Asymmetric construction of quaternary stereocenters: Synthesis of enantiopure amino acid-based tricyclic α,β-enones through an ipso-Friedel-Crafts/Michael addition cascade

Article abstract of DOI:10.1002/adsc.201100497

An efficient reaction of the (2R,1′S)- or (2S,1′S)-N,N-bis(p- methoxybenzyl)-2-(1-aminoalkyl)epoxides, derived from α-amino acids, with boron trifluoride-phosphoric acid complex is described. This process affords highly elaborated enantiopure tricyclic α,β-enones in high yields, through an ipso-Friedel-Crafts/Michael addition cascade. Copyright

Full text of DOI:10.1002/adsc.201100497

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DOI: 10.1002/adsc.201100497
Asymmetric Construction of Quaternary Stereocenters: Synthesis
of Enantiopure Amino Acid-Based Tricyclic a,b-Enones through
an ipso-Friedel–Crafts/Michael Addition Cascade
Humberto Rodrꢀguez-Solla,a,* Carmen Concellꢁn,a Paula Tuya,a
Santiago Garcꢀa-Granda,b and M. Rosario Dꢀazb
a
Departamento de Quꢀmica Orgꢂnica e Inorgꢂnica, Facultad de Quꢀmica, Universidad de Oviedo, Juliꢂn Claverꢀa 8, 33071
Oviedo, Spain
E-mail: hrsolla@uniovi.es
b
Departamento de Quꢀmica Fꢀsica y Analꢀtica, Facultad de Quꢀmica, Universidad de Oviedo, Juliꢂn Claverꢀa 8, 33071
Oviedo, Spain
Received: June 28, 2011; Revised: October 19, 2011; Published online: February 9, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100497.
Abstract: An efficient reaction of the (2R,1’S)-
or (2S,1’S)-N,N-bis(p-methoxybenzyl)-2-(1-amino-
ACHTUNGTRENNUNGalkyl)epoxides, derived from a-amino acids, with
boron trifluoride-phosphoric acid complex is de-
scribed. This process affords highly elaborated
enantiopure tricyclic a,b-enones in high yields,
through an ipso-Friedel–Crafts/Michael addition
cascade.
lyzed intramolecular ipso-Friedel–Crafts allylic alkyla-
tions of phenols.[9] It is noteworthy that all these re-
ported methodologies are very limited in terms of
enantioselectivity since no asymmetric versions have
been developed.
We have previously reported an efficient synthesis
of enantiopure (2R,1’S)- or (2S,1’S)-2-(1-aminoalkyl)-
AHCTUNGTRENNUNG
epoxides,[10] which can be transformed into a variety
of enantiopure compounds employing a combination
of different boron trifluoride complexes and nucleo-
philes.[11–17] Interested as we are in the development
of new methods for the construction of asymmetric
quaternary stereocenters, we contemplated the possi-
bility of using our previously reported enantiopure
amino epoxides for building up complex architectures
bearing these challenging synthetic motifs.
Keywords: amino acids; boron; enones; Friedel–
Crafts reaction; Michael addition; quaternary cen-
ters
The synthetic design of complex compounds bearing
Due to our previous experience with Friedel–Crafts
quaternary stereocenters is a challenging task for syn- reactions on N,N-dibenzyl-2-(1-aminoalkyl)epox-
thetic organic chemists.[1] The construction of quater- ides,[17] we considered the aim of carrying out the re-
nary stereocenters employing the methods used for action utilizing p-methoxybenzyl (electron-rich aro-
preparing tertiary ones is not straightforward.[1f] For matic ring) rather than benzyl as the amino protecting
this reason, asymmetric procedures aiming to obtain group with the object of exploring new synthetic pos-
fully substituted carbon centers are of great value.
sibilities of this process. Thus, we report herein the re-
In this communication we report the synthesis of sults of a novel and efficient transformation of
new amino acid-derived enantiopure tricyclic a,b- (2R,1’S)- or (2S,1’S)-N,N-bis(p-methoxybenzyl)-2-(1-
enones bearing an asymmetric quaternary center. aminoalkyl)epoxides into highly elaborated enantio-
Similar structures have found applications such as pure tricyclic a,b-enones through a ipso-Friedel–
novel alkaloid natural products[2] and were also evalu- Crafts/Michael addition cascade, promoted by boron
ated for their anti-HBV (hepatitis B virus) activity.[3] trifluoride-phosphoric acid complex (BF3·H3PO4).
Several methodologies have been previously de-
anti/syn-Amino epoxides 1 and 3 were prepared by
scribed for the synthesis of some related structures: using a similar method to that previously reported for
(i) radical cyclizations;[4] (ii) arene-Ru complex-medi- the synthesis of N,N-dibenzyl-2-(1-aminoalkyl)epox-
ated dearomatization;[5] (iii) Cu-catalyzed oxygenation ides (see Experimental Section).[10] As it can be envis-
of a-azido-N-arylamides;[6] (iv) hypervalent iodine re- aged in Scheme 1, N,N-bis(p-methoxybenzyl)-2-(1-
agents;[7] (v) ipso-halocyclizations[8] and (vi) Pd-cata- aminoalkyl)epoxides can be easily obtained from the
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Scheme 1. Synthesis of N,N-bis(p-methoxybenzyl)-2-(1-aminoalkyl)epoxides 1 and 3.
corresponding amino esters III. Thus, for the synthesis ces were observed when the reaction was carried out
of anti-amino epoxides 1 a reduction, Swern oxidation on other amino epoxides 1d and 1e derived from nat-
and iodomethylation protocol is followed. In the case ural (O-protected l-serine R=TBSOCH2) or unnatu-
of syn-amino epoxides 3, synthesis of the correspond- ral (R=cC6H11CH2) a-amino acids. It is noteworthy
ing chloromethyl ketones VI, their reduction to chlo- that, in the case of reaction of 1d, the O-deprotection
ACHTUNGTRENNUNGrohydrins VII and their further treatment with meth- took place under the reaction conditions and the O-
yllithium afforded the requisite substrates.
desylilated tricyclic a,b-enone 2d was isolated in 77%
ACHTUNGTRENNUNG(2S,1’S)-2-(1-Aminoalkyl)epoxide 1a, derived from yield.
alanine, was used as a starting material for screening
To establish the scope of our reaction protocol syn-
different reaction conditions. Preliminary studies amino epoxides 3 were also reacted under our final
showed that the reaction of 1a (1 equiv.) with reaction conditions. In these cases, as expected, a dif-
BF3·H3PO4 complex (3 equiv.), in dry dichlorome- ferent diasteroisomeric tricyclic core 4, was isolated in
thane, for 6 h afforded, after hydrolysis, the corre- high yields and good stereoselectivities (Table 2).
sponding tricyclic a,b-enone 2a in high yield after pu-
rification by flash chromatography (Table 1). To our
Table 2. Synthesis of enantiopure tricyclic a,b-enones 2.
delight, when this process was extended to other anti-
amino epoxides 1b (derived from Leu), and 1c (readi-
ly obtained from Phe), the corresponding tricyclic
a,b-enones 2b and 2c were isolated, respectively, in
high yields (>80%, Table 1). No significant differen-
Entry
3
4
R
dr[a]
Yield [%][b]
Table 1. Synthesis of enantiopure tricyclic a,b-enones 2.
1
2
3
4
3a 4a Me
3b 4b i-Bu
3c 4c TBSOCH2
3d 4d c-C6H11CH2 93/7 (94/6)
90/10 (92/8) 83
95/5 (95/5)
91/9 (94/6)
87
75
84
[c]
[a]
As determined by 1H NMR analysis of crude reaction
mixtures; dr of amino epoxides 3 is given in brackets.
Isolated yields of analytically pure compounds 4.
Compound 4c was obtained as its O-desylilated deriva-
tive.
Entry
1
2
R
dr[a]
Yield [%][b]
[b]
[c]
1
2
3
4
5
1a 2a Me
1b 2b i-Bu
1c 2c PhCH2
1d 2d TBSOCH2
1e 2e c-C6H11CH2
96/4 (96/4) 87
91/9 (92/8) 84
96/4 (98/2) 80
91/9 (93/7) 77
91/9 (92/8) 86
[c]
When the reaction was performed on the syn-
amino epoxide 3c (derived from Phe), the corre-
sponding enantiopure tetrahydronaphthalene 5 was
obtained instead of the expected tricyclic enone
(Scheme 2). This result is not surprising taking into
account that a similar behaviour for phenylalanine-
[a]
As determined by 1H NMR analysis of crude reaction
mixtures; dr of amino epoxides 1 is given in brackets.
Isolated yields of analytically pure compounds 2.
Compound 2d was obtained as its O-desilylated deriva-
tive.
[b]
[c]
296
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Asymmetric Construction of Quaternary Stereocenters
Scheme 2. Synthesis of tetrahydronaphthalene 5 from 3c.
derived syn-amino epoxides has been previously ob-
served by our group.[17]
Figure 1. NOESY effect observed on compounds 2b and 4b.
Looking for possible future applications of our
methodology, the N-p-methoxybenzyl protecting
group of tricyclic a,b-enones 2c and 4b could be
easily removed upon treatment with an aqueous solu-
tion of cerium(IV) ammonium nitrate (CAN), accord-
ing to a method previously reported in the litera-
ture.[18] As a consequence, compounds 6 and 7 were
isolated in 85 and 83% yield respectively (Scheme 3).
Figure 2. ORTEP diagram for 2a.
Scheme 3. Deprotection of tricyclic a,b-enones 2c and 4b.
cyclic a,b-enones different to 2a, 2b, or 4b were as-
signed by analogy.
The total regio- and stereoselectivity of the reaction
From a mechanistic point of view, the synthesis of
was established by H and 13C NMR spectroscopic ex- tricyclic a,b-enones 2 and 4 can be explained from a
periments on the crude reaction mixtures. The analy- cascade-type process. First of all, we assume that
sis of the spectra showed that all tricyclic a,b-enones phosphoric acid and boron trifluoride are reversibly
were isolated as a mixture of diastereoisomers that released from the complex BF3·H3PO4. Then, coordi-
feature the same relationship to that displayed from nation of the epoxide with boron trifluoride, or with
the amino epoxides 1 and 3, used as starting materials the acidic proton of phosphoric acid, generates inter-
respectively (Table 1 and Table 2). Therefore, the mediate 8, where an ipso-Friedel–Crafts-type addition
1
ring-opening process seems to be stereospecific.
reaction takes place.[20] The opening of the oxirane
The structures of tricyclic a,b-enones 2 and 4 were ring by the ipso-carbon of the N-p-methoxybenzylic
1
assigned based on H, 13C, HMBC and HSQC NMR group occurs on the more substituted carbon atom of
experiments. The absolute configuration was estab- the cycle to afford the Michael acceptor 9. Finally a
lished from NOESY experiments showing a cis dispo- 1,4-addition of alcoholate 9 gives enol ether 10 which,
sition of the Hb,c and Ha protons on compound 2b, after hydrolysis from the acidic medium, yields tricy-
and a cis disposition for protons Ha’,bꢀ and Hcꢀ in the clic a,b-enones 2 and 4a, b (Scheme 4).
case of compound 4b (Figure 1). Given that the ste-
However, when the reaction is carried out on the
reochemistry of the CHN carbon center is fixed in the syn-amino epoxide 3c, a different intramolecular Frie-
starting material, the results of nOe experiments were del–Crafts-type reaction takes place. In this case, the
also used as a proof for elucidating the absolute ste- eletrophilic substitution occurs on the phenyl group
reochemistry of compounds 2 and 4.
of the amino epoxide backbone, rather than on the
Furthermore, the assigned absolute configuration of N-p-methoxyphenyl group. Also, the oxirane ring-
compound 2a was unambiguously confirmed by opening process takes place on the less substituted
single-crystal X-ray diffraction (Figure 2).[19] The carbon center instead of on the most substituted one
structure and the absolute configuration of other tri- (Scheme 5).[17]
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Humberto Rodrꢀguez-Solla et al.
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Scheme 4. Proposed mechanism for the synthesis of compounds 2 and 4a, b from 1, and 3a, b, respectively.
chloride (21 mmol) were added. The resulting solution was
refluxed for 12 h, then allowed to reach room temperature,
and diluted with water. The aqueous layer was extracted
with AcOEt (3ꢄ20 mL), and the combined organic layers
washed with water and brine, dried over Na2SO4 and con-
centrated under reduced pressure. Purification by flash chro-
matography (hexane/EtOAc 5/1) afforded the N,N-protect-
ed amino esters III.
Synthesis of Amino Epoxides 1
To a 0 8C stirred solution of the corresponding N,N-protect-
ed ester III (3 mmol) in dry THF, LiAlH4 (0.9 mL of 1.0M
solution in THF, 0.9 mmol) was added under N2. The result-
ing reaction mixture was stirred for 6 h, then quenched with
ice-water and filtered through Celite. The filtrate was ex-
tracted with Et2O (3ꢄ10 mL), dried (Na2SO4), and solvents
were eliminated under reduced pressure, obtaining the
amino alcohols IV.
Scheme 5. Proposed mechanism for the synthesis of com-
pound 5 from 3c.
In conclusion, a novel BF3·H3PO4 complex-promot-
ed cascade is reported. Thus, the reaction of
BF3·H3PO4 with a selection of enantiopure N,N-(p-
methoxybenzyl)amino epoxides derived from differ-
To a solution of oxalyl chloride (3.52 mmol) in dry di-
ent a-amino acids afforded in a stereoselective chloromethane (2.8 mL), DMSO (7.04 mmol) in CH2Cl2
(2.8 mL) was added at À638C and under N2. After stirring
manner enantiopure tricyclic a,b-enones bearing an
for 20 min, a solution of the corresponding alcohol IV
(3.2 mmol) in CH2Cl2 (23 mL) was added dropwise at the
same temperature, and stirred for 30 min. Then, a solution
of triethylamine (16 mmol) in CH2Cl2 (5 mL) was added
asymmetric quaternary center, in high yields under
very mild conditions. This protocol constitutes the
first example of a sequential ipso-Friedel–Crafts-type
process followed by a Michael addition promoted by
and, after 30 min, the resulting mixture was quenched with
the phosphoric acid and boron trifluoride complex.
water (100 mL) and allowed to warm to room temperature.
Studies directed toward the development of other
The aqueous layer was extracted with CH2Cl2 (3ꢄ20 mL)
synthetic applications of BF3·H3PO4 in asymmetric
synthesis are currently under investigation in our lab-
oratory.
and the organic layers were washed with brine, then dried
over Na2SO4, and concentrated under vacuum, affording the
amino aldehydes V.
To a À788C stirred solution of the corresponding a-amino
aldehyde V (2.5 mmol) and diiodomethane (5 mmol) in dry
THF (10 mL) was added methyllithium (3.3 mL of 1.5M so-
lution in diethyl ether, 5 mmol) dropwise. After stirring at
À788C for 30 min, the mixture was allowed to warm to
room temperature. Stirring was continued for 2 h at room
temperature and then the reaction was quenched with satu-
rated aqueous NH4Cl (4 mL) and extracted with ether (3ꢄ
10 mL). The combined organic layers were dried (Na2SO4)
and the solvents were removed under vacuum. Column flash
chromatography over silica gel (15: 1 hexane-ethyl acetate)
provided pure anti-amino epoxides 1.
Experimental Section
Synthesis of Amino Esters III
Ethyl a-amino esters were obtained from natural l-amino
acids by esterification with ethanol in the presence of
TMSCl.[21]
To a suspension of the corresponding ethyl a-amino ester
(10 mmol, 1 equiv.) in THF (30 mL) and DMSO (7 mL),
NaHCO3 (35 mmol) NaI (5 mmol) and p-methoxybenzyl
298
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Asymmetric Construction of Quaternary Stereocenters
References
Synthesis of Amino Epoxides 3
To a À908C stirred solution of the corresponding protected
a-amino ester III (10 mmol), chloroiodomethane (25 mmol)
in dry THF (40 mL) was added methyllithium (25 mmol,
1.5M solution in diethyl ether) dropwise over 5 min. After
stirring at À908C for 60 min, the mixture was treated with a
saturated aqueous solution of NH4Cl (5 mL) and extracted
with diethyl ether (3ꢄ20 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated under
vacuum. The crude ketones VI were reduced without fur-
ther purification. So, to a À1008C stirred solution of the cor-
responding ketone (3 mmol) in dry THF (15 mL) was added
LiAlH4 (0.9 mL of 1M solution in THF, 0.9 mmol). After
stirring for 6 h at À1008C the reaction was carefully
quenched with water, and the mixture was filtered through
Celiteꢅ and extracted with dichloromethane (3ꢄ20 mL).
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organic layers were dried over Na2SO4, filtered, and concen-
trated under vacuum. Column flash chromatography over
silica gel (10/1 hexane-ethyl acetate) provided pure syn-
amino epoxides 3.
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Tetahydronaphthalene 5
To a solution of the amino epoxide 1 or 3 (0.2 mmol) in
2 mL of CH2Cl2, 0.6 mmol of BF3·H3PO4 complex was added
at room temperature. The reaction mixture was stirred at
the same temperature for 6 h. Then, a saturated solution of
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extracted with CH2Cl2 (3ꢄ5 mL). The organic layers were
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Supporting Information
Characterization data, including H/13C NMR spectra of all
1
new compounds 2, 4–7 are available in the Supporting Infor-
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Acknowledgements
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We are grateful for financial support from Spanish Ministerio
de Ciencia e Innovacion (CTQ2010-14959, MAT2006-01997,
MAT2010-15094 and Factorꢁa de Cristalizaciꢂn Consolider
Ingenio 2010), and FEDER. C.C.F. and P.T. thanks MICINN
for a Juan de la Cierva contract and a predoctoral FPU fel-
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COMMUNICATIONS
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