Ruthenium-catalyzed asymmetric N -demethylative rearrangement of isoxazolidines and its application in the asymmetric total syntheses of (-)-(1 r,3 s)-hpa-12 and (+)-(1 s,3 r)-hpa-12

Article abstract of DOI:10.1021/ol503261h

An asymmetric N-demethylative rearrangement of 1,2-isoxazolidines catalyzed by ruthenium is described. Enantioenriched syn-1,3-aminoalcohols as well as cis-1,3-oxazinanes, which are useful building blocks, can be efficiently prepared stereospecifically by this reaction in good yields, via the isoxazolidine intermediates in situ generated from a nitrone bearing a chiral auxiliary and styrenes. This asymmetric reaction was also applied in the asymmetric total syntheses of both (-)-(1R,3S)-HPA-12 and (+)-(1S,3R)-HPA-12.

Full text of DOI:10.1021/ol503261h

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Asymmetric N‑Demethylative Rearrangement
of Isoxazolidines and Its Application in the Asymmetric Total
Syntheses of (−)-(1R,3S)‑HPA-12 and (+)-(1S,3R)‑HPA-12
Zu-Feng Xiao, Chuan-Zhi Yao, and Yan-Biao Kang*
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
S
* Supporting Information
ABSTRACT: An asymmetric N-demethylative rearrangement
of 1,2-isoxazolidines catalyzed by ruthenium is described.
Enantioenriched syn-1,3-aminoalcohols as well as cis-1,3-
oxazinanes, which are useful building blocks, can be efficiently
prepared stereospecifically by this reaction in good yields, via
the isoxazolidine intermediates in situ generated from a nitrone
bearing a chiral auxiliary and styrenes. This asymmetric reaction was also applied in the asymmetric total syntheses of both
(−)-(1R,3S)-HPA-12 and (+)-(1S,3R)-HPA-12.
1,3-Oxazinanes,1 especially chiral 1,3-oxazinanes,2 are important
subunits in natural products3 and useful building blocks among
which some can be easily hydrolyzed to 1,3-aminoalcohols.4,5
However, efficient and stereospecific routes to NH cis-1,3-
oxazinane are rare.2 Enantioenriched syn-1,3-aminoalcohols are
useful synthetic intermediates or targets for bioactive
compounds; thus, it is important to develop divergent methods
to afford different syn-1,3-aminoalcohols. Although types of
enantioselective reduction of β-hydroxyl imines6 or β-amino
ketones7 and intramolecular allylic functionalization or
substitutions8 have been well established to prepare enantioen-
riched syn-1,3-aminolalcohols, normally it is difficult to furnish
syn specific 1,3-aminoalcohols in the reduction. Among
different derivatives of 1,3-aminolalcohol, HPA-12 is a novel
inhibitor of ceramide trafficking from the endoplasmic
reticulum to the site of sphingomyelin synthesis.9 HPA-12
was first synthesized in 2002 and assigned as 1,3-anti by
Kobayashi et al.9a In 2011, the stereoconfiguration of HPA-12
of ent-3e. For the aliphatic substituents, several alkenes such as
1-octene and allylbenzyl ether were also tested (not shown in
the table). The reaction afforded an inseparable mixture of the
diastereomers. Thus, only aryl alkenes are so far reported here.
Generally, all the aromatic alkenes investigated gave corre-
sponding enantioenriched oxazinane products in good yields.
After establishing the method, it was applied in a gram-scale
asymmetric total synthesis of each enantiomer of HPA-12
(Scheme 1). First, NH cis-oxazinane 3h was prepared from 1
and styrene in 55% yield. After acylation with lauroyl chloride,
the intermediate was subjected to the hydrolysis−oxidation−
reduction procedure12 to produce the alcohol intermediate 4.
Final target (−)-(1R,3S)-HPA-12 5 (1.2 g) was obtained in
overall 18.2% yield via a mild hydrolysis of 4 with NH2OH·HCl
in wet acidic methanol.13 The enantiomeric excess value of the
product (−)-5 was determined to be 99.6% by HPLC on a
20
chiral AD-H column. The [α]D value was −38.9 (c 0.36,
CHCl3), which matched the literature report (−34.4).10 To
further confirm the stereoconfiguration of 5, its enantiomer
(+)-(1S,3R)-HPA-12 (ent-5) was also synthesized from ent-1
using the same procedure and obtained in 19.5% yield (1.27 g,
was revised as syn by Berkes
̌
et al.10 Then Kobayashi et al.
confirmed the stereochemistry.11 The problem emerging in the
assignment of stereoconfiguration was partially due to the
original synthetic procedure. Thus, a reliable, highly efficient,
and stereoselective method for the asymmetric cis-specific
synthesis of HPA-12 is still valuable. In this work, we wish to
report a highly efficient stereospecific synthesis of enantioen-
riched syn-1,3-aminoalcohols and cis-1,3-oxazinanes via a
ruthenium-catalyzed asymmetric N-demethylative rearrange-
ment of 1,2-isoxazolidines.
Chiral nitrone ent-1 bearing a chiral auxiliary was subjected to
the ruthenium-catalyzed N-demethylative rearrangement of the
in situ generated isoxazolidine intermediate, affording the chiral
cis-1,3-oxazinane ent-3a in 84% yield as a single diastereomer
(Table 1). Other products bearing substituents such as 4-
fluruophenyl, 4-methylphenyl, and 1-naphthyl were all obtained
in good yields. The phenyl with a strong electron-donating
group such as a methoxyl group afforded a relatively lower yield
20
99.4% ee). The [α]D value of ent-5 was determined to be
+36.1, which was comparable to that of 5.
The stereochemistry of this reaction could probably be
understood using the model demonstrated in Scheme 2. The
chiral auxiliary on nitrone 1 effects the steric hindrance in the
transition state, where 1 could be attacked by styrene from both
sides. Whereas the left side (a) has a larger steric hindrance,
which gives rise to a disfavored transition state, the right side
(b) attack is favored, which gives the (3R,5S)-diastereomer as
the major isoxazolidine intermediate. The cis-selectivity for the
isoxazolidine intermediate arises from the intrinsic exo-selective
nature of 1,3-dipolar cycloaddition of an N-Me nitrone and
Received: November 10, 2014
© XXXX American Chemical Society
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dx.doi.org/10.1021/ol503261h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Ruthenium-Catalyzed Asymmetric Synthesis of N-H
1,3-Oxazinanes via the N-Demethylative Rearrangement of
Isoxazolidines
Scheme 1. Asymmetric Synthesis of HPA-12 via the N-
Demethylative Rearrangement of Isoxazolidines
a
Scheme 2. Possible Model for the Stereochemistry
a
Reaction conditions: ent-1 (0.5 mmol), 2 (2 mmol), H2O (1.0
mmol), K2CO3 (0.5 mmol), toluene (2 mL), 110 °C; then [RuCl2(p-
cymene)]2 (5 mol %), p-TsOH·H2O (15 mol %), 110 °C. See
b
Supporting Information for details. Isolated yields.
styrene, whose transition state needs to avoid the steric
hindrance between the N-Me and the phenyl on the styrene.
The cis-specific rearrangement of the N-Me isoxazolidine
intermediate probably arises from the difference in steric
hindrance between the Ru-catalyst and cis- or trans-
isoxazolidine.5a
In conclusion, a highly efficient ruthenium-catalyzed
asymmetric N-demethylative rearrangement of isoxazolidines
has been developed. This reaction has been used as a powerful
scaffold for the synthesis of optically active syn-1,3-amino-
alcohols as well as syn-1,3-oxazinanes. This asymmetric reaction
was also applied in the asymmetric total syntheses of
(−)-(1R,3S)-HPA-12 and (+)-(1S,3R)-HPA-12. Easily available
chiral substrates, highly cis-specific reactivity, and synthetic
usefulness are all highlights of this reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectroscopic data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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dx.doi.org/10.1021/ol503261h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ybkang@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC 21404096), the Fundamental Research Funds for the
Central Universities of China (WK2060190022,
WK2060190026), and USTC for financial support.
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