Construction of an asymmetric quaternary carbon via an asymmetric aza-Claisen rearrangement and its application in the total synthesis of (+)-α-cuparenone

Article abstract of DOI:10.1016/j.tetasy.2012.05.016

Excess lithium hexamethyldisilazide (LHMDS) with LiCl prompted the asymmetric aza-Claisen rearrangement of carboxamide and retarded the decomposition of its amide enolate. The addition of these two reagents was a key step that led to the total synthesis o

Full text of DOI:10.1016/j.tetasy.2012.05.016

Tetrahedron: Asymmetry 23 (2012) 739–741
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Construction of an asymmetric quaternary carbon via an asymmetric
aza-Claisen rearrangement and its application in the total synthesis
of (+)-a-cuparenone
Takeshi Nishii, Fumiaki Miyamae, Makoto Yoshizuka, Hiroto Kaku, Mitsuyo Horikawa, Makoto Inai ,
⇑
Tetsuto Tsunoda
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Excess lithium hexamethyldisilazide (LHMDS) with LiCl prompted the asymmetric aza-Claisen rearrange-
ment of carboxamide and retarded the decomposition of its amide enolate. The addition of these two
Received 10 April 2012
Accepted 9 May 2012
Available online 18 June 2012
reagents was a key step that led to the total synthesis of (+)-
center.
a-cuparenone with a stereogenic quaternary
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
O
The aza-Claisen rearrangement is a powerful tool used in syn-
thetic organic chemistry and has attracted much attention.1,2 We
have previously reported the synthesis of several natural products
through the asymmetric aza-Claisen rearrangements of various
types of carboxamides 1 (Scheme 1).3
1) LHMDS (5 equiv), toluene, 78 °C
2) 120 °C, 6 h
N
Ph
Et
2
O
O
O
O
O
O
N
N
N
N
+
+
aza-Claisen
H
H
H
R2
R1
R2
R1
H
natural
N
Ph
N
Ph
products
H
Et
Et
Et
Et
3
4
5
6
1
major product
88 / 12
Scheme 1. Aza-Claisen rearrangement for the synthesis of natural products.
Scheme 2. Aza-Claisen rearrangement of amide
2 to generate an asymmetric
quaternary carbon center.
Recently, we found that the rearrangement of the enolate of
amide 2 in the presence of a large excess of base provided an asym-
metric quaternary carbon center with excellent yield and good ste-
reoselectivity (Scheme 2, 98%, 3/4/5/6 = 88/12/0/0).4 The
enantioselective construction of defined quaternary stereogenic
centers is a difficult challenge for synthetic chemists,5 and there
have been several reports on the application of the Claisen rear-
rangement, accomplished utilizing a chiral auxiliary6 or a chiral li-
gand,7 to form asymmetric quaternary carbon centers.
synthesis of 7 has interested organic chemists worldwide due to its
structural framework with two contiguous quaternary centers, one
of which is stereogenic; roughly 19 asymmetric syntheses have
been reported so far.9
Our retrosynthetic analysis of 7 is illustrated in Scheme 3. From
our previous results,4 we expected that the asymmetric aza-Clais-
en rearrangement of 8 bearing an (R)-phenethyl group on the
amide nitrogen as a chiral auxiliary would provide the stereogenic
center of 7 via the rearrangement product 9.
Herein we have chosen (+)-a-cuparenone 7, isolated from May-
ur pankhi by Chetty and Dev,8 as a synthetic target to demonstrate
the applicability of the asymmetric aza-Claisen rearrangement. The
2. Results and discussion
For the preparation of the rearrangement of precursor
8
⇑
Corresponding author. Tel.: +81 88 6028452; fax: +81 88 6553051.
(Scheme 4), we chose p-methylacetophenone 10 as a starting
material and converted it into the unsaturated ester 11 with E-
geometry at the double bond by the Horner–Wadsworth–Emmons
E-mail address: tsunoda@ph.bunri-u.ac.jp (T. Tsunoda).
Present address: School of Pharmaceutical Science, University of Shizuoka, 52-1
Yada, Suruga-ku Shizuoka 422-8526, Japan.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.016

740
T. Nishii et al. / Tetrahedron: Asymmetry 23 (2012) 739–741
O
8 (entry 1). However, the use of 5 equiv of LHMDS gave the desired
O
product in 57% yield with moderate stereoselectivity (9/15 = 77/
23) without the other isomers 16 and 17 (entry 2). Furthermore,
the addition of a greater excess of base gave incremental improve-
ments in the yields and/or stereoselectivities, such that the addi-
tion of 20 equiv of LHMDS gave acceptable results (entries 3–5).
In accordance with our earlier studies, the addition of excess base
prevented decomposition of the amide enolate in undesirable side
reactions and promoted the desired rearrangement.4
Streitwieser et al. reported that aggregation reduced the nucle-
ophilicity of the lithium enolates of ketones in alkylation reac-
tions.13 They proposed that within an aggregate, the close
proximity of two or more lithium cations to the enolate oxygen de-
O
aza-Claisen
N
Ph
N
Ph
E
H
p-tolyl
p-tolyl
8
9
(+)-α-cuparenone 7
Scheme 3. Retrosynthesis of (+)-
a-cuparenone 7.
reaction.10 Alcohol 12, obtained by reduction with LAH, was sub-
jected to the Fukuyama method11 using TMAD-PBu3 to afford
12
allylic amine 14, which was acylated to give propanamide 8.
With the desired precursor 8 in hand, rearrangement in the
presence of lithium hexamethyldisilazide (LHMDS) as a base was
attempted at 120 °C for 6 h (Table 1). When 3 equiv of the base
was used, the reaction afforded a complex product mixture with
none of the desired rearranged products and the starting material
creased the electron density on the
a-carbon of the lithium eno-
late, thus making the enolate a poorer nucleophile. As a result,
we suspected that the decomposition of the amide enolate aggre-
gates was retarded by the presence of a large excess LHMDS, thus
favoring the aza-Claisen rearrangement. Therefore we predicted
that the addition of some types of lithium salt instead of LHMDS
would decrease the required amount of added base. The addition
of 5 equiv of LiCl14 with LHMDS (10 equiv) gave almost the same
results as the reaction with 15 equiv of the base (Table 1, entries
6 vs 4). The best result was obtained in the presence of 10 equiv
of LiCl with LHMDS (10 equiv) (entry 7).15
Table 1
Aza-Claisen Rearrangement of 8 in the Presence of LHMDS and LiCl.
O
1) LHMDS (equiv), LiCl (equiv)
Amide 9, purified by SiO2 column chromatography, was reduced
toluene-hexane, 78 °C
N
Ph
with diphenylsilane-Ti(O-iPr)4 followed by cyclization using the
17
2) 120 °C, 6 h
Wilkinson complex18 in an ethylene saturated CHCl3 solution,19
to be converted into cyclopentanone derivative 19, which was sub-
sequently alkylated with methyl iodide using NaH to afford the de-
p-tolyl
8
O
O
O
O
N
N
H
N
N
+
+
H
H
H
O
O
Ph2SiH2
p-tolyl
p-tolyl
p-tolyl
p-tolyl
Ti(O-iPr)4
RhCl(PPh3)3
H
N
Ph
9
16
15
17
H
ethylene in CHCl3
rt, 3 h
rt, 44 h
85%
p-tolyl
75%
9
18
Entry
LHMDS (equiv)
LiCl (equiv)
Yield (%)
Ratio (2S/2R)
O
O
a
b
c
1
2
3
4
5
6
7
3
5
—
—
—
—
—
—
a
57
68
74
83
77
83
77/23
87/13
88/12
88/12
90/10
88/12
MeI, NaH
a
10
15
20
10
10
a
diglyme
a
0 oC to rt, 24 h
65%
—
5
10
19
a
b
c
(+)-α-cuparenone 7
None.
Complex mixture.
Not determined.
Scheme 5. Synthesis of (+)-a-cuparenone 7.
CO2Et
Ns
OH
N
H
Ph
O
Ns
(EtO)2P(O)CH2CO2Et
LiAlH4
Et2O
N
Ph
TMAD, Bu3P
NaH, EtOH, reflux, 20 h
93%
toluene, rt, 24 h
93%
0 °C to rt, 2 h
quant.
10
p-tolyl
12
11
13
O
O
O
H
Cs2CO3, PhSH
N
Ph
N
Ph
O
, Et3N
MeCN
50 °C, 2 h
93%
CH2Cl2, 0 °C ~ rt, 2 h
95%
E
p-tolyl
p-tolyl
14
8
Scheme 4. Preparation of the rearrangement precursor 8.

T. Nishii et al. / Tetrahedron: Asymmetry 23 (2012) 739–741
741
sired ketone (+)-7 (Scheme 5).20 The enantiomeric purity of (+)-7
was confirmed to be as high as 99% ee21 by the comparison with
racemic 7, which was synthesized by the same route, but starting
from racemic 8.
7. Gu, Z.; Herrmann, A. T.; Stivala, C. E.; Zakarian, A. Synlett 2010, 1717–1722.
8. Chetty, G. L.; Dev, S. Tetrahedron Lett. 1964, 5, 73–77.
9. (a) Zhang, P.; Le, H.; Kyne, R. E.; Morken, J. P. J. Am. Chem. Soc. 2011, 133, 9716–
9719; (b) Natarajan, A.; Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Angew. Chem., Int.
Ed. 2007, 46, 6485–6487. and references cited therein.
10. (a) Horner, L.; Hoffman, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499–
2505; (b) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733–1738; (c) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
11. (a) Kan, T.; Fukuyama, T. J. Syn. Org. Chem. Jpn. 2001, 59, 779–789; (b) Kan, T.;
Fukuyama, T. Chem. Commun. 2004, 353–359.
12. (a) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Itô, S. Chem. Lett. 1994, 539–5420; (b)
Tsunoda, T.; Yamamiya, Y.; Kawamura, Y.; Itô, S. Tetrahedron Lett. 1995, 36,
2529–2530.
13. (a) Abu-Hasanayn, F.; Stratakis, M.; Streitwieser, A. J. Org. Chem. 1995, 60,
4688–4689; (b) Wang, D. Z.-R.; Streitwieser, A. Can. J. Chem. 1999, 77, 654–658;
(c) Streitwieser, A.; Wang, D. Z.-R. J. Am. Chem. Soc. 1999, 121, 6213–6219; (d)
Abbotto, A.; Leung, S. S.-W.; Streitwieser, A.; Kilway, K. V. J. Am. Chem. Soc.
1998, 120, 10807–10813.
3. Conclusion
We have achieved the total synthesis of (+)-a-cuparenone 7 by
utilizing an asymmetric aza-Claisen rearrangement as a key step
and found that excess LHMDS with LiCl prompted the desired
rearrangement and retarded the decomposition of enolates. Fur-
thermore, the stereochemistry accomplished by the asymmetric
aza-Claisen rearrangement was confirmed by this synthesis.
14. Several lithium salts such as LiF, LiBr, LiCl, LiI, LiOTf and Li2CO3 were employed,
and LiCl gave the best results.
Acknowledgements
15. The typical procedure for an aza-Claisen rearrangement with LiCl. To
a
suspension of LiCl (666 mg, 15.7 mmol) and LHMDS (1.0 M in n-hexane,
15.6 mL, 15.6 mmol) in toluene (3 mL) was added a toluene solution (2 mL) of
carboxamide 8 (502 mg, 1.56 mmol) at ꢀ78 °C under an argon atmosphere in a
pressure tube.16 After 30 min of stirring, the reaction mixture was allowed to
warm to room temperature and was sealed. After heating of the sealed solution
at 120 °C for 6 h, saturated NH4Cl aqueous solution (24 mL) was added and the
mixture was extracted with CH2Cl2 (30 mL), dried (Na2SO4), and evaporated.
The residual mixture was purified by SiO2-column chromatography (n-hexane/
EtOAc = 10/1) to give 414 mg of a mixture of 9 and 15 [83%, (2S)/(2R) = 88/12]
as colorless needles. The mixture was purified again by SiO2-column
chromatography (n-hexane/EtOAc = 10/1) to obtain 9.
This work was supported partially by a Grant-in-Aid for Scien-
tific Research (C) from MEXT (the Ministry of Education, Culture,
Sports, Science and Technology of Japan). We are also thankful to
MEXT-Senryaku, 2008–2012.
References
1. Recent reviews of the aza-Claisen rearrangement: (a) Majumdar, K. C.;
Bhattacharyya, T.; Chattopadhyay, B.; Sinha, B. Synthesis 2009, 2117–2142;
(b) Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002; (c) Nubbemeyer, U.
Synthesis 2003, 961–1008.
16. An air-tight cylinder for high pressure experiments was available at Alltech
Associates, Inc.
17. Bower, S.; Kreutzer, K. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 1996, 35, 1515–
1516.
2. Davies, S. G.; Garner, A. C.; Nicholson, R. L.; Osborne, J.; Roberts, P. M.; Savory, E.
D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2009, 7, 2604–2611.
3. (a) Tsunoda, T.; Tatsuki, S.; Kataoka, K.; Itô, S. Chem. Lett. 1994, 543–546; (b)
Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.; Yamamoto, H.; Itô, S.
Tetrahedron Lett. 1996, 37, 2463–2466; (c) Tsunoda, T.; Nishii, T.; Yoshizuka,
M.; Yamasaki, C.; Suzuki, T.; Itô, S. Tetrahedron Lett. 2000, 41, 7667–7671; (d)
Nishii, T.; Suzuki, S.; Yoshida, K.; Arakaki, K.; Tsunoda, T. Tetrahedron Lett. 2003,
44, 7829–7832; (e) Inai, M.; Nishii, T.; Mukoujima, S.; Esumi, T.; Kaku, H.;
Tominaga, K.; Abe, H.; Horikawa, M.; Tsunoda, T. Synlett 2011, 1459–1461.
4. Yoshizuka, M.; Nishii, T.; Sasaki, H.; Kitakado, J.; Ishigaki, N.; Okugawa, S.; Kaku,
H.; Horikawa, M.; Inai, M.; Tsunoda, T. Synlett 2011, 2967–2970.
5. Christoffers, J.; Baro, A. Quaternary Stereocenters: Challenges and Solutions for
Organic Synthesis; Wiley-VCH: Weinheim, 2005.
6. (a) Chillous, S. E.; Hart, D. J.; Hutchinson, D. K. J. Org. Chem. 1982, 47, 5418–
5420; (b) Spino, C.; Godbout, C.; Beaulieu, C.; Harter, M.; Mwene-Mbeja, T. M.;
Boisvert, L. J. Am. Chem. Soc. 2004, 126, 13312–13319.
18. The total synthesis of (-) –a- cuparenone utilizing Wilkinson complex has been
achieved. See Kametani, T.; Kawamura, K.; Tsubuki, M.; Honda, T. Chem. Pharm.
Bull. 1985, 33, 4821–4828.
19. Lochow, C. F.; Miller, R. G. J. Am. Chem. Soc. 1976, 98, 1281–1283.
20. (+)-a-Cuparenone (7): mp 56.5–57.2 °C (n-hexane/EtOAc). ½ ꢁ ¼ þ187 (c
a 2D1
0.50, CHCl3) {lit9a. ½a D20
ꢁ
¼ þ170 (c 0.14, CHCl3)}. 1H NMR (300 MHz, CDCl3)
d = 7.13–7.31 (m, 4H), 2.61–2.74 (m, 1H), 2.37–2.59 (m, 2H), 2.34 (s, 3H), 1.86–
1.97 (m, 1H), 1.26 (s, 3H), 1.17 (s, 3H), 0.61 (s, 3H). 13C NMR (75 MHz, CDCl3)
d = 222.5, 141.8, 135.7, 128.9, 126.3, 53.2, 48.3, 33.7, 29.6, 25.3, 22.1, 20.8, 18.4.
IR (ATR) 2968, 1736 cmꢀ1. MS (EI) m/z 216 (M+), 145 (base peak). HRMS m/z
(M+) calcd for C15H20O: 216.1514; found: 216.1498.
21. HPLC with CHIRALCEL OJ was used to determine the enantiomeric purity of (+)-
7 by comparison with racemic 7, which was synthesized using the same route
but without the use of a chiral auxiliary.