Stereocontrolled concise synthesis of (±)-halosaline through intramolecular C-H amination

Article abstract of DOI:10.1016/j.tetlet.2019.05.068

Total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloid (±)-halosaline is described from 7-octen-4-ol using a Rh-catalyzed chemo- and diastereo-selective intramolecular C–H amination of sulfamate ester, ring-closing metathesis, and S_N2 displa

Full text of DOI:10.1016/j.tetlet.2019.05.068

Accepted Manuscript
Stereocontrolled concise synthesis of (±)-halosaline through intramolecular C-
H amination
Chun-Yan Meng, Xiao Liang, Hongbin Zhang, Kun Wei, Yu-Rong Yang
PII:
S0040-4039(19)30529-5
https://doi.org/10.1016/j.tetlet.2019.05.068
TETL 50840
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 March 2019
29 May 2019
31 May 2019
Please cite this article as: Meng, C-Y., Liang, X., Zhang, H., Wei, K., Yang, Y-R., Stereocontrolled concise synthesis
of (±)-halosaline through intramolecular C-H amination, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.05.068
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Stereocontrolled concise synthesis of ()-halosaline
through intramolecular C-H amination
Leave this area blank for abstract info.
Chun-Yan Meng, Xiao Liang, Hongbin Zhang, Kun Wei and Yu-Rong Yang

1
Tetrahedron Letters
Stereocontrolled concise synthesis of ()-halosaline through intramolecular C-H
amination
a,b
a
b
a,
a,
Chun-Yan Meng , Xiao Liang , Hongbin Zhang , Kun Wei * and Yu-Rong Yang *
a
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201,
China
b
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming 650091, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloid ()-halosaline is described from 7-
octen-4-ol using a Rh-catalyzed chemo- and diastereo-selective intramolecular C-H amination of
Received in revised form
Accepted
sulfamate ester, ring-closing metathesis, and S
ring sulfamidate as the key steps.
N
2 displacement reaction of the six-membered
Available online
2
018 Elsevier Ltd. All rights reserved.
Keywords:
C-H amination
Halosaline
Ring-closing metathesis
Total synthesis
C-H bond amination has emerged as an effective means for the
synthesis of complex nitrogen-containing molecules. Following
the early discoveries by Breslow and Gellman, Du Bois and co-
Piperidine alkaloids are widely distributed in nature and found
12
to exhibit a broad spectrum of biological activities. In particular
2-(2-hydroxy substituted)-piperidine alkaloids (Figure 1) have
attracted considerable attention due to their potent biological
1
workers revolutionized this domain of chemistry by developing
protocols for practical, efficient, and predictable reactions for
1
3
activities such as memory-enhancing properties. These alkaloids
generally differ by the side chain and also stereochemistry of 1,3-
aminoalcohols. Halosaline 1, a representative 2-(2-hydroxy
substituted)-piperidine alkaloid was isolated from Haloxylon
2
oxidative C-H amination. In this regard, dirhodium (II)
tetracarboxylate catalysts were shown to be particularly effective.
3
4
5
6
Other catalysts such as ruthenium, manganese, silver, and iron
1
4
complexes have also been developed for this important reaction.
Given the prevalence of nitrogen functionalities in biologically
active molecules and the relative difficulty of incorporating
nitrogen into molecular frameworks, C-H amination has found a
unique place in total synthesis, examples of which include the
Salicornicum. Although there are several literature reports on
15
the synthesis of halosaline, C-H amination strategy has never
been explored. Here we wish to report our own results.
7
8
preparation of ()-tetrodotoxin, (+)-saxitoxin, manzacidins A
9
10
and C, ()-agelastatin A, and ()-N-methylwelwitindolinone C
1
1
isothiocyanate. These works underscore the robustness of C-H
amination for streamlining total synthesis.
Scheme 1. Retrosynthetic analysis of ()-halosaline
As illustrated in Scheme 1, we envisioned that the anti 1,3-
aminoalcohol unit of halosaline 1 could be obtained from syn
sulfamidate 6 through a S 2 displacement at the final stage. The
N
piperidine ring of 6 was envisioned to arise from two sequences
involving hydrogenation of the olefin 7 and formation of the
double bond through a ring-closing metathesis reaction. Thus,
diene 8 would be a logical precursor to 7. Further analy
Figure 1. 2-(2-Hydroxy substituted)-piperidine alkaloids

2
Tetrahedron Letters
Scheme 2. Reagents and conditions. (a) NaBH , MeOH, 92%; (b) ClSO NCO, HCOOH, Et N, DCM, 80%; (c) Rh (OAc) , MgO,
4
2
3
2
4
PhI(OAc) , DCM, 40 C, 63%; (d) 4-bromobut-1-ene, NaH, DMF, 77%; (e) Grubbs II catalyst, DCM, 40 C, 96%; (f) Pd/C, MeOH,
2
9
7%; (g) KOAc, DMF, 80 C; (h) K CO , MeOH, 40%, 2 steps; (i) Ts O, Et N, DMAP, DCM, 35%, 2 steps; (j) K CO , MeOH, 80%;
2
3
2
3
2
3
(
k) Na HPO , Na/Hg (10%), MeOH, reflux, ref 15c; (l) Dioxane, 4N HCl, 140 C; (m) TsCl, Et N, DCM, 45%, 2 steps.
2
4
3
revealed that diene 8 could be derived from an N-alkylation of
sulfamidate 9. Six-membered ring sulfamidate 9 is a key
intermediate in our design because we could exploit C-H
amination in its preparation. Similar to what has been shown in
easily purified than piperidine 13 and could be obtained in high
purity. After removal of the acetate, the same compound 15
reported by Blechert could be delivered. Cleavage of the tosyl-
group of 15 was achieved using Na/Hg in methanolic phosphate
buffer according to Blechert’s procedure, providing ()-
halosaline 1.
1
5c
6
a
the literature, we hypothesized that allylic C-H bond in
sulfamate ester 10 could be differentiated and selectively
functionalized by sulfamate insertion. Furthermore, this C-H
amination would demonstrate excellent 1,3-diastereoselective
induction due to the cyclization event proceeding through a
Considering water might be a better nucleophile in the ring-
opening of heterocycle 6 because its product would be halosaline
1 directly, we followed the literature procedure by using vigorous
2
b
16
chairlike transition state. In this way, the stereogenic amine
center from remote alcohol group could be easily established.
Notably, this C-H amination strategy is suited ideally for the
preparation of halosaline 1 given the effectiveness of the
stereocontrol in the sulfamate ester cyclization with sulfamidate
ring opening protocol.
conditions (4N HCl, dioxane, 140 C). Although the SN2
displacement reaction of sulfamidate 6 indeed took place, the
product was turned out to be a chloride 16 whose structure was
unanimously assigned by X-ray crystallographic analysis of its
derivative 17. In this case, not surprisingly, chlorine atom from
HCl acts a nucleophile.
In conclusion, we have disclosed a short diastereoselective
total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloid ()-
halosaline 1. The highlights include a Rh-catalyzed chemo- and
diastereo-selective intramolecular C-H amination of sulfamate
Our synthetic pathway towards ()-halosaline 1 is outlined in
Scheme 2. Reduction of known 7-octen-4-one 11 with NaBH4
gave 7-octen-4-ol 12, which was further converted to sulfamate
ester 10 employing sulfamoyl chloride that was generated from
ester, ring-closing metathesis, and S 2 displacement reaction of
N
ClSO NCO and formic acid. The sulfamate ester 10 reacted
2
the six-membered ring sulfamidate. It is noteworthy that the
strategy described herein would be applicable to its asymmetric
rapidly at 40 C with PhI(OAc) , MgO, and 10 mol % Rh (OAc)
2
2
4
to afford the corresponding six-membered ring insertion product
version because enantioselective preparation of alcohols such as
9
through a chemo- and diastereo-selective allylic C-H insertion.
17
1
2 is not difficult.
With syn sulfamidate 9 in hand, the stage was set to install the
piperidine ring. To this end, N-alkylation of sulfamidate 9 with
NaH and 4-bromobut-1-ene provided diene 8 in 77% yield.
Subsequent ring-closing metathesis of diene 8 with Grubbs II
Acknowledgments
We thank the NSFC (21672224), the Key Research Program
of the Frontier Sciences of CAS (Grant No. QYZDB-SSW-
SMC026) and the Government of Yunnan Province
catalyst delivered bicycle
hydrogenation of the alkene 7 afforded piperidine 6 in nearly
quantitative yield. Ring-opening of sulfamidate with
7
in 96% yield. Catalytic
6
(
2017FA002) for financial support.
nucleophilic acetate anion at 80 C underwent smoothly to afford
piperidine 13. The resulting acetate group of crude 13 was
cleaved with potassium carbonate, providing ()-halosaline 1 in
moderate yield for two steps. Alternatively, treatment of
piperidine 13 with Ts O gave 14. Compound 14 was much more
2

3
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at
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4
Tetrahedron Letters
A short total synthesis of 2-(2-hydroxyalkyl)-

piperidine alkaloid ()-halosaline is described.
Rh-catalyzed chemo- and diastereo-selective
intramolecular C-H amination of sulfamate
ester was strategically employed.


Ring-closing metathesis and S 2 displacement
N
reaction of the six-membered ring sulfamidate
are the key steps.