Dihydropyridones: Catalytic asymmetric synthesis, N- to C-sulfonyl transfer, and derivatizations

Article abstract of DOI:10.1002/anie.201109061

Benzotetramisole (1) promotes the reaction of ammonium enolates derived from arylacetic acids with N-tosyl-α,β-unsaturated ketimines, thus giving dihydropyridones with high diastereo- and enantiocontrol (see scheme). These products readily undergo N- to C-sulfonyl photoisomerization and are derivatized to afford stereodefined piperidines and tetrahydropyrans.

Full text of DOI:10.1002/anie.201109061

Angewandte
Chemie
DOI: 10.1002/anie.201109061
Asymmetric Catalysis
Dihydropyridones: Catalytic Asymmetric Synthesis, N- to C-Sulfonyl
Transfer, and Derivatizations**
Carmen Simal, Tomas Lebl, Alexandra M. Z. Slawin, and Andrew D. Smith*
The piperidine and dihydropyridone motifs are a recognized
feature of numerous structurally diverse natural products and
bioactive pharmaceuticals.[1] Among the synthetic methods
developed for the preparation of these derivatives in enan-
tiomerically pure form,[2] the aza-Diels–Alder reaction is an
important and versatile route.[3] Since the introduction of
uncatalyzed inverse-electron-demand aza-Diels–Alder cyclo-
addition processes by Boger and Kasper,[4] and Hsung and
Berry,[5] few catalytic asymmetric methods for the promotion
of this reaction have been developed.[6,7] The state-of-the-art
N-heterocyclic carbene promoted[8] organocatalytic methods
of Bode and co-workers (using enals and N-sulfonyl-a,b-
unsaturated aldimines),[9] and those of Ye and co-workers
(arylalkylketenes and N-sulfonyl butenoates)[10] furnish dihy-
dropyridones with high diastereo- and enantioselectivity; on
the otherhand Chen and co-workers have employed enam-
ine[11] and dienamine[12] catalysis in the transformation of N-
sulfonyl-a,b-unsaturated ketimines[13] into pyridinols with
high enantioselectivity. To date, processes that utilize enolate
equivalents that have been prepared directly from readily
available and bench-stable carboxylic acids have not been
developed.[14]
idines, and tetrahydropyrans with high stereocontrol
(Scheme 1).
Initial investigations probed the viability of this Michael/
lactamization sequence using phenylacetic acid (1) and
ketimine 2 (Table 1). Initial screening of a number of
Scheme 1. Versatile route to N- and O-heterocyclic building blocks.
Ts =p-toluenesulfonyl, LB=Lewis base.
Within this area, Romo and co-workers,[15] and our-
selves[16] have utilized Lewis base catalyzed[17] in situ activa-
tion of a carboxylic acid,[18] in combination with chiral
isothioureas[19] (introduced as acyl transfer catalysts by
Birman et al.),[20] to promote asymmetric aldol- and
Michael/lactonization processes, respectively. To date, the
only intermolecular process using this strategy requires a-
keto-b,g-unsaturated esters as the Michael acceptor, with
chalcones being unreactive. To build upon this work, we
envisaged that the electron-withdrawing N-sulfonyl group
within N-tosyl-a,b-unsaturated ketimine derivatives would
facilitate intermolecular organocatalytic Michael/lactamiza-
tion, furnishing directly stereodefined dihydropyridones from
arylacetic acids under isothiourea-mediated catalysis. We
detail herein our studies toward this goal, as well as a range of
derivatization procedures and a new N- to C-sulfonyl photo-
isomerization process, for the efficient asymmetric synthesis
of polysubstituted dihydropyridones, dihydropyridines, piper-
isothioureas showed that benzotetramisole (4)[21] was a com-
petent catalyst for this transformation,[22] thus giving 3 with
promising diastereo- and enantioselectivity (entry 1; 92:8 d.r.,
71% ee).[23] Using an excess (2 equivalents) of phenylacetic
acid (1) gave higher yield of isolated product, whereas
lowering the reaction temperature led to higher enantiose-
lectivity, but modest conversion into product (entries 2–4).
Switching the solvent from CH2Cl2 to THF led to increased
yield and enantioselectivity, with good reaction conversion
within 2 hours at room temperature (entry 5; 88:12 d.r.,
96% ee). The reduction of catalyst loading to 5 mol% had
a detrimental effect on product yield and ee value (entries 5–
7). An investigation of different activating groups and the
order of addition of the reagents led to improved enantiose-
lectivity;[24] although the use of TsCl or (4-MeOC4H6CO)2O
led to good yield and enantioselectivity (entries 8 and 9), the
use of pivaloyl chloride led to optimal enantioselectivity and
gave 3 in 79% yield after 2 hours at room temperature
(entry 10).[25]
[*] Dr. C. Simal, Dr. T. Lebl, Prof. A. M. Z. Slawin, Dr. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, Fife (UK), KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
Subsequent studies probed the generality of this Michael
addition/lactamization process, with initial work focusing
upon variation of the arylacetic acid component, with 2 as the
standard ketimine (Scheme 2).[26] Under the optimized reac-
tion conditions this process readily accommodates substitu-
tion at the 2-, 3- and/or 4-position of the aryl unit with
Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/
[**] The authors thank the Royal Society (A.D.S.) and the EU (IEF for
C.S.) for funding, and the EPSRC Mass Spectrometry Service Centre.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109061.
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Table 1: Optimization Studies.[a]
Entry
4
T
Activating
agent
d.r.[b]
92:8
Yield[c] ee
[%][d]
(mol%) [8C]
1[e,f]
2[e,f]
3[e,f]
4[e,f]
5[f,h]
6[f,h]
7[f,h]
8[h,i]
9[h,i]
10[h,i]
20
20
20
20
20
10
5
20
20
20
RT (CH3)3CCOCl
RT (CH3)3CCOCl
61
71
90:10 66[g]
89:11 52[g]
83:17 33[g]
88:12 79[g]
88:12 51[g]
88:12 46[g]
77
76
94
96
79
77
94
91
99
0
(CH3)3CCOCl
À78 (CH3)3CCOCl
RT (CH3)3CCOCl
RT (CH3)3CCOCl
RT (CH3)3CCOCl
RT TsCl
92:8
75[g]
RT (4-MeOC6H4CO)2O 90:10 81[g]
RT (CH3)3CCOCl
88:12 79[g]
[a] Reaction Conditions: Benzotetramisole (4; 5–20 mol%), activating
agent (up to 2 equiv.), iPr2NEt (up to 4.5 equiv.), solvent, T.
[b] Determined by 1H NMR spectroscopic analysis of the crude reaction
product. [c] Yield of isolated major diastereoisomer of 3 (d.r.ꢀ95:5).
[d] Determined by HPLC analysis. [e] Solvent CH2Cl2. [f] Benzotetrami-
sole (4) added to mixture of acid 1, ketimine 2, activating agent and base.
[g] 2 equivalents of acid were used. [h] Solvent THF. [i] Ketimine 2 and
benzotetramisole (4) added to a mixture of acid 1, activating agent and
base.
electron-withdrawing and electron-donating substituents, as
well as with heteroaryl substituents. Notably, the presence of
an electron-withdrawing 4-CF3C6H4 substituent led to re-
duced product enantioselectivity (product 8, 85% ee).[27]
Reduced product diastereoselectivity was observed with 2-
tolyl, 2-chloro or N-Me-3-indole substitution (products 15,[28]
16, 21, and 22), although the anti diastereoisomer was isolated
with high ee values in each case (up to 99% ee). Also
noteworthy is that this Michael/lactamization sequence was
carried out on a preparative scale, with the reaction of
phenylacetic acid (1) and ketimine 2 on a 4.15 mmol scale
giving approximately 1.5 g of dihydropyridone 3 (88:12 d.r.;
after chromatography: 71% yield, 98:2 d.r., and 94% ee).
The treatment of phenylacetic acid with a number of N-
tosyl-a,b-unsaturated ketimines[29] was then explored
(Scheme 3). For the ketimine, aryl units containing electron-
donating or electron-withdrawing substitutents at C(1) and
C(3), as well as heteroaryl substitution at C(3), are readily
tolerated, thus giving preferentially the corresponding anti
dihydropyridones 23–27 in excellent enantioselectivity (up to
99% ee).
Scheme 2. Variation of the acid component. [a] Determined by
1H NMR spectroscopic analysis of the crude reaction product. [b] Yield
of isolated product (ꢀ95:5 d.r.). [c] Determined by HPLC analysis.
[d] Yield of isolated 7 (d.r. 93:7). [e] Yield of isolated 12 (d.r. 89:11).
[f] Yield of isolated 15 (d.r. 94:6). [g] Yield of isolated 19 (d.r. 92:8).
We postulate that the catalytic cycle for these trans-
formations proceeds through the initial formation of the
mixed anhydride from the arylacetic acid and pivaloyl
chloride, followed by formation of the corresponding acyl
ammonium ion. Deprotonation of the acyl ammonium ion
will generate the Z enolate, which then undergoes stereose-
lective Michael addition, followed by intramolecular cycliza-
tion, to generate the corresponding dihydropyridone
(Scheme 4).
A series of simple but versatile derivatizations were next
examined to showcase the utility of these products as building
blocks in synthesis. Interestingly, upon prolonged storage,
these dihydropyridones, such as 17, undergo isomerization to
the corresponding C(5)-sulfonyl products, such as 28 (isolated
as a single diastereoisomer), without significant loss of
enantiopurity (Scheme 5).[30] This sulfonyl transfer also
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Scheme 5. N- to C-sulfonyl transfer of dihydropyridones. [a] Deter-
mined by HPLC analysis. [b] Yield of isolated product (d.r. 99:1).
Alternatively, N-deprotection and reduction of 3 (d.r.
98:2, 99% ee) was readily achieved through sequential
removal of the N-tosyl group,[38] LiAlH4 reduction, and
hydrogenation to give piperidine 33 as a single diastereoiso-
mer in 99% ee[39] and 74% overall yield over three steps
(Scheme 6). Further investigation showed that reduction of 3
Scheme 3. Variation of the ketimine component. [a] Determined by
1H NMR spectroscopic analysis of the crude reaction product. [b] Yield
of isolated major diastereoisomer (d.r. 98:2) unless otherwise stated.
[c] Determined by HPLC analysis. [d] Yield of isolated 24 (d.r. 93:7).
[e] Yield of isolated 25 (d.r. 94:6). [f] Yield of isolated 27 (d.r. 88:12).
Scheme 6. Derivatization and functionalization of 3. [a] Yield of iso-
lated product. [b] Determined by HPLC analysis. [c] Determined by
1H NMR spectroscopic analysis of the crude reaction product.
(98:2 d.r., 99% ee) with LiAlH4, followed by addition of
either aqueous HCl or MeOH, gave enamide 34 (78% yield
and 99% ee) or amino lactol 35[40] containing a quaternary
stereogenic center as a single diastereoisomer (52% yield,
99% ee), respectively.[41] Enamide 34 can be converted into 35
(d.r. 99:1) simply by stirring in EtOAc at room temperature.
To conclude, benzotetramisole mediates the transforma-
tion of a range of arylacetic acids and N-tosyl-a,b-unsaturated
ketimines into dihydropyridones with high diastereo- and
enantiocontrol (up to 90:10 d.r., 99% ee) by an asymmetric
Michael/lactamization process. The dihydropyridone prod-
ucts undergo efficient N- to C-sulfonyl photoisomerization,
and are readily derivatized to a range of stereodefined
synthetic building blocks. Current research is directed toward
the development of alternative uses of isothioureas and other
Lewis bases in asymmetric catalysis.
Scheme 4. Proposed mechanism of dihydropyridone formation
occurs upon heating in EtOAc, with 3 being converted into 29
(61% yield) over 72 hours.[31] However, efficient N- to C-
sulfonyl transfer was achieved quantitatively through photo-
isomerization,[32] generating C-sulfonyl 29 (92% yield,
99% ee), which can be readily reduced with LiAlH4 to
generate dihydropyridine 30 in 60% yield and 99% ee.[33]
Whereas photochemically promoted N- to C-sulfonyl transfer
of sulfonamides,[34] sulfonylureas,[35] and sulfonyloxypyrimi-
dines,[36] which often lead to product mixtures have been
reported,[37] to the best of our knowledge this is the first
selective example of an N- to C-sulfonyl photoisomerization
reaction of dihydropyridones.
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[14] Alternative strategies, such as NHC-catalyzed aza-Claisen
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Received: December 22, 2011
Published online: March 1, 2012
Keywords: asymmetric synthesis · dihydropyridone ·
.
Lewis bases · organocatalysis · photoisomerization
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[22] See the Supporting Information for full catalyst screening
results.
[29] See the Supporting Information for the preparation of N-tosyl-
a,b-unsaturated ketimines.
[30] The relative and absolute configuration of 28 was confirmed by
X-ray crystal structure analysis. CCDC 851659 (28) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[31] The relative configuration within 29 (CCDC 851660) was con-
firmed by X-ray crystal structure analysis. The bond connectivity
and relative configuration of 29 was also confirmed through
a combination of 15N NMR spectroscopic investigations and
coupling constant analysis. See the Supporting Information for
further details.
[32] Photoisomerization of 3 (100 mg, 0.2 mm in EtOAc) was carried
out at RT through pyrex and unfiltered light from 12xPhillips
Cleo 15W UVA bulbs for 16 h was used.
[33] Treatment of 30 with Pd/C and H2 (10 bar) resulted in hydro-
genation and hydrogenolysis, giving piperidine 33 as a single
diastereoisomer in quantitative yield.
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[23] Racemic (Æ)-3 was prepared using the achiral isothiourea
DHPB (3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole), giving
(Æ)-3 (87:13 d.r.) in 66% yield upon isolation (98:2 d.r. after
purification). Racemic samples of all products for unambiguous
HPLC analysis were subsequently made using DHPB as
a catalyst.
[24] In the absence of the isothiourea catalyst a significant (presum-
ably base-promoted) background reaction is observed with
pivaloyl chloride, giving (Æ)-3 in 25% yield (87:13 d.r.).
Minimization of this competitive background reaction leads to
improved enantioselectivity and can be achieved with dropwise-
addition of the isothiourea and ketimine to a solution of the pre-
formed mixed anhydride (from phenylacetic acid and pivaloyl
chloride). This optimized process can lead to dramatically
improved enantioselectivities in some cases; for example, see:
Ref. [27].
[25] The relative and absolute configuration of 3 was assigned by
analogy to the absolute configurations of 28 and 35, which were
assigned by X-ray crystal structure analyses; all other derivatives
were assigned by analogy. See Refs. [30] and [40] for further
information.
[26] At the moment this process is limited to arylacetic acid
derivatives; for example the use of trifluoropropionic acid or
2-nitroacetic acid under standardized reaction conditions
returned only starting material. Current investigations are
underway to further the scope of this process.
[27] We postulate that this reduced ee value may be due to
a competitive racemic background reaction as mentioned in
Ref. [24]. Under optimized conditions 8 was obtained with an ee
value of 85%; without using this dropwise-addition process an ee
value of 39% was obtained (d.r. 94:6, 79% yield).
[38] The relative configuration of 31 (CCDC 851661) was confirmed
by X-ray crystal structure analysis.
[39] The ee value of 33 was confirmed by HPLC analysis of the
corresponding N-tosyl derivative 36. The relative configuration
of N-tosyl derivative 36 was also confirmed through NMR
spectroscopic investigations using a combination of NOE and
coupling constant analysis. See the Supporting Information for
further details.
[28] Transformation of 2-tolylacetic acid gave, following purification,
15 in a 50:50 d.r. (44% yield, 98% ee). The anti isomer of 15 was
assigned on the basis of coupling constant analysis (JC(3)HÀC(4)H
=
11.3 Hz; the typical JC(3)HÀC(4)H value for the anti diasteromer of
most examples in this manuscript is 10–12 Hz). The syn
diastereoisomer was isolated, although contaminated with an
unknown impurity, and showed a characteristic smaller coupling
constant (JC(3)HÀC(4)H = 6.0 Hz). See the Supporting Information
for further information.
[40] The relative and absolute configuration of 35 (CCDC 851662)
was confirmed by X-ray crystal structure analysis.
[41] Presumably 35 arises from the initial formation of 34, followed
by enamide to imine tautomerization and in situ cyclization. See
the Supporting Information for a plausible stereochemical
rationale for this transformation.
Angew. Chem. Int. Ed. 2012, 51, 3653 –3657
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3657