Concise total synthesis of (±)-crinine

Article abstract of DOI:10.1055/s-0029-1218296

The concise total synthesis of (±)-crinine was accomplished in 24% overall yield and eleven steps starting from an easily available allylic alcohol. The key step of the current synthesis involved the NBS-promoted semipinacol rearrangement reaction of ally

Full text of DOI:10.1055/s-0029-1218296

3040
LETTER
Concise Total Synthesis of ( )-Crinine
Concise
T
i
otal
S
y
a
nthesis of
(
n
)-Crinine -Dong Liu, Shao-Hua Wang, Fu-Min Zhang, Yong-Qiang Tu,* Yong-Qiang Zhang
State Key Laboratory of Applied Organic Chemistry & Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: tuyq@lzu.edu.cn
Received 7 July 2009
In connection with our current interests on the semipina-
Abstract: The concise total synthesis of ( )-crinine was accom-
col rearrangement of allylic alcohols and its synthetic ap-
plished in 24% overall yield and eleven steps starting from an easily
available allylic alcohol. The key step of the current synthesis in-
volved the NBS-promoted semipinacol rearrangement reaction of
plications,3 recently we have further explored its potential
in the total synthesis of Amaryllidaceae alkaloid crin-
allylic alcohols. The hydroindole skeleton with the sterically con- ine.3e–g Over the past four decades, several strategies for
gested quaternary carbon center was established concisely by utiliz-
the synthesis of crinine had been developed to give access
ing this semipinacol rearrangement followed by a combination of
to the vital quaternary carbon center, which have included
intramolecular aldol and aza-Michael reactions.
Claisen rearrangement,4a aza-cope rearrangement/Man-
nich cyclization,4c–e thermal N-vinyl-aziridine rearrange-
Key words: aldol reaction, alkaloids, aza-Michael reaction, semi-
ment,4b intramolecular [3+2] cycloaddition,4g inter-
pinacol rearrangement, total synthesis
molecular [4+2] reaction,4i alkylation of carbonyl deriva-
tives,4f as well as intramolecular Heck reaction.4h Our cur-
Crinine-type alkaloids (e.g., 1 and 2 in Figure 1) isolated
from Amaryllidaceae,1 which possess a wide range of bi-
ological activity,1a,2 represent an important subclass with-
in the large family of Amaryllidaceae alkaloids. Their
typical structural feature is the cis-arylhydroindole core
bearing a crucial all-carbon quaternary center, and the ef-
ficient and stereoselective establishment of this core
structure is one of the central synthetic challenges in the
efficient synthesis of cis-arylhydroindole alkaloids.
rent total synthesis, however, is distinguished by the
application of NBS-promoted semipinacol rearrangement
reaction of allylic alcohols. Herein we present our results
concerning the concise total synthesis of ( )-crinine.
Our retrosynthetic analysis is shown in Scheme 1. The tar-
get molecule 1 could be achieved by methylenation of
arylhydroindole enone 3 through Pictet–Spengler cycliza-
tion. The construction of the crucial C–N bond in 3 was
envisioned by acid-mediated in situ intramolecular aza-
Michael addition of primary aliphatic amine 4. The requi-
site double bond in 4 could be derived from the intramo-
lecular aldol reaction of dicarbonyl compound 5. As one
of the key steps, the sterically congested quaternary car-
bon center in 5 could be efficiently established by the
NBS-promoted semipinacol rearrangement of allylic al-
cohol 6.
5
6
3
OH
OH
4
MeO
MeO
7a
7
2
O
O
3a
H
H
N
N
1
( )-crinine (1)
( )-maritidine (2)
Our synthesis commenced with the preparation of allylic
alcohol 6 from the commercially available ethyl acetoac-
etate (7). As shown in Scheme 2, the alkylation of the eno-
Figure 1 Two representative molecules of the crinine-type Amaryl-
lidaceae alkaloids
Scheme 1 Retrosynthetic analysis of ( )-crinine; Ar = 3,4-methylenedioxyphenyl
SYNLETT 2009, No. 18, pp 3040–3042
x
x
.x
x
.2
0
0
9
Advanced online publication: 13.10.2009
DOI: 10.1055/s-0029-1218296; Art ID: W10709ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Concise Total Synthesis of ( )-Crinine
3041
H
late of 7 with 2,3-dibromopropene and the hydrolysis of
the ester followed by the in situ decarboxylation furnished
5-bromo-5-hexen-2-one (8).5 Sequentially, the carbonyl
group of 8 was protected with ethylene glycol in the pres-
ence of PTSA to give the vinyl bromide 9. The desired al-
lylic alcohol 6 was readily afforded by lithium–bromide
exchange of 9 followed by the addition of piperonal.
H
Ar
Ar
a
b
c
O
O
6
O
88%
98%
90%
Br
O
Br
O
10
5
Ar
Ar
Ar
Br
Br
CN
d
e
O
O
76%
92%
O
O
O
O
a
b
O
O
Br
11
12
13
O
60%
94%
Ar
Ar
7
8
f
g
OH
O
O
O
96%
90%
NH2
N
O
O
O
c
O
O
H
O
Boc
Br
80%
4
14
9
6
Scheme 3 Construction of the arylhydroindole skeleton 14.
Reagents and conditions: (a) N-bromosuccinimide (NBS), acetone,
r.t.,10 min; (b) 10% HCl, THF, 12 h; (c) proline, PPTS, MeCN, 40 °C,
12 h; (d) ethylene glycol, PPTS, benzene, reflux, 5 h; (e) NaCN, 18-
crown-6, 4 Å MS, DMSO, 80 °C, 2 d; (f) LiAlH4, Et2O, 0 °C to r.t., 1
h; (g) (i) 10% HCl, THF, reflux, 2 h; (ii) (Boc)2O, Et3N, CH2Cl2, r.t.,
2 h.
Scheme 2 Preparation of allylic alcohol 6. Reagents and conditions:
(a) (i) NaOEt, EtOH, 20 min; (ii) 2,3-dibromopropene, 30 min; (iii)
50% NaOH, reflux, 1 h, then concd HCl, reflux, 2 h; (b) ethylene gly-
col, PTSA, benzene, reflux, 12 h; (c) (i) n-BuLi, THF, –78 °C; (ii) Ar-
CHO, THF, –78 °C.
With the allylic alcohol 6 in hand, we then focused on our
synthetic efforts towards the construction of the cis-aryl-
hydroindole core. According to our proposed synthetic
strategy depicted in Scheme 1, allylic alcohol 6 was sub-
jected to the NBS-promoted semipinacol rearrangement
protocol, which was recently developed in our group, to
stereoselectively deliver the 2-quaternary-1,3-diheteroat-
om units; the desired 2-quaternary-3-bromoaldehyde 10
was smoothly obtained in 88% yield (Scheme 3). Hydro-
lysis of the ketal moiety followed by proline-mediated in-
tramolecular aldol reaction furnished the enone 11. Then
the carbonyl of the resulting enone 11 was protected with
ethylene glycol to afford the bromide 12. In order to intro-
duce the amino group, one-carbon homologation by cya-
nation of the related bromide was conducted;6 the
corresponding cyanide 13 was then reduced with LiAlH4,
giving the primary aliphatic amine 4. Accompanied by the
deprotection of the ketal in 4, the in situ aza-Michael
reaction under acidic conditions proceeded smoothly in
one pot, yielding the expected cis-arylhydroindole 14 af-
ter Boc-protection of the resulting secondary amine
(Scheme 3).
After the expeditious establishment of the cis-arylhy-
droindole skeleton, the installation of the C4=C5 double
bond and the total synthesis of ( )-crinine (1) were then
investigated. As shown in Scheme 4, the regioselective
dehydrogenation at C4–C5 of the ketone 14 was readily
achieved by LDA-mediated enolization of the carbonyl
group and the sequential TMSCl silylation followed by di-
rect Pd(OAc)2-mediated oxidation of the crude resulting
silyl enol ethers,7 furnishing the key intermediate enone 3
in 85% yield over two steps. The subsequent reduction of
enone 3 by the bulky reductive reagent L-selectride af-
forded two separable diastereoisomers 15a and 15b
(15a:15b = 1:3) in 95% yield, in which the relative con-
figuration of major isomer 15b was confirmed by compar-
ison of further cyclization product 1 with the literature.4g
After removal of the Boc-protecting groups of 15b and
15a with TFA, the Pictet–Spengler reaction was conduct-
ed in one pot, to readily give the desired ( )-crinine (1)
and ( )-epi-crinine, respectively, in good yields.
Ar
d
( )-crinine (1)
86%
N
HO
H
Boc
Ar
4
15b
5
1) a
c
14
separable diastereoisomer
2) b
95%
N
6
Ar
O
85% over
two steps
H
Boc
d
3
( )-epi-crinine
87%
N
HO
H
Boc
15a
(15a/15b = 1:3)
Scheme 4 Accomplished total synthesis of ( )-crinine (1) and its epimer. Reagents and conditions: (a) LDA, TMSCl, THF, –78 °C; (b)
Pd(OAc)2, MeCN, r.t., 12 h; (c) L-Selectride, THF, –78 °C, 15 min; (d) TFA, ClCH2CH2Cl, r.t., 5 h; then 37% aq HCHO, 6N HCl, MeOH, 5 h.
Synlett 2009, No. 18, 3040–3042 © Thieme Stuttgart · New York

3042
J.-D. Liu et al.
LETTER
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In conclusion, an expeditious and concise total synthesis
of ( )-crinine (1) was accomplished in eleven steps and
24% overall yield starting from the easily available allylic
alcohol 6. The key step in our present total synthesis con-
sists of the NBS-promoted semipinacol rearrangement re-
action of allylic alcohols, wherein the construction of the
hydroindole nucleus with the crucial quaternary carbon
center was achieved by our semipinacol rearrangement
protocol followed by the combination of intramolecular
aldol and aza-Michael reactions. The current synthesis
should demonstrate its value in the synthesis of related al-
kaloids with the unique quaternary carbon units.
Supporting Information for this article is available online at
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Acknowledgment
This work was financially supported by the NSFC (No. 20621091,
20672048, 20732002) and the ‘111’ Program of Chinese Education
Ministry. Prof. Dr. Chun-An Fan is gratefully acknowledged for
helpful discussions.
References and Notes
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Alkaloids, Vol. 30; Academic Press: New York, 1987, 251.
(b) Hoshino, O. The Amaryllidaceae Alkaloids, In The
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Synlett 2009, No. 18, 3040–3042 © Thieme Stuttgart · New York

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