Biomimetic 2-Imino-Nazarov Cyclizations via Eneallene Aziridination

Article abstract of DOI:10.1021/jacs.0c02441

Amidoallyl cations are appealing three-carbon synthons for the preparation of complex amine-containing carbocycles; however, methods to generate and utilize these reactive species are limited and underexplored compared to those for oxallyl cations. Here we disclose a bioinspired strain-driven ring opening of bicyclic methyleneaziridines to 2-amidopentadienyl cation intermediates that readily engage in Nazarov cyclizations. Advantages of this strategy include ease of generation and improved reactivity compared to 3-pentadienyl cations, control over the ultimate position of the alkene, the potential for high dr between vicinal stereocenters, and the ability to further elaborate the products to fully substituted aminocyclopentanes. Experimental and computational studies support a dual role for the Rh₂L_n complex as both a nitrene transfer catalyst and a Lewis acid promoter, insight that provides a framework for the future development of asymmetric 2-imino-Nazarov cyclizations.

Full text of DOI:10.1021/jacs.0c02441

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Communication
Biomimetic 2-Imino-Nazarov Cyclizations via Eneallene Aziridination
Joshua Corbin, Devin R. Ketelboeter, Israel Fernandez, and Jennifer M. Schomaker
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02441 • Publication Date (Web): 06 Mar 2020
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Journal of the American Chemical Society
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Biomimetic 2-Imino-Nazarov Cyclizations via Eneallene
Aziridination
Joshua R. Corbin†, Devin R. Ketelboeter†,§, Israel Fernández‡,* and Jennifer M. Schomaker†,*
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†Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, United States
‡Departmento de Quimíca Orgánica I and Centro de Innovación en Quimíca Avazanda (ORFEO-CINQA), Facultad
de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Supporting Information Placeholder
Selected aminated cyclopentanes in drugs and natural products
A
ABSTRACT: Amidoallyl cations are appealing 3-carbon
O
NMe2
synthons for the preparation of complex amine-containing
carbocycles; however, methods to generate and utilize these
reactive species are limited and underexplored compared to
oxallyl cations. In this report, we disclose a bio-inspired,
strain-driven ring opening of bicyclic methyleneaziridines to
2-amidopentadienyl cation intermediates that readily engage
in Nazarov cyclizations. Advantages of this strategy include
ease of generation and improved reactivity compared to 3-
pentadienyl cations, control over the ultimate position of the
alkene, the potential for high dr between vicinal stereocenters,
and the ability to further elaborate the products to fully-
Et
Et
HN
H
HN
OH
C5H11
H
H
N
HO
Me
HO
HO
jogyamycin
NH2
N
H
OH
O
N
H2N
Ac
H
HO2C
OH
nitriloprostaglandin I2
HN
CO2H
peramivir
Inspiration from plant prostanoid biosynthesis via 2-oxypentadienyl cations
B
Et
Et
allene oxide
synthase
O
2
1
O
Et
6CO2H
)
2
allene oxide
cyclase
3
HOO
(
CO2H
H2O
6 CO2H
)
( )
6
1
(
2b
2a
4
5
C This work: Biomimetic imino-Nazarov via a 2-amidopentadienyl cation 4
substituted
aminocyclopentanes.
Experimental
and
a
computational studies support a dual role for the Rh2Ln
complex as both a nitrene transfer catalyst and a Lewis acid
promoter, insight that provides a framework for the future
development of asymmetric 2-imino-Nazarov cyclizations.
O O
R4
[Rh2]
H
[Rh2]
N
R4
O
O
2
O
S
R4
Rh2Ln
R3
R1
strain
release
R2
O
S
3
O
2
N
O
R2
R1
S
O
1
2
NH2 PhIO
R2
3b
R3
3a
R3
R1
H
labile bond
3c
easily prepared
4
a
O
O
O
O
3e
facile 4a cyclization of amidoallyl cations
S
[Rh2]
R4
S
N
O
N
O
R4
controlled formation of C=N and C-C bonds
3
2
1
2
vicinal stereocenters with good dr
Flexible methods to construct functionalized, densely
substituted carbocycles have long been of intense interest to
the synthetic community, as these motifs occur frequently in
useful bioactive molecules and natural products. For example,
amine-bearing cyclopentanes are found in diverse natural
products and pharmaceuticals, including the anti-protozoal
compound jogyamycin, the anti-influenza drug peramivir,
and nitriloprostaglandin I2 (PGI2), which is used in the
treatment of arteriosclerosis, cardiac failure and thrombosis
(Scheme 1A).
The aza version of the classic Nazarov cyclization1 of divinyl
ketones to prepare 2-cyclopenten-1-imines is challenging. This
is due to better stabilization of the key pentadienyl cation in a
'3-imino-Nazarov' as compared to the 3-oxyallyl cation
intermediates implicated in a typical Nazarov reaction.2 Tius,
Hsung, West, Huang, and others have reported creative
solutions to overcome this issue;3 nonetheless, reaction
development has beenhampered by the dearth of methods for
convenient generation of 3-amidoallyl cation intermediates.4
The aza-Piancatelli reaction, which moves the N to C1, has also
been used to address this challenge;5 however, it benefits from
a ‘push-pull’ enol-iminium intermediate that ultimately
furnishes the amine-substituted cyclopentenone product.
dual role of Rh2Ln : catalyst and Lewis acid R2
[Rh2]
R2
3d
R3
R1
R3
R1
Scheme 1. Background and proposed 2-imino-Nazarov
reaction.
Our work was inspired by the biosynthesis of epi-jasmonic
acid (Scheme 1B), which proceeds via a Nazarov-type
electrocyclization of allene oxide 2a to furnish -
unsaturated cyclopentenone 2b. This enzyme-catalyzed
process readily controls the site of unsaturation in the product
and yields excellent dr and ee of the new vicinal stereocenters.6
We envisaged a nitrogen version of this process could be
readily
mimicked
by
a
tandem
allene
aziridination/electrocyclization (Scheme 1C) from easily
obtained eneallenes of the form 3a. Rh2-catalyzed nitrene
transfer yields conjugated bicyclic methyleneaziridine 3b,
analogous to 2b. The ring strain inherent in 3b (~35 kcal/mol)
provides kinetically competent access to versatile 2-amidoallyl
cation intermediate 3c without the need for stoichiometric
Lewis or Brønsted acids7 or competing formation of
iminocyclopropanes.6d,f Additionally, the modified 2-N-
positioning in 3c reduces stabilization of the pentadienyl
cation relative to traditional intermediate 1b to facilitate
productive cyclization. A 4π-conrotatory electrocyclization of
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3c to 3d and subsequent loss of the Rh complex furnishes 3e,
With optimized conditions in hand, the scope of the tandem
allene aziridination/2-imino-Nazarov was explored (Table 2).
All substrates were either racemic or a 1:1 racemic mixture of
diastereomers. Freshly prepared 4 provided 4a in 63% yield
and a dr >19:1, bearing an anti relationship between the
hydrogens at the two newly formed stereocenters through a
thermally-allowed, conrotatory 4π-electrocyclization (Table 2,
entry 1). Engaging cis-eneallene 5 gives 5a in moderate yield
(entry 2), favoring the syn isomer (NOESY-NMR studies
detailed in the SI); we considered the lower dr compared to 4a
could result from isomerization of the alkene geometry in 5,
partial epimerization of 5a under the reaction conditions, or a
competing ‘non-Nazarov’ pathway. Control experiments
confirm the alkene of 5 does not isomerize in the presence of
Rh2TPA4 or PhIO, while epimerization of 5a is unlikely, as we
would expect a similar dr for 4a if this pathway were operative.
Isomerization of intermediate species or a competing non-
Nazarov pathway cannot be ruled out.
Isopropyl substitution was tolerated in 6 to give 6a in 74%
yield in excellent dr (entry 3). To our delight, the preparation
of 6a could be run on a 1 g scale to give a 79% yield and dr
>19:1. Protected alcohols were suitable precursors, with 7
giving a 65% yield of 7a in >19:1 dr (entry 4). The ability of an
external stereocenter in 8 to control dr in the all-carbon
stereotriad 8a was investigated (entry 5); while the dr between
a and b was >19:1, the dr between a/b and c was only
moderately improved to 1.2:1.
Substitution at C3 (R4) and C4 (R2) in 9 and 10 (entries 6-7)
gave 9a and 10a in good yield; NOE correlations for 10a show
anti stereochemistry in the major diastereomer. Here,
moderate dr may result from isomerization of either the
precursor or intermediates, although a competing non-
Nazarov pathway is also possible. Extending the conjugation
of the alkene in styrenyl allene 11 (entry 8) resulted in an
unoptimized 36% yield of 11a in >19:1 dr, though this substrate
was prone to decomposition at high temperatures. Increased
steric congestion in eneallenes 12 (entry 9), where both R1 and
R3 are alkyl substituents, gave lower yields, but excellent dr in
forming a challenging all-carbon quaternary center in 12a.
Eneallenes 13-15, where both R1 and R2 are substituted, gave
good yields of the 2-cyclopenten-1-imines 13a-15a. As the
alkene in these cases cannot undergo isomerization, the less-
than-perfect dr is puzzling. Prolonged exposure of 14a as a
mixture to the reaction conditions revealed no change in dr
over 24 h, while resubjecting diastereomerically pure anti-14a
(dr >19:1) to the reaction conditions gave no change in the dr,
providing support for lack of epimerization of the imine itself
(see the SI for details). The isopropenyl substituent on
cyclohexene 15a promotes high anti selectivity between
adjacent stereocenters a/b.
1
2
3
4
5
6
7
8
ideally in high dr. The intermediacy of 3d enables formation
of 3e with predictable positioning of the alkene, as substrate-
controlled elimination present in the typical Nazarov is not
operative here. In fact, no elimination or tautomerization is
required from 3d in this oxidative manifold, which avoids loss
of stereochemical information between vicinal stereocenters
installed in conrotatory cyclization of 3c.8 This
communication describes our '2-imino-Nazarov' reaction,
including factors influencing the mechanism and
stereoselectivity of the cyclization, the elaboration of products
to increase molecular complexity from simple precursors and
details potential strategies to secure enantioenriched
products.
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Hydrozirconation/Zr=O elimination of allyl propargyl
alcohol with Schwartz's reagent enables rapid access to
eneallene 4 (Table 1).9 Preliminary studies found sulfamates
were the best nitrene precursors and a two-carbon tether
between the allene and the sulfamate was optimal. Nitrene
transfer conditions previously reported by our group served as
a starting point for investigating the feasibility of 2-imino-
Nazarov reaction of 4.7a Catalytic Rh2(TPA)4 (TPA
=
triphenylacetate) transformed 4 to 4a in 24% yield and >19:1
dr (entry 1). Varying the concentration (entries 2-3) had little
impact; however, increasing the temperature to 50 °C (entry 1
vs. 4) improved the yield of 4a to 41%. Adding the catalyst last,
as opposed to the oxidant, was not beneficial (entry 5).
Table 1. Selected optimization studies.
H
H
TBSO
1.6 equiv Cp2Zr(H)Cl
0.5 equiv Et2Zn
HO
OTBS
0.5 equiv ZnCl2
H3C
toluene/THF, rt
then 2 steps
H3C
O
O
S
O
H
H
N
x mol % Rh2Ln
1.5 equiv PhIO, 4 A MS
O
S
NH2
O
H3C
O
0.1 M solvent
temp, 1 h
4
4a
CH3
temp (oC) % yielda
entry
solvent
CH2Cl2
catalyst (mol %)
notes
1
2
Rh2(TPA)4 (1)
Rh2(TPA)4 (1)
Rh2(TPA)4 (1)
Rh2(TPA)4 (1)
Rh2(TPA)4 (1)
Rh2(TPA)4 (1)
rt
rt
24
28
33
41
15% rsm
CH2Cl2 (0.2 M)
-
-
-
CH2Cl2 (0.05 M)
3
4
rt
CH2Cl2
CH2Cl2
CH2Cl2
MeNO2
CH2Cl2
50
5
6
7
8
50
50
45
50
33 catalyst added last
21
23
PhI(OAc)2
-
Rh2(TPA)4 (1)
Rh2(TPA)4 (5)
55 LUMO = -2.90 eV
0.05 equiv PhIOx3
9
CH2Cl2
ClCH2CH2Cl
CH2Cl2
Rh2(TPA)4 (5)
50
58
added every 20 min
10
11
12
Rh2(TPA)4 (5)
Rh2(OAc)4 (5)
Rh2(esp)2 (5)
80
50
50
49
-
42 LUMO = -2.68 eV
41 LUMO = -2.71 eV
CH2Cl2
aNMR yields using mesitylene as internal standard
DFT calculations (see SI for computational details) were
carried out to gain more insight into the mechanism of this
unusual 2-imino-Nazarov reaction (Figure 1). The fate of the
methyleneaziridine 16, readily formed upon reaction of
eneallene 4a with Rh2-catalyst in the presence of PhIO, was
explored first. Exothermic coordination of the aziridine
nitrogen to the Rh2-catalyst leads to INT1, which evolves to
amidoallyl cation INT2 through TS1, a saddle point associated
with aziridine ring-opening (∆E≠ = 13.6 kcal/mol). The
intermediacy of this achiral intermediate was supported by
subjecting enantioenriched 4 (92% ee, see SI for details) to the
standard conditions and noting degradation of the axial
Switching the oxidant to PhI(OAc)2 (entry 6) or the solvent
to MeNO2 (entry 7) gave low yields of 21% and 23%,
respectively. However, increasing the loading of Rh2(TPA)4 to
5 mol % (entries 8-9) in CH2Cl2 improved the yield of 4a to
58%; further increases in temperature in DCE (entry 10) were
not beneficial. Interestingly, Rh2(OAc)4 (entry 11) and
Rh2(esp)2 (entry 12) were inferior to Rh2(TPA)4. Computations
of the LUMO energies for Rh2(TPA)4 (-2.90 eV), Rh2(OAc)4 (-
2.68 eV), and Rh2(esp)2 (-2.71 eV) suggested that Lewis acidity
of the catalyst was important to reaction success (see the SI
for details).
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chirality to only 12% ee in the product 4a. Ring closure
converts INT2 into bicyclic INT3 via TS2, which is associated
Table 2. Scope of the tandem allene aziridination/2-imino-Nazarov reaction.
with the formation of a new C–C
1
2
3
4
5
6
7
8
9
O
O
N
O
O
O
O
H
O O
[Rh2]
O
O
[Rh2]
R4
S
O
[Rh2]
Rh (TPA)
[Rh2]
S
5 mol %
S
R4
4
1.5 equiv2PhIO
4 A MS
N
O
S
O
O
S
N
N
2
N
O
R43
R4
R3
R1
1
4 R4
3
O
O
R4
-[Rh2]
a
1
R2
2
S
R3
5
R3
O
NH2
4
R3
s-cis
H
0.1 M CH2Cl2
R2
s-trans
H
5
R2
R2
50 o
C
4
R3
R2
R2
(rac)-4a-15a
R3
R1
R1
(rac)-4-15
R1
R1
R1
% yielda, dr
R1-R4
R1-R4
R1-R4
entry
product
% yielda, dr entry
product
% yielda, dr entry
product
10
11
12
13
14
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16
17
18
19
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O
O
O
O
O
O
S
S
S
N
N
R1 = (E)-C11H19
O
R1 = Ph(CH)CH3
R2, R3 = H
R4 = H
8a
71%
N
O
O
R1 = Me
R2 = H
63%c
4a
5
dra,b >19:1
R2 = H
R3 = Me
R4 = H
9
dr > 19:1
a
1
2
12a
13a
R3, R4 = H
31%
drab,c 1.2:1
dr >19:1
b
H
CH3
O
H3C
CH3
O
c
O
Ph
O
O
S
O
N
O
R1 = H
S
S
N
O
62%
N
R2, R4 = H
R3 = Me
O
R1, R2 = (CH2)3
R1 = Me
5a
6a
36%
9a
65%
dr = 14:1
H3C
dr = 2.4:1
R2 = H
R3 = H
R4 = Me
10
11
dr 4.1:1
R3 = H
6
7
R4 = H
CH3
O
CH3
O
S
O
O
S
O
N
O
O
S
R1 = iPr
R2 = H
N
74%
O
R1 = Me
R2 = Me
R3, R4 = H
14a
N
O
74%
dr > 19:1
3
46%b
R1, R2 = (CH2)4
R3, R4 = H
10a
dr = 3.0:1
dr = 3.9:1
R3 = H
79%, 1 g scale
R4 = H
iPr
H3C
O
CH3
O
O
S
O
S
N
O
O
O
N
R1 = (CH2)3OBPS
O
65%
dr > 19:1
a
7a
S
R1 = Ph
R2 = H
R3 = H
R4 = H
N
R2 = H
R3 = H
R4 = H
R1, R2 = ring
O
4
15a
dra,b >19:1
77%
12
b
11a
36%
8
R3 = H
dr > 19:1
R4 = H
c
drab,c 1.2:1
OBPS
aIsolated yield. bUsed 1 mol % Rh2(TPA)4. cYield decreases as allene ages.
Ph
O
O
TS1-Z
S
N
O
TS1
3.5
TS1
0.9
16-Z
16
Me
1.1
0.0
O
2.085
O
Rh
[
2] = Rh2(OAc)4
S
N
TS2-Z
N
O
Rh
+ [
]
2
2.380
–4.6
16
O
O
O
Me
Rh
]
2
[
O
S
TS2
O
Rh
[
]
O
2
S
N
O
O
O
O
N
S
Rh
INT1-Z
–10.4
[
]
2
S
O
N
O
TS2
O
O
INT1
Rh
[
]
2
S
H
INT1-Z
Me
–11.1
O
N
INT1
Me
H
Me
Me
5a
–12.5
INT2-Z
–12.6
–42.3
O
O
O
O
Rh
INT2
–16.1
O
H
S
S
Me
N
4a
–44.0
O
H2N
O
Rh
4
enantiomer
a
O
INT3-Z
–54.1
O
S
O
O
O
O
N
O
O
47%, >19:1 dr
er = 60:40
O
Rh
]
2
[
S
H
H
Rh
[
]
2
O
S
Rh
N
– [
]
O
N
2
O
N
4
(rac)-
4a
(+)- and (-)-
4b
CH3
–55.9
INT3
Rh2(R-PTAD)4
a5 mol% Rh2(R-PTAD)4, 1.5 equiv PhIO, 4 A MS, CH2Cl2, 50 o
H
CH3
H
INT2
Me
C
Me
Me
Figure 1. Computed reaction profile for the 2-imino-Nazarov of aziridine 16. Relative energies and bond distances given in
kcal/mol and angstroms, respectively. All data computed SMD(CH2Cl2)-B3LYP-D3/def2-TZVPP//SMD(CH2Cl2)-B3LYP-D3/def2-
SVP level.
bond. The lower barrier (∆E≠ = 5.0 kcal/mol) of this step is
consistent with its computed high exothermicity (∆ER = –39.8
kcal/mol); however, the barrier is similar to an aza-Piancatelli
reaction, with the N at C1, highlighting the favorable
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electronic benefits of positioning the N at C2 vs. C3.5
ates the fused pyrrolidine 18 in 64% yield over two steps (>19:1
dr), showcasing one of many potential uses of the tether.6a
Higher-order cuprates, such as Bu2Cu(CN)Li2, gave
diastereoselective 1,4-addition to 6a; subsequent protonation
of the metalloenamine and imine reduction affords 19 in >19:1
dr. Lastly, to demonstrate the application of 6a to the
synthesis of fully-substituted aminated cyclopentanes,
nucleophilic epoxidation with H2O2 and catalytic NaOH
provides 20 in 58% yield and >19:1 dr.
1
2
3
4
5
6
7
8
Decoordination of the Rh2-fragment gives the observed
product 4a and releases the catalyst. The reaction profile for
the corresponding Z-eneallene isomer 16-Z was computed to
be higher in energy than the energies computed for 16 along
the entire reaction coordinate. In addition, the E/Z
isomerization barriers computed for either INT1 or INT2 are
much higher (>20 kcal/mol, see Figure S-2 in the
computational portion of the SI) than the barriers associated
with the ring opening and subsequent cyclization. This
finding could help to explain the higher yields noted with 4 vs.
5.
In conclusion, we have developed an efficient 2-imino-
Nazarov cyclization reaction from simple precursors.
Stereocontrolled, site-selective Rh2-catalyzed eneallene
aziridination initiates an electrocyclization that furnishes
structurally diverse -iminocyclopentene scaffolds in good
yield and dr. Investigation of the reaction mechanism
suggests formation of discrete achiral intermediates, implying
strain-promoted methyleneaziridine ring opening to a 2-
amidopentadienyl cation is operative. Computations indicate
that the nitrene transfer catalyst remains associated during
cyclization as a mild Lewis acid, providing a new framework
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The dual role of the Rh2Ln nitrene transfer catalyst as a Lewis
acid promoter was intriguing; while these modes of reactivity
are precedented individually, there are few examples where
both features of a Lewis acidic dinuclear Rh catalyst are
utilized in a synergistic fashion.10 During optimization studies,
higher catalyst loadings of the most Lewis acidic Rh2Ln
complex gave more efficient cyclization. Dissociation of
Rh2OAc4 prior to cyclization had a prohibitively large
computed energy barrier, leading to the hypothesis that the
use of a racemic allene with a chiral Rh2Ln catalyst might
generate enantioenriched products. Indeed, subjecting (rac)-
4 (Figure 1, inset) to the reaction conditions using Rh2(R-
PTAD)4 produced (+)-4a and (-)-4b in a 60:40 er, a promising
result when considering the large distance between the
catalyst and the site of the stereodetermining C–C bond
formation event. Efforts to identify better chiral Rh2Ln
catalysts and counteranions for accessing enantioenriched,
densely functionalized aminocyclopentenes are currently
underway. This result also provides compelling evidence that
Rh2 is involved in promoting cyclization as a Lewis acid, in
addition to facilitating the nitrene transfer.
for
developing
asymmetric
2-imino-Nazarov
electrocyclizations.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information contains experimental
procedures and spectroscopic data for all new compounds.
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Authors
Finally, the 2-cyclopenten-1-imine products of tandem allene
aziridination/2-imino-Nazarov reaction proved flexible
intermediates for preparation of complex aminated
*E-mail: schomakerj@chem.wisc.edu (J.M.S).
*E-mail: israel@quim.ucm.es (I.F.).
cyclopentanes. As shown in Scheme 3,
a variety of
Present Address
§D.R.K.: Department of Chemistry, University of Florida, 214
Leigh Hall P.O. Box 117200 Gainesville, FL 32611, USA.
transformations were successfully carried out on 6a (see the
SI for conditions). Global reduction of 6a with NaBH3CN
produces 17 in 82% yield and 4.8:1 dr. Boc-protection of the
amine, separation of the diastereomers, and double
displacement with NaI/NaH, gener-
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Scheme 3. Flexible transformations of 6a.
O
O
J.M.S. thanks the NIH 1R01GM132300-01 for support of this
work. The NMR facilities at UW-Madison are funded by the
National Science Foundation (NSF; CHE-9208463, CHE-
9629688) and National Institutes of Health (NIH; RR08389-
01). The Q-Exactive mass spectrometer was acquired from an
NIH-S10 award (NIH-1S10OD020022-1). I.F. acknowledges
financial support from the Spanish MINECO-FEDER (Grants
CTQ2016-78205-P and CTQ2016-81797-REDC). Dr. Charlie Fry
of the University of Wisconsin–Madison is thanked for
assistance with NMR spectroscopy, while Dr. Martha Vestling
of UW–Madison is thanked for assistance with collecting
HRMS data. J.R.C. thanks Dr. Steven Schmid for helpful early
discussions and Amirah Mat Lani for a generous gift of PhIO.
Boc
S
N
1) Boc2O, Et3N,
cat. DMAP, CH2Cl2
HN
O
2) NaI, DMF, then NaH
82%
NaBH3CN, AcOH
MeCN
CH3
CH3
H3C
H3C
18
O
O
17 dr = 4.8:1
O
O
S
79%
64%
dr >19:1
HN
O
S
1) Bu2Cu(CN)Li2, THF
2) NaBH3CN, AcOH
THF/MeOH
1 g scale
N
O
6a
CH3
iPr
19
H3C
CH3
O
O
43% over 2 steps
S
H2O2
cat. NaOH
MeOH
N
O
dr >19:1
O
20
58%
dr >19:1
CH3
REFERENCES
H3C
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Page 6 of 6
O
O
O
O
1
2
S
S
N
O
O
N
H2N
R1
R4
R3
R2
cat. Rh2TPA4
H
PhIO, CH2Cl2, 50 o
C
3
4
R3
R1
R2
R4
5
6
7
8
[Rh2]
N
general, oxidative 2-imino-Nazarov
stereocontrolled, new C=N/C-C bonds
control over position of alkene
R4
O
R3
O
key
intermediate
S
O
access to substituted cyclopentanes
R1 R2
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