Intramolecular conjugate addition of α,β-unsaturated lactones having an alkanenitrile side chain: Stereocontrolled construction of carbocycles with quaternary carbon atoms

Article abstract of DOI:10.1055/s-0031-1290074

An efficient method for constructing carbocycles with all-carbon quaternary stereocenters has been developed on the basis of a stereoselective cyclization reaction of ,-unsaturated lactones having an alkanenitrile side chain. Treatment of the substrate with lithium hexamethyldisilazide (LiHMDS) in the presence of triisopropylsilyl chloride (TIPSCl) led to the generation of the corresponding -cyano carbanion species which readily underwent an intramolecular conjugate addition reaction. It was found that thecombined use of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and triethylamine is also effective for the cyclization reaction without using a strong base. Interestingly, different ste-reochemical outcomes were observed in the two cyclization methods. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290074

LETTER
251
Intramolecular Conjugate Addition of a,b-Unsaturated Lactones Having an
Alkanenitrile Side Chain: Stereocontrolled Construction of Carbocycles with
Quaternary Carbon Atoms
S
tereocontroll
u
m
C
arbocycles
i
ith Q
u
h
aternary Ca
i
A
k
s
o Yoshimura,* Makoto Torizuka, Genki Mori, Keiji Tanino*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
Fax +81(11)7064920; E-mail: fumi@sci.hokudai.ac.jp; E-mail: ktanino@sci.hokudai.ac.jp
Received 13 October 2011
The result led us to investigate the intramolecular version
Abstract: An efficient method for constructing carbocycles with
all-carbon quaternary stereocenters has been developed on the basis
of a stereoselective cyclization reaction of a,b-unsaturated lactones
having an alkanenitrile side chain. Treatment of the substrate with
of a conjugate addition reaction using an a-cyano carban-
ion species (Scheme 2).3,4 With a view to inducing selec-
tive formation of an a-cyano carbanion, a,b-unsaturated
lithium hexamethyldisilazide (LiHMDS) in the presence of triiso- lactone 3 possessing no enolizable proton was designed as
propylsilyl chloride (TIPSCl) led to the generation of the corre-
the cyclization precursor.
sponding a-cyano carbanion species which readily underwent an
intramolecular conjugate addition reaction. It was found that
O
O
O
the combined use of trimethylsilyl trifluoromethanesulfonate
(TMSOTf) and triethylamine is also effective for the cyclization
reaction without using a strong base. Interestingly, different ste-
reochemical outcomes were observed in the two cyclization meth-
ods.
O
O
O
base
H
H
CN
Me
CN
Me
CN
Me
+
Me
Me
Me
Key words: carbocycles, cyclization, Michael addition, nitriles,
4a
4b
3
stereoselective synthesis
O
O
O
O
Development of an efficient method for the construction
of polysubstituted carbocycles in a stereoselective manner
remains a considerable challenge in organic synthesis. In
particular, carbocyclization reactions leading to the for-
mation of an all-carbon quaternary stereogenic center are
very important in total synthesis of various natural prod-
ucts.1
N–
Me
C
Me
Me
C
Me
N–
B
A
Scheme 2 An intramolecular conjugate addition reaction of an a,b-
unsaturated lactone having an alkanenitrile side chain
Recently, we reported the asymmetric total synthesis of
glycinoeclepin A on the basis of the cyclopentene annula- On treatment with a base, 3 would afford an a-cyano car-
tion method for the preparation of the key intermediate 2 banion species which may undergo intramolecular conju-
(Scheme 1).2 The contiguous all-carbon quaternary ste- gate addition reaction through transition state A or B. We
reogenic centers of bicyclic enone 2 were constructed by envisioned that the formation of bicyclic compound 4a
the highly stereoselective conjugate addition reaction us- through transition state A may be preferred, because an-
ing an a-cyano carbanion species generated from nitrile 1. other transition state B leading to epimer 4b suffers from
the steric repulsion between the two 1,3-diaxial methyl
CN OBn
groups. In addition, the use of a cyano group, which is
much less sterically demanding than an ester group,5 in
substrate 3 would be effective for increasing the energy
difference between the transition states A and B.
Me
Me
TBSO
TBSO
TBSO
Me
Me
CN
Me
Me
1
CN
KHMDS
AcOH (aq)
100 °C
then
Ac2O
At first, the cyclization precursor 3 was synthesized from
commercially available ethyl tiglate (5) as shown in
Scheme 3. Deconjugative a-alkylation of 5 with 3-chloro-
1-iodopropane followed by a three-step manipulation of
the functional groups afforded primary alkyl iodide 7. The
nitrile moiety was introduced via a substitution reaction of
7 with the carbanion species generated from propionitrile.
Construction of the lactone ring was achieved through
conversion of THP ether 8 to the corresponding acrylate 9
followed by ring-closing metathesis (RCM) catalyzed by
Umicore M2.6
BnO
AcO
O
O
(dr = 96:4)
2
Scheme 1 The stereoselective intermolecular conjugate addition
reaction of nitrile 1 under basic conditions
SYNLETT 2012, 23, 251–254
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290074; Art ID: U54811ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
2

252
F. Yoshimura et al.
LETTER
1) DIBAL-H, Et2O
–78 to 0 °C
97% (2 steps)
LDA
Cl(CH2)3I
DMPU
LDA, EtCN
HMPA
O
OTHP
O
EtO
Cl
I
EtO
Me
THF
–78 to 0 °C
Me
2) DHP, p-TsOH
CH2Cl2, 98%
3) NaI, acetone, 71%
Me
THF
Me
5
–78 °C to r.t.
7
6
84%
O
O
Mes
N
N Mes
OTHP
1) p-TsOH, MeOH
THF, 97%
Umicore M2
Ph
O
O
(9 mol%)
Cl
CN
Me
Ru
Cy3P
CN
Me
CN
Me
toluene
(0.04 M)
110 °C
2) CH2=CHCOCl
Et3N, DMAP
CH2Cl2, 81%
Cl
Me
Me
Me
8
9
3
81%
Umicore M2
Scheme 3 Synthesis of lactone 3 having an alkanenitrile side chain
With unsaturated lactone 3 in hand, we investigated the
cyclization reaction mediated by an amide base (Table 1).
When 3 was treated with potassium hexamethyldisilazide
(KHMDS) or sodium hexamethyldisilazide (NaHMDS)
in THF, a complex mixture containing small amounts of
bicyclic lactones 4a and 4b7 along with the recovery of 3
was obtained (Table 1, entries 1 and 2). On the other hand,
the use of lithium hexamethyldisilazide (LiHMDS) led to
a rather better result, and higher conversion of the reaction
was observed without formation of any side products
(Table 1, entry 3). While the combination of LiHMDS
and hexamethylphosphoric triamide (HMPA) was found
to enhance both yield and diastereomeric ratio of the prod-
ucts (51%, 4a/4b = 86:14), the conditions also caused a
considerable increase in the amount of the side products
(Table 1, entry 4).
OTIPS
H
O
O
LiHMDS (2 equiv)
HMPA (5 equiv)
TIPSCl (1.5 equiv)
then
O
1 M HCl
CN
CN
R
THF, –78 °C
Me
R
Me
10: R = H
3: R = Me
11: R = i-Pr
O
O
Yield
(a/b)
R
O
O
H
H
12a,b
H
79% (72:28)
CN
R
CN
R
4a,b Me 93%
13a,b i-Pr 81%
(90:10)
(92: 8)
+
Me
Me
a
b
Scheme 4 Improved method for the intramolecular conjugate addi-
tion reactions of lactones 3, 10, and 11
These results suggested that the lactone enolate formed by
the intramolecular conjugate addition reaction may under-
go degradation or an intermolecular addition reaction. In
order to exclude these possibilities, the reactions in the
presence of a silylating reagent for trapping the lactone
enolate were examined. We were pleased to find that the
use of triisopropylsilyl chloride (TIPSCl) gave a good re-
sult as shown in Scheme 4.8
Thus, upon treatment of 3 with LiHMDS (2 equiv) and
TIPSCl (1.5 equiv) in the presence of HMPA (5 equiv) at
–78 °C, the intramolecular conjugate addition reaction
proceeded smoothly to afford the cyclic ketene silyl ace-
tal. Treatment of the reaction mixture with 1 M HCl in one
pot gave a diastereomeric mixture of bicyclic lactones 4a
and 4b in 93% isolated yield.9,10 Similarly, substrates 10
Table 1 Intramolecular Conjugate Addition Reactions of Lactone 3 under Basic Conditionsa
O
O
O
O
O
O
base (1.5 equiv)
additive
H
H
CN
Me
CN
Me
CN
Me
+
Me
Me
Me
THF
–78 °C, 1 h
3
4a
4b
Entry
Base
Additive
Yield (%)b
4a/4bb
1:99
Recovery (%)b
1
2
3
4
KHMDS
NaHMDS
LiHMDS
LiHMDS
–
11
20
29
51
35
25
49
7
–
15:85
50:50
86:14
–
HMPA
a Typical reaction conditions: lactone 3 (0.2 mmol), base (0.3 mmol), additive (1.0 mmol), THF (2 mL), –78 °C.
b Determined by 1H NMR.
Synlett 2012, 23, 251–254
© Thieme Stuttgart · New York

LETTER
Stereocontrolled Construction of Carbocycles with Quaternary Carbon Atoms
253
and 11,11 possessing a different a-substituent on the nitrile Et3N (Scheme 6). For example, carbocyclization of cou-
moiety, were transformed into the corresponding bicyclic marin derivative 18, which was readily synthesized from
lactones 12 and 13, respectively.
2,6-dihydroxybenzaldehyde in three steps,11 proceeded
smoothly to afford the tricyclic lactones 19 in 76% yield
in a stereoselective manner (86:14). On the other hand,
LiHMDS/TIPSCl-mediated cyclization of 18 did not give
satisfactory results, where 19 was obtained only in 11%
yield (19a/19b = 50:50).
The steric effect of the a-substituent plays an important
role to control the diastereoselectivity in the cyclization
reactions (Scheme 4). Thus, increasing the steric hin-
drance of the a-substituent in the cyclization precursor (H
< Me < i-Pr) tends to increase the diastereomeric ratio of
the product (72:28 < 90:10 < 92:8). It is noteworthy that
these stereochemical outcomes are consistent with that
supposed from the transition state models A and B in
Scheme 2.
O
O
O
LiHMDS
TIPSCl
HMPA
H
H
O
O
O
CN
Me
CN
Me
CN
Me
+
Me
Me
Me
THF, –78 °C
then 1 M HCl
During the course of the studies to find a suitable silylat-
ing reagent in the carbocyclization reaction, we realized
that a similar transformation can be achieved without us-
ing a strong base such as LiHMDS (Scheme 5). Thus,
when 3 was treated with TMSOTf (2 equiv) in the pres-
ence of Et3N (4 equiv) in 1,2-dichloroethane (DCE) at
50 °C for 1.5 hours, carbocyclization proceeded smoothly
to afford 4a and 4b in 84% yield.12,13 Interestingly, this
new method showed complementary steteochemical out-
come on the newly formed quaternary stereogenic center
as compared to the LiHMDS/TIPSCl system; as a result,
4b was obtained as a major isomer to 4a in a 67:33 ratio.
The reaction mechanism of this cyclization would require
further analysis; mechanistic investigations are currently
ongoing in our laboratory.14
94%
14
15a
15b
(70:30)
TMSOTf, Et3N
DCE, 50 °C
15a + 15b (48:52)
14
97%
O
O
O
LiHMDS
TIPSCl
HMPA
H
H
O
O
O
CN
Me
CN +
Me
CN
Me
THF, –78 °C
then 1 M HCl
Me
Me
Me
80%
16
17a
17b
(57:43)
TMSOTf, Et3N
DCE, 50 °C
93%
17a + 17b (43:57)
16
O
O
O
O
O
O
O
O
O
O
O
O
TMSOTf
Et3N
TMSOTf (2 equiv)
Et3N (4 equiv)
H
H
H
H
CN
Me
CN
+
CN
Me
CN
Me
CN
CN
Me
+
Me
DCE
50 °C
Me
Me
Me Me
DCE
50 °C, 1.5 h
4a
4b
3
18
19a
19b
76%
84%
(86:14)
(4a/4b = 33:67)
Scheme 6 Carbocyclization of various substrates
Scheme 5 Alternative method for carbocyclization of lactone 3
To conclude, an efficient method for constructing car-
bocycles with all-carbon quaternary stereocenters has
been developed on the basis of a stereoselective cycliza-
tion reaction of a,b-unsaturated lactones having an al-
kanenitrile side chain. Treatment of the substrate with
LiHMDS in the presence of TIPSCl and HMPA led to the
generation of the corresponding a-cyano carbanion spe-
cies which readily underwent an intramolecular conjugate
addition reaction. It was found that the combined use of
TMSOTf and Et3N is also effective for the cyclization re-
action without using a strong base. Interestingly, different
stereochemical outcomes were observed in the two cy-
clization methods. Application of this methodology to
natural product synthesis is in progress, and will be report-
ed in due course.
Having established the efficient carbocyclization proce-
dures, the scope of these reactions was investigated by us-
ing several substrates as shown in Scheme 6. While the
LiHMDS/TIPSCl-mediated cyclization of the precursor
1411 having a g-lactone moiety afforded the cis-fused cy-
clohexane derivative 15 in 94% yield, the diastereomeric
ratio of 15 was lower than that of bicyclic lactone 4. The
cyclization of 14 by using the TMSOTf/Et3N system pro-
vided 15 in excellent yield with complementary stere-
ochemistry on the newly formed quaternary stereogenic
center similar to the case of 4. Formation of a five-mem-
bered ring was examined by the reaction of 1611 having a
shorter side chain. Although the carbocyclization reaction
proceeded smoothly in both procedures to afford 17, poor
stereoselectivity was observed in these cases, suggesting
that the rigid chairlike six-membered transition state as
depicted in Scheme 2 is essential in high stereoselectivity.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
It is noteworthy that a base-sensitive substrate could be ef-
ficiently cyclized by the combination of TMSOTf and
© Thieme Stuttgart · New York
Synlett 2012, 23, 251–254

254
F. Yoshimura et al.
LETTER
Acknowledgment
O
O
We acknowledge Dr. Eri Fukushi and Mr. Kenji Watanabe (GC-MS
& NMR Laboratory, Graduate School of Agriculture, Hokkaido
University) for their mass spectral measurements. This work was
supported by a Grant-in-Aid for Young Scientists (B) (No.
22710206) and the Global COE Program (Project No. B01: Cataly-
sis as the Basis for Innovation in Materials Science) from the Mini-
stry of Education, Culture, Sports, Science and Technology, Japan.
LiHMDS
HMPA
O
O
H
CO2Et
Me
CO2Et
Me
TIPSCl
s.m.
63%
+
Me
Me
THF
–78 °C, 7 h
then 1 M HCl
15%
single isomer
Scheme 7
References and Notes
(10) General Experimental Procedure for the
Carbocyclization by Using the LHMDS/TIPSCl System
To a cooled mixture of a,b-unsaturated lactone 3 (32.4 mg,
0.156 mmol), TIPSCl (49.8 mL, 0.235 mmol), and HMPA
(136 mL, 0.782 mmol) in THF (1.6 mL) was slowly added a
freshly prepared 1.0 M THF solution of LiHMDS (312 mL,
0.312 mmol) at –78 °C. After stirred at this temperature for
7 h, the reaction was quenched with aq 1 M HCl (1.6 mL).
The mixture was stirred at r.t. for 1.5 h and then diluted with
EtOAc. After the layers were separated, the aqueous layer
was extracted with EtOAc. The combined organic layers
were washed successively with H2O and brine, dried over
MgSO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on
silica gel (hexane–EtOAc = 5:1 to 1:1) to afford 4a (27.3 mg,
84%) and 4b (2.9 mg, 9%).
(1) For representative reviews of the stereoselective
construction of all-carbon quaternary stereogenic centers,
see: (a) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005,
347, 1473. (b) Denissova, I.; Barriault, L. Tetrahedron
2003, 59, 10105. (c) Fuji, K. Chem. Rev. 1993, 93, 2037.
(2) (a) Shiina, Y.; Tomata, Y.; Miyashita, M.; Tanino, K. Chem.
Lett. 2010, 39, 835. (b) Tanino, K.; Tomata, Y.; Shiina, Y.;
Miyashita, M. Eur. J. Org. Chem. 2006, 328.
(3) There are a few examples of the intramolecular conjugate
addition reaction involving an a-cyano carbanion
intermediate: (a) Condon, S.; El Ouarradi, A.; Métay, E.;
Léonel, E.; Bourdonneau, M.; Nédélec, J.-Y. Tetrahedron
2008, 64, 9388. (b) Shia, K.-S.; Jan, N.-W.; Zhu, J.-L.; Ly,
T. W.; Liu, H.-L. Tetrahedron Lett. 1999, 40, 6753.
(4) The intramolecular alkylation reactions of nitriles provide
useful carbocyclization method. For an excellent review of
nitrile anion cyclization, see: Fleming, F. F.; Shook, B. C.
Tetrahedron 2002, 58, 1.
(5) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994, 696–697.
(6) Clavier, H.; Nolan, S. P. Chem. Eur. J. 2007, 13, 8029.
(7) The configurations of 4a and 4b were unambiguously
determined by 1H NMR NOE experiments. See Supporting
Information for details.
(8) The use of sterically demanding silylating reagent is of
critical importance in this reaction. For example, the reaction
in the presence of the less bulky triethylsilyl chloride
(TESCl) was accompanied by the formation of the a-silyl
nitrile through trapping of the a-cyano carbanion before
cyclization.
(11) See Supporting Information for the synthesis.
(12) Controlled experiments showed that neither TMSOTf nor
Et3N alone promoted this carbocyclization.
(13) General Experimental Procedure for the
Carbocyclization by Using the TMSOTf/Et3N System
To a mixture of a,b-unsaturated lactone 3 (18.5 mg, 89.0
mmol) and Et3N (50.2 mL, 0.357 mmol) in DCE (0.45 mL)
was added TMSOTf (32.3 mL, 0.179 mmol) at r.t. After
stirred at 50 °C for 1.5 h, the mixture was cooled to r.t., and
a sat. aq NaHCO3 solution was added. The layers were
separated, and then the aqueous layer was extracted with
EtOAc. The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography on
silica gel (hexane–EtOAc = 5:1 to 1:1) to afford 4a (5.1 mg,
28%) and 4b (10.3 mg, 56%).
(9) It should be noted that the use of a nitrile group was
indispensable for the LiHMDS/TIPSCl-mediated
cyclization. For example, when a nitrile group was replaced
to an ester group, the reaction did not proceed efficiently; the
bicyclic lactone was obtained only in 15% yield along with
the recovery of the starting material in 63% yield
(Scheme 7).
(14) We could not detect any silyl ketene imine intermediates in
the cyclization of 3 by using the TMSOTf/Et3N system when
monitoring the reaction by 1H NMR and 13C NMR
spectroscopy. In this context, Denmark and Wilson have
recently reported the Lewis base catalyzed intermolecular
conjugate addition of silyl ketene imines to a,b-unsaturated
carbonyl compounds, see: Denmark, S. E.; Wilson, T. W.
Synlett 2010, 1723.
Synlett 2012, 23, 251–254
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