6, 23.2, 30.1, 31.4, 31.6, 31.8, 33.3,
35.4, 35.6, 37.3, 47.7, 48.9, 52.8, 55.2 and 55.4 (2£CH3O),
69.8 (C-3), 84.8 (C-17), 114.3 (C-4), 118.2 and 118.9
(2£CuN), 153.5 and 153.8 (2 x OCOO), 155.1 (C-5);
HRMS m/z calculated for C25H32O6N2 [M1] 456.2260,
found 456.2265.
4-Cyano-4-(methoxycarbonyloxy)heptane (entry 39).
Colorless oil; IR (®lm) n 2240 (CuN), 1760 (CvO,
1
carbonate); H NMR (CDCl3) d 0.93 (t, Jˆ7.3 Hz, 6H,
CH3), 1.47 (m, 4H, 2£CH2), 1.93 (m, 4H, 2£CH2), 3.77
(s, 3H, CH3O); 13C NMR (CDCl3) d 13.6 (2£), 17.0
(2£), 38.5 (2£), 55.1 (CH3O), 76.6 (C-4), 117.8 (CuN),
153.1 (OCOO); LRMS m/z 217.3 [M1NH4]1, 200.2
[M1H]1.
3,17a-Dicyano-3,17b-bis(methoxycarbonyloxy)-4-andro-
stene (entry 43c). White solid; IR (®lm) n 2255 (CuN),
1760 (CvO, carbonates); 1H NMR (CDCl3) d 0.94 (s, 3H,
CH3-18), 1.07 (s, 3H, CH3-19), 1.00±3.00 (m, 19H), 3.83 (s,
6H, 2£CH3O), 5.60 (s, 1H, CH-4); 13C NMR (CDCl3) d
12.9, 18.5, 20.4, 23.3, 29.7, 31.6, 31.7, 33.1, 33.2, 35.4,
35.8, 37.5, 47.7, 48.8, 52.5, 55.2 and 55.3 (2£CH3O), 72.5
(C-3), 84.8 (C-17), 115.5 (C-4), 117.9 and 118.1 (2£CuN),
153.2 and 153.8 (2£OCOO), 153.4 (C-5); HRMS m/z calcu-
lated for C25H32O6N2 [M1] 456.2260, found 456.2251.
1-Cyano-1-(methoxycarbonyloxy)cyclooctane (entry 40).
Colorless oil; IR (®lm) n 2240 (CuN), 1759 (CvO, car-
1
bonate); H NMR (CDCl3) d 1.40±1.70 (m, 10H, 5£CH2),
2.23 (m, 4H, 2£CH2), 3.78 (s, 3H, CH3O); 13C NMR
(CDCl3) d 20.9 (2£), 24.1, 27.2 (2£), 33.0 (2£), 55.0
(CH3O), 77.9 (C-1), 118.6 (CuN), 152.9 (OCOO); LRMS
m/z 229.0 [M1NH4]1, 212.1 [M1H]1.
1-Cyano-1-(methoxycarbonyloxy)-1,2-(40-methoxyphenyl)-
ethane (entry 44). Colorless oil; IR (®lm) n 1765 (CvO,
carbonate); 1H NMR (CDCl3) d 3.25 and 3.48 (2 d,
Jˆ14 Hz, 2H, CH2-Ph), 3.76 (s, 3H, CH3O), 3.77 (s, 3H,
CH3O), 3.82 (s, 3H, CH3O), 6.77 (d, Jˆ8.5 Hz, 2H), 6.89 (d,
Jˆ8.9 Hz, 2H), 6.97 (d, Jˆ8.5 Hz, 2H), 7.32 (d, Jˆ8.8 Hz,
2H); 13C NMR (CDCl3) d 47.5, 55.1 (CH3O), 55.3
(2£CH3O), 79.8 (C-1), 113.6 (2£), 114.1 (2£), 116.9
(CuN), 124.2, 126.6 (2£), 128.0, 132.0 (2£), 152.8
17b-(t-Butyldimethylsilyloxy)-3-cyano-3-(methoxycarbonyl-
oxy)-4-androstene (entry 41). White solid, diastereomeric
mixture (in proportion 1:5); IR (®lm) n 1760 (CvO, car-
bonate); 1H NMR (CDCl31CD3OD) d 20.003 and 0.003 (2
s, 6H, (CH3)2Si), 0.72 (s, 3H, CH3-18), 0.87 (s, 9H,
(CH3)3C±Si), 1.06 (s, 3H, CH3-19), 1.10±2.50 (m, 19H),
3.54 (t, Jˆ8.2 Hz, 1H, CH-17), 3.84 (s, 3H, CH3O), 5.57
and 5.81 (2 s, 1H, CH-4 two isomers); 13C NMR
(CDCl31CD3OD) d 25.0, 24.7, 11.1, 17.9, 18.4, 20.5
(20.7), 23.3, 25.7 (3£), 29.7, 30.7, 31.9, 33.1, 35.6, 36.6,
37.6, 43.3, 49.9 (2£), 53.6 (53.8), 55.1 (CH3O), 72.7 (C-3),
81.4, 112.0 (114.5), 118.3 (CuN), 153.3 (OCOO), 154.8;
(OCOO),
159.2,
160.2;
LRMS
m/z
266.1
[M2OCOOCH3]1.
1-Cyano-5-methoxy-1-(methoxycarbonyloxy)-1,2,3,4-
tetrahydronaphthalene (entry 45). Yellow oil; IR (®lm) n
1
1759 (CvO, carbonate); H NMR (CDCl3) d 1.99 (m, 2H,

6002
D. Berthiaume, D. Poirier / Tetrahedron 56 (2000) 5995±6003
CH2-3), 2.56 (m, 2H, CH2-2), 2.73 (m, 2H, CH2-4), 3.83 (s,
6H, 2£CH3O), 6.88 (d, Jˆ7.8 Hz, 1H, CH-6), 7.27 (t,
Jˆ8.0 Hz, 1H, CH-7), 7.37 (d, Jˆ8.0 Hz, 1H, CH-8); 13C
NMR (CDCl3) d 17.5, 22.1, 32.6, 55.2 (CH3O), 55.5
(CH3O), 74.0 (C-1), 110.9, 114.2, 118.5 (CuN), 120.6,
126.4, 127.1, 131.6, 153.0 (OCOO), 157.0; LRMS m/z
279.4 [M1NH4]1.
Procedure for the cleavage of the protective group
(Table 8)
Three different procedures were used to cleave the protec-
tive group. (i) A solution of K2CO3 (1%, w/v) in MeOH/
H2O (3:1) (5 mL) was added to a solution of the carbonyl 2
(0.27 mmol) in MeOH (10 mL). After 18 h at room
temperature, water was added and the mixture was acidi®ed
with aqueous HCl (10%) before being neutralized with a
saturated NaHCO3 aqueous solution. Methanol was evapo-
rated in vacuo and the resulting aqueous mixture was
extracted with CH2Cl2 (3£). The combined organic layers
were dried over MgSO4 and evaporated in vacuo. (ii) A
solution of K2CO3 (1%, w/v) in MeOH/H2O (3:1) (5 mL)
was added to a solution of carbonyl 2 (0.27 mmol) in
acetone (10 mL). After 18 h at room temperature, water
was added and the mixture was acidi®ed with aqueous
HCl (10%) before being neutralized with a saturated
NaHCO3 aqueous solution. Organic solvents were then
evaporated in vacuo and the resulting aqueous mixture
was extracted with CH2Cl2 (3£). The combined organic
layers were dried over MgSO4 and evaporated in vacuo.
(iii) A solution of NaOMe (25% w/v) in MeOH (115 mL)
was added to a solution of carbonyl 2 (0.14 mmol) in dry
THF (5 mL). After 15 min at room temperature, water was
added and the mixture was acidi®ed with aqueous HCl
(10%) before being neutralized with a saturated NaHCO3
aqueous solution. The resulting aqueous mixture was then
extracted with diethylether (3£). The combined organic
layers were dried over MgSO4 and evaporated in vacuo.
Puri®cation of the crude products was performed by ¯ash
column chromatography with an appropriate mixture of
ethyl acetate and hexanes as eluent.
1-Cyano-1-(40-cyclohexenyl)-1-(methoxycarbonyloxy)-
methane (entry 46). Colorless oil; IR (®lm) n 2252 (CuN),
1760 (CvO, carbonate); 1H NMR (CDCl3) d 1.50 (m, 1H),
1.80±2.30 (m, 6H), 3.84 (s, 3H, CH3O), 5.10 (d, Jˆ6.3 Hz,
1H, CH-1), 5.66 (m, 2H, CHvCH); 13C NMR (CDCl3) d
23.7, 24.0, 26.4, 36.2 (36.3), 55.7 (CH3O), 68.6 (68.7) (C-1),
115.6 (CuN), 124.0 (124.1), 126.9 (127.0), 154.3 (OCOO);
HRMS m/z calculated for C10H12O3N [M2H]1 194.0817,
found 194.0815.
1-Cyano-1-(methoxycarbonyloxy)-3-phenylpropane
(entry 47). Colorless oil; IR (®lm)n 2254 (CuN), 1766
1
(CvO, carbonate); H NMR (CDCl3) 2.28 (m, 2H, CH2-
2), 2.86 (t, Jˆ7.7 Hz, 2H, CH2-3), 3.87 (s, 3H, CH3O), 5.16
(t, Jˆ7.5 Hz, 1H, CH-1), 7.19±7.33 (m, 5H); 13C NMR
(CDCl3) d 30.4, 33.8, 55.7 (CH3O), 64.1 (C-1), 116.2
(CuN), 126.7, 128.3 (2£), 128.7 (2£), 138.8, 154.1
(OCOO); HRMS m/z calculated for C12H13O3N [M1]
219.0895, found 219.0886.
3,17b-Bis(t-butyldimethylsilyloxy)-16a-[30-cyano-30-(meth-
oxycarbonyloxy)propyl]estra-1,3,5(10)-triene (entry 48).
White solid; IR (®lm) n 2256 (CuN), 1763 (CvO, car-
1
bonate); H NMR (CDCl3) d 0.07 (s, 6H, (CH3)2Si), 0.19
(s, 6H, (CH3)2Si), 0.79 (s, 3H, CH3-18), 0.90 and 0.91 (2 s,
9H, (CH3)3C±Si), 0.98 (s, 9H, (CH3)3C±Si), 1.00±2.50 (m,
16H), 2.79 (m, 2H, CH2-6), 3.25 (d, Jˆ7.1 Hz, 1H, CH-17),
3.87 (s, 3H, CH3O), 5.21 (q, Jˆ6.6 Hz, 1H, CH-30), 6.55 (d,
Jˆ2.2 Hz, 1H, CH-4), 6.61 (dd, J1ˆ2.2 Hz and J2ˆ8.4 Hz,
1H, CH-2), 7.11 (d, Jˆ8.4 Hz, 1H, CH-1); 13C NMR
(CDCl3) d 24.4, 24.1, 23.9 (2£), 12.1, 18.1 (2£), 25.7
(3£), 25.9 (3£), 26.2, 27.2, 29.1, 29.3, 29.6, 31.6, 37.3,
38.6, 43.2 (43.4), 44.0, 44.3, 48.3, 55.7 (CH3O), 64.8
(65.0), 87.6, 116.4 (116.5) (CuN), 117.2, 119.9, 126.1,
133.0, 137.8, 153.3, 154.3 (OCOO); LRMS m/z 659.5
[M1NH4]1, 642.5 [M1H]1.
Acknowledgements
The authors thank the Medical Research Council of Canada
Â
Â
(MRC) and the Fonds de la Recherche en Sante du Quebec
(FRSQ) for their ®nancial support. We are grateful to the
Laboratory of Molecular Endocrinology for providing the
chemical facilities. We also want to thank Roch Boivin,
Â
Â
FrancËois Marquis and Marie Berube for their collaboration
in this project and Marie-Claude Trottier for numerous
NMR spectra acquisitions. Helpful discussions with Martin
1-Cyano-1-(methoxycarbonyloxy)-3(S),7-dimethyl-6-
octene (entry 49). Colorless oil; IR (®lm) n 1762 (CvO,
Â
Tremblay, Richard Labrecque, Yvon Frechette and
Alexandre Cote were also greatly appreciated.
à Â
1
carbonate); H NMR (CDCl3) 0.96 (m, 3H, CH3), 1.1±1.5
(m, 2H), 1.59 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.72, (m, 2H),
1.98 (m, 3H), 3.85 (s, 3H, CH3O), 5.05 (t, Jˆ6.4 Hz, 1H,
CH-6), 5.23 (m, 1H, CH-1); 13C NMR (CDCl3) d 18.9
(19.1), 25.0, 25.6, 28.5 (28.7), 36.5 (36.6), 39.1 (39.3),
51.6, 55.7 (CH3O), 63.4 (63.8), 116.5 (116.7) (CuN),
123.7, 131.9, 154.3 (OCOO); HRMS m/z calculated for
C13H13O3N [M1] 239.1521, found 239.1525.
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