Desymmetrization of meso [3.2.1]oxabicyclic systems using metal-catalysed asymmetric intramolecular C-H insertion

Article abstract of DOI:10.1016/j.tetlet.2011.10.026

Diazoketone derivatives of meso 8-oxabicyclo[3.2.1]octen-3-ones were desymmetrized by an intramolecular C-H insertion mediated by chiral copper and dirhodium catalysts to generate oxatricyclic systems with up to 5 contiguous stereogenic centres and 50% ee

Full text of DOI:10.1016/j.tetlet.2011.10.026

Tetrahedron Letters 52 (2011) 6763–6766
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Tetrahedron Letters
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Desymmetrization of meso [3.2.1]oxabicyclic systems using metal-catalysed
asymmetric intramolecular C–H insertion
Xiaomei Zhang , Zhengning Li à, John C. K. Chu, Pauline Chiu
⇑
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, Hong Kong
a r t i c l e i n f o
a b s t r a c t
Article history:
Diazoketone derivatives of meso 8-oxabicyclo[3.2.1]octen-3-ones were desymmetrized by an intramolec-
ular C–H insertion mediated by chiral copper and dirhodium catalysts to generate oxatricyclic systems
with up to 5 contiguous stereogenic centres and 50% ee.
Received 21 July 2011
Revised 30 August 2011
Accepted 6 October 2011
Available online 15 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Desymmetrization
Oxabicyclic compounds
C–H insertion
Carbene
Diazo compounds
8-Oxabicyclo[3.2.1]oct-6-en-3-ones such as 1a and 1b are use-
ful substrates in organic synthesis (Fig. 1).1 Their utility has been
inextricably linked to their ready accessibility from (4 + 3) cycload-
ditions of oxyallyl cations with furans,2 and the resultant rigid and
sterically biased frameworks, which allow functional group con-
versions to proceed stereoselectively and in a predictable manner.3
These and related oxabicyclic compounds have already been used
in the synthesis or synthetic studies of many natural products,
including crocacin C,4 scopoline derivatives,5 ionomycin,6 and cal-
lystatin A,7 and cortistatin A.8
In addition, meso oxabicyclic compounds such as 1a–d (Fig. 1),
having up to five pro-stereogenic centres, are poised for desym-
metrization to yield enantiomerically enriched products as inter-
mediates for the synthesis of natural products. Various strategies
have been employed to accomplish enantioselective desymmetri-
zation. The use of a stoichiometric amount of chiral base generates
enantiomerically enriched enolates which are captured as silyl
enol ethers, or acylated to give desymmetrized b-ketoesters.9
Alternatively, desymmetrization has been achieved using Brown’s
asymmetric hydroboration on the alkene.10 Enantioselective alky-
lative and reductive ring opening desymmetrization strategies
have also been developed to yield highly functionalized and stereo-
defined homochiral cycloheptanes.11
The insertion of a carbene, generated from the decomposition of
-diazocarbonyl compounds,12 into a C–H bond is an established
a
reaction to synthesize rings, particularly five-membered rings.13
This transformation can be achieved with only catalytic amounts
of metal complexes, and generates nitrogen as the only by-product.
Furthermore, a wealth of chiral dirhodium or copper catalysts has
already been developed for metal carbene formation from diazo
substrates, and provides a rich resource for tuning the selectivity.
We proceeded to investigate a C–H insertion strategy to achieve
the desymmetrization of the oxabicyclo[3.2.1]octane framework,
which was unprecedented in the literature. We envisioned that
an intramolecular asymmetric C–H insertion reaction could con-
comitantly desymmetrize the meso bicyclic system as well as esca-
late the molecular complexity through a C–C bond formation,
yielding a [5,7]-fused carbobicyclic ring system. Our first study
examined the use of chiral rhodium catalysts which achieved up
to 44% ee in the desymmetrization.14 We herein communicate
our further studies of this C–H insertion reaction in the context
of oxabicyclic diazoketoester, diazoketone and diazoester sub-
strates, and the screening of chiral copper catalysts.
O
O
O
OTBS
O
O
O
O
⇑
Corresponding author. Tel.: +852 2859 8949; fax: +852 2857 1586.
E-mail address: pchiu@hku.hk (P. Chiu).
O
O
1a
1b
1c
Present address: Key Laboratory for Asymmetric Synthesis and Chirotechnology
of Sichuan, Chengdu Institute of Organic Chemistry, Chengdu, PR China.
1d
à
Present address: College of Environmental and Chemical Engineering, Dalian
University, Dalian, PR China.
Figure 1. Meso oxabicyclo[3.2.1]octane derivatives.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.026

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X. Zhang et al. / Tetrahedron Letters 52 (2011) 6763–6766
In our previous work,14 we have described our efforts to desym-
metrize oxabicyclic diazoketoester 2a by enantioselective C–H
O
O
OH
O
SmI2
insertion. After screening a range of chiral dirhodium catalysts,
the enantioselectivities observed for 3a were generally low.15 The
IPA/THF
49%
16a
1a
highest ee obtained was 30% using Rh2(S-BPTTL)4
(Fig. 2) in
5
refluxing dichloroethane (Table 1, entry 1).
O
O
O
In an effort to improve the enantioselectivity, we synthesized
and subjected the substrates 2b and 2c to reaction to probe
whether the size of the ester group (R1) in diazoketoesters 2 would
have an impact (Table 1).17 In the event, although moderate to
good yields of insertion product 3a were still obtained, the ee’s
were inferior compared to the reaction of 2a, whether R1 was more
or less sterically demanding (Table 1, entries 2–4). Whereas the
size of the R1 group in diazoketoester derivatives has been found
to affect the enantioselectivity in the rhodium carbene C–H inser-
tion reactions,18 in this particular C–H insertion it appeared to have
little effect. We also synthesized diazoketone 2d to examine
whether a bulkier protecting group on the hydroxyl functionality
would have any impact on the reaction. However, this only led to
a deteriorated yield, without any improvement in the enantiose-
lectivity (Table 1, entries 4 and 5).
O
O
N2
O
O
O
1. 4-AcNHC6H4SO2N3,
NEt3
O
O
5
5
150 o
C
2. LiOH
97%
90% (2 steps)
4a
6
Ph
N2
O
O
Ph
O
O
O
4-AcNHC6H4SO2N3
BnCOCl
NEt3
DBU
O
70% (2 steps)
7
4b
Scheme 1. Synthesis of 4a and 4b.
Substrates 2 were not highly reactive for carbene formation and
C–H insertion, because these diazoketoesters were stabilized by
two electron-withdrawing groups. Carbene formation required rel-
atively high reaction temperatures, which are not conducive to
promote good enantioselectivities in the subsequent C–H insertion
reaction.
Therefore, we turned our attention to another class of sub-
strates, diazoesters 4a–b, which should yield to carbene formation
readily. These substrates are synthesized as shown in Scheme 1.
Stereoselective reduction of 1a with SmI2 provided equatorial alco-
hol 5.19,20 Alcohol 5 reacted with an acyl ketene generated from the
thermolysis of 2,2,6-trimethyl-4H-1,3-dioxin-4-one to afford b-
ketoester 6.21 Deacetylative diazo transfer secured 4a.22 Diazoester
4b was synthesized from alcohol 5 in one-pot through acylation
and diazo transfer.
Indeed for diazoesters 4a and 4b, carbene formation occurred
upon treatment with rhodium catalysts at room temperature or
below. Unfortunately, neither afforded the desired C–H insertion
product. Diazoester 4a underwent dimerization when treated with
rhodium under typical reaction conditions.23 When a syringe
pump was employed to minimize the reaction concentration of
4a, O–H insertion was the predominant pathway to give 8a as
product (Scheme 2).24 Similarly, 4b underwent O–H insertion un-
der rhodium catalysis to give 8b.25 A possible explanation for 4a
and 4b being unwilling to undergo C–H insertion was that the ester
preferred to adopt an extended conformation,26 thus disfavouring
cyclization and undermining the C–H insertion process, giving
way to other carbene reaction pathways.
Finally, we examined the desymmetrization of diazoketones
9a–b, which was also more reactive towards carbene formation
compared with diazoketoesters 2. The synthesis of these substrates
had been described previously.14 Indeed, the treatment of 9a with
Rh2(OAc)4 at room temperature for 2 h resulted in an 85% yield of
10a (Table 2, entry 1). Our previous study on rhodium catalysis of
this reaction found that Rh2(S-BPTTL)4 promoted the conversion of
9a to 10a with ee up to 44% (Table 2, entry 2). We proceeded to
also screen some chiral copper complexes as catalysts in this reac-
tion (Fig. 3),27 as there has been cases in which copper has been
O Rh
O
N
O Rh
N
O
O S O
O
O
Rh Rh
C12H25
Rh2(R-DOSP)4
4
16a
16b
Rh2(S-BPTTL 4
)
Figure 2. Chiral dirhodium catalysts.16
Table 1
Desymmetrization of 2b–2d
O
O
O
O
OR2
R1O2C
2 mol%
OR2
OR2
R1O
NaCl
Rh2(S-BPTTL)4
DCE reflux
O
O
N2
O
O
O
DMSO
reflux
N2
HO
O
O
O
O
2
mol% Rh2(S-BPTTL)4
2a-d
3a: R2= TMS
3b: R2= TBS
rt, CH2Cl2, slow addition
63%
4a
8a
Entry
Substrate
Yield (%)
eea (%)
Ph
N2
O
1b
2
2a, R1 = Et, R2 = TMS
2b, R1 = Me, R2 = TMS
2b, R1 = Me, R2 = TMS
2c, R1 = t-Bu, R2 = TMS
2d, R1 = t-Bu, R2 = TBS
3a, 73
3a, 83
3a, 83
3a, 89
3b, 64
30.3
22.4
25.4
23.0
25.2
O
HO
Ph
O
O
O
O
3c
4
2 mol% Rh2(R-DOSP)4
0 oC, CH2Cl2
76%
5
a
b
c
Absolute configuration of the major enantiomer was not determined.
Ref. 14.
4b
8b
Reaction was carried out at 60 °C.
Scheme 2. Attempted desymmetrization of 4a and 4b.

X. Zhang et al. / Tetrahedron Letters 52 (2011) 6763–6766
6765
Table 2
Table 3
Desymmetrization of 9a
Desymmetrization of 9b
O
O
O
O
N2
O
N2
SiEt2
O
OTMS
OTMS
OTES
OTES
2 mol% Catalyst
2 mol% Catalyst
rt, solvent
+
H
O
O
O
O
O
CH2Cl2, Temperature, time
9b
10b
11
9a
10a
eea (%)
Entry
Catalyst/solvent
Yield (%)
10b
ee (%) of 10ba
Entry
Catalyst/temperature
Time (h)
Yield (%)
1b
2b
3
4
5
6
7
8
9
Rh2(OAc)4/rt
2
85
85
75
72
76
74
68
71
77
—
44.0
11
Rh2(S-BPTTL)4/rt
[Cu(L1)](OTf)2/rt
[Cu(L2)](OTf)2/rt
[Cu(L3)](OTf)2/ rt
[Cu(L4)](OTf)2/rt
[Cu(L5)](OTf)2/rt
[Cu(L2)](OTf)2/À20 °C
[Cu(L3)](OTf)2/À20 °C
10
12
12
12
12
12
18
18
1b
2b
3
4
5
Rh2(OAc)4/CH2Cl2
77
33
14
0
57
50
—
0.0
À20.1c
À22.4c
2.8
Rh2(S-BPTTL)4/CH2Cl2
[Cu(L2)](OTf)2/CH2Cl2
[Cu(L3)](OTf)2/CH2Cl2
[Cu(L2)](OTf)2/CHCl3
[Cu(L3)](OTf)2/CHCl3
17.2
À22.6c
—
NR
31
73
0
0
À44.2
À2.7c
À32.0c
À14.6c
6
À50.3
a
b
c
Absolute configuration of the major enantiomer not determined.
Ref. 14.
A minus sign indicates the opposite enantiomer.
a
b
c
Absolute configuration of the major enantiomer was not determined.
Ref. 14.
A minus sign indicates the opposite enantiomer.
catalyst in chloroform to generate [5,7]-fused carbobicyclic ketone
10b bearing four stereocentres with up to 50% ee. This is one of the
few cases in which chiral copper catalysts mediated a carbene
reaction with higher chemoselectivity and enantioselectivity than
chiral rhodium catalysts. Additional chiral copper complexes,
anion and solvent effects will be studied in the future.
O
O
O
O
O
O
N
N
N
N
N
N
N
Ph
Ph
t-Bu
t-Bu
Ph
Ph
Ph
HO
L1
L2
L3
Ph
Acknowledgments
O
O
HO
N
N
This work was supported by the University of Hong Kong and
by the Research Grants Council of the Hong Kong SAR, PR of China
(General Research Fund 7103/00P, 7081/07P, Collaborative Re-
search Fund 2009–2009).
Ph
Ph
L4
L5
Figure 3. Chiral ligands for copper employed in our studies.27
Supplementary data
superior to chiral rhodium catalysts in some C–H insertion reac-
tions.28 Although enantioselectivities of about 20% ee were ob-
served at room temperature, using [Cu(L2)](OTf)2 at a lower
reaction temperature of À20 °C resulted in an improved ee of
32% (Table 2, entries 4, 8).29
Supplementary data (the detailed experimental procedures syn-
theses of substrates, desymmetrization reactions and the charac-
terizations of all compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.10.026.
For the less hindered diazoketone substrate 9b, which does not
possess flanking methyl substituents, reaction with Rh2(OAc)4 also
proceeded readily at room temperature (Table 3, entry 1).30 Previ-
ous studies found that the highest ee attained in the desymmetri-
zation of 9b was only 17% ee with Rh2(S-BPTTL)4 as catalyst (Table
3, entry 2).14 In fact, the carbene predominantly underwent an-
other C–H insertion reaction at the triethylsilyl group to afford
siloxane 11 as the major product.31 The use of [Cu(L2)](OTf)2 pro-
moted the formation of the desired 10b, but also accompanied by
11 as the major product (Table 3, entry 3). When solvent was
switched to CHCl3, another medium commonly used in carbene
formations, a dramatic improvement in both chemoselectivity
and enantioselectivity was observed. Using [Cu(L2)](OTf)2 as cata-
lyst, 10b was obtained as the exclusive product, albeit in a moder-
ate yield (Table 3, entry 5). Finally, when [Cu(L3)](OTf)2 was
employed, the yield of 10b improved to 73%, along with attaining
the highest ee of 50% in the desymmetrization reaction (Table 3,
entry 6).32
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best desymmetrization result was achieved for diazoketone 9b,
which reacted with chiral copper complex [Cu(L3)](OTf)2 as
12. For recent reviews on the reactions of
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decarboxylation to yield 3a or 3b in one-pot.
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previously, see Ref. 14 Detailed experimental procedures can be found in the
Supplementary data of this Letter.
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29. Athough Cu(OTf)2 has been used in the preparation of the complex, Cu(II) is
reduced to Cu(I) in the presence of diazo compounds, which is the generally
accepted reactive species.
30. A methine C–H bond is more reactive than a methylene C–H bond towards
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Hrytsak, M.; Durst, T. Heterocycles 1987, 26, 2393–2409.
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a position of a silyl group, see:
32.
A
A
0.002 mmol) and L3 (0.006 mmol) in CHCl3 (1.0 mL) was stirred at room
temperature for 30 min. A solution of 9b (0.0310 g, 0.100 mmol) in CHCl3
(1.0 mL) was added. The resulting mixture was stirred at room temperature until
all 9b was consumed, as indicated by TLC. The solvent was removed in vacuo. The
residue was purified by flash chromatography (10% EtOAc in hexane) to afford
10b as a colorless oil. 10b: Rf (20% EtOAc in hexane): 0.46; IR (CH2Cl2): 2957,
23. For examples of metal carbene-mediated dimerization of
a-diazocarbonyl
compounds, see: (a) Zotto, A. D.; Baratta, W.; Verardo, G.; Rigo, P. Eur. J. Org.
Chem. 2000, 2795–2801; (b) Wenkert, E.; Guo, M.; Pizzo, F.; Ramachandran, K.
Helv. Chim. Acta 1987, 70, 1429–1438; (c) Mateos, A. F.; Barba, A. M. L. J. Org.
Chem. 1995, 60, 3580–3585; (d) Rosenfeld, M. J.; Shankar, R.; Shechter, H. J. Org.
Chem. 1988, 53, 2699–2705.
2914, 2878, 1745, 1463 cmÀ1 1H NMR (300 MHz, CDCl3) d 4.36–4.32 (m, 1H),
;
4.22 (d, J = 7.5 Hz, 1H), 2.65–2.46 (m, 2H), 2.43–2.41 (m, 2H), 2.36–2.20 (m, 3H),
2.03–1.88 (m, 2H), 1.75 (d, J = 2.9 Hz, 2H), 0.97 (t, J = 7.6 Hz, 9H), 0.615 (q,
J = 7.6 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3) d 214.3, 75.4, 74.9, 55.9, 49.1, 41.7,
41.5, 28.0, 27.4, 7.1, 6.5 ppm; EI-MS (20 eV) m/z 296 (M+, 1), 267 (100), 249 (11),
199 (13); EI-HRMS m/z calcd for C16H28SiO3 (M+): 296.
24. For a review on metal carbene-mediated O–H insertion, see: Miller, D. J.;
Moody, C. J. Tetrahedron 1995, 51, 10811–10843.
25. These results are not due to our inability to exclude moisture rigorously under
the reaction conditions. Using other substrates with a similar handling and