Enantioselective access to bicyclo[4.2.0]octanes by a sequence of [2+2] photocycloaddition/reduction/fragmentation

Article abstract of DOI:10.1002/chem.201302882

Tricks of the trade: Because intramolecular Cu-catalyzed access to bicyclo[4.2.0]octanes is not feasible, an oxygen bridge was introduced to facilitate the [2+2] photocycloaddition. Starting from compounds similar to 1, products such as 2 could be obtaine

Full text of DOI:10.1002/chem.201302882

COMMUNICATION
DOI: 10.1002/chem.201302882
Enantioselective Access to Bicyclo
ACHTUNGTRENNUNG
Photocycloaddition/Reduction/AHCUTNGTRENNUNG
Guoyin Yin, Eberhardt Herdtweck, and Thorsten Bach*[a]
Cyclobutanes are most concisely synthesized by [2+2] cy-
cloaddition reactions upon thermal or photochemical activa-
tion.[1] Enantioselective access to chiral cyclobutanes can be
achieved either by appropriately modifying the reaction con-
ditions of the [2+2] cycloaddition reaction[2,3] or by subse-
quent transformations of a pre-formed cyclobutane.[4] A fre-
quently encountered structural motif, in which a cyclobutane
Figure 2. General structures A and B as well as specific structures 1 and
2 of bridged substrates, which allow for an enantiotopos-differentiating
ring opening to the bicycloACTHNUTRGNEUGN[4.2.0]octane skeleton.
is involved, is the bicycloACTHNURTGNEU[GN 4.2.0]octane skeleton of several
natural products[5] (Figure 1).
tions with Z=CO and only the enzymatic Baeyer–Villiger
oxidation of ketone 1 was shown to be a sufficiently enan-
tioselective process (Figure 2). When considering alternative
ring-opening procedures, the 1,2-elimination of oxygen-
bridged products of type B attracted our attention. It was
envisaged that enantioselectivity could be achieved by em-
ploying precursors, which would facilitate elimination reac-
tions and which would be readily available from furan.
Indeed, it has now been found that imides 2 are suitable for
this purpose and preliminary results of our experiments in
this area are reported herein.
To access products 2, a Diels–Alder reaction of imides 3
with furan[9] was followed by a ring-opening metathesis reac-
tion with ethylene (Table 1; Grubbs I: [RuCl2ACHTUNGTRENNUNG(PCy3)2=
CHPh],[10] Cy=cyclohexyl).[11] The resulting 1,6-dienes 5
were subjected to typical conditions of a Cu-catalyzed
[2+2] photocycloaddition reaction employing CuACHTUNGTRENNUNG(OTf)2
Figure 1. Examples of natural products, which display
ACHTUNGTRENNUNG[4.2.0]octane skeleton.
a bicyclo-
(10 mol%) as the catalyst[12] (l=254 nm, room temperature,
c=15 mm in Et2O). Surprisingly, this reaction when per-
formed with substrate 5a, turned out to be sluggish and de-
livered after 17 h of irradiation only 21% of product 2a
(d.r.=exo/endo=76/24) and very little recovered starting
material. Toluene emerged as the solvent of choice from a
subsequently performed screen of solvents. Under otherwise
identical conditions, the reaction in toluene delivered 89%
yield of product 2a (d.r.=82/18). The diastereoselectivity
improved when the reaction temperature was lowered
(d.r.=91/9 at ꢀ508C), but the reaction was also significantly
slower, which led us to run all other reactions (Table 1) at
ambient temperature. Although exo- and endo-dia-
Although an intermolecular [2+2] photocycloaddition re-
action of enones to form bicyclo
[4.2.0]octanes is feasible,[6]
AHCTUNGTRENNUNG
enantioselective access to this skeleton has only been possi-
ble by the use of stoichiometric auxiliaries.[7] An alternative
approach, which we have tried to employ for some time,
relies on an intramolecular Cu-catalyzed [2+2] photocy-
cloaddition[8] to products of general type A and their subse-
quent desymmetrization by chiral reagents.[4e,f] However, it
turned out to be difficult to perform desymmetrization reac-
[a] Dr. G. Yin, Dr. E. Herdtweck, Prof. Dr. T. Bach
Department Chemie and Catalysis Research Center (CRC)
Technische Universitꢀt Mꢁnchen
AHCTUNGTREGsNNNU tereoisomers 2 could not be separated at this stage (see
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax : (+49)89 289 13315
E-mail: thorsten.bach@ch.tum.de
below), the major product was clearly shown to be the exo-
product based on NOE data (see Supporting Information
for further details). In general, diastereomeric ratios were
high (d.r.=80/20 to 91/9). Only in the case of product 2e,
there was a significant decrease in selectivity (d.r.=66/34).
Homepage: http://www.oc1.ch.tum.de/home_en/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302882.
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Table 1. Preparation of tetracyclic 12-oxa-4-azatetracyclo[5.4.1.02,6.08,11]dodecan-3,5-
diones by a sequence of Diels–Alder reaction, ring opening metathesis, and intramo-
lecular [2+2] photocycloaddition.
The desymmetrization of compounds 2 by an
enantiotopos-selective reduction of the imide car-
bonyl groups[15,16] turned out to be the most reliable
way to access enantioenriched compounds with a
bicycloACHTNUTRGNE[UNG 4.2.0]octane skeleton. After initial reduction
to a hydroxylactam the reduction was completed
with triethylsilane in trifluoroacetic acid (TFA) and
the enantiomeric excess of the resulting products 6
was determined. Optimization experiments were
performed with the N-benzyl-substituted substrate
2e. The best compromise between high chemoselec-
tivity and high enantioselectivity was to run the re-
action with stoichiometric amounts of borane and
an oxazaborolidine catalyst[17] derived from (1S,2R)-
cis-1-amino-2-indanol in THF as the solvent at
408C. After 12 h the reaction was stopped and
product 6e was separated from remaining starting
material (15%). Higher enantioselectivities as com-
pared to the 86% ee recorded for exo-6e in Table 2
were achieved with a higher catalyst loading (up to
91% ee). Oxazaborolidines derived from other
amino alcohols or with other boron substituents
than methyl did not show an improved perform-
ance.
From the data presented in Table 2, it is apparent
that the general procedure optimized for substrate
2e was ideally suited for the enantioselective reduc-
tion of N-aryl (2c, 2d) and N-benzyl (2e–2g)
imides but it was less suited to achieve an enantio-
selective reduction of N-alkyl imides (2a, 2b). In
most cases, the chiral reagent showed no significant
differentiation in the reduction of either exo- or
endo-substrate and the d.r. of products 6 was similar
to the d.r. of substrates 2. Also the enantiomeric
excess for exo- or endo-product did not vary exten-
Substrate
R1
Yield[a]
4 [%]
Yield
Yield[b]
d.r.[c]
ACHTUNGTRENUN(NG exo/endo)
5 [%][d]
2 [%][d]
3a
3b
90
90
87
75
89
88
82/18
89/11
3c
3d
3e
81
59
77
76
69
79
74[e]
97
82/18
91/9
91
66/34
3 f
3g
76
83
72
62
95
94
80/20
83/17
[a] The minor diastereoisomer of the Diels–Alder reaction could be separated by
column chromatography. Yields refer to the isolated diastereoisomer 4 depicted in the
reaction equation. [b] All [2+2] photocycloaddition reactions were conducted using a
RPR-100 reactor with 16 Rayonet RPR-2540 ꢃ lamps (quartz apparatus) as the irradi-
ation source in deaerated toluene (c=15 mm, t=20 h). [c] Diastereomeric products
exo-2 (Figure 2) and endo-2 were not separable by flash chromatography. The dia-
ACHTUNGTRENNUNG
stereomeric ratio (d.r.) was determined by 1H NMR integration of the product mix-
ture. [d] Yields refer to isolated products after chromatographic purification. [e] 24%
of starting material was re-isolated.
The reaction sequence 3 ! 2 proceeded smoothly for all
substrates and only a few issues require special comment. In
the Diels–Alder reaction, major product 4 was formed to-
gether with a diastereomeric by-product. The separation of
the latter compound was facile and products 4 were ob-
tained as single diastereoisomers. In the photocycloaddition
of substrate 5c, the reaction did not go to complete conver-
sion after 20 h, which may be due to competing absorption
by the N-phenyl chromophore. No side reactions were ob-
served, though, and the yield based on conversion was 97%.
Attempts to achieve the conversion of products 2 to chiral
ring-opening products by elimination were performed with
different bases.[13] Unfortunately, the reactions did not lead
to homogenous products but rather to product mixtures.
Due to the fact that the a-carbonyl protons are more readily
accessible in the endo-diastereoisomer endo-2, elimination
products turned out to be enriched in the respective endo-
isomer. Attempted ring-opening reactions with Lewis
acids,[14] for example with BBr3 in CH2Cl2, led to a cleavage
of the central ether bond by nucleophilic displacement. The
resulting halohydrins were unstable, however, and could not
be isolated in enantiomerically pure form.
sively. Only with R=ortho-methoxybenzyl (substrate 2g)
was the endo-product apparently more readily reduced than
the exo-product and the d.r. changed from 83/17 to 70/30.
Separation of the diastereoisomers exo-6 and endo-6 was
not possible by flash chromatography.
Gratifyingly, base treatment of compounds 6 not only in-
duced the desired ring-opening of the central ether bond
but it also led to products 7, the two diastereoisomers of
which were readily separable. Lithium bis(trimethylsilyl)-
AHCTUNGTRENNUNG
amide (LHMDS) was the base of choice[18] for this transfor-
mation. Upon elimination, major exo-isomers exo-7 were ac-
cessed as shown for substrate 6c in Scheme 1. In these com-
pounds five contiguous stereogenic centers around the cen-
tral bicycloACTHNUGRTNEUNG[4.2.0]octane skeleton exhibit a defined absolute
and relative configuration. Apart from the depicted exo-
product exo-7c the endo-isomer endo-7c was isolated in
18% yield. The total yield of the elimination was conse-
quently 94%. As expected there was no significant change
in the enantiomeric excess and product exo-7c was obtained
in 97% ee.
To substantiate the presumed relative configuration of
product exo-7c and its congeners, the compound was con-
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BicycloACHTUNGTRENNUNG[4.2.0]octanes
COMMUNICATION
Table 2. Enantioselective reduction of imides 2 in the presence of a chiral oxazaboro-
lidine catalyst followed by reduction to amides 6.
methyl group can be readily cleaved from product
exo-7 f under oxidative conditions[21] (see Support-
ing Information for further details).
In summary, we have delineated and executed an
enantioselective access to molecules with a bicyclo-
AHCTUNGTREGUN[NN 4.2.0]octane skeleton, which rests on three key
steps. An intramolecular [2+2] photocycloaddition
serves to generate the strained cyclobutane ring.
Enantioselectivity is induced by an oxazaborolidine
catalyzed desymmetrization, which is followed by a
base-induced fragmentation of the central ether
bond. It is believed that the method holds promise
for a wider application in medicinal chemistry and
in natural product total synthesis.
Substrate
R1
Yield[a]
[%]
d.r.[b]
(exo/endo)
ee[c]
exo [%]
ee[c]
endo [%]
G
2a
2b
73
53
82/18
88/12
74
84
79
83
2c
2d
2e
71
75
77
85/15
92/8
95
93
93[d]
86
93[d]
89
66/34
Experimental Section
2 f
2g
78
75
82/18
70/30
89
88
87
82
General procedure for Cu-catalyzed intramolecular [2+2] pho-
tocycloaddition reaction: A 15 mL quartz tube with a rubber
seal was charged with CuACTHNUTRGNE(UGN OTf)2 (5.4 mg, 10 mol%), compound
5 (0.15 mmol) and anhydrous solvent (10 mL) under argon,
and the solution was degassed by purging with argon in an ul-
trasonicating bath for 15 min. The tube was irradiated at room
temperature (l=254 nm, Rayonet RPR-2537 ꢃ) until conver-
sion was complete (by GLC and TLC analysis). The solvent
was removed under reduced pressure, and then the residue
was directly subjected to purification by flash silica gel column
[a] Yields refer to isolated products after chromatographic purification. [b] Diastereo-
meric products exo-6 and endo-6 were not separable by flash chromatography. The
diastereomeric ratio was determined by 1H NMR integration of the product mixture.
[c] The enantiomeric excess (ee) was determined by chiral HPLC analysis (see the
Supporting Information). [d] The ee was determined after ring opening (see Figure 4
and Supporting Information).
chromatography to give compound 2.
Acknowledgements
G. Y. acknowledges the Alexander von Humboldt Foundation for a post-
doctoral fellowship.
Scheme 1. Base-induced ring opening of the oxygen bridge in the central
oxybicyclo[2.2.1]heptane ring of substrates 6c and conversion of product
ACHTUNGTRENNUNG
exo-7c into the respective nosylate 8
verted into the crystalline para-nitrobenzenesulfonate 8[19]
(Figure 3). Single-crystal X-ray analysis[20] indeed established
the relative configuration as exo but also proved the abso-
lute configuration. The outcome of the desymmetrization is
in line with previous work[15b–e] and suitable models to ex-
plain the preferential attack at one of the two enantiotopic
imide carbonyl groups exist.
When submitting the other products 6d–g to the elimina-
tion reaction conditions, the respective tricyclic products
exo-7d–g were formed in high yields (Figure 4). The enan-
tiomeric excess remained essentially unchanged and prod-
ucts exo-7 offer a wide range of options for further function-
alization. It was shown for example that the para-methoxy-
Figure 3. Structure of nosylate 8 in the crystal as determined by anoma-
lous X-ray diffraction.
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Keywords: asymmetric
enantioselectivity · photochemistry · reduction
synthesis
·
cycloaddition
·
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BicycloACHTUNGTRENNUNG[4.2.0]octanes
COMMUNICATION
24.2296(10) ꢃ, V=1996.95(13) ꢃ3, Z=4, l
0.207 mmꢀ1 1calcd =1.465 gcmꢀ3
T=123(1) K,
G
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif; for more details, see Supporting Information.
[21] a) J.-R. Choi, S. Han, J. K. Cha, Tetrahedron Lett. 1991, 32, 6469–
6472; b) D. C. Kapeller, F. Hammerschmidt, Chem. Eur. J. 2009, 15,
5729–5739.
,
,
F
A
=
25.38, R1=0.0260 (3402 observed data), wR2=0.0629 (all 3640
data), GOF=1.06, 360 parameters, D1max/min =0.20/ꢀ0.22 eꢃꢀ3
;
CCDC-945497 (8) contains the supplementary crystallographic data
Received: July 23, 2013
for this paper. These data can be obtained free of charge from The
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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T. Bach et al.
Photochemistry
G. Yin, E. Herdtweck,
T. Bach* ....................... &&&& — &&&&
Tricks of the trade: Because an intra-
molecular Cu-catalyzed access to
bicycloACTHNUGRTNEUNG[4.2.0]octanes is not feasible, an
oxygen bridge was introduced to facili-
Starting from compounds similar to 1,
products such as 2 could be obtained
enantioselectiviely in three steps after
ring-opening metathesis (see scheme).
Enantioselective Access to Bicyclo-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
tate the [2+2] photocycloaddition.
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www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!