Central-axial-central chirality transfer: Asymmetric synthesis of highly substituted indenes bearing a stereogenic quaternary carbon center from optically active propargyl alcohols

Article abstract of DOI:10.1039/c4cc08034c

An asymmetric synthesis of highly substituted indenes 3, bearing a quaternary stereogenic carbon center, has been developed via the central-axial-central chirality transfer from optically active propargyl alcohols 1. This transformation involves the addition/rearrangement of 1 and ynamides 2 to give tetra-substituted allenes 4 and further cyclization of 4.

Full text of DOI:10.1039/c4cc08034c

ChemComm
View Article Online
View Journal
COMMUNICATION
Central–axial–central chirality transfer:
asymmetric synthesis of highly substituted
indenes bearing a stereogenic quaternary carbon
center from optically active propargyl alcohols†
Cite this:DOI: 10.1039/c4cc08034c
Received 10th October 2014,
Accepted 4th November 2014
Masahiro Egi,* Kaori Shimizu, Marin Kamiya, Yuya Ota and Shuji Akai‡
DOI: 10.1039/c4cc08034c
www.rsc.org/chemcomm
An asymmetric synthesis of highly substituted indenes 3, bearing a
quaternary stereogenic carbon center, has been developed via
the central–axial–central chirality transfer from optically active
propargyl alcohols 1. This transformation involves the addition/
rearrangement of 1 and ynamides 2 to give tetra-substituted allenes
4 and further cyclization of 4.
Indenes are important structural motifs, widely found in bio-
logically active natural products and pharmaceutical drugs.1
In addition, they serve as functional materials for electronics
and optoelectronics2 and as valuable ligands for transition
metal complexes.3 Consequently, organic chemists have focused
on developing a number of synthetic routes towards indene
derivatives.4 Some representative methods include the carbo-
cyclization of aryl-substituted propargyl alcohols or allyl alcohols,5
the cyclization of aryl alkynes through sp3 C–H activation,6 the
annulation of aryl allenes,5c,e,g,7 the [3+2] annulation of alkynes
Scheme 1 A strategy for the transformation of optically active propargyl
alcohols 1 into highly substituted indenes 3, bearing a quaternary stereo-
genic carbon center, via tetra-substituted allenes 4 with chirality transfer.
with aryl carbonyl or imine compounds,8 and the ring expansion devoted to the synthesis of allenes,12 methods for supplying
of cyclopropanes or cyclopropenes bearing aryl groups.9 Among optically active tetra-substituted allenes are still largely limited.13
these reports, however, only a few describe the synthesis of This is ascribed to the lack of an efficient and general synthetic
optically active indene derivatives, in particular, those bearing a protocol for tetra-substituted allenes even in the racemic manner,
quaternary stereogenic carbon center.10
and the facile racemization of optically active allenes in the
We envisioned an asymmetric synthesis of highly substi- presence of transition metals.14,15 Here, we describe the studies
tuted indene derivatives 3, bearing a quaternary stereogenic of the transition metal-catalyzed conversion of propargyl alcohols 1
carbon center, by a transformation of optically active aryl into tetra-substituted allenes 4 via the addition of 1 to ynamides 2
propargyl tertiary alcohols 1 and ynamides 2 (Scheme 1). The followed by the [3,3]-sigmatropic rearrangement of the inter-
essential points of our transformation relied on the formation mediate propargyl vinyl ethers and the intramolecular cyclization
of optically active tetra-substituted allenes 4 and on the intra- of 4 to give highly substituted indenes 3. This multistep reaction
molecular cyclization of 4 into 3, while maintaining the chiral proceeds with the retention of chiral integrity of 1.
integrity of 1 during the central–axial–central chirality transfer.11
It is known that transition metal-induced p-activated triple
The asymmetric synthesis of indenes using optically active allenes bonds of ynamides undergo nucleophilic addition at the a-position
has not been previously described. Although much effort has been of the nitrogen atom.16 We hypothesized that sterically hindered
tertiary propargyl alcohols 1 might add to ynamides 2 to in situ
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
provide propargyl vinyl ethers 5, which would serve as the precursor
for the [3,3]-sigmatropic rearrangement. In addition, these two
steps might proceed continuously at ambient temperature, in
Shizuoka, 422-8526, Japan. E-mail: egi@u-shizuoka-ken.ac.jp
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral data for all new compounds. See DOI: 10.1039/c4cc08034c
which the catalyst used for the nucleophilic addition could also
‡ Present address: Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
promote the subsequent rearrangement into allenes 4. In order
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Synthesis of tetra-substituted allenes 4a–4j from 1a–1j and 2a
in the presence of AgOTf
(Scheme 2). Although transition metals often cause the (partial)
racemization of optically active allenes,14,15 we were pleased
to find that the addition–rearrangement reactions of 1k–1n19
with 2a underwent with the complete retention of the optical
purities during the central-to-axial chirality transfer. We think
that the key factor to suppress the racemization is the low
affinity of silver catalysts for allenes and the small amount
(1 mol%) of AgOTf used.14b,20 To the best of our knowledge, this
is the first example of the preparation of optically active tetra-
substituted allenes by the [3,3]-sigmatropic rearrangement of
propargyl vinyl ether derivatives.14a,d,21
With tetra-substituted allenes 4 in hand, the intramolecular
cyclization of 4 into indenes 3 became our next concern. As a
model study, the conversion of 4a into 3a was investigated in
toluene (Table 2). The AgOTf-catalyzed reaction of 4a, either at
room temperature or at 80 1C, did not give the desired product
3a at all (entries 1 and 2). When (Ph3P)AuOTf (5 mol%) or InCl3
(5 mol%) was used, the reaction led to the isomerization to
produce the conjugate dienylamide 6a as a main product
(entries 3 and 4). It was found that 3a could be obtained in
good yield when PtCl2 was employed (entry 5).22 In addition,
Substrate 1
Product 4
Yielda (%)
Time
(h)
Entry
R1
R2
R3
1
2
3
4
1a Me
1b Me
1c Me
1d Me
1e (CH2)5
Me
Me
Me
CH2OTBS
Ph
1
2
2
3
1
3
1
1
4a 75 (38)b
4b 64
4c 70
4d 83
4e 60
4f 77
4g 58
4h 55
4i 73
4j 59
C6H4-4-OMe
C6H4-4-Cl
Ph
5
Ph
6c
7
1f CH2OCMe2OCH2 Ph
1g Me
1h Ph
1i Et
1j Me
Me
Ph
Ph
Me
N-Boc-indol-5-yl
Me
Me
(CH2)2Ph
8d
9
2.5
0.5
10
b
Mbs = 4-methoxybenzenesulfonyl. a Yield of the isolated product. Use
of (Ph3P)AuOTf, generated from (Ph3P)AuCl and AgOTf (1 mol% each),
c
instead of AgOTf. Further addition of AgOTf (1 mol%) and 2a (1.2 equiv.)
d
after 1 h. Use of AgOTf (5 mol%).
to examine the feasibility of our hypothesis, the reaction of 1 with 2 the choice of the solvent proved to have a significant influence
was first investigated in either a prochiral or racemic form. Mixing on the ratio of 3a and 6a, and THF afforded 3a in quantitative
1a and 2a17 in toluene at room temperature led to the recovery yield and complete selectivity (entry 6), while toluene, CH2Cl2,
of starting materials. In the presence of highly alkynophilic and DMF resulted in the formation of mixtures of 3a and 6a.
(Ph3P)AuOTf (1 mol%), the addition of 1a to 2a proceeded smoothly
The optimized reaction conditions were applicable to the
at room temperature to directly afford tetra-substituted allene 4a in synthesis of a wide range of highly substituted indenes 3, as
38% yield (Table 1, entry 1 in parentheses). We reasoned that the shown in Scheme 3. In particular, sterically demanding
facile rearrangement of 5a to 4a could be ascribed to the high products (3d, 3e, and 3l) were obtained in high yields, albeit
nucleophilicity of the amide enol moiety of 5a and to the activation longer reaction times were required. The intramolecular cycli-
of a C–C triple bond in 5a by the gold catalyst, which enhanced the zation of indole derivative 4g took place exclusively at the
electrophilicity of the acetylene. Screening of various catalysts18 C4 position to give 3g, and in the cases of 4h and 4i, where
revealed AgOTf to be the most effective catalyst, which provided 4a R2 = phenyl, the cyclization occurred at the allene moiety,
in 75% yield (entry 1). The substrate scope of the two-step cascade forming indenes 3h and 3i, respectively, with the acetamide
transformation was then investigated and it was found that various group at the C1 position.
tertiary propargyl alcohols 1b–1j (1.0 equiv.) react with 2a (1.2 equiv.),
Having established the basic study, we finally undertook an
in the presence of AgOTf (1 mol%), to provide tetra-substituted intramolecular cyclization of enantioenriched allenes
4
allenes 4b–4j in good-to-excellent yields (entries 2–10). The reaction (Scheme 4). Although electron-rich allenes are prone to the
time required to reach completion was typically less than 3 h, and
when R3 was an aryl, a heteroaryl, or an alkyl group, the rearrange-
ment proceeded. Notably, this method was compatible with acid-
Table 2 Catalyst screening for the intramolecular cyclization of tetra-
substituted allene 4a
labile protecting groups such as OTBS, acetal, and Boc groups
(entries 4, 6, and 7).
We next investigated the chirality transfer from optically
active propargyl alcohols 1 into tetra-substituted allenes 4
Entry Catalyst
Temp. (1C) Time (h) 3aa (%)
6aa (%)
1
2
3
4
5
6c
AgOTf
AgOTf
rt
80
12
12
1
4
1
0
0
0
0
9
100
83
9
(Ph3P)AuOTf b rt
InCl3
PtCl2
PtCl2
50
80
Reflux
Trace
73
1
100 (98)d
0
a
NMR yield using 1,4-dimethoxybenzene as the internal standard.
b
c
Generated from (Ph3P)AuCl and AgOTf (5 mol% each). The reaction
d
Scheme 2 Central-to-axial chirality transfer from optically active 1k–1n
to optically active 4k–4n.
was performed in THF. Yield of the isolated product is shown in
parentheses.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
the central chirality of 1 was effectively transferred into that of
3. This was achieved via the temporary formation of tetra-
substituted allenes 4 by the central–axial–central chirality
transfer. Moreover, our method provides a new synthetic route
towards the less accessible racemic and optically active tetra-
substituted allenes. Additional investigation to determine the
absolute stereochemistries of 4 and 3 and a practical extension
of this method are currently in progress.
M.E. gratefully acknowledges financial support in the form
of the Grant-in-Aid for Scientific Research (C) (No. 24590016).
Notes and references
1 (a) G. Majetich and J. M. Shimkus, J. Nat. Prod., 2010, 73, 284; (b) B.-F.
Li, W. J. Moree, J. Yu, T. Coon, S. Zamani-Kord, S. Malany, K. Jalali,
J. Wen, H. Wang, C. Yang, S. R. J. Hoare, R. E. Petroski, A. Madan,
P. D. Crowe and G. Beaton, Bioorg. Med. Chem. Lett., 2010, 20, 2629;
´
´
`
(c) E. Alcalde, N. Mesquida, J. Frigola, S. Lopez-Perez and R. Merce,
Org. Biomol. Chem., 2008, 6, 3795; (d) D.-C. Oh, P. G. Williams,
C. A. Kauffman, P. R. Jensen and W. Fenical, Org. Lett., 2006,
8, 1021; (e) Y. Wang, S.-Y. Mo, S.-J. Wang, S. Li, Y.-C. Yang and
J.-G. Shi, Org. Lett., 2005, 7, 1675.
2 (a) L. Liu, Y. Fan, Q. He, Y. Zhang, D. Zhang-Negrerie, J. Huang,
Y. Du and K. Zhao, J. Org. Chem., 2012, 77, 3997; (b) X. Zhu,
C. Mitsui, H. Tsuji and E. Nakamura, J. Am. Chem. Soc., 2009,
131, 13596; (c) J. Yang, M. V. Lakshmikantham, M. P. Cava,
D. Lorcy and J. R. Bethelot, J. Org. Chem., 2000, 65, 6739.
Scheme 3 Pt-catalyzed intramolecular cyclization of 4 into highly substituted
indenes 3.
3 (a) B. Wang, Coord. Chem. Rev., 2006, 250, 242; (b) H. G. Alt and
¨
A. Koppl, Chem. Rev., 2000, 100, 1205.
4 For selected recent examples, see: (a) X.-Y. Shi and C.-J. Li, Org. Lett.,
2013, 15, 1476; (b) K. B. S. Magar and Y. R. Lee, Org. Lett., 2013,
15, 4288; (c) X. Jia, D. A. Petrone and M. Lautens, Angew. Chem., Int.
¨
Ed., 2012, 51, 9870; (d) A. S. K. Hashmi, I. Braun, P. Nosel,
¨
J. Schadlich, M. Wieteck, M. Rudolph and F. Rominger, Angew.
Chem., Int. Ed., 2012, 51, 4456; (e) F. Zhou, X. Han and X. Lu, J. Org.
Chem., 2011, 76, 1491; ( f ) C.-R. Liu, F.-L. Yang, Y.-Z. Jin, X.-T. Ma,
D.-J. Cheng, N. Li and S.-K. Tian, Org. Lett., 2010, 12, 3832.
5 For the synthesis of indenes from propargyl alcohols, see: (a) J. Zhao
and D. A. Clark, Org. Lett., 2012, 14, 1668; (b) K. V. Sajna and
K. C. Kumara Swamy, J. Org. Chem., 2012, 77, 5345;
(c) P. N. Chatterjee and S. Roy, J. Org. Chem., 2010, 75, 4413;
(d) S. Wang, Y. Zhu, Y. Wang and P. Lu, Org. Lett., 2009, 11, 2615;
(e) X. Zhang, W. T. Teo and P. W. H. Chan, Org. Lett., 2009, 11, 4990;
( f ) W. Huang, P. Zheng, Z. Zhang, R. Liu, Z. Chen and X. Zhou,
Scheme 4 Axial-to-central chirality transfer from allenes 4m, 4k, and 4l.
´
´
J. Org. Chem., 2008, 73, 6845; (g) N. Marion, S. Dıez-Gonzalez, P. de
´
Fremont, A. R. Noble and S. P. Nolan, Angew. Chem., Int. Ed., 2006,
45, 3647. For the use of allyl alcohols as substrate, see:
a
(h) J. Panteleev, R. Y. Huang, E. K. J. Lui and M. Lautens, Org. Lett.,
2011, 13, 5314; (i) S. Guo and Y. Liu, Org. Biomol. Chem., 2008,
6, 2064.
6 (a) S. Yang, Z. Li, X. Jian and C. He, Angew. Chem., Int. Ed., 2009,
48, 3999; (b) M. Tobisu, H. Nakai and N. Chatani, J. Org. Chem.,
2009, 74, 5471.
7 (a) B. Meng and S. Ma, Org. Lett., 2012, 14, 2674; (b) C.-R. Liu,
T.-T. Wang, Q.-B. Qi and S.-K. Tian, Chem. Commun., 2012,
48, 10913; (c) M. Asikainen and S. Woodward, Tetrahedron, 2012,
68, 5492; (d) Z.-X. Ma, S. He, W. Song and R. P. Hsung, Org. Lett.,
2012, 14, 5736; (e) S. Yamazaki, Y. Yamamoto, Y. Fukushima,
M. Takebayashi, T. Ukai and Y. Mikata, J. Org. Chem., 2010,
75, 5216; ( f ) G.-Y. Lin, C.-Y. Yang and R.-S. Liu, J. Org. Chem.,
2007, 72, 6753.
8 (a) K. Muralirajan, K. Parthasarathy and C.-H. Cheng, Angew. Chem.,
Int. Ed., 2011, 50, 4169; (b) F. W. Patureau, T. Besset, N. Kuhl and
F. Glorius, J. Am. Chem. Soc., 2011, 133, 2154; (c) E. J. Park, S. H. Kim
and S. Chang, J. Am. Chem. Soc., 2008, 130, 17268; (d) Y. Kuninobu,
Y. Tokunaga, A. Kawata and K. Takai, J. Am. Chem. Soc., 2006,
128, 202.
transition metal-catalyzed racemization,14b,15c we were pleased
to find out that the transformation of 4m (92% ee), having an
electron-rich aryl group, occurred with the complete transfer of
its axial chirality to the newly formed quaternary stereogenic
carbon center in 3m. The cyclization of 4k (97% ee) produced
indene 3k quantitatively, with 86% ee.23 Reducing the reaction
temperature to 60 1C slightly improved the optical purity of 3k
(89% ee). The little loss of the optical purity may be due to a
platinum-catalyzed racemization of allene prior to the cycliza-
tion. In the case of 4l, having a sterically demanding isopropyl
group, a high level of chirality transfer was achieved, albeit the
reaction time was longer.
In summary, we have reported a new, convenient, and
environmentally benign route for synthesising a variety of
highly substituted indene derivatives 3 bearing a quaternary
stereogenic carbon center. The reaction occurs between tertiary
propargyl alcohols 1 and ynamide 2a, and for the first time,
9 (a) B. Hu, S. Xing and Z. Wang, Org. Lett., 2008, 10, 5481; (b) Z.-B.
Zhu and M. Shi, Chem. – Eur. J., 2008, 14, 10219; (c) V. K. Yadav,
N. V. Kumar and M. Parvez, Chem. Commun., 2007, 2281.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.

View Article Online
Communication
ChemComm
10 For the asymmetric synthesis of enantioenriched indenes bearing 15 The transition-metal-catalyzed reaction of optically active allenes
quaternary stereogenic carbon centers, see: (a) Z. Chai and
T. J. Rainey, J. Am. Chem. Soc., 2012, 134, 3615; (b) W. Rao,
M. J. Koh, P. Kothandaraman and P. W. H. Chan, J. Am. Chem.
Soc., 2012, 134, 10811; (c) D. N. Tran and N. Cramer, Angew. Chem.,
Int. Ed., 2011, 50, 11098. For other asymmetric synthesis of indenes,
frequently causes the (partial) racemization, see: (a) H. Liu, D. Leow,
K.-W. Huang and C.-H. Tan, J. Am. Chem. Soc., 2009, 131, 7212;
(b) J. H. Lee and F. D. Toste, Angew. Chem., Int. Ed., 2007, 46, 912;
¨
(c) C. Deutsch, B. Gockel, A. Hoffmann-Roder and N. Krause, Synlett,
2007, 1790; (d) Z. Liu, A. S. Wasmuth and S. G. Nelson, J. Am. Chem.
Soc., 2006, 128, 10352.
´
´
´
´
´
see: (d) A. Martınez, P. Garcıa-Garcıa, M. A. Fernandez-Rodrıguez,
´
F. Rodrıguez and R. Sanz, Angew. Chem., Int. Ed., 2010, 49, 4633; 16 G. Evano, A. Coste and K. Jouvin, Angew. Chem., Int. Ed., 2010,
(e) J. A. Brekan, T. E. Reynolds and K. A. Scheidt, J. Am. Chem. Soc., 49, 2840.
2010, 132, 1472; ( f ) F. Zhou, M. Yang and X. Lu, Org. Lett., 2009, 17 Various ynamides were screened in the AgOTf-catalyzed reaction
´
11, 1405; (g) P. Dube and F. D. Toste, J. Am. Chem. Soc., 2006,
128, 12062; (h) R. Shintani, K. Okamoto and T. Hayashi, Chem. Lett., 18 For additional catalysts examined, such as gold, silver, and ruthe-
2005, 34, 1294. nium compounds, see ESI†.
11 D. Campolo, S. Gastaldi, C. Roussel, M. P. Bertrand and M. Nechab, 19 (a) V. J. Forrat, O. Prieto, D. J. Ramon and M. Yus, Chem. – Eur. J.,
with 1a, and 2a gave the best results. For details, see ESI†.
´
Chem. Soc. Rev., 2013, 42, 8434.
12 For selected reviews, see: (a) S. Yu and S. Ma, Chem. Commun., 2011,
2006, 12, 4431; (b) L. Liu, R. Wang, Y.-F. Kang, H.-Q. Cai and
C. Chen, Synlett, 2006, 1245.
47, 5384; (b) M. Ogasawara, Tetrahedron: Asymmetry, 2009, 20, 259; 20 N. Kern, A. Blanc, S. Miaskiewicz, M. Robinette, J.-M. Weibel and
(c) K. M. Brummond and J. E. DeForrest, Synthesis, 2007, 795. P. Pale, J. Org. Chem., 2012, 77, 4323 and references cited therein.
13 (a) T. Hashimoto, K. Sakata, F. Tamakuni, M. J. Dutton and 21 (a) Z.-B. Zhu and S. F. Kirsch, Chem. Commun., 2013, 49, 2272;
K. Maruoka, Nat. Chem., 2013, 5, 240; (b) B. M. Partridge,
L. Chausset-Boissarie, M. Burns, A. P. Pulis and V. K. Aggarwal,
Angew. Chem., Int. Ed., 2012, 51, 11795; (c) Z. Li, V. Boyarskikh,
J. H. Hansen, J. Autschbach, D. G. Musaev and H. M. L. Davies,
J. Am. Chem. Soc., 2012, 134, 15497; (d) T. Miura, M. Shimada,
S.-Y. Ku, T. Tamai and M. Murakami, Angew. Chem., Int. Ed., 2007,
46, 7101.
(b) D. V. Vidhani, M. E. Krafft and I. V. Alabugin, Org. Lett., 2013,
15, 4462; (c) T. Cao, J. Deitch, E. C. Linton and M. C. Kozlowski,
Angew. Chem., Int. Ed., 2012, 51, 2448; (d) O. F. Jeker and
E. M. Carreira, Angew. Chem., Int. Ed., 2012, 51, 3474; (e) C. Wang,
W. Zhao, H. Li and L. Guo, Green Chem., 2009, 11, 843;
( f ) M. O. Frederick, R. P. Hsung, R. H. Lambeth, J. A. Mulder and
M. R. Tracey, Org. Lett., 2003, 5, 2663.
14 (a) D. Wang, L. N. S. Gautam, C. Bollinger, A. Harris, M. Li and 22 Although a one-pot transformation from 1a to 3a by the use of a
X. Shi, Org. Lett., 2011, 13, 2618; (b) V. K.-Y. Lo, C.-Y. Zhou, M.-K.
Wong and C.-M. Che, Chem. Commun., 2010, 46, 213; (c) B. Trillo,
catalytic amount of PtCl2 should be more attractive, some trials on
the application of PtCl2 for the reaction of 1a and 2a resulted in
failure (for details, see ESI†).
´
´
F. Lopez, S. Montserrat, G. Ujaque, L. Castedo, A. Lledos and
˜
J. L. Mascarenas, Chem. – Eur. J., 2009, 15, 3336; (d) B. D. Sherry and 23 Reducing the reaction time (0.5 h) produced a 1.8 : 1 mixture of 3k
´
F. D. Toste, J. Am. Chem. Soc., 2004, 126, 15978; (e) A. Horvath and
J.-E. Backvall, Chem. Commun., 2004, 964; ( f ) A. Claesson and L.-I.
Olsson, J. Chem. Soc., Chem. Commun., 1979, 524.
(91% ee) and recovered 4k (88% ee), suggesting that the platinum-
catalyzed racemization of 4k gradually took place prior to its
intramolecular cyclization.
¨
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2014