Enantioselective Synthesis of Highly Functionalized Phosphonate-Substituted Pyrans or Dihydropyrans Through Asymmetric [4+2] Cycloaddition of β,γ-Unsaturated α-Ketophosphonates with Allenic Esters

Article abstract of DOI:10.1002/anie.201206958

Tell me which you want: Catalytic asymmetric [4+2] cycloadditions of β,γ-unsaturated α-ketophosphonates with allenic esters catalyzed by organocatalysts derived from different cinchona alkaloids have been developed, affording phosphonate-substituted funct

Full text of DOI:10.1002/anie.201206958

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Angewandte
Communications
DOI: 10.1002/anie.201206958
Asymmetric Organocatalysis
Enantioselective Synthesis of Highly Functionalized Phosphonate-
Substituted Pyrans or Dihydropyrans Through Asymmetric [4+2]
Cycloaddition of b,g-Unsaturated a-Ketophosphonates with Allenic
Esters**
Cheng-Kui Pei, Yu Jiang, Yin Wei,* and Min Shi*
The phosphonate group, commonly used as a phosphate
mimic in biological systems,[1] is generally regarded as
a bioisostere of a carboxylic acid group in drug design.[2] In
contrast to carboxylic acid, the phosphonic acid has higher
acidity and stronger electrostatic interaction with the guani-
dine group.[3] Some drugs, such as tamiphosphor, guanidino-
tamiphosphor, phosphono-zanamivir and phosphono-glycosyl
acetates, which bear a phosphonic acid group instead of
a carboxylic acid group, possess more inhibitory activity
against the neuraminidases of the influenza viruses;[4a–c] also,
phosphorus-chromones are important intermediates for pro-
ducing platelet-aggregation inhibitors (Figure 1).[4d] Recently,
allenoates have been found to be an attractive substrate class
for Lewis base catalyzed reactions and have attracted
synthetic interest.[5] A large number of phosphine-catalyzed
Figure 1. Phosphorus-substituted biologically active compounds.
cycloaddition reactions of allenoates have been reported after
the pioneering work by Lu and co-workers in 1995.[6–8] In
contrast to the well-developed phosphine-catalyzed alle-
noate-cycloaddition reactions, the corresponding amine-cata-
lyzed analogues are relatively less developed and only a few
examples have been reported.[9] Although this area is less
explored, the development of asymmetric allenoate-cyclo-
addition reactions has attracted much attention.[10] The group
of Masson and Zhu first reported asymmetric [2+2] cyclo-
additions between allenoates and imines in 2011 in the
presence of cinchona-alkaloid-derived bifunctional 6’-deoxy-
6’-acylaminoquinidine.[10a] Subsequently, Tong et al. and
Borhan et al. also reported asymmetric [4+2] cyclization of
allenoates with b,g-unsaturated ketone to afford dihydro-
pyran derivatives in good yields and high ee values using
cinchona-alkaloid-derived organocatalysts.[10b,c] In this regard,
we have recently reported a highly efficient 1,4-diazabicyclo-
[2,2,2]octane (DABCO)-catalyzed [4+2] cycloaddition of b,g-
unsaturated a-ketophosphonates or b,g-unsaturated a-
ketoesters with allenic esters to give the corresponding
highly functionalized pyran and dihydropyran derivatives in
good to excellent yields and moderate to good regioselectiv-
ities under different conditions.[9n] Herein, we wish to report
the asymmetric [4+2] cycloaddition of b,g-unsaturated a-
ketophosphonates with allenic esters to afford either phos-
phonate-substituted pyran or phosphonate-substituted dihy-
dropyran derivatives as the major products, which are
structural subunits in many natural products, drugs, and
biologically active molecules,[4] in good yields and high ee
values using different organocatalysts derived from cinchona
alkaloids.
We initially utilized (E)-diisopropyl cinnamoylphospho-
nate 1a (0.1 mmol, 1.0 equiv) and ethyl 2,3-butadienoate 2a
(0.12 mmol, 1.2 equiv) as the substrates, and b-isocupreidine
(b-ICD, 20 mol%; see Table 1 for structure) as the catalyst in
acetonitrile at room temperature to examine the reaction
outcome and the result is shown in entry 1 of Table 1. It was
found that the corresponding cyclic products, 3aa and 4aa,
were obtained in 72% combined yield and a 3aa/4aa ratio of
4:1, but with low ee for both. To improve the reaction
outcome, we screened various catalysts derived from cin-
chona alkaloids[11] for this reaction, and the results are
summarized in Table 1. As can be seen, C8 was the best
[*] Dr. C.-K. Pei, Y. Jiang, Prof. Dr. M. Shi
Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology
130 Mei Long Road, Shanghai 200237 (China)
Y. Wei, Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
E-mail: weiyin@mail.sioc.ac.cn
Mshi@mail.sioc.ac.cn
[**] We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), the National Basic Research Program of
China (973)-2010CB833302, and the National Natural Science
Foundation of China for financial support (21072206, 20472096,
20872162, 20672127, 21121062 and 20732008).
Supporting information, including spectroscopic data and HPLC
traces of the compounds shown in Tables 1–3 and Scheme 1, for
this article is available on the WWW under http://dx.doi.org/10.
1002/anie.201206958.
11328
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Chemie
Table 1: Screening of catalysts for asymmetric [4+2] cyclization.[a]
Having identified the best organocatalyst to afford 3aa as
the major reaction product, we next carried out the reaction
of 1a and 2a with catalyst C8 (20 mol%) in various solvents
to examine the solvent effects on this reaction, and found that
CH3CN was the solvent of choice (Supporting Information,
Table SI-1, entries 1–7). Lowering the reaction temperature
to ꢀ408C allowed the isolation of 3aa in 60% yield and 90%
ee (3aa/4aa 5:1; Table SI-1, entries 8–10). Adding 4 ꢀ molec-
ular sieves (50 mg for 0.1 mmol of 1a) improved the yield of
3aa to 70% with 90% ee (Table SI-1, entry 11 and Table 2,
entry 1).
Entry
Catalyst
Yield
[%][b]
3aa/4aa[c]
ee of 3aa
ee of 4aa
[%][d]
[%][d]
1
2
3
4
5
6
7
8
b-ICD
C1
C2
C3
C4
C5
C6
C7
C8
72
73
70
68
75
65
70
70
80
65
77
68
75
90
75
22
4:1
2:1
3:1
3:1
6:1
3:1
5:1
6:1
4:1
4:1
5:1
1:1
1:3
<1:20
1:20
1:10
60
68
68
67
64
66
73
62
78
59
64
60
45
–
48
45
43
43
35
32
38
24
35
19
23
40
80
94
90
88
Table 2: Substrate scope of the C8-catalyzed asymmetric [4+2] cycliza-
tion of phosphonates 1 and 2.[a]
9
10
11
12
13
14
15
16
C9
C10
C11
C12
C13
C14
C15
–
46
Entry
R1
R2
Product
3/4[c]
ee of 3
(% yield)[b]
[%][d]
[a] All reactions were carried out using 1a (0.10 mmol) and 2a
(0.12 mmol) at room temperature for 24 h. [b] Total yield of isolated
product(s). [c] Determined by 1H NMR spectroscopy. [d] Determined by
HPLC analysis on a chiral stationary phase.
1
2
3
4
5
6
7
8
C6H5 (1a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Bn (2b)
3aa (70)
3ba (69)
3ca (65)
3da (67)
3ea (75)
3 fa (69)
3ga (70)
3ha (65)
3ia (68)
3ja (70)
3ka (77)
3la (72)
3ab (65)
5:1
5:1
3:1
4:1
7:1
4:1
6:1
4:1
4:1
6:1
7:1
6:1
4:1
90
84
83
90
90
90
90
87
90
87
90
90
92
4-ClC6H4 (1b)
4-BrC6H4 (1c)
4-MeC6H4 (1d)
4-MeOC6H4 (1e)
3-MeOC6H4 (1 f)
3-MeC6H4 (1g)
2-MeOC6H4 (1h)
2-furyl (1i)
1-naphthyl (1j)
Me (1k)
n-propyl (1l)
C6H5 (1a)
9
10
11
12
13
[a] All reactions were carried out using 1 (0.10 mmol) and 2 (0.12 mmol)
in CH3CN 2.00 (mL) for 24 h. [b] Yield of isolated product. [c] Deter-
mined by 1H NMR spectroscopy. [d] Determined by HPLC analysis on
a chiral stationary phase. Bn=benzyl.
Having established the optimal reaction conditions for the
formation of 3aa as the major product, we surveyed the scope
of the reaction by varying the structure of phosphonates 1 and
allenoates 2. As shown in Table 2, regardless of whether
electron-donating or electron-withdrawing groups were intro-
duced in ortho-, meta- or para-positions of the benzene rings
of 1, these substrates were equally well-tolerated in the
reaction, giving the corresponding major products 3 in good
yields and high ee values (Table 2, entries 2–8). Heterocyclic
substrate 1i was also suitable in this reaction, and gave 3ia as
the major product in 68% yield and 90% ee (Table 2, entry 9).
The substrate 1j, in which R1 is a 2-naphthyl group, was also
tolerated in this reaction, providing the corresponding major
product 3ja in 70% yield with 87% ee (Table 2, entry 10). As
for substrates 1k and 1l, in which R1 is an aliphatic group, the
reactions also proceeded smoothly to give the desired major
products 3ka and 3la in 77% yield with 90% ee and 72%
yield with 90% ee, respectively (Table 2, entries 11 and 12).
Changing the ester moiety of allenic esters 2 from OEt to
catalyst for the reaction, affording 3aa and 4aa in 80%
combined yield and with 3aa as the major product (3aa/4aa
4:1); also, ee values of 78% ee and 35% ee were obtained for
3aa and 4aa, respectively (Table 1, entry 9). Moreover, 4aa
was obtained in 90% yield and as the sole product in 94% ee
when C13 was used as catalyst (Table 1, entry 14). When using
C14 (an analogue of C12 which possesses a OMe group
instead of a OH group), the total yield did not change,
however, the amount of product 4aa significantly increased
(Table 1, entry 15). For comparison with C13, catalyst C15,
which possesses a OH group instead of a OMe group, was
synthesized and was found to give the desired products in
lower total yield and with less 4aa (Table 1, entry 16).
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OBn provided a similar outcome, furnishing the desired
major product 3ab in 65% yield and 92% ee (Table 2,
entry 13). Products 3 have been assigned an S configuration
by X-ray diffraction analysis of 3ja (Supporting Information,
Figure SI-1).[13] The structure of 3 is closely related with
phosphorus-chromones.[4d]
Furthermore, the results shown in entry 14 of Table 1
encouraged us to further screen various solvents in the
reaction of 1a and 2a with C13 as the catalyst. The
examination of solvent effects revealed that CH3CN was the
best solvent for this reaction, providing 4aa as the sole
product in 90% yield and 94% ee (Supporting Information,
Table SI-2, entries 1–8). Lowering the reaction temperature
to 08C or ꢀ158C and reducing the catalyst loading to
10 mol% did not improve the reaction outcomes (Table SI-
2, entries 9–11).
Product 4ab can be easily transformed into tetrahydro-
pyran 5ab as a single stereoisomer after hydrogenation with
Pd/C in THF and condensation with aniline in 73% yield and
96% ee in two steps. The crystal structure of 5ab has been
determined by X-ray diffraction and the ORTEP drawing is
shown in Figure SI-2 in the Supporting Information,[13] which
provides information on the absolute stereochemistry of
products 4 (S configuration) as well (Scheme 1). The structure
of 5ab is also very similar to that of phosphono-glycosyl
acetates.[3a]
Under the optimized conditions to produce 4aa as the sole
reaction product in good yield and high ee value, the reaction
scope was investigated by using various phosphonates 1 with
several allenic esters 2; the results of these experiments are
summarized in Table 3. As can been seen, the reactions
produced cycloadducts 4 in high yields and high enantiomeric
excesses for a wide range of substrates 1 with various aromatic
groups, heteroaromatic rings, alkyl or naphthyl groups
(Table 3, entries 1–12). When the ester moiety of the phos-
phonates was changed from OiPr to OMe or OtBu, the
reactions also proceeded smoothly to give the desired
products 4ma and 4na in 87% yield with 93% ee and 83%
yield with 95% ee, respectively (Table 3, entries 13 and 14).
Changing the ester moiety of allenic esters 2 from OEt to
OBn provided a similar outcome, affording the desired
product 4ab in 85% yield and 96% ee (Table 3, entry 15).
Scheme 1. Transformation of Product 4ab. Bn=benzyl, DMF=dime-
thylformamide, EDCI=N’-(ethylcarbonimidoyl)-N,N-dimethyl 1,3-pro-
panediamine, HOBT=hydroxybenzotriazole.
Based on the above experimental results and our previous
mechanistic studies on the formation of racemic cycloaddition
products,[9n] we have done theoretical investigations on
transition state (TS) models A–D (Scheme 2), which have
been proposed as the key transition states for the formation of
products 3 and 4. These TS structures (see Figure 2) were
optimized at the mPW1K/6-31G(d) level of theory, and their
relative energies were calculated at the mPW1K/6-31 +
G(2d)//mPW1K/6-31G(d) level of theory.[12] When C8 is
used in the reaction, the energy of key TS A, which leads to
product 3, and involves a hydrogen bond between the CONH
moiety in C8 and the carbonyl group and phosphonate moiety
in substrate 1, is lower than that of the TS B leading to
product 4 by 18.2 kJmolꢀ1. Thus, when C8 is used as the
catalyst, product 3 is the major product. When C13, which
lacks a hydrogen bond donor, is used as the catalyst, it cannot
form hydrogen bonds with the substrates. Furthermore, we
determined that the energy of the key TS C leading to product
3 is higher than that of the TS D leading to product 4 by
6.4 kJmolꢀ1, owing to the steric repulsion between the
naphthyl moiety of C13 and the phosphonate group of 1.
In conclusion, we have developed a novel asymmetric
[4+2] cycloaddition of b,g-unsaturated a-ketophosphonates
with allenic esters catalyzed by organocatalysts derived from
cinchona alkaloids, which affords the corresponding major
adducts (phosphonate-substituted functionalized pyran or
dihydropyran derivatives) in high yields and enantioselectiv-
ities. Calculations indicate that stereocontrol is determined by
hydrogen-bonding effects or steric interactions. Cinchona-
alkaloid-derived organocatalysts which possess either a hydro-
gen bond donor or a sterically bulky group can give different
cycloadducts. These reactions differ from previous [4+2]
cycloadditions through steric interactions;[10b,c] herein, we first
report that different types of cycloadducts can be afforded
through hydrogen-bonding interactions or pure steric repul-
sion. These corresponding phosphonate-substituted function-
Table 3: Substrate scope of the C13-catalyzed asymmetric [4+2] cycli-
zation of phosphonates 1 and 2.[a]
Entry R1
R2
R3
Product
ee of 4
(% yield)[%][b] [%][c]
1
2
3
4
5
6
7
8
C6H5 (1a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Me
4aa (90)
4ba (92)
4ca (91)
4da (93)
4ea (90)
4 fa (88)
4ga (89)
4ha (91)
4ia (85)
4ja (87)
4ka (87)
4la (85)
4ma (87)
94
92
91
95
95
94
95
93
90
94
94
94
93
95
96
4-ClC6H4 (1b)
4-BrC6H4 (1c)
4-MeC6H4 (1d)
4-MeOC6H4 (1e)
3-MeOC6H4 (1 f)
3-MeC6H4 (1g)
2-MeOC6H4 (1h) Et (2a)
9
2-furyl (1i)
1-naphthyl (1j)
Me (1k)
n-propyl (1l)
C6H5 (1m)
C6H5 (1n)
C6H5 (1a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
10
11
12
13
14
15
tBu 4na (83)
4ab (85)
Bn (2b) iPr
[a] All reactions were carried out using 1 (0.10 mmol) and 2 (0.12 mmol)
in CH3CN (2.00 mL) for 24 h. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis on a chiral stationary phase.
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Experimental Section
General Procedure: Under an argon atmos-
phere, allenoate 2 (0.12 mmol) was added to
a solution of b,g-unsaturated a-ketophosph-
onates 1 (0.1 mmol) and catalyst C8 or C13
(0.02 mmol) in CH3CN (2.0 mL) and stirred
at either ꢀ408C or room temperature for
24 h. The solvent was removed under re-
duced pressure and the residue was chro-
matographed on silica gel (petroleum ether/
ethyl acetate 4:1!2:1) to provide com-
pound 3 or 4, as desired.
Ethyl-6-(diisopropoxyphosphoryl)-2-
methyl-4-phenyl-4H-pyran-3-carboxylate
(3aa): a slightly yellow liquid (28.6 mg,
70%); this is
a
known compound;[9n]
1H NMR (CDCl3, 400 MHz, TMS): d =
1.09 (t, J = 6.8 Hz, 3H), 1.31 (d, J = 6.4 Hz,
6H), 1.35 (d, J = 6.4 Hz, 3H), 1.37 (d, J =
6.4 Hz, 3H), 2.40 (s, 3H), 3.97–4.06 (m,
2H), 4.44 (d, J = 4.8 Hz, 1H), 4.65–4.73 (m,
2H), 6.10 (dd, J = 10.4 Hz, 4.8 Hz, 1H),
7.18–7.22 (m, 3H), 7.28–7.30 ppm (m, 2H);
Scheme 2. Key transition state models. Relative energies DH298(kJmolꢀ1): A 0.0, B 18.2; C 6.4, D
0.0.
20
½aꢁD ¼ꢀ100.8 (c = 0.95, CH2Cl2; 90% ee);
Chiralcel AD-H, n-hexane/iPrOH = 95:5,
0.6 mLminꢀ1
,
254 nm,
tmajor =
16.02 min, tminor = 19.55 min.
(E)-Ethyl-2-(6-(diisopropoxy-
phosphoryl)-4-phenyl-3,4-dihydro-
2H-pyran-2-ylidene)acetate
(4aa):
a
slightly yellow liquid (36.7 mg,
90%); this is a known compound;[9n]
1H NMR (CDCl3, 300 MHz, TMS):
d = 1.23 (t, J = 7.2 Hz, 3H), 1.35 (d,
J = 6.3 Hz, 6H), 1.39 (d, J = 6.3 Hz,
6H), 3.10 (dd, J = 16.8 Hz, 9.9 Hz,
1H), 3.64–3.71 (m, 2H), 4.07–4.16
(m, 2H), 4.71–4.80 (m, 2H), 5.65 (s,
1H), 6.27 (dd, J = 10.2 Hz, 6.9 Hz,
1H), 7.19–7.26 (m, 3H), 7.30–
20
7.35 ppm (m, 2H); ½aꢁD ¼ꢀ151.1 (c
0.70, CH2Cl2) (94% ee); Chiralcel
AD-H,
n-hexane/iPrOH = 95:5,
254 nm, tmajor =
0.6 mLminꢀ1
,
30.15 min, tminor = 27.52 min.
Received: August 28, 2012
Published online: October 8, 2012
Keywords: asymmetric catalysis ·
.
cycloaddition · cinchona alkaloids ·
dihydropyrans · organocatalysis
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[13] CCDC 862127 (3ja) and 871503 (5ab) contain the supplemen-
tary crystallographic data for this paper. These data can be
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material is available free of charge via the Internet at the
website.
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