Synthesis of oxaspirannic building blocks by regioselective Nitroso-Diels-Alder reactions

Article abstract of DOI:10.1002/chem.201300195

Spirocyclic structures: Nitroso-Diels-Alder reactions of 1,3-disubstituted cyclohexadienes were found to be regiodivergent, depending on the nitroso derivative used. Cycloaddition with Wightman's chloronitroso derivative was totally regio- and stereoselec

Full text of DOI:10.1002/chem.201300195

COMMUNICATION
DOI: 10.1002/chem.201300195
Synthesis of Oxaspirannic Building Blocks by Regioselective
Nitroso-Diels–Alder Reactions
Pierre Sancibrao,[a] Didier Gori,[a, b] Cyrille Kouklovsky,*[a] and Guillaume Vincent*[a, b]
Spirocyclic structures containing heteroatoms, such as
oxygen or nitrogen atoms, are valuable building blocks that
may be found in several natural products, but are also used
as molecular scaffolds for drug discovery.[1] Recent examples
have shown that functionalized aza- or oxaspirannic deriva-
tives could be used as surrogates for many common hetero-
cycles.[2] In this context, we were interested in the synthesis
thesis of azaspiro backbones has been accomplished by
using dipolar cycloadditions,[7] Diels–Alder reactions,[8] nu-
cleophilic additions to cyclic imines,[9] Dieckmann reac-
tion[10] or oxidative phenolic coupling with nitrogen.[11] Syn-
thetic strategies for oxaspiro derivatives include intramolec-
ular alkylation methods,[12] ring-closing metathesis,[13] or
other transition-metal-based processes.[14]
of chiral, functionalized aza- or oxaspiro
[5,5]undecanes, as these bicyclic structures may provide
access to natural products or analogues thereof. For in-
stance, the 8-hydroxy 1-azaspiro bicycloACHTNUTRGNEUNG[4,5]decane back-
bone may be found in FR-901483 (1), a natural product with
[4,5]decanes or
In our ongoing studies concerning the synthetic applica-
tions of nitroso-Diels–Alder reactions,[15] we sought to syn-
thesize chiral oxa- and azaspiro derivatives by following a
unified strategy including the nitroso-Diels–Alder reaction
of a substituted cyclohexadiene bearing a functionalized
À
side chain at the C1-position, followed by N O bond cleav-
age and cyclization: this strategy would provide a short, con-
cise, and stereoselective access to these spirannic structures
(Figure 1).
In this strategy, the nitroso-Diels–Alder reaction could be
performed by using either an acylnitroso derivative, such as
tert-butoxycarbonyl (Boc)-nitroso, an aryl nitroso derivative,
or a chloronitroso reagent. The main feature of this reaction
would be its regioselectivity, as the two regioisomers, the
proximal and the distal isomer, would lead to each of the
target spirannic derivatives.
In the recent years, the nitroso-Diels–Alder reaction has
been the subject of intense studies that have unleashed the
synthetic potential of this reaction.[16] Major achievements in
this field were the development of a catalytic asymmetric
nitroso-Diels–Alder of 2-pyridylnitroso derivatives by using
chiral copper complexes.[17] Although most of the nitroso-
Diels–Alder reactions are performed with symmetrical
dienes, some regiochemical studies with unsymmetrical
dienes have been undertaken.[18] In a seminal paper, Studer
and co-workers studied the regio- and enantioselectivities of
copper-catalyzed nitroso-Diels–Alder reactions of 2-nitroso
pyridine 3 with substituted 1,3-cyclohexadienes in the pres-
ence of Walphos-CF3 ligand (Table 1).[17d] The reaction with
1-methyl-cyclohexadiene (4a) was moderately regioselective
in favor of 5a. The presence of a substituent at C3 was inves-
tigated and, interestingly, although electron-donating
groups, such as OTBS favored exclusively the formation of
the proximal isomer 6b, the distal isomer 5c was the major
compound when a triflate was used.
potent immunosuppressant activities, whereas the synthetic
9-amino-1-oxaspiroACHTUNGTRENNUNG[5,5]undecane 2 was designed as a con-
formationally restricted analogue of the antibiotic paroma-
mine.[3]
Various strategies have been undertaken for access to
these structures,[4–6] depending on ring size and/or the pres-
ence and position of functional groups: for example, the syn-
[a] Dr. P. Sancibrao, D. Gori, Prof. C. Kouklovsky, Dr. G. Vincent
Institut de Chimie Molꢀculaire et des Matꢀriaux d’Orsay
Universitꢀ de Paris-Sud, Bꢁtiment 410, 91405 Orsay (France)
Fax : (+33)1-69-15-46-79
E-mail: cyrille.kouklovsky@u-psud.fr
guillaume.vincent@u-psud.fr
This study revealed the influence of the electronic proper-
ties of the C3 (triflate or silyl ether) substituent on the regio-
selectivity of the reaction. It appeared that a dienophile
bearing both a triflate substituent on C3 and an alkyl chain
[b] D. Gori, Dr. G. Vincent
CNRS, F-91405 Orsay (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300195.
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With the dienes in hand,
their cycloaddition reactions
were investigated. We first per-
formed the copper-catalyzed ni-
troso-Diels–Alder reaction with
Walphos-CF3 ligand as descri-
bed by Studer and co-work-
ers,[17c,d] by using 6-methyl-2-ni-
troso pyridine (13) as the sub-
strate with protected dienes
10a–b. Under these conditions,
cycloaddition led to the exclu-
sive formation of the distal iso-
mers 14a–b (Scheme 2), prov-
ing the synergic effects between
the alkyl substituent at C1 and
the electron-withdrawing group
Figure 1. Synthesis of oxa- and azaspiro derivatives by nitroso-Diels–Alder reactions.
Table 1. Studerꢃs study of the regioselectivity for the copper-catalyzed cy-
cloaddition between 2-nitroso-pyridine 3 and susbtituted 1,3-cyclohexa-
dienes 4a–c.
Entry
Diene
R1
R2
Yield [%]
Ratio 5/6
ee[a] [%]
Scheme 1. Synthesis of dienes 10–12a–b. TBAF=tetrabutylammonium
fluoride. TBS=tert-butyldimethylsilyl.
1
2
3
4a
4b
4c
Me
H
H
H
OTBS
OTf
92
99
99
2:1
1:99
2:1
93
93
98
[a] The ee value of the major product.
on C1 would be a good combination for a regioselective
Diels–Alder reaction. Moreover, this approach would pro-
vide greater access to molecular diversity, since the enol tri-
flate may be replaced by alkyl or aryl groups by organome-
tallic coupling reactions.
The target dienes 10a–b were prepared as shown in
Scheme 1. 3-Ethoxy-2-cyclohexen-1-one (7) was treated with
the Grignard reagents derived from 3-chloropropanol or 4-
chlorobutanol[19] to give the substituted cyclohexenones 8a–
b, which were protected as their TBS ethers. Enolization
with potassium hexamethyl disilazide (KHMDS) and treat-
ment with N-phenyltriflimide gave the dienes 10a–b in good
overall yield. As we wanted to prepare a diene with a leav-
ing group on the side chain, the mesylates 12a–b were pre-
pared by desilylation of dienes 10a–b followed by mesyla-
tion of the resulting alcohols 11a–b.
Scheme 2. Copper-catalyzed Diels–Alder reactions between 2-nitroso-6-
methyl pyridine 13 and dienes 10a–b.
at C3. However, although the regioselectivity was complete,
yields and enantioselectivities were strongly diminished,
dienes 10a–b being poorly reactive at low temperature.[21]
The low yields and enantioselectivities obtained in the
copper-catalyzed reaction prompted us to find another
method for the asymmetric nitroso-Diels–Alder reaction.
We selected Wightmanꢃs chloronitroso reagent 15 as a chiral
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Chem. Eur. J. 2013, 19, 5557 – 5560

Synthesis of Oxaspirannic Building Blocks
COMMUNICATION
dienophile. This carbohydrate-derived reagent has been de-
signed as a simple, easily available, and highly efficient dien-
ophile for stereoselective nitroso-Diels–Alder reactions with
simple dienes.[22]
The Wightman reagent was prepared according to the lit-
erature procedure. Cycloadditions were performed not only
with dienes 10a–b, but also with mesylate derivatives 12a–b.
The cycloadditions between Wightman reagent 15 and
dienes 10a–b and 12a–b were performed at room tempera-
ture in CHCl3/isopropanol. After completion of the reaction,
the crude mixture was hydrolyzed (1n HCl), then neutral-
ized and treated with Boc anhydride. All assignments
(yields, regioselectivities, enantiomeric excesses) were made
on Boc carbamates 16/17. Results are presented in Table 2.
Compounds 16a–d were obtained in moderate to good
yields after three transformations in one pot: cycloaddition,
hydrolysis of the chiral auxiliary, and Boc protection.[23]
Moreover, cycloaddition with OTBS-protected dienes 10a–b
occurred with in situ deprotection of the silyl ether, giving
the free hydroxyl group (Table 2, entries 1 and 2). The reac-
tions proceeded in a highly regioselective fashion, giving for
each diene a single regioisomer. Furthermore, the regiose-
lectivity was opposite to that obtained in the copper-cata-
lyzed cycloaddition of 6-methyl-2-nitroso pyridine 13, as the
proximal isomer 16 was obtained. Although the electronic
requirements of a chloronitroso (compared to a pyridyl-
Figure 2. Proposed transition states for the cycloaddition between Wight-
man reagent 15 and 1,3-disubstituted cyclohexadienes.
ence on selectivity. In all cases, the cycloadducts were ob-
tained in high enantiomeric excesses.[24]
Transformation of cycloadducts 16a–d into spirocyclic
À
structures requires cleavage of the N O bond and cycliza-
À
tion. Reductive cleavage of the N O bond was achieved by
using SmI2 as the reducing reagent.[25] Thus, cycloadducts
16a and b bearing a free hydroxyl group were converted to
diols 18a–b (Scheme 3). Tetrapropylammonium perruthen-
ate (TPAP) oxidation[26] cleanly gave the spirolactones 19a–
ACHTUNGTRENNUNG
nitroso) must be taken into consideration,[18a] we assume
that the reactive conformation of the chloronitroso 15 is as
represented in Figure 2 based on the X-ray crystallographic
analysis of 15 reported by Wightman.[22b] Contrary to the
Wightman proposal, in our model, the diene approaches
from the face opposite to the particularly hindered
CH2OTBDPS (west face, Figure 2) via an endo transition
state. In this facial approach, the transition state leading to
the distal isomer is disfavored due to steric repulsions be-
tween the side chain and the acetonide group. The nature of
the functional group located on the side chain has no influ-
Scheme 3. Synthesis of spiroethers and spirolactones from cycloadducts
16a–d. NMO=N-methylmorpholine-N-oxide.
Table 2. Nitroso Diels–Alder reactions between Wightman reagent 15 and dienes 10a–b and 12a–b.[a]
b. On the other hand, reductive
cleavage of the mesylate cyclo-
adduct 16d with SmI2 was fol-
lowed by treatment under basic
conditions and gave the spi-
roether 20 in a single opera-
tion. All these reactions were
compatible with the presence
of the vinyl triflate.
Finally, the late-stage func-
tionalization of our spirocyclic
building blocks by selective
palladium-catalyzed reactions
of the vinyl triflate moiety
demonstrated that molecular
diversity could be accessed. For
example, Miyaura–Suzuki cou-
pling with phenylboronic acid
Entry
1
Diene
n
R
Product
R
H
Yield [%]
29
Ratio 16/17[b]
>99:1
ee[c] [%]
10a
1
TBS
98
16a/17a
16b/17b
16c/17c
16d/17d
2
3
4
10b
12a
12b
2
1
2
TBS
Ms
H
60
50
45
>99:1
>99:1
>99:1
96
95
95
Ms
Ms
Ms
[a] TBDPS=tert-butyldiphenylsilyl. [b] Ratio determined by 1H NMR spectroscopy. [c] Determined by HPLC
analysis.
Chem. Eur. J. 2013, 19, 5557 – 5560
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www.chemeurj.org
5559

C. Kouklovsky, G. Vincent et al.
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In conclusion, functionalized heterospirocyclic molecular
scaffolds could be prepared in an enantiomerically pure
form by using a regio- and stereoselective nitroso-Diels–
Alder reaction as the key step. The synthetic sequence was
compatible with sensitive functional groups, such as an alkyl
mesylate or a vinyl triflate. A remarkable feature in this
strategy is the regiochemical issue of the nitroso-Diels–
Alder reaction by using different nitroso reagents. Obvious-
ly, further regiochemical studies for this reaction are needed
to provide a rationale. Studies towards the synthesis of
enantiopure azaspirannic bicycles are also underway.
Acknowledgements
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This research was supported by the CNRS, Universitꢀ de Paris-Sud and
Ministꢄre de la Recherche et de l’Enseignement Supꢀrieur (doctoral
grant to P.S.). We are grateful to A.D. Santos and J.-P. Baltaze for assis-
tance with NMR spectroscopic experiments.
Keywords: asymmetric synthesis · cycloaddition · Diels–
Alder reaction · nitroso · regioselectivity
[20] The regioselectivities were assigned by 2D NMR spectroscopic ex-
periments (see the Supporting Information).
[21] Enantiomeric ratios were determined by HPLC analysis on a chiral
column (see the Supporting Information).
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[23] The lower isolated yield of product 16a is probably due to the diffi-
cult separation of 16a from carbohydrate byproducts.
[24] Absolute configurations were assigned by analogy with Studerꢃs
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pounds 16a–d.
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Received: January 18, 2013
Published online: March 18, 2013
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