Auxiliary-controlled asymmetric [3+2]-dipolar cycloaddition of azomethine ylides generated from Au-catalyzed intramolecular redox reaction of nitronyl alkynes

Article abstract of DOI:10.1002/asia.201100159

As strong as an aux: An electronically-tuned hydroxylamine functions as an excellent chiral auxiliary for [3+2] cycloaddition of the azomethine ylides generated in-situ from gold-catalyzed redox reaction of alkynyl nitrones.

Full text of DOI:10.1002/asia.201100159

DOI: 10.1002/asia.201100159
Auxiliary-Controlled Asymmetric [3+2]-Dipolar Cycloaddition of
Azomethine Ylides Generated from Au-Catalyzed Intramolecular Redox
Reaction of Nitronyl Alkynes
Jaewon Jeong,[a] Hyun-Suk Yeom,[a] Ohyun Kwon,*[b] and Seunghoon Shin*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
1,3-Dipolar cycloaddition of azomethine ylides is one of
the most-powerful approaches for the synthesis of pyrroli-
dine derivatives because it can create a large number of ste-
reogenic centers in a single step.[1] Pyrrolidines occur widely
in natural products and pharmaceuticals and, therefore, de-
livering these skeletons in their optically active forms repre-
sents a highly desirable goal.[2] Recently, we reported that
gold-catalyzed redox reactions of nitronyl alkynes can gener-
ate an azomethine ylide for [3+2]-dipolar cycloaddition.[3]
ꢀ
Such a N O bond redox process can bypass the preparation
of diazo-precursors that could entail an explosion hazard
Scheme 1. Asymmetric dipolar cycloaddition using chiral hydroxylamine
auxiliary by electronic tuning.
and/or atom-inefficiency and multiple bonds in the complex
bicyclic skeleton are stereoselectively formed in an efficient
manner from readily available precursors. Exploiting this
synthetic equivalence between 3-oxidopyridinium betaines
(A) and nitronyl alkynes (B, Scheme 1a),[4] the incorpora-
tion of chirally modified hydroxylamine derivatives (C) af-
a-methylbenzylamine derivatives (Xc) as a removable auxili-
ꢀ
ary effectively controls the C N rotamers and thus results in
an excellent level of diastereofacial control in the intramo-
lecular [3+2] cycloaddition of azomethine ylides generated
forded the azabicyclo
[3,2,1]octanes in an optically active
in-situ from goldACTHNGUTERN(UNG III)-catalyzed redox reactions.
At the outset of our study, we decided to study the influ-
ence of the steric and electronic environments of azome-
thine ylides on the asymmetric dipolar cycloaddition. De-
spite significant efforts to modify chiral azomethine ylides,
there has been limited success in improving facial selectivi-
ties, often requiring the introduction of additional chiral ele-
ments.[5c,d] Surprisingly, the effect of electronic tuning of N-
a-methylbenzyl azomethine ylides has not been examined to
our knowledge. Our initial study (Table 1) started with hy-
droxylamines (1a–b) derived from simple amino acids,
which gave poor diastereoselectivities (Table 1, entries 1 and
2). On the other hand, cyclohexanone-derived hydroxyla-
mines (1c–e) gave a satisfactory selectivity, but an attenuat-
ed reactivity presumably owing to the sterically hindered
chiral environment (Table 1, entries 3–5) and presented fur-
ther problems associated with their later detachment. We
next turned to a-methylbenzyl hydroxylamine derivatives
(1 f–I; Table 1, entries 6–9). Chiral racemic 1 f gave medio-
cre facial selectivity (4.34:1) owing to free rotation around
[a] J. Jeong, H.-S. Yeom, Prof. Dr. S. Shin
Department of Chemistry and Research Institute
for Natural Sciences
Hanyang University
Seoul 133-791 (Korea)
Fax : (+82)2-2299-0762
E-mail: sshin@hanyang.ac.kr
[b] Dr. O. Kwon
Research Institute
Samsung Mobile Display Co. Ltd.
Mt. 24-1, Nongseo-dong, Giheung-gu, Yongiin-si
Gyeonggi-do 446-711 (Korea)
Fax : (+82)31-209-7607
E-mail: okwon68@gmail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100159.
Chem. Asian J. 2011, 6, 1977 – 1981
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1977

COMMUNICATION
Table 1. Effect of hydroxylamine scaffolds on the diastereoselectivity.
Entry[a]
1
R*NHOH
Yield[b]
50
d.r.[c]
1a
1b
2.71:1
2
3
78
63
2.34:1
1c
1d
>20:1
4
59
50
>20:1
>20:1
5
1e
Figure 1. ORTEP of chiral 3ai obtained from (S)-(+)-1i: Determination
of absolute and relative stereochemistry.[9]
6[d]
7[d]
8[d]
9[d]
1 f (X=H)
1g (X=4-OMe)
1h (X=4-Cl)
55
67
62
78
4.34:1
3.86:1
7.59:1
>20:1
mic hydroxylamines 1i using diastereomeric salt formation.
After some trials, we found that (R)-(ꢀ)-mandelic acid is an
effective resolving agent for 1i. After a single recrystalliza-
tion from propan-2-ol, (S)-(+)-1i·MA (mandelate) was ob-
tained in 47% ee from the crystal, along with 33% ee of
(R)-(ꢀ)-1i·MA in the mother liquor. Iterative recrystalliza-
tion of (S)-(+)-1i·MA (47% ee) twice increased the enan-
tioselectivity to 95.4% ee (31% overall yield).[9] For (R)-
(ꢀ)-1i·MA, anion exchange with tartrate was found to be
more efficient, which similarly gave crystals of (R)-(ꢀ)-
1i·TA (tartrate) with >95% ee after iterative recrystalliza-
tions (x5) from ethanol.
With either enantiomeric forms of 1i in hand, we exam-
ined the scope of this chiral auxiliary in the gold-catalyzed
redox-[3+2]-dipolar cycloaddition tandem reaction. Direct
condensation of the (S)-(+)-1i·MA salt (95.4~98.6% ee)
with the corresponding enyne–aldehyde precursors provided
1i (X=4-NO2)
[a] Nitrone 2a-i were prepared by condensation of the aldehyde precur-
sor with the corresponding hydroxylamines. [b] Yield of isolated product
after column chromatography on silica gel. [c] Diastereoselectivity was
determined from the crude 1H NMR spectra as well as HPLC analysis.
[d] Racemic hydroxylamines 1 were used.
ꢀ
the C N bond, in line with the intermolecular results by
Padwa et al.[5a] To our delight, with N-(1-(para-nitropheny-
l)ethyl) hydroxyl amine (1i), both satisfactory yield (78%)
and a clean single diastereomer was observed in the crude
1H NMR spectrum (d.r.>20:1; Table 1, entry 9). Intriguing-
ly, we noticed a trend that electron-deficient derivatives
showed both higher selectivity and higher yield than those
ꢀ
with electron-rich substituents. It is noteworthy that the C
N bond rotation (and thus the facial selectivity on azome-
thine ylides, see below, Figure 1) could be completely con-
trolled simply by tuning of the
electronic properties of the a-
methylbenzyl group, without
the need for a conformational-
ly rigid cyclic azomethine
ylide.[5e]
We next prepared 1i in its
optically
active
form
(Scheme 2). Whilst the proce-
dure for converting amines
into their corresponding hy-
droxylamines reported by Fu-
kuyama and co-workers could
be applicable to the synthesis
of optically active 1i,[8] the op-
tically pure a-methyl-para-ni-
trobenzylamine precursor for
1i was rather expensive and
thus we sought to resolve race-
Scheme 2. Preparation of optically active hydroxylamine 1i. a) NH2OH·HCl, CH2Cl2; b) NaBH3(CN), MeOH;
c) (R)-mandelic acid (MA) in iPrOH; d) 1m NaOH (aq.); e) l-(+)-tartaric acid (TA) in EtOH.
1978
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Chem. Asian J. 2011, 6, 1977 – 1981

Asymmetric [3+2]-Dipolar Cycloaddition of Azomethine Ylides
Table 2. Scope of the hydroxylamine (1i)-directed [3+2] dipolar cycloaddition of azomethine ylides, generated in-situ from a gold-catalyzed cascade re-
action.[a,b]
ntramolecular cycloaddition (X=CACHTNUGTRNEUNG(CO2Et)2, Ar=para-nitrophenyl.
(intermolecular cycloaddition)
[a] Optical purity of (S)-(+)-1i (95.4~98.6% ee, Chiralcel OJ-H);% ee value refers to the 1i used assuming the optical purity do not change (see text).
[b] Reaction condition: [substrate]=0.1m in CH3NO2, 5 mol% of AuCl3, 708C, 2 h. [c] Enantiomeric (R)-(ꢀ)-1i was used (ent). [d] The% ee of the
major diastereomer.
the substrates for the intra- and intermolecular cycloaddi-
tion reactions [Equation (1), Table 2]. A series of tethered
enynes, 2ai–2li, containing various tether and dipolarophile
groups, underwent a smooth reaction in excellent diastereo-
selectivity (typically>90% d.e.) and the respective single
diastereomers of 3ai–3li were isolated in good to moderate
yields.[10] The optical purities in the products remained es-
sentially unchanged from the starting (S)-(+)-1i·MA salt, as
determined by HPLC analysis of 3ai and 3di (chiralcel OD
column). The assignment of the relative and absolute stereo-
chemistry of 3s was based on the X-ray crystallographic
data on 3ai (Figure 2).
However, tri-substituted olefin substrate 2ii and those
devoid of an aromatic core (2ji–2li) led to lower yields. No-
tably, a longer tether (3 fi, 79%), an alkyl tether (3li, 48%)
and a nitrogen tether (3gi, 75%) were also accommodated
successfully. The intermolecular cycloaddition reaction was
then attempted with 2mi–2oi in the presence of diethyl
acetylene dicarboxylate (2 equiv). Substrate 2mi, which has
a terminal alkyne group, showed poor diastereoselectivity.
Interestingly, however, internal alkyne substrates 2ni and
2oi gave higher diastereomeric ratio of ca. 3:1.
From these data for the intra-/intermolecular cycloaddi-
tion reactions and the relative stereochemistry observed in
Figure 2, we proposed the fol-
lowing model for asymmetric
induction (Scheme 3): among
the Felkin–Anh-type confor-
mations of E1–E3,[5a] E2 has a
1,3-allylic interaction between
Chem. Asian J. 2011, 6, 1977 – 1981
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1979

O. Kwon and S. Shin et al.
COMMUNICATION
Finally, we examined condi-
tions for removing the para-ni-
trobenzyl auxiliary, as shown in
Equation (2). Under hydroge-
nolysis conditions, the para-
nitro group is initially convert-
ed into the aniline and in the
presence of an additional ben-
ꢀ
zylic C N bond at the bridge-
head carbon, the bond connect-
ing the auxiliary could be selec-
tively removed when treated
with
Pd(OH)2/C
H2
(balloon)
(20 mol%
and
Pd)
[Eq. (1)] to give 3a. Alterna-
tively, in the presence of Pd/C
and 5 atm of H2, the ketone
could be reduced concomitant-
ly, delivering amino alcohol 4a
(75%). Importantly, in the se-
quence
of
transformations
Figure 2. Potential energy surface diagram for the transformation of E1 (and E2/E3) into the product.
the alkynyl substituent R and the methyl group on the auxil-
iary and thus should be disfavored relative to E1. The in-
crease in diastereoselectivity from 3mi to 3ni/3oi, are in
good agreement with this. To explain the observed increase
in diastereoselectivity with decreasing aryl electron density
on the auxiliary (Table 1), we propose that the electron den-
sity of electron-rich azomethine ylide is best stabilized when
Table 3. Calculated energies of the ground and transition state conform-
ers and the product.
Species
Absolute energy
(hartree)
Relative energy
No. of imaginary
frequency
(kcalmolꢀ1
)
E1
E2
E3
ꢀ1265.301008
ꢀ1265.292180
ꢀ1265.276958
0.00
5.54
15.09
19.05
22.76
ꢀ25.49
0
0
1
1
1
0
TS1 (E1) ꢀ1265.270656
TS2 (E2) ꢀ1265.264742
ꢀ
the electron-poor aryl group (C Ar bond) is aligned per-
pendicular to the azomethine ylide as in E1 (rather than
E3), so that the s*CꢀAr orbital lies parallel to the p-orbital of
azomethine ylide.[11] To support this explanation, we have
conducted a DFT computational study using the Gaussian
03 program (B3LYP/6-31G(d) level).[12] For simplification, a
simplified azomethine ylide was used analogous to those ob-
Final
product
ꢀ1265.341622
(from 1i to 3a/4a) comprising nitrone condensation, tandem
redox cycloaddition, and detachment of the auxiliary, no
erosion of optical purity in the original 1i (98.5% ee) could
be detected.
tained with 2ai (X=CACHTUNTRGENNUG(CH3)2 instead of CCAHUTGNTREN(NUGN CO2Et)2) with
the gold-catalyst detached. As shown in Figure 1, the overall
kinetic profile falls into Curtin–Hammet regime, where E1
and E2 equilibrates rapidly with E3 as the transition state.
In conclusion, we have reported an auxiliary-controlled
asymmetric [3+2]-dipolar cycloaddition of azomethine ylide
generated in-situ from gold-catalyzed redox reactions of ni-
tronyl alkynes. We showed that electronically tuned hydrox-
ylamine 1i performed excellently as an auxiliary for the in-
¼
The TS1 (close to E1) has the lowest energy path (DDH =
3.71 kcalmolꢀ1 compared to TS2 (close to E2)), en route to
ꢀ
the final product (Table 3).
tramolecular cycloaddition by controlling the C N rotation
and was easily cleaved later under hydrogenolysis condi-
tions. Further implications of
1i to control rotamers in other
dipolar cycloadditions, such as
those of nitrones, are currently
underway in our laboratory.
Experimental Section
AuCl3 (1.5 mg, 0.0049 mmol) was
added to a solution of nitrone (+)-2ai
(50.0 mg, 0.0987 mmol, 98.6% ee) in
nitromethane (1.0 mL). The resulting
Scheme 3. Stereochemical rationale for the asymmetric induction.
1980
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Chem. Asian J. 2011, 6, 1977 – 1981

Asymmetric [3+2]-Dipolar Cycloaddition of Azomethine Ylides
[5] For
acyclic
a-methylbenzyl
amine derivatives as N-modified
chiral auxiliaries in intermolecu-
lar [3+2] cycloaddition reac-
tions, see: a) A. Padwa, Y. Y.
Chen, U. Chiacchio, W. Dent,
Tetrahedron 1985, 41, 3529; b) J.
Rouden, J. Royer, H. P. Husson,
Tetrahedron Lett. 1989, 30, 5133;
c) P. Deprez, J. Royer, H. P.
mixture was heated at 708C for 1 h. The residue was concentrated to dry-
ness and the resulting mixture was purified by column chromatography
on silica gel (EtOAc/Hex=1:4) to give 39.0 mg (78%) of 3ai as pale
yellow solid (½aꢁD23 =+162.5 (c=1.21, CHCl3)).
Pd/C (0.20 equiv) was added to a solution of 3ai (50 mg, 0.0987 mmol,
98.6% ee) in EtOH (0.5 mL) and stirred under H2 (5 atm) at RT for
12 h. The reaction mixture was filtered through a Celite pad and washed
with MeOH and CH2Cl2. The solvent was removed and the residue was
purified by column chromatography on silica gel (EtOAc/Hex=2:1, 1%
MeOH) to give 4a (26.6 mg, 75%, ½aꢁ2D7 =+18.6 (c=1.23, CHCl3)) as pale
yellow solid. The optical purity of 4a was measured by HPLC analysis to
be 98.7% ee on Chiralcel OD-H column (n-hexane: iPrOH=97:3,
0.5 mLminꢀ1, tr =22.2 min for (+)-4a (major) and 30.2 min for (ꢀ)-4a
(minor)).
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[6] Our initial efforts to use AuI- or AuIII complexes with chiral ligands
(including binap, quinap, and Segphos-derivatives) led to a virtually
racemic mixture of products or little conversion, if any, presumably
owing to a premature turnover of the catalyst from D (Scheme 1b).
The reactions with AuI complexes were also accompanied by the for-
mation of isoindole side-products (Ref. [3a] and [3b]).
[7] Asymmetric activation of alkynes with a AuIII-complex has not been
reported to our knowledge. For recent reviews on asymmetric gold-
catalyzed transformations, see: a) R. A. Widenhoefer, Chem. Eur. J.
2008, 14, 5382; b) S. Sengupta, X. Shi, ChemCatChem 2010, 2, 609.
Recently, PtII-catalyzed asymmetric dipolar cycloaddition was re-
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Acknowledgements
Financial support from the National Research Foundation of Korea
(KRF-2009-0803) is gratefully acknowledged. This work was supported
by Hi Seoul Science Humanities Fellowship (to H.S.Y.) from the Seoul
Scholarship Foundation.
[8] a) H. Tokuyama, T. Kuboyama, A. Amano, T. Yamashita, T. Fu-
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Keywords: ACHTUNGTRENNUNG[3+2] dipolar cycloaddition · chiral auxiliaries ·
gold · hydroxylamines · ylides
[9] Assignment of the absolute stereochemistry of 1i is based on the X-
ray crystallography on 2i (Figure 2, see the Supporting Information
for details of the X-ray crystallographic procedure). Repeated re-
crystallization (x5) increased the enantioselectivity of (S)-(ꢀ)-1i
to>99% ee.
[10] In cases where lower yields were obtained, the reaction was accom-
panied by unidentified decomposition products (observed in the
crude 1H NMR spectrum), possibly owing to the regio-isomeric
redox process (e.g. to form isoindole and/or its decomposition by-
products: see Ref. [3b]). However, these side-products were not the
corresponding diastereomers, as indicated by the absence of the
characteristic AB quartet pattern and the presence of messy olefinic
resonances in the crude 1H NMR spectrum. The desired isomer 3
was cleanly separated by column chromatography on silica gel in
the indicated yields.
[11] For the analogous polar effect in carbonyl additions, see: a) M.
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mation).
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Received: February 15, 2011
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Published online: June 27, 2011
Chem. Asian J. 2011, 6, 1977 – 1981
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1981