Synthesis of N-heterocycles via lactam-derived ketene aminal phosphates. Asymmetric synthesis of cyclic amino acids

Article abstract of DOI:10.1039/a804198i

A variety of N-heterocycles can be synthesized from lactams via Pd⁰-catalyzed couplings of their corresponding enol phosphates.

Full text of DOI:10.1039/a804198i

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Synthesis of N-heterocycles via lactam-derived ketene aminal phosphates.
Asymmetric synthesis of cyclic amino acids.
K. C. Nicolaou,* Guo-Qiang. Shi, Kenji Namoto and Federico Bernal
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, California 92037, USA and Department of Chemistry and Biochemistry, University of California, San
Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
A variety of N-heterocycles can be synthesized from lactams
via Pd0-catalyzed couplings of their corresponding enol
phosphates.
The synthesis of ketene aminal diphenylphosphates 1a,b is
accomplished from the eight-membered N-Boc or N-CO2Ph
protected lactams via their potassium enolates. These com-
pounds proved quite stable at ambient temperatures and to silica
gel flash chromatography, entering a variety of coupling
reactions with appropriate partners under palladium(0) or
nickel(0) catalyzed conditions, (Scheme 2). All of these
reactions proceeded smoothly in good to excellent yields,
furnishing a variety of products capable of further functional-
ization.
The generality and scope of the present technology was
further illustrated by synthesizing ketene aminal phosphates of
different ring sizes, as shown in Table 1. Two useful
applications of the newly synthesized dienes4 (Table 1) are
shown in Scheme 3. Thus, diene 4† enters smoothly into a
Diels–Alder reaction with benzoquinone affording, after silica
gel-induced tautomerization, hydroquinone 22, while diene 17
reacted with singlet oxygen to afford endoperoxide 23. The
latter compound was reduced to diol 24 in 57% overall yield
upon treatment with aluminium amalgam.
Due to the rich chemistry and biology of nitrogen-containing
compounds, the synthesis of N-heterocycles has been a central
and important theme within organic chemistry. The functional-
ization of lactams to substituted heterocycles via the corre-
sponding enol triflates has been reported.1 However, the triflate-
based methodology has been proven cumbersome due to the
rather unstable, difficult-to-isolate nature of the triflates and the
necessity to use unconventional and expensive triflating
reagents. Here we report the synthesis of lactam-derived ketene
aminal phosphates2 and their utilization for the construction of
a variety of N-heterocycles, including enantiomerically en-
riched cyclic amino acids. In contrast to their triflate counter-
parts, these phosphate intermediates enjoy remarkable stability,
efficiency of formation and reactivity, as well as easy access and
versatility (Scheme 1).3
O
Table 1 Preparation and Stille coupling of lactam-derived ketene aminal
phosphates
P(OPh)2
N
P
O
N
P
O
N
P
R
Entry Phosphatea
Yield (%) Coupling productb
Yield (%)
O
CO2Me
H
O
N
P
CO2Me
N
P
65
1
P(OPh)2
5
N
5
9 93
O
N
CO2Ph
16
CO2Ph
P = Protecting group
10
O
Scheme 1
6
9 95
9 91
2
3
6
80
76
P(OPh)2
N
O
N
CO2Ph
CO2Ph
17
11
N
H
7
O
7
Boc
N
N
Boc
9
N
R
P(OPh)2
N
CO2Me
O
Ph
2
CO2Ph
3
CO2Ph
viii
ii
i
12a R = Boc
b R = CO2PhPh
18
8
85
4
9 96
8
O
O
vii
iii
N
R
P(OPh)2
N
P(OPh)2
O
N
R
O
N
Boc
4
N
TMS
Boc
1a R = Boc
R = CO2Ph
Boc
8
b
1a R = Boc
4
b R = CO2Ph h
iv
vi
v
4 41c
9
5
6
7
94
81
73
9
O
N
N
P(OPh)2
O
N
Boc
7
N
Boc
5
N
Boc
6
SnMe3
CO2Ph
19
CO2Ph
13
TMS
O
O
P(OPh)2
8 81
9 96
13
13
N
Scheme 2 Reagents and conditions: i, Et3Al (1
M in hexanes, 2.0 equiv.),
N
CO2Ph
CO2Ph
Pd(PPh3)4 (0.05 equiv), THF, 6 h, 92%; ii, CO (1 atm), Pd(OAc)2 (0.1
equiv.), PPh3 (0.2 equiv.), MeOH (3.0 equiv.), Et3N (3.0 equiv.), DMF, 60
°C, 4 h, 72%; iii, Bu3SnCH§CH2 (2.0 equiv.), Pd(PPh3)4 (0.05 equiv.), LiCl
(3.0 equiv.), THF, heat, 3 h, 85%; iv, (Me3Sn)2 (2.0 equiv.), Pd(PPh3)4 (0.05
equiv.), LiCl (3.0 equiv.), THF, heat, 3 h, 77%; v, Me3SiC°CH (3.0 equiv.),
Pd(PPh3)4 (0.1 equiv.), CuI (0.1 equiv.), Et2NH–THF (2:1), 25 °C, 4 h,
84%; vi, Bu3SnCH2CH§CH2 (2.0 equiv.), Pd(PPh3)4 (0.05 equiv.), LiCl
(3.0 equiv.), THF, heat, 4 h, 93%; vii, Me3SiCH2MgCl (3.0 equiv.),
Ni(acac)2 (0.05 equiv.), Et2O, 25 °C, 1 h, 88%; viii, PhZnCl (2.0 equiv.),
Pd(PPh3)4 (0.05 equiv.), THF, 50 °C, 1 h, 87%
14
20
16
16
O
P(OPh)2
N
N
O
CO2Ph
15CO
2Ph
21
a
Conditions: (PhO)2P(O)Cl (1.5 equiv.), KHMDS (1.2 equiv.), THF,
278 °C, 0.5 h; add base to lactam and phosphoryl chloride. Coupling
conditions as described in Scheme 2 for compound 1a. KHMDS (1.0
b
c
equiv.) was used.
Chem. Commun., 1998
1757

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HO
O
O
L
i,ii
*
+
N
CO2Me
Rh
L
CO2Me
N
CO2Me
OPh
N
H
OH
N
O
O
PhO
O
PhO
N
Boc
4
A
B
C
Boc
22
Scheme 4
OH
O
iii
O
iv
the preferred one (Scheme 4). However, the five- and six-
membered ring compounds 25 and 26 show the presence of only
one rotamer, assumed to be rotamer A, in their NMR spectra.
Through variable temperature NMR experiments, it was found
that the rotamer B of 26 appears at around 70 °C. It is, however,
rotamer B that enables the formation of the requisite chelation
complex C which could result in asymmetric induction during
hydrogenation.6 This phenomenon can also explain the lack of
reactivity of 25 and 26 under standard conditions.
The chemistry described herein demonstrates the potential of
cyclic ketene aminal phosphates as substrates for the construc-
tion of a variety of N-heterocycles, including alkaloid structures
and unnatural amino acids through transition metal catalyzed
reactions. Multiple applications in synthesis are envisioned for
this new synthetic technology.
N
N
OH
N
CO2Ph
17
CO2Ph
CO2Ph
24
23
Scheme 3 Reagents and conditions: i, benzoquinone (5.0 equiv.), toluene,
heat, 24 h; ii, silica gel, Et2O, 12 h, 86% (2 steps); iii, O2, tetra-
phenylporphine (trace), CCl4, 500 W halogen lamp, 15 min, ; iv, Al-Hg
(excess), THF–H2O (10:1), 1.5 h, 57%
The chemistry of ketene aminal phosphates was explored
further through their Pd-catalyzed carbonylation and sub-
sequent asymmetric hydrogenation. Thus, a series of com-
pounds arising from carbonylation of the ketene aminal
phosphates were synthesized in good yields (Table 2). They
were then subjected to asymmetric hydrogenation6,7 in the
presence of a catalytic amount of [Rh(COD)-(2)-(R,R)-(Et-
DuPHOS)]OTf.8 This afforded the corresponding cyclic amino
acids in excellent yields and with high enantioselectivities
except for the five- and six-membered rings, which resisted
hydrogenation under standard conditions and gave low enantio-
selectivities at high pressures. Inspection of the NMR spectra of
the compounds with larger ring sizes (7–16) revealed that the
unsaturated esters exist as two rotamers, with rotamer A being
We thank Professor K. B. Sharpless, Dr L. Gooben, and Dr
K. R. Dress for assistance with chiral HPLC and high pressure
equipment. This work was financially supported by the National
Institutes of Health, USA (G. M.) and The Skaggs Institute for
Chemical Biology.
Notes and References
Table 2 Synthesis of cyclic dehydroamino acids from carbonylation of
† Synthetic procedure for 4: To a solution of N-CO2Ph protected
ketene aminal phosphates and subsequent asymmetric hydrogenation
2-azacycloctanone (1.16 g, 4.7 mmol) and (PhO)2P(O)Cl (1.46 ml, 7.0
mmol) in THF (80 ml) at 278 °C was added KHMDS (0.5
ml, 7.0 mmol). After being stirred at 278 °C for 30 min, the reaction
mixture was treated with 1 aq. NH3 (80 ml) for 10 min. The organic phase
M in toluene, 14.1
Yield
Phosphate Carbonylationa (%)
Yield Ee
(%)
Hydrogenationb
(%)c
M
was separated and the aqueous layer was extracted with Et2O (33 20 ml).
The combined organic phases were dried (MgSO4) and concentrated. The
residue was subjected to flash column chromatography (silica gel, 1:1
Et2O–hexanes containing 2% Et3N) to give phosphate 1b (2.18 g, 96%). A
solution of 1a (0.24 g, 0.52 mmol), anhydrous LiCl (66 mg, 1.57 mmol), tri-
n-butyl(vinyl)tin (0.31 ml, 1.05 mmol) and Pd(PPh3)4 (53 mg, 0.046 mmol)
in THF (20 ml) was heated at 70 °C under Ar for 3 h. The solution was then
diluted with Et2O and filtered through silica gel. The filtrate was
concentrated and the residue was subjected to flash column chromatography
(silica gel, 1:9 Et2O–hexanes) to give diene 4 (105 mg, 85%).
CO2Me
5
5
N
70d
8
84
0.4
CO2Me
10
11
N
H
CO2Ph
CO2Ph
31
25
6
CO2Me
6
78
82
72
H
95e
96
26.5
94.8
97.0
N
N
CO2Me
CO2Ph
CO2Ph
32
26
12b
1b
b
7
CO2Me
N
N
CO2Me
H
CO2Ph
CO2Ph
27
33
1 For the use of lactam-derived enol triflates in carbon–carbon bond
forming reactions, see: T. Okita and M. Isobe, Synlett, 1994, 589; T.
Okita, and M. Isobe, Tetrahedron, 1995, 51, 3737; T. Luker, H. Hiemstra
and W. N. Speckamp, Tetrahedron Lett., 1996, 37, 8257; T. Luker, H.
Hiemstra and W. N. Speckamp, J. Org. Chem., 1997, 62, 3592; T. Luker,
H. Hiemstra and W. N. Speckamp, J. Org. Chem., 1997, 62, 8131.
2 For the use of lactone-derived ketene acetal phosphates, see: K. C.
Nicolaou, G.-Q. Shi, J. L. Gunzner, P. Gärtner and Z. Yang, J. Am. Chem.
Soc., 1997, 119, 5467.
8
8
96
CO2Me
N
N
H
CO2Me
CO2Ph
CO2Ph
34
3
13
9
9
79
97
94.5
CO2Me
N
N
H
CO2Me
CO2Ph
CO2Ph
28
35
3 The larger lactams were synthesized from the corresponding ketones via
a Beckmann rearrangement, see: G. A. Olah and A. P. Fung, Synthesis,
1979, 537.
4 W. J. Scott and J. K. Stille, J. Am. Chem. Soc., 1986, 108, 3033.
5 BINAP has been previously used as a superior ligand to monodentate and
other bidentate systems in aromatic amination; see: J. P. Wolfe, S.
Wagaw and S. L. Buchwald, J. Am. Chem. Soc., 1996, 118, 7215.
6 For a catalytic hydrogenation review, see: R. Noyori, Asymmetric
Catalysis In Organic Synthesis, Wiley-Interscience, New York, 1994,
ch. 2.
7 To the best of our knowledge, there is only one example of a catalytic
asymmetric hydrogenation of a cyclic dehydroamino acid derivative, see:
C. J. Foti and D. L. Comins J. Org. Chem., 1995, 60, 2656.
8 M. J. Burk, M. F. Gross, T. Gregory, P. Harper, C. S. Kalberg, J. R. Lee
and J. P. Martinez, Pure Appl. Chem., 1996, 68, 37.
14
15
CO2Me
89d,f
96
86
91.3
86.0
13
CO2Me
CO2Ph
13
H
N
N
CO2Ph
29
36
86d,f
16
8
16
CO2Me
N
CO2Me
N
H
CO2Ph
30
CO2Ph
37
a Conditions: CO (1 atm), Pd(OAc)2 (0.1 equiv.), PPh3 (0.2 equiv.), MeOH
(40 equiv.), Et3N (2.0 equiv.), DMF, 60 °C, 3–6 h; b Conditions: H2 (90 psi),
[Rh(COD)-(2)-(R,R)- Et-DuPHOS)]OTf (0.06 equiv.), MeOH, room
c
temp., 24 h. Determined by HPLC on a Chiralcel OD using hexanes–
PriOH (7:1) as eluent (for compounds 31–33) or an AD column using
hexanes–PriOH (97:3) as eluent (for compounds 34–37). d (R)-(+)-BINAP
e
(0.1 equiv.) was used instead of PPh3 (see ref. 5). Reaction performed
under H2 (400 psi) at 70 °C in EtOH. f Yield based on 77% conversion.
Received in Corvallis, OR, USA, 2nd June 1998; 8/04198I
1758
Chem. Commun., 1998