Synthesis of spirocyclopentene-indolines by intramolecular alkylidine insertion reactions

Article abstract of DOI:10.1016/j.tetlet.2008.07.043

Intramolecular 1,5 CH insertion of unstabilized carbenes into the tertiary carbon of a substituted indoline generates spiro[cyclopent[2]ene-1,2′-indolines] in good yields and excellent enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2008.07.043

Tetrahedron Letters 49 (2008) 5508–5510
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Synthesis of spirocyclopentene-indolines by intramolecular
alkylidine insertion reactions
*
Christopher J. Whipp, Felix Gonzalez-Lopez de Turiso
Medicinal Chemistry, Chemistry Research and Development, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular 1,5 CH insertion of unstabilized carbenes into the tertiary carbon of a substituted indoline
generates spiro[cyclopent[2]ene-1,20-indolines] in good yields and excellent enantioselectivities.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 3 June 2008
Revised 24 June 2008
Accepted 7 July 2008
Available online 11 July 2008
Indolines containing chiral quaternary carbons are common
architectures in a number of natural products and biologically
active compounds. For instance, this chemical motif can be found
in natural products such as the antiviral pseudoindoxyl alkaloid
11 or in substances such as the peptidomimetic inhibitor of
Hepatitis C 2 (Fig. 1).2
Traditionally, these compounds have been synthesized using
metal-catalyzed processes,3 radical-mediated reactions,1 or direct
alkylation strategies.2 However, many of these methods present
limitations, such as the lack of stereocontrol of the newly formed
quaternary carbon, and/or the use of toxic reagents.4 Recently,
Hayes and co-workers have reported an innovative approach
toward the synthesis of N-bearing quaternary stereocenter struc-
tures that resolves the issues of stereocontrol and scalability.5
The strategy relies on the use of unstabilized carbene intermedi-
ates, a field pioneered by Ohira,6 Gilbert,7 and Taber,8 and has been
successfully applied to the synthesis of a number of substances
such as pyrrolidine 3 (Fig. 2).
In order to expand the scope of this methodology, we decided to
investigate the viability of this approach toward the synthesis of
chiral spirocycloindolines such as 4. In an analogous fashion to
Hayes’ strategy, a 1,5 CH insertion reaction of an unstabilized
alkylidine carbene was viewed as the key step in the elaboration
of these heterocyclic structures (Scheme 1).
The study started with the synthesis of cyclization precursors 5
and 6. Thus, oxidation of the enantiomerically pure alcohol 79 to
the corresponding aldehyde using Dess–Martin periodinane
followed by treatment with acetylmethylene triphenylphospho-
rane gave enone 8 in 73% overall yield. Catalytic hydrogenation
(Pd/C, H2, EtOAc) of 8 provided ketone 5 in 99% yield. Subsequent
Wittig olefination of 5 was carried out using NaHMDS as the base
and gave vinyl chloride 6 in 60% yield as a 1:1 mixture of E:Z iso-
S
O
CO2H
O
H
N
CHF2
CO2H
H
N
N
H
N
H
O
MeO
O
OMe
O
2
1
Figure 1.
TBSO
TBSO
KHMDS
93%
N
Boc
N
Boc
Cl
3
Figure 2. Hayes’ synthesis of enantiomerically enriched pyrrolidines.
mers.10 With these precursors in hand, we were in a position to
test the key 1,5 CH insertion reaction. Gratifyingly, we found that
treatment of chloride derivative 6 with KHMDS in Et2O at room
temperature for 5 h provided spirocycloindoline 4 in 64% yield
(Scheme 2).11 Alternatively, 4 was also obtained in 60% yield when
the cyclization was performed with the ketone precursor 5 under
Ohira conditions and using THF as the solvent.6b The stereochem-
ical integrity of the spirocyclic structure 4 was confirmed by
synthesizing a racemic sample of this compound and resolving
the mixture by chiral HPLC. Subsequent injection of the indoline
412 showed that its ee was greater than 95%.
The spiroindoline
4 could be transformed into the ring
expanded product 10 via oxidative cleavage of 4, followed by
intramolecular aldol reaction of keto aldehyde 9 and subsequent
* Corresponding author. Tel.: +1 650 244 2356; fax: +1 650 837 9369.
E-mail address: felgonza@amgen.com (F. Gonzalez-Lopez de Turiso).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.043

C. J. Whipp, F. Gonzalez-Lopez de Turiso / Tetrahedron Letters 49 (2008) 5508–5510
5509
Br
Br
O
1,5 C-H
i
ii
OH
N
Boc
N
N
N
Boc
insertion
Boc
Boc
12
4
11
Br
Br
iii
N
Boc
N
Boc
O
N
N
14
O
13
Boc
Boc
Cl
Scheme 4. Reagents and conditions: (i) (a) Dess–Martin periodinane, DCM,
NaHCO3; (b) acetylmethylene triphenylphosphorane, 65% from 7; (ii) H2, Pd/C,
70%; (iii) BuLi, TMSCHN2, ꢁ78 °C to rt, 61%.
5
6
Scheme 1. Proposed alkylidene 1,5 C–H insertion reaction.
methyl cuprate and enone 8.14 This reaction gave a diastereomeric
mixture of ketones 15a and 15b (in a ratio of 1:7) that were sepa-
rated by column chromatography. Each diastereomer was treated
with (chloromethyl) triphenylphosphonium chloride in the pres-
ence of NaHMDS to give the desired compounds 16a and 16b,
respectively (Scheme 5).15
O
ii
i
OH
N
N
Boc
Boc
8
7
With both precursors in hand the cyclization was attempted
under the previous reaction conditions (i.e., KHMDS, Et2O, rt,
5 h). Aqueous work-up followed by analysis of the crude 1H NMR
of both reaction mixtures, showed that only diastereomer 16a
had proceeded in the expected cyclization mode. Flash chromato-
graphy of the crude reaction mixture of 16a provided the spiro-
iii
N
Boc
6
N
Boc
5
O
Cl
v
iv
cyclic compound 17 in 63% yield as
a single diastereomer
(Scheme 6).15 In contrast to 16a, the cyclization of 16b resulted
in a mixture of unidentified products.16
N
Boc
With this limitation in mind, we decided to investigate the
scope of this 1,5 CH insertion reaction in other substituted indoline
precursors. The synthesis of these compounds was carried out by
addition of different alkyl groups into enone 8. The corresponding
(R,S) isomers 18(a–c) were separated by column chromatography
and converted into the vinyl chloride precursors 19(a–c) (Scheme
7).17 The results of the cyclization experiments with these precur-
sors are summarized in Table 1.
4
Scheme 2. Reagents and conditions: (i) (a) Dess–Martin periodinane, DCM,
NaHCO3; (b) acetylmethylene triphenylphosphorane, 73% from 7; (ii) H2, Pd/C,
99%; (iii) (chloromethyl) triphenylphosphonium chloride, NaHMDS, 60%; (iv)
KHMDS, rt, Et2O, 64%; (v) BuLi, TMSCHN2, THF, ꢁ78 °C to rt, 60%.
dehydration.5a Thus, this method provides a versatile strategy to-
ward the synthesis of enantiomerically enriched indolines that
contain quaternary carbons (Scheme 3).
In order to evaluate if the methodology could be used for the
synthesis of more functionalized spirocycloindolines, we applied
this route to the bromo indoline 11. Thus, oxidation of alcohol
1113 with Dess–Martin periodinane, followed by enone formation
and Pd-catalyzed hydrogenation provided precursor 13 in good
overall yield. We were pleased to find that when ketone 13 was
treated under Ohira cyclization conditions,6b it gave the bromi-
nated spirocycloindoline 14 in 61% yield (see Scheme 4).
O
H
i
8
N
Me
Boc
15a= (R,S)
15b= (R,R)
ii
Cl
Cl
H
H
Due to these encouraging results we decided to investigate the
1,5 CH insertion reaction with precursors bearing an alkyl group on
the indoline side chain. We first started this study by synthesizing
vinyl chloride derivatives 16a and 16b, which contain a methyl
side chain with different relative stereochemistry. The required
cyclization precursors were prepared via 1,4-addition reaction of
N
Boc
Me
N
Me
Boc
16a = (R,S) diastereomer
16b = (R,R) diastereomer
Scheme 5. Reagents and conditions: (i) MeLi, CuBr, 85%; (ii) (chloromethyl)
triphenylphosphonium chloride, NaHMDS (71–83%).
O
iii, iv
i, ii
O
4
N
Boc
i
N
Boc
CHO
16a
N
9
10
Boc
Scheme 3. Reagents and conditions: (i) K2OsO4ꢀ2H2O (3%), NMO, acetone/H2O
(10:1), 91%; (ii) NaIO4, THF/H2O (2:1), 83%; (iii) EtONa, EtOH, 85%; (iv) MsCl, Et3N,
DCM, 70%.
17
Scheme 6. Reagents and conditions: (i) KHMDS, rt, Et2O, 63%.

5510
C. J. Whipp, F. Gonzalez-Lopez de Turiso / Tetrahedron Letters 49 (2008) 5508–5510
J. Tetrahedron Lett. 2002, 43, 3541; (f) Green, M. P.; Prodger, J. C.; Sherlock, A. E.;
O
Hayes, C. J. Org. Lett. 2001, 3, 3377; (g) Gabaitsekgosi, R.; Hayes, C. J. Tetrahedron
Lett. 1999, 40, 7713. Bonjoch and co-workers have also reported work in this
area. See: (h) Diaba, F.; Ricou, E.; Bonjoch, J. Tetrahedron: Asymmetry 2006, 17,
1437.
H
i
ii
8
N
R
6. (a) Ohira, S.; Ishi, S.; Shinohara, K.; Nozaki, H. Tetrahedron Lett. 1990, 31, 1039;
(b) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992, 721.
7. Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J. Org. Chem. 1985, 50, 2557.
8. (a) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143; (b) Taber, D. F.; Han,
Y.; Incarvito, C. D.; Rheingold, A. L. J. Am. Chem. Soc. 1998, 120, 13285; (c) Taber,
D. F.; Meagley, R. P.; Walter, R. J. Org. Chem. 1994, 59, 6014; (d) Taber, D. F.;
Meagley, R. P.; Doren, D. J. J. Org. Chem. 1996, 61, 5723.
9. The compound was prepared according to the synthetic procedure described
in: Lee, S.; Yi, K. Y.; Kim, S.-K.; Suh, J.; Kim, N. J.; Yoo, S.-e.; Lee, B. H.; Seo, H. W.;
Kim, S.-O.; Lim, H. Eur. J. Med. Chem. 2003, 38, 459.
Boc
18a, R= Et
18b, R= Bu
18c, R = Phenyl
R
Cl
H
iii
N
N
R
Boc
19a, R= Et
19b, R= Bu
19c, R = Phenyl
Boc
10. Hayes and co-workers have shown that there is little difference in reactivity
between the E and Z isomers when a related substrate was subjected to the
spirocyclization conditions. See: Auty, J. M. A.; Churcher, I.; Hayes, C. J. Synlett
2004, 1443.
11. Typical procedure for the 1,5 CH insertion reaction: To a stirred solution of 6
(1.15 g, 3.57 mmol) in Et2O (30 mL) was added a 0.5 M solution of KHMDS in
toluene (14.3 mL, 7.15 mmol). The reaction mixture was stirred for 5 h at room
temperature and then it was washed with citric acid and brine. The organic
layer was dried over Na2SO4, filtered, and evaporated in vacuo. The crude
product was purified by column chromatography (gradient of elution 0–3%
20a, R= Et
20b, R= Bu
20c, R = Phenyl
Scheme 7. Reagents and conditions: (i) RLi, CuBr (67–82%); (ii) (chloromethyl)
triphenylphosphonium chloride, NaHMDS (55–65%); (iii) KHMDS, rt, Et2O.
EtOAc in hexanes) to give 0.65 g (64%) of spirocycloindoline 4. [a] +65.9 (c
D
Table 1
0.75, CH2Cl2). 1H NMR (400 MHz, DMSO-d6) d ppm 7.68 (d, J = 8.2 Hz, 1H),
7.13–7.09 (m, 2H), 6.90 (t, J = 7.4 Hz, 1H), 5.37 (d, J = 1.6 Hz, 1H), 3.06–3.04 (m,
2H), 2.40–2.25 (m, 3H), 2.06–2.02 (m, 1H), 1.73 (s, 3H), 1.43 (s, 9H); 13C NMR
(100 MHz, DMSO-d6) d ppm 151.8 (C), 142.8 (C), 139.1 (C), 129.5 (CH), 128.6
(C), 127.0 (CH), 124.3 (CH), 121.9 (CH), 114.3 (CH), 79.6 (C), 78.2 (C), 43.1 (CH2),
37.4 (CH2), 34.8 (CH2), 27.9 (CH3), 16.3 (CH3).
Cyclization of precursors 19a–c
Entry
Precursor
Conditions
Product
Yielda,b (%)
1
2
3
19a
19b
19c
KHMDS, 25 °C, 5 h
KHMDS, 25 °C, 5 h
KHMDS, 25 °C, 5 h
20a
20b
20c
70
68
51c
12. Experiment was carried out with the chiral indoline 4 derived from ketone 5.
HPLC was performed using a chiral AD column and 1% IPA in hexanes as eluant.
13. The compound was prepared according to the synthetic procedure described
in: Ori, M.; Toda, N.; Takami, K.; Tago, K.; Kogen, H. Tetrahedron 2005, 61, 2075.
14. Mackay, D.; Neeland, E. G.; Taylor, N. J. J. Org. Chem. 1986, 51, 2351.
15. The relative stereochemistry of 15a,b and 16a,b was assigned based on NOE
a
Isolated yield after column chromatography over silica gel.
Reactions carried out using Et2O as the solvent.
Isolated yield after column chromatography over basic alumina.
b
c
irradiation experiments on the cyclization product 17. Thus, in
a NOESY
experiment we observed the following strong NOE signals, which allowed us to
assign the relative stereochemistry of these compounds.
In these experiments, we observed that when precursors
19(a–c) were treated under the standard cyclization conditions
(KHMDS, Et2O, rt, 5 h) the reactions proceeded in good yields with
both the alkyl and phenyl substituents (entries 1–3). The resulting
spirocycloindoline products from these reactions 20(a–c) were
obtained as single diastereomers and were purified by column
chromatography (Table 1).
n.O.e
n.O.e
n.O.e
H
H
H
H
In summary, we have expanded the use of 1,5 CH carbene
insertion reactions to the synthesis of chiral spirocyloindolines.
The methodology provides a new entry into functionalized chiral
indoline structures, although the cyclization is dependent on the
relative stereochemistry of the precursors.
N
Boc
H
16. The different outcome of these two reactions can be rationalized in terms of
the relative energy of their transition states. Thus, the transition state required
for spirocyclization is lower in energy for 16a than for 16b. This difference in
energy can be attributed to the unfavorable steric interaction between the Boc
and methyl groups for the transition state of 16b, and leads this precursor to
undergo alternative cyclization pathways.
Acknowledgments
We thank Smriti Khera and David Chow for elucidating the ste-
reochemistry of compound 17 and the ‘Amgen Summer Internship
program’ for financial support. We also thank Steve Olson, Daqing
Sun, and Julio Medina for proof reading this manuscript.
16a
17
N
Boc
References and notes
H
1. Takayama, H.; Kurihara, M.; Subhadhirasakul, S.; Kitajima, M.; Aimi, N.; Sakai,
S.-I. Heterocycles 1996, 42, 87; Takayama, H.; Ishikawa, H.; Kurihara, M.;
Kitajima, M.; Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.;
Yamamoto, L. T.; Watanabe, K. J. Med. Chem. 2002, 45, 1949.
2. Ontoria, J. M.; Di Marco, S.; Conte, I.; Di Francesco, M. E.; Gardelli, C.; Koch, U.;
Matassa, V. G.; Poma, M.; Steinkühler, C.; Volpari, C.; Harper, S. J. Med. Chem.
2004, 47, 6443.
3. Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am. Chem. Soc. 1980, 102, 3583.
4. For reviews on the synthesis of asymmetric quaternary stereocentres, see: (a)
Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388; (b) Fuji, K.
Chem. Rev. 1993, 93, 2037.
5. For examples on the application of 1,5 CH insertion reactions in the synthesis of
N-bearing structures see: (a) Asari, A.; Angelov, P.; Auty, J. M. A.; Hayes, C. J.
Tetrahedron Lett. 2007, 48, 2631; (b) Hayes, C. J.; Bradley, D. M.; Thomson, N. M.
J. Org. Chem. 2006, 71, 2661; (c) Hayes, C. J.; Sherlock, A. E.; Selby, M. D. Org.
Biomol. Chem. 2006, 4, 193; (d) Bradley, D. M.; Mapitse, R.; Thomson, N. M.;
Hayes, C. J. J. Org. Chem. 2002, 67, 7613; (e) Green, M. P.; Prodger, J. C.; Hayes, C.
H
Undesired
cyclization
pathways
16b
N
Boc
17. The (R,S) to (R,R) ratio of diastereomers for the 1,4-addition reactions were
found to be dependent on the alkyl group. Thus, the observed (R,S) to (R,R)
ratios of products were 18a (1:3.3), 18b (1:2.7), and 18c (1–18). The
stereochemistry of these products was assigned based on the ability of
substrates 19a–c (derived from 18a–c) to undergo the 1,5 CH insertion
reaction.