Formal synthesis of (-)-cephalotaxine based on a tandem hydroamination/semipinacol rearrangement reaction

Article abstract of DOI:10.1002/asia.201101029

Catalytic asymmetric formal synthesis of (-)-cephalotaxine has been accomplished based on an efficient tandem intramolecular hydroamination/ asymmetric semipinacol rearrangement reaction catalyzed by chiral silver phosphate. During the course of the study it was observed that an advanced intermediate could be obtained in enantiopure form by enantiomer separation on silica gel.

Full text of DOI:10.1002/asia.201101029

COMMUNICATION
DOI: 10.1002/asia.201101029
Formal Synthesis of (À)-Cephalotaxine Based on a Tandem Hydroamination/
Semipinacol Rearrangement Reaction
Qing-Wei Zhang, Kai Xiang, Yong-Qiang Tu,* Shu-Yu Zhang, Xiao-Ming Zhang,
Yu-Ming Zhao, and Tian-Cai Zhang[a]
(À)-Cephalotaxine 1 was first isolated from Cephalotaxus
drupacea and C. fortunei as a major alkaloid among a series
of its ester derivatives in 1963.[1] Much attention has been
paid towards the studies of cephalotaxine due to the unique
pentacyclic structure and antileukemic activity of its deriva-
tives.[2] As a classic target for organic chemists, the syntheses
of cephalotaxine have been continuing since the pioneering
work of Weinreb and Semmelheck in 1972.[3–5] Among the
various strategies reported, the establishment of the 1-
asymmetric synthesis of this kind of azaspirocycles has not
been reported. In connection with our longstanding works
on the semipinacol rearrangement reaction and its applica-
tion in total synthesis of polycyclic alkaloids,[9] we intended
to develop a highly efficient catalytic asymmetric formal
synthesis of (À)-1, taking advantage of the tandem hydroa-
mination/semipinacol rearrangement reaction.[10–11]
As shown in Scheme 1, according to the procedure by
Isono and Mori, (À)-cephalotaxine 1 could be obtained in
four steps from 3, which has generally been introduced as
azaspiroACHTUNGTRENNUNG[4.4]nonane ring system 2 followed by benzazepine
formation were most frequently introduced (Figure 1). Thus,
an effective construction of this unit would be of great im-
portance in the synthesis of cephalotaxine and other struc-
turally related alkaloids such as serratine and stemona-
mine.[6]
Scheme 1. Retrosythetic analysis of (À)-cephalotaxine.
an advanced intermediate in the formal synthesis of (À)-
1.[5a] We envisioned that 3 could be derived from the useful
building block 1-azaspirocycle 4. As the key step, we pro-
posed that upon the catalysis of transition metal M and
chiral phosphoric acid 5, alkyne 8 would first undergo 5-
endo-dig intramolecular hydroamination[10] to form the cor-
responding enamine followed by proton exchange to pro-
duce the iminium ion 6. Intermediate 6 would then undergo
an enantioselective ring expansion-type semipinacol rear-
rangement to furnish the relevant azaspirocycle 4.[11]
To check our hypothesis regarding the key reaction, we
performed a divergent strategy that would enable the syn-
thesis of 8 with different protecting groups (Scheme 2). The
1, 2-addition of the lithium reagent derived from homopro-
pargylic alcohol 9 to cyclobutanone afforded diol 10 in 62%
Figure 1. (À)-Cephalotaxine and the key 1-azaspiro
ACHTUNGTREN[NUGN 4.4]nonane unit.
Azaspiro
recognized as useful building blocks and recently been se-
lected as templates for pharmaceutical investigations.[7]
ACHTUNGTRENNUNG[4.4]nonane 2-type azaspirocycles have long been
A
number of methods have been developed to construct this
structural unit in the context of total synthesis. However,
these methods often require multiple manipulations, instal-
ling the aza-quaternary carbon center and each of the spiro
rings in separate steps.[7–8] Additionally, chiral syntheses of
this unit are mainly based either on chiral auxiliaries or
chiral starting materials. As far as we are aware, catalytic
[a] Q.-W. Zhang, K. Xiang, Prof. Dr. Y.-Q. Tu, Dr. S.-Y. Zhang,
X.-M. Zhang, Dr. Y.-M. Zhao, T.-C. Zhang
State Key Laboratory of Applied Organic Chemistry
and Department of Chemistry
Lanzhou University
Lanzhou 730000 (P. R. China)
Fax : (+86)931-8912582
E-mail: tuyq@lzu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201101029.
Scheme 2. Synthesis of model substrate 8a.
894
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 894 – 898

Table 2. Tandem intramolecular hydroamination/asymmetric semipinacol
rearrangement.[a]
yield. Mitsunobu reaction of 10 followed by replacing the
protecting group with tosyl group furnished the model sub-
strate 8a in 22% overall yield from 9.
With 8a in hand, the aforementioned tandem reaction
was then extensively examined, as shown in Table 1. Initially
Entry
R
8
4
Yield[b]
ee[c]
Table 1. Optimization for the formation of 4a.[a]
1
2
3
4
Ts
C6H5SO2
8a
8b
8c
8d
8e
8 f
8g
8h
8l
4a
4b
4c
4d
4e
4 f
4g
4h
4l
99
90
96
99
96
92
98
82
67
62
66
79
82
70
2-MeC6H4SO2
3-MeC6H4SO2
4-BrC6H4SO2
4-ClC6H4SO2
4-FC6H4SO2
4-IC6H4SO2
4-tBuC6H4SO2
4-CF3C6H4SO2
4-OMeC6H4SO2
1- C10H7SO2
2- C10H7SO2
5[f]
6[f]
7[f]
8[f]
9
99(75)[d]
94
98
99
92
90
78(93)[e]
71
72
65
55
66
Entry Catalyst (10%)
Solvent
CH2Cl2
t
Yield [%][b] ee[c]
1
2
3
4
5
6
7
8
9
[Ph3PAuCl][d]/p-TsOH
24 h 37
–
10
11
12
13
8j
8k
8l
4j
4k
4l
[Ph3PAuOTf][d]/p-TsOH CH2Cl2
4 h
4 h
4 h
36 h 99
36 h 99
90
95
93
–
[Ph3PAuOTf][d]/5a
[Ph3PAugOTf][d]/5a
[Ph3PAuOTf][d]/5b
5b
CH2Cl2
CCl4
CCl4
10
50
81
81
78
81
81
8m
4m
[a] Conditions: 0.1 mmol 8, 20 mol% (R)-5b, and 100 mg 5 ꢁ molecular
sieve in 1.0 mL CCl4 stirred in the dark at 258C for 24 h. [b] Isolated
yield. [c] Determined by chiral-HPLC analysis. [d] Yield after recrystalli-
zation. [e] ee of mother liquid after recrystallization. [f] 36 h was needed.
CCl4
5b
Mesitylene 8 h
99
5b
(recycled)
CCl4
CCl4
36 h 99
24 h 99
5b[e]
[a] Conditions: 0.04 mmol 8a, 10 mol% cat., and 40 mg 5 ꢁ molecular
sieve in 0.4 mL solvent stirred in the dark at 258C. [b] Isolated yield.
[c] Determined by chiral-HPLC analysis. [d] 5% catalyst was added.
[e] 20% catalyst was added. For further conditions screened, see the Sup-
porting Information. p-TsOH=p-toluenesulfonic acid. Ts=p-toluenesul-
fonyl.
lute configuration of 4h was determined to be S by X-ray
analysis (see the Supporting Information).[16] Due to the po-
tential bioactivities of the azaspirocycles, these compounds
could serve as candidates for medicinal evaluations.
Based on the results of Table 2, 4a’ with same configura-
tion as natural (À)-cephalotaxine could be easily obtained
through 8a with (S)-5b as catalyst. Thus, a concise and
facile strategy for 8a was developed. As shown in Scheme 3,
trimethylsilylacetylene 12 was lithiated by nBuLi and
trapped with tosylaziridine followed by deprotection of the
TMS group to afford the tosyl homopropargyl amine 13 in
one pot with 63% yield. The tandem reaction substrate 8a
we examined the cooperative gold and Brønsted acid cataly-
sis.[12–13] When [Ph3PAuCl] (5 mol%) and p-toluenesulfonic
acid (p-TsOH, 10 mol%) were stirred in CH2Cl2, 4a could
be obtained in 37% yield within 24 hours (entry 1). A 90%
yield was observed when [Ph3PAuOTf] (5 mol%) obtained
from [Ph3PAuCl] and AgOTf, was used in the presence of p-
TsOH (entry 2). Compound 4a could also be obtained in
high yield (95%) with low enantioselectivity (10% ee)
under the catalysis of [Ph3PAuOTf] and phosphoric acid 5a
in CH2Cl2 (entry 3). A better result (50% ee, 93% yield)
was observed with the same catalyst in the nonpolar solvent
carbon tetrachloride (CCl4, entry 4). The enantiomeric
excess could be further improved to 81% when the chiral
silver phosphate 5b was used instead of phosphoric acid
(entry 5).[11 g] In all cases in which [Ph3PAuOTf] served as
the transition metal catalyst, the intermediate 7a could be
detected by TLC (entries 2–5, Tables S1 and S2 in the Sup-
porting Information)
Next, a series of cyclobutanols 8 differing in the amino
protecting group were synthesized and tested under the op-
timized conditions to potentially find a better substrate.
When 8a was subjected to the reaction conditions (Table 2,
entry 1), the enantiomeric excess slightly increased to 82%
with excellent yield. Other arylsulfonyl protected com-
pounds 8 were then used as substrates and all proceeded
well, resulting in 90–99% yield and 55–82% ee (entries 2–
13). The enantiomeric excess of 4h could be increased to
93% after one recrystallization (75% yield) and the abso-
Scheme 3. Formal synthesis of (À)-cephalotaxine.
Chem. Asian J. 2012, 7, 894 – 898
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
895

Formal Synthesis of (À)-Cephalotaxine
COMMUNICATION
was delivered in 75% yield (97% based on recovered 13)
through 1, 2-addition of lithiated 13 to cyclobutanone. The
key reaction was readily performed to give spirocycle 4a’ in
99% yield and 80% ee in gram-scale quantity (7 mmol,
2.05 g). Subsequently, 4a’ was transformed into triflate 14 by
enolization with lithium hexamethyldisilazide (LHMDS)
and captured with PhNTf2. Reduction of 14 under the catal-
Scheme 4. Catalytic asymmetric semipinacol rearrangement for the syn-
thesis of spirolactam.
ysis of [PdACHTUNGTRENNUNG(PPh3)2Cl2] with formic acid as hydrogen source
afforded 15, a key intermediate in the racemic synthesis of
cephalotaxine reported by Stoltz and coworkers.[5h] Follow-
ing elimination of the tosyl group and reductive amination
with aldehyde 17, amine 18 was obtained in 63% yield.[5h,17]
Finally, pentacyclic compound 3 was obtained in 69% yield
through a Heck reaction performed under previously report-
ed conditions[5d], and the enantiomeric excess was deter-
mined to be 80% by chiral high-performance liquid chroma-
tography (chiral HPLC).
Based on these results, we propose the following mecha-
nism for the stereocontrol of the catalytic asymmetric semi-
pinacol rearrangement reaction (Figure 2): First, upon the
During the purification of 3 by column chromatography
on silica gel using ethyl acetate as eluant, we found that the
two fractions of purified 3 showed different enantiomeric
excess values (89% and 65% ee, respectively). We are
aware that the phenomenon of enantiomer separation prob-
ably resulted from different affinities of aggregates of com-
pound 3 on silica gel.[20] Thus, further validation of this find-
ing was carried out by column chromatography on silica gel
of the first fraction with 89% ee (9.0 mg). As shown in
Table 3, the first two fractions had increased ee values while
those of the last three fractions were decreased. Significant-
Figure 2. Rationalization of the absolute configuration obtained in the
semipinacol rearrangement reaction.
catalysis of 5b, the in situ generated 7 or lactam alcohol 19
would undergo isomerization to afford the zwitterionic inter-
mediate forming an intimate counterion pair. Next, the AgI
from catalyst 5b (H+ for 5a) would bind with the cyclobuta-
nol unit; simultaneously, the P=O group stabilizes the imini-
um ion and shields the Si face of the azacycle. Enantioselec-
tive ring expansion of the cyclobutanol would yield the
Table 3. Enantiomer separation of 3 on silica gel.[a]
Fraction
1
2
3
4
5
Weight [%][b]
35.5
>99
27.2
96
16.8
82
4.7
76
15.8
68
ee [%][b]
[a] See the Supporting Information. [b] Calculated from HPLC analysis.
product with S configuration. However, the mechanism sug-
[22–23]
´
ly, the first fraction could be obtained in 35.5% yield with
>99% ee, thus providing a practical method for the prepa-
ration of enantiopure 3 from enantiomer-enriched material
simply by column chromatography. To our knowledge, this
is the first such example discovered in the synthesis of a nat-
ural product and it could be anticipated that this phenomen-
on also exists in more complex compounds which should at-
tract more attention.[20g]
gested by List and ðoric might also be operative.
In conclusion, the catalytic asymmetric formal synthesis of
(À)-cephalotaxine has been accomplished using a highly ef-
ficient tandem intramolecular hydroamination/asymmetric
semipinacol rearrangement reaction under mild conditions.
We also found that the generally employed intermediate ex-
hibits the enantiomer separation phenomenon on silica gel.
To further validate the feasibility of the enantioselective
semipinacol rearrangement reaction for other types of sub-
strate, we performed the catalytic asymmetric reaction with
19. The chiral auxiliary-controlled diastereoselective semipi-
nacol rearrangement of 19 has been reported by the group
of Royer in the elegant total synthesis of (À)-cephalotaxine.
Using the optimized conditions, this reaction also proceeded
well to give the desired product 20. (Scheme 4) The absolute
configuration was determined to be S by comparing the op-
tical rotation with that previously reported[21]; this indicates
that enantiocontrol in the semipinacol rearrangement in-
volves a similar mechanism as that in the tandem reac-
tion.[11g]
Experimental Section
Typical procedure for the tandem reaction: Substrate 8 (0.1 mmol), cata-
lyst (R)-5b (0.02 mmol), 5 ꢁ molecular sieve (100 mg), and solvent
(1.0 mL) were added to a Schlenk tube and stirred in the dark at 258C
for the indicated time. The reaction mixture was then directly subjected
to column chromatography on silica gel (petroleum ether/EtOAc 4:1).
Acknowledgements
We gratefully acknowledge financial support from the NSFC (Nos.
20921120404, 21072085, 20732002, and 20972059), “973” program of
896
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 894 – 898

Yong-Qiang Tu et al.
2010CB833203, “111” program of MOE, the fundamental research funds
for the central universities (lzujbky-2009–158) and a scholarship award
for excellent doctoral student of MOE (86007). We also thank Professor
Chun-An Fan for insightful discussions.
[9] a) Z.-L. Song, C.-A. Fan, Y.-Q. Tu, Chem. Rev. 2011, 111, 7523; b) B.
Wang, Y. Q. Tu, Acc. Chem. Res. 2011, 44, 1207; c) T. J. Snape,
Chem. Soc. Rev. 2007, 36, 1823.
[10] For review see: a) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36,
1407; b) T. E. Mꢂller, M. Beller, Chem. Rev. 1998, 98, 675. For exam-
ples see: c) M. Kimura, S. Kure, Z. Yoshida, S. Tanaka, K. Fugami,
Y. Tamaru, Tetrahedron Lett. 1990, 31, 4887; d) J. A. Marshall, C. A.
Sehon, J. Org. Chem. 1995, 60, 5966; e) Y. Koseki, S. Kusano, T. Na-
gasaka, Tetrahedron Lett. 1998, 39, 3517; f) S. Agarwal, H.-J. Knolk-
er, Org. Biomol. Chem. 2004, 2, 3060; g) R. S. Robinson, M. C.
Dovey, D. Gravestock, Eur. J. Org. Chem. 2005, 505; h) B. C. J. va-
n Esseveldt, P. W. H. Vervoort, F. L. van Delft, F. P. J. T. Rutjes, J.
Org. Chem. 2005, 70, 1791; i) D. K. Barange, T. C. Nishad, N. K.
Bandameedi, V. Swamy, D. Kumar, B. R. Sreekanth, K. Vyas, M.
Pal, J. Org. Chem. 2007, 72, 8547.
[11] a) T. Seiser, T. Saget, D. N. Tran, N. Cramer, Angew. Chem. 2011,
123, 7884; Angew. Chem. Int. Ed. 2011, 50, 7740; b) B. M. Trost, T.
Yasukata, J. Am. Chem. Soc. 2001, 123, 7162; c) B. M. Trost, J. Xie,
J. Am. Chem. Soc. 2006, 128, 6044; d) B. M. Trost, J. Xie, J. Am.
Chem. Soc. 2008, 130, 6231; e) F. Kleinbeck, F. D. Toste, J. Am.
Chem. Soc. 2009, 131, 9178; f) E. Zhang, C.-A. Fan, Y.-Q. Tu, F.-M.
Zhang, Y.-L. Song, J. Am. Chem. Soc. 2009, 131, 14626; g) Q. W.
Zhang, C. A. Fan, H. J. Zhang, Y. Q. Tu, Y. M. Zhao, P. Gu, Z. M.
Chen, Angew. Chem. 2009, 121, 8724; Angew. Chem. Int. Ed. 2009,
48, 8572; h) T. Liang, Z. Zhang, J. C. Antilla, Angew. Chem. 2010,
122, 9928; Angew. Chem. Int. Ed. 2010, 49, 9734; i) Z.-M. Chen, Q.-
W. Zhang, Z.-H. Chen, H. Li, Y.-Q. Tu, F.-M. Zhang, J.-M. Tian, J.
Am. Chem. Soc. 2011, 133, 8818; j) H. Li, F.-M. Zhang, Y.-Q. Tu, Q.-
W. Zhang, Z.-M. Chen, Z.-H. Chen, J. Li, Chem. Sci. 2011, 2, 1839;
k) B.-S. Li, E. Zhang, Q.-W. Zhang, F.-M. Zhang, Y.-Q. Tu, X.-P.
Cao, Chem. Asian J. 2011, 6, 2269; l) H. Mꢂller, M. Wilking, A.
Rꢂhlmann, B. Wibbeling, U. Hennecke, Synlett 2011, 2043.
[12] a) Chem. Rev. 2007, 107, special issue on organocatalysis; b) B. List,
Chem. Commun. 2006, 819–824; c) D. W. C. MacMillan, Nature
2008, 455, 304–308; d) P. Melchiorre, M. Marigo, A. Carlone, G.
Bartoli, Angew. Chem. 2008, 120, 6232–6265; Angew. Chem. Int.
Ed. 2008, 47, 6138–6171; e) A. Dondoni, A. Massi, Angew. Chem.
2008, 120, 4716–4739; Angew. Chem. Int. Ed. 2008, 47, 4638–4660;
f) C. F. Barbas, III., Angew. Chem. 2008, 120, 44–50; Angew. Chem.
Int. Ed. 2008, 47, 42–47. For recent example in our group see: M.
Yang, Y.-M. Zhao, S.-Y. Zhang, Y.-Q. Tu, F.-M. Zhang, Chem. Asian
J. 2011, 6, 1344.
[13] a) Z. Shao, H. Zhang, Chem. Soc. Rev. 2009, 38, 2745; b) P. de Ar-
mas, D. Tejedor, F. Garcꢃa-Tellado, Angew. Chem. 2010, 122, 1029;
Angew. Chem. Int. Ed. 2010, 49, 1013; c) A. S. K. Hashmi, C. Hub-
bert, Angew. Chem. 2010, 122, 1026; Angew. Chem. Int. Ed. 2010,
49, 1010; d) M. Rueping, R. M. Koenigs, I. Atodiresei, Chem. Eur. J.
2010, 16, 9350; e) C. Zhong, X. Shi, Eur. J. Org. Chem. 2010, 2999.
For recent example see: f) M. Rueping, A. P. Antonchick, C. Brink-
mann, Angew. Chem. 2007, 119, 7027; Angew. Chem. Int. Ed. 2007,
46, 6903; g) Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am.
Chem. Soc. 2009, 131, 9182; h) X.-Y. Liu, C.-M. Che, Org. Lett.
2009, 11, 4204; i) D. Monge, K. L. Jensen, P. T. Franke, L. Lykke,
K. A. Jørgensen, Chem. Eur. J. 2010, 16, 9478.
Keywords: azaspirocycle
·
cephalotaxine
·
enantiomer
separation · hydroamination · organocatalysis
[1] W. W. Paudler, G. I. Kerley, J. McKay, J. Org. Chem. 1963, 28, 2194.
[2] a) S. M. Weinreb, M. F. Semmelhack, Acc. Chem. Res. 1975, 8, 158;
b) L. Huang, Z. Xue, The Alkaloids, Vol. 23, Academic Press, New-
York, 1984, p. 157; c) M. A. JalilMiah, T. Hudlicky, J. W. Reed, The
Alkaloids, Vol. 51, Academic Press, San Diego, 1998, p. 199.
[3] a) J. Auerbach, S. M. Weinreb, J. Am. Chem. Soc. 1972, 94, 7172;
b) M. F. Semmelhack, B. P. Chong, L. D. Jones, J. Am. Chem. Soc.
1972, 94, 8629.
[4] For recent examples of the synthesis of (Æ)-cephalotaxine, see:
a) T. P. Burkholder, P. L. Fuchs, J. Am. Chem. Soc. 1990, 112, 9601;
b) H. Ishibashi, M. Okano, H. Tamaki, K. Maruyama, T. Yakura, M.
Ikeda, J. Chem. Soc. Chem. Commun. 1990, 1436; c) M. Ikeda, M.
Okano, K. Kosaka, M. Kido, H. Ishibashi, Chem. Pharm. Bull. 1993,
41, 276; d) X. Lin, R. W. Kavash, P. S. Mariano, J. Am. Chem. Soc.
1994, 116, 9791; e) X. Lin, R. W. Kavash, P. S. Mariano, J. Org.
Chem. 1996, 61, 7335; f) L. F. Tietze, H. Schirok, Angew. Chem.
1997, 109, 1159; Angew. Chem. Int. Ed. Engl. 1997, 36, 1124; g) Y.
Koseki, H. Sato, Y. Watanabe, T. Nagasaka, Org. Lett. 2002, 4, 885;
h) W.-D. Z. Li, Y.-Q. Wang, Org. Lett. 2003, 5, 2931; i) W.-D. Z. Li,
B.-C. Ma, J. Org. Chem. 2005, 70, 3277; j) B.-C. Ma, Y.-Q. Wang, W.-
D. Z. Li, J. Org. Chem. 2005, 70, 4528; k) W.-D. Z. Li, X.-W. Wang,
Org. Lett. 2007, 9, 1211; l) N. Y. Kuznetsov, G. D. Kolomnikova,
V. N. Khrustalev, D. G. Golovanov, Y. N. Bubnov, Eur. J. Org. Chem.
2008, 5647; m) Y.-M. Zhao, P. Gu, H.-J. Zhang, Q.-W. Zhang, C.-A.
Fan, Y.-Q. Tu, F.-M. Zhang, J. Org. Chem. 2009, 74, 3211; n) M.-r.
Sun, H.-t. Lu, Y.-z. Wang, H. Yang, H.-m. Liu, J. Org. Chem. 2009,
74, 2213; o) W.-D. Z. Li, W.-G. Duo, C.-H. Zhuang, Org. Lett. 2011,
13, 3538.
[5] For the synthesis of (À)-cephalotaxine, see: a) N. Isono, M. Mori, J.
Org. Chem. 1995, 60, 115; b) T. Nagasaka, H. Sato, S. Saeki, Tetrahe-
dron: Asymmetry 1997, 8, 191; c) M. Ikeda, S. A. A. El Bialy, K.
Hirose, M. Kotake, T. Sato, S. M. M. Bayomi, I. A. Shehata, A. M.
Abdelal, L. M. Gad, T. Yakura, Chem. Pharm. Bull. 1999, 47, 983;
d) L. F. Tietze, H. Schirok, J. Am. Chem. Soc. 1999, 121, 10264; e) L.
Planas, J. Perard-Viret, J. Royer, J. Org. Chem. 2004, 69, 3087;
f) J. D. Eckelbarger, J. T. Wilmot, D. Y. Gin, J. Am. Chem. Soc.
2006, 128, 10370; g) Z. Zhao, P. S. Mariano, Tetrahedron 2006, 62,
7266; h) Q. Liu, E. M. Ferreira, B. M. Stoltz, J. Org. Chem. 2007, 72,
7352; i) W. R. Esmieu, S. W. Worden, D. Catterick, C. Wilson, C. J.
Hayes, Org. Lett. 2008, 10, 3045; j) T. Taniguchi, H. Ishibashi, Org.
Lett. 2008, 10, 4129; k) A. Hameed, A. J. Blake, C. J. Hayes, J. Org.
Chem. 2008, 73, 8045.
[14] a) J.-M. Weibel, A. L. Blanc, P. Pale, Chem. Rev. 2008, 108, 3149;
ˇ
b) M. ꢄlvarez-Corral, M. Munoz-Dorado, I. Rodrꢃguez-Garcꢃa,
[6] a) “Lycopodium Alkaloids: Isolation and Asymmetric Synthesis”:
M. Kitajima, H. Takayama in Topics in Current Chemistry (Ed.: H.-
J. KnÅlker), Springer, Berlin, 2011, DOI: 10.1007/128_2011_126;
b) R. A. Pilli, G. B. Rosso, M. C. F. de Oliveira, Nat. Prod. Rep.
2010, 27, 1908.
Chem. Rev. 2008, 108, 3174; c) M. Naodovic H. Yamamoto, Chem.
Rev. 2008, 108, 3132; d) Z. Li, C. He, Eur. J. Org. Chem. 2006, 4313.
[15] G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science 2007, 317,
496.
[16] CCDC 809194 (4h) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[17] A. D. Brosius, L. E. Overman, L. Schwink, J. Am. Chem. Soc. 1999,
121, 700.
[7] For reviews, see: a) S. A. A. El Bialy, H. Braun, L. F. Tietze, Synthe-
sis 2004, 2249; b) G. Dake, Tetrahedron 2006, 62, 3467. For racemic
syntheses of azaspirocycles via semipiancol rearrengenment see:
c) M. D. B. Fenster, B. O. Patrick, G. R. Dake, Org. Lett. 2001, 3,
2109; d) G. R. Dake, M. D. B. Fenster, P. B. Hurley, B. O. Patrick, J.
Org. Chem. 2004, 69, 5668.
[18] a) W. A. Herrmann, C. Brossmer, K. ꢅfele, C.-P. Reisinger, T. Prier-
meier, M. Beller, H. Fischer, Angew. Chem. 1995, 107, 1989; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1844; b) M. Beller, H. Fischer, W. A.
[8] a) L. I. Palmer, J. R. deAlaniz, Angew. Chem. 2011, 123, 7305;
Angew. Chem. Int. Ed. 2011, 50, 7167; b) Z.-H. Chen, Y.-Q. Tu, S.-Y.
Zhang, F.-M. Zhang, Org. Lett. 2011, 13, 724.
Chem. Asian J. 2012, 7, 894 – 898
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
897

Formal Synthesis of (À)-Cephalotaxine
COMMUNICATION
Herrmann, K. ꢅfele, C. Brossmer, Angew. Chem. 1995, 107, 1992;
Angew. Chem. Int. Ed. Engl. 1995, 34, 1848.
[23] The anthracenyl group of the catalyst would block the migration of
bond b’, thus affording the ring expansion (bond b migration) prod-
uct with S configuration.
[19] 3 was produced by mixing equal amounts of (+)-3 and (À)-3.
[20] For reviews, see: a) J. Han, D. J. Nelson, A. E. Sorochinsky, V. A.
Soloshonok, Curr. Org. Synth. 2011, 8, 310; b) I. Weissbuch, M.
Lahav, Chem. Rev. 2011, 111, 3236; c) F. Faigl, E. Fogassy, M.
Nꢆgrꢇdi, E. Pꢇlovics, J. Schindler, Org. Biomol. Chem. 2010, 8, 947;
For selected examples, see: d) K. C. Cundy, P. A. Crooks, J. Chroma-
togr. 1983, 281, 17; e) W.-L. Tsai, K. Hermann, E. Hug, B. Rohde,
A. S. Dreiding, Helv. Chim. Acta 1985, 68, 2238; f) P. Diter, S. Tau-
dien, O. Samuel, H. B. Kagan, J. Org. Chem. 1994, 59, 370; g) V. A.
Soloshonok, Angew. Chem. 2006, 118, 780; Angew. Chem. Int. Ed.
2006, 45, 766.
[21] L. Planas, J. Pꢈrard-Viret, J. Royer, M. Selkti, A. Thomas, Synlett
2002, 1629.
Received: December 19, 2011
Published online: March 1, 2012
´
[22] B. List, I. ðoric, Synfacts 2009, 12, 1400.
898
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 894 – 898