Double hetero-Michael addition of N -substituted hydroxylamines to quinone monoketals: Synthesis of bridged isoxazolidines

Article abstract of DOI:10.1021/ol401235z

A general synthesis of bridged isoxazolidines from a double hetero-Michael addition of N-substituted hydroxylamines to quinone monoketals has been developed. The different addition order of N-benzylhydroxylamine and N-Boc hydroxylamine is also discussed.

Full text of DOI:10.1021/ol401235z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Double Hetero-Michael Addition
of N‑Substituted Hydroxylamines
to Quinone Monoketals: Synthesis
of Bridged Isoxazolidines
Zhiwei Yin,†,‡ Jinzhu Zhang,†,‡ Jing Wu,†,‡ Che Liu,†,‡ Kate Sioson,†,‡
Matthew Devany,†,‡ Chunhua Hu,§ and Shengping Zheng*,†,‡
Department of Chemistry, Hunter College, 695 Park Avenue, New York,
New York 10065, United States, The Graduate Center, The City University of New York,
365 Fifth Avenue, New York, New York 10016, United States, and Department of
Chemistry, New York University, New York, New York 10003, United States
szh0007@hunter.cuny.edu
Received May 2, 2013
ABSTRACT
A general synthesis of bridged isoxazolidines from a double hetero-Michael addition of N-substituted hydroxylamines to quinone monoketals
has been developed. The different addition order of N-benzylhydroxylamine and N-Boc hydroxylamine is also discussed. Moreover, the various
functionalities in the isoxazolidine products allow facile derivatization.
Isoxazolidines are important synthetic intermediates
that have attracted attention in organic synthesis1 and
drug discovery.2 Furthermore, natural products contain-
Scheme 1. Synthesis of Bridged Isoxazolidines
ing the isoxazolidine moiety have also been isolated from
marine sponges3 and plants.4 Reductive cleavage5 of the
labile NꢀO bond in isoxazolidines produces 1,3-amino
† Hunter College.
‡ The City University of New York.
§ New York University.
(1) For a review, see: Frederickson, M. Tetrahedron 1997, 53, 403.
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r
10.1021/ol401235z
XXXX American Chemical Society

the 1,3-dipolar cycloaddition of nitrones to alkenes.7
Intramolecular nitroneꢀalkene cycloaddition provides
fused and/or bridged isoxazolidines,8 which can equilibrate
under thermal conditions9 (Scheme 1). Bridged isoxazoli-
dines are a good source of syn-1,3-amino alcohols, which
often serveascritical precursors to many biologically active
compounds, such as glucosidase inhibitor N-octyl-4-epi-β-
valienamine (NOEV),10 anti-influenza drug Tamiflu,11 and
antiangiogenic natural product cortistatin A12 (Figure 1).
Herein, we report a synthesis of bridged bicyclic isoxazoli-
dines via a double hetero-Michael addition of N-substituted
hydroxylamines to quinone monoketals (Scheme 1).
unsaturated keto and allylic ketal moieties, it is known
that they can undergo 1,4-,15 1,2-16 nucleophilic addition
and SN2017 addition with a variety of nucleophiles (O, N, S,
C, etc.). As part of our interest in the nucleophilic addition
to quinone monoketals, we recently developed a one-pot
synthesis of indoles via condensation of quinone mono-
ketals and aliphatic hydrazine hydrochlorides via 1,2-
addition.18 We envisioned that an N-substituted hydro-
xylamine would favor 1,4-addition and eventually lead
to the bridged isoxazolidine system. A literature search
reveals that hydroxylamine (NH2OH) reacted with santo-
nin to afford a side product isoxazolidine through a double
conjugate addition.19 However, it is known that condensa-
tion of hydroxylamine with quinone monoketals did not
provide the doubleconjugateaddition product, but instead
led to nitroso products through a 1,2-addition and an ensuing
aromatization.20 Although hydroxylamine and monosubsti-
tuted hydrazines lead to 1,2-addition with quinone mono-
ketals, it occurred to us that an N-substituted hydroxylamine
would favor a double hetero-Michael addition to afford
isoxazolidines.
Figure 1. syn-1,3-Amino alcohol/ether-containing bioactive
compounds.
Gratifyingly, when quinone monoketal ketal 2a was
subjected to treatment with N-benzylhydroxylamine hy-
drochloride 1a in acetonitrile in the presence of DBU,
bridged isoxazolidine 3aa was obtained in 97% yield. With
this result in hand, we explored the scope of the reac-
tion with a variety quinone monoketals and N-substituted
hydroxylamines (Table 1). Quinone monoketals are
readily accessible in one step from phenols,13,21 while
Quinone monoketals are regiospecifically differentiated
quinone equivalents that can be easily made from phenols
in a single step by the TamuraꢀPelter protocol.13 They
have been widely used in the synthesis of structurally com-
plex molecules.14 Because quinone monoketals possess
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Org. Lett., Vol. XX, No. XX, XXXX

a reaction between monosubstituted quinone monoketals
and N-substituted hydroxylamines, the chemoselectivity of
both nucleophiles (N vs O) and electrophiles (substituted
enone vs unsubstituted enone) determines which products
are obtained. Although the yields of double Michael
products are moderate, the unambiguous structure eluci-
dation by X-ray diffraction and NOESY would shed light
on the order of the double hetero-Michael addition. It
is well-known that N-substituted hydroxylamines can act
as ambident nucleophiles, which readily alkylate on nitro-
gen but often acylate and phosphorylate on oxygen.22 For
N-alkylhydroxylamine, the first conjugate addition would be
the N addition to the more electrophilic double bond.19b,23
2-Methyl- and 3-methyl-quinone monoketal gave only one
regioisomer as the product since the more electrophilic
double bond is also the sterically less hindered (cf. 3ag and
3ah). On the other hand, for 2-chloro-quinone monoketal,
an inseparable mixture of regioisomers was obtained as the
product. In this case, the more electrophilic double bond is
the one with a chloro substituent, which is also more sterically
hindered. The opposite electronic and steric effect results
in a mixture of regioisomers. 3-Chloroquinone monoketal
gave decomposition. No desired bridged isoxazolidine can
be isolated, presumably due to displacement of the chloro
substituent and subsequent decomposition. We then evalu-
ated N-Boc hydroxylamine as a nucleophile. It has been
shown that N-Boc hydroxylamine can act as both an oxygen
and a nitrogen nucleophile in various reactions, sometimes
leading to a mixture of both products.24 Compared to
N-benzylhydroxylamine, steric effect plays a more impor-
tant role in the addition of N-Boc hydroxylamine since the
oxygen added to the less hindered double bonds, even in the
2-chloro-quinone monoketal case (cf. 3bgꢀ3bi, Figure 2).25
Table 1. Synthesis of Bridged Isoxazolidines
a Isolated yield.
N-hydroxylamines are commercially available. Since
N-benzylhydroxylamine (1a) and N-Boc hydroxylamine
(1b) gave better yields than N-methylhydroxylamine (1c)
and N-acetylhydroxylamine (1d), we used the former to
test the generality of quinone monoketals. Unsubsituted
quinone monoketals generally gave good to excellent yields.
Among them, mixed quinone monoketals gave a mixture of
isomers as a result of a lack of facial selectivity. Their ratio
was calculated from the proton NMR of the product
mixture. According to NOESY, the major isomers are those
where the nucleophiles approach from the less hindered
(methoxy) face. The double Michael addition is affected
by the substitution on the double bonds; monosubstituted
quinone monoketals generally gave moderate yields. For
Figure 2. X-ray crystal structures of 3ai, 3bh, and 3bi.
The order of the cyclization was further supported by
isolation of the mono-Michael addition product 4 and its
cyclization to bridged isoxazolidine 3ah (Scheme 2).
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Org. Lett., Vol. XX, No. XX, XXXX
C

as a minor product (see the Supporting Information).
The structure of 9 was confirmed by single-crystal X-ray
diffraction analysis (see the Supporting Information).31
The relative stereochemistry in the three consecutive chiral
centers in 9 is in accord with that of Tamiflu, NOEV, and
cortistatin A (cf. Figure 1).
Scheme 2. Isolation of Mono-Michael Addition Intermediate
Scheme 3. Synthesis of Aminocyclitol Derivative
The bridged isoxazolidines are rich in various function-
alities, such as two differentiable carbonyl groups (one as
its ketal form), which are ready for further transformation.
As an example, synthesis of an aminocyclitol derivative is
shown in Scheme 3.
Aminocyclitols are cyclohexanes with at least one amino
group and three or more additional hydroxyl goups on
the ring.26 They possess a variety of biological activities.27
From mixed quinone monoketal 2j,13,28 double Michael
addition afforded a mixture of inseparable facial isomers
of 3bj. Reduction of the keto group and subsequent
acylation afforded 5 in 69% yield. Mo(CO)6-mediated
cleavage of the NꢀO bond29 led to separable alcohol 6
(67%) and 7 (16%). From 6, K2CO3-catalyzed trans-
silylation30 afforded ketone 8 in 91% yield. Reduction of
ketone 8 followed by acetylation gave two separable
aminocyclitol derivatives 9 (47%) and its C-2 epimer 10
In summary, we have developed an expedient synthesis
of bridged isoxazolidines from a double hetero-Michael
addition of N-substituted hydroxylamines to quinone
monoketals. This method complements the existing nitroneꢀ
alkene cycloaddition route. The various functionalities in the
isoxazolidines allow facile derivatization. Application of
this method to the synthesis of bioactive compounds is
underway.
Acknowledgment. This paper is dedicated to Prof. Koji
Nakanishi on the occasion of his 88th birthday. We
are grateful to Drs. James McNamara, Richard Franck,
Randy Mootoo, and Klaus Grohmann at Hunter College
for helpful discussions. We also thank Drs. Cliff Soll
(Hunter College) and Lijia Yang (CCNY) for mass spec-
trometric assistance. Financial support from the Bertha
and Louis Weinstein Research Grant and PSC-CUNY
Award is gratefully acknowledged. C.H. acknowledges
the support from the Molecular Design Institute at the
Department of Chemistry of New York University.
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(25) Another subtle stereoelectronic effect on conjugate addition, see:
Zhang, J.; Wu, J.; Yin, Z.; Zeng, H.; Khanna, K.; Hu, C.; Zheng, S. Org.
Biomol. Chem. 2013, 11, 2939.
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´
Supporting Information Available. Experimental details
and characterization data for all new compounds. This
material is available freeof chargevia the Internetat http://
pubs.acs.org.
(28) Stern, A.; Swenton, J. S. J. Org. Chem. 1987, 52, 2763.
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1982, 877. (b) Ritter, A. R.; Miller, M. J. J. Org. Chem. 1994, 59, 4602.
(30) (a) Banwell, M. G.; Edwards, A. J.; McLeod, M. D.; Stewart,
S. G. Aust. J. Chem. 2004, 57, 641. (b) Zanardi, F.; Curti, C.; Sartori, A.;
Rassu, G.; Roggio, A.; Battistini, L.; Burreddu, P.; Pinna, L.; Pelosi, G.;
Casiraghi, G. Eur. J. Org. Chem. 2008, 2273.
(31) X-ray data have been deposited with the Cambridge Crystal-
lographic Database, deposition numbers 931741 (3ah), 919302 (3ai),
919301 (3bh), 919300 (3bi), 931740 (4), and 921687 (9).
The authors declare no competing financial interest.
D
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