Highly stereoselective synthesis of substituted γ-lactams from acylsilanes

Article abstract of DOI:10.1002/anie.200705229

(Chemical Presented) It takes three : The stereoselective synthesis of highly substituted γ-lactams from amide enolates, acylsilanes, and imines is reported. This multicomponent reaction accesses γ-amino-β-hydroxy amides in a single flask with good yields and excellent levels of diastereoselectivity (see scheme). Exposure of the linear products to microwave irradiation and acidic conditions promotes a cyclization to form the corresponding γ-lactams in excellent yields.

Full text of DOI:10.1002/anie.200705229

Communications
DOI: 10.1002/anie.200705229
Multicomponent Reactions
Highly Stereoselective Synthesis of Substituted g-Lactams from
Acylsilanes**
Robert B. Lettan, II, Chase C. Woodward, and Karl A. Scheidt*
The synthesis of substituted g-lactams is an important goal
because of their use as key intermediates in the synthesis of
biologically and pharmaceutically relevant molecules. Com-
pounds containing g-lactams have direct applications in the
treatment of epilepsy,[1,2] HIV,[3,4] neurodegenerative diseases,
and depression.[5,6] Because of the prevalence of this valuable
heterocycle in pharmaceutical development, natural products,
and materials research, methods for the efficient stereoselec-
tive synthesis of highly substituted g-lactams are important
objectives for the synthetic community.[7–11] Herein we report
a highly stereoselective approach to b-hydroxy-g-lactams
from the multicomponent reaction of amides, acylsilanes, and
imines [Eq. (1)]. This modular addition/cyclization process
readily provides lactams in good yields with excellent levels of
stereoselectivity.
Scheme 1. Silyloxy homoenolates from acylsilanes. EWG=electron-
withdrawing group.
generated homoenolates for new bond forming reactions
(path B). For example, the use of aldehydes as the second
electrophile affords the b,g-dihydroxy amides in good yields.
By employing this distinctive characteristic of acylsilanes,[24–33]
an intriguing possibility is the addition of an imine with an
appropriate activating electron-withdrawing group to access
highly substituted g-amino-b-hydroxy amides. Importantly,
the cyclization to the corresponding g-lactam might be
accomplished directly if the activating group on the nitrogen
atom is easily removed.
We are currently developing new reactions that employ
unconventional nucleophiles derived from acylsilanes.[12–19]
From these endeavors, we have devised an efficient synthesis
of b-hydroxy amides by combining amide enolates and
acylsilanes to access b-silyloxy homoenolate reactivity
(Scheme 1). The acylsilane acts sequentially as an electro-
philic/nucleophilic moiety in this process by undergoing a 1,2-
silyl group migration (1,2-Brook rearrangement).[20,21] We can
shut down the reaction pathway leading to substituted
cyclopropanols (path A; first observed by Takeda et al.)[22,23]
by employing amide enolates, and instead utilize the in situ
Our initial reaction was conducted with dimethylaceta-
mide and benzoyltrimethylsilane, and diphenylphosphoryl
protected benzylimine as the electrophile (Table 1, entry 1).
Table 1: Synthesis of g-amino-b-hydroxy amides.[a]
[*] R. B. Lettan, II, C. C. Woodward, Prof. K. A. Scheidt
Department of Chemistry
Entry
R1
R2
Yield [%][b]
d.r.[c]
1
2
3
4
5
6
7
8
H
H
H
H
Ph
74
71
70
71
80
84
78
75
>20:1 (1)
>20:1 (2)
>20:1 (3)
>20:1 (4)
>20:1 (5)
>20:1 (6)
>20:1 (7)
>20:1 (8)
Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
Fax: (+1)847-467-2184
4-ClPh
4-BrPh
4-OMePh
2-furyl
Ph
E-mail: scheidt@northwestern.edu
H
[**] Support has been provided in part by the NSF (CHE-0348979), the
PRF (Type G), and Northwestern University. We thank Abbott
Laboratories, Amgen, AstraZeneca, GlaxoSmithKline, 3M, and
Boehringer-Ingelheim for generous unrestricted research support,
Wacker Chemical Corp. and FMCLithium for providing reagents,
and Troy Reynolds (NU) for assistance with X-ray crystallography.
K.A.S. is a fellow of the Alfred P. Sloan Foundation.
Me
Me
CH2Ph
4-BrPh
Ph
[a] Acylsilane and imine are added sequentially to a 0.1m enolate
solution in THF at À788C. Silyl ether products treated with nBu4NF
(TBAF) in THF prior to purification. LDA=lithium diisopropylamide.
[b] Yield of isolated product. [c] Determined by 500 MHz 1H NMR
spectroscopy.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Table 2: g-Lactam formation.[a]
We chose the diphenylphosphoryl group because of a) its
electron-withdrawing capacity, b) the steric magnitude asso-
ciated with this functionality, which might provide nonbond-
ing interactions during the addition event and influence
diastereoselection, and c) the ease of removal of this group
under acidic conditions, which could facilitate cyclization to
the g-lactam.[34–41] Gratifyingly, this three-component reaction
provided the g-amino-b-hydroxy amide in 74% yield and
greater than 20:1 diastereomeric ratio after desilylation
(Table 1, entry 1). An examination of the imine scope of the
reaction demonstrates that the reaction proceeds in good
yields in the presence of both electron-deficient (Table 1,
entries 2 and 3) and electron-rich (Table 1, entries 4 and 5)
aromatic systems. We have also used a-substituted amides
(R1 = Me or CH2Ph) and isolated the a-substituted g-amino-
b-hydroxy amides with excellent levels of diastereoselection
(Table 1, entries 6–8).[42]
Entry
R1
R2
Conditions[b]
Yield [%][c]
d.r.[d]
>20:1 (9)
>20:1 (10)
>20:1 (11)
>20:1 (12)
– (13)
>20:1 (13)
1:4 (14)
>20:1 (14)
>20:1 (15)
>20:1 (16)
1
2
3
4
5
6
7
8
9
10
H
H
H
H
H
H
Me
Me
Me
Bn
Ph
A
A
A
A
A
B
A
B
B
B
98
97
93
94
0[e]
97
92
96
98
90
4-ClPh
4-BrPh
4-OMePh
2-furyl
2-furyl
Ph
Ph
4-BrPh
Ph
[a] A solution of the amide (0.1m) in THF/3m aqueous HCl (1:1) was
heated utilizing microwave irradiation. Silyl ether products treated with
nBu4NF in THF prior to purification. [b] Condition A=1508C for 5 min.;
Condition B=708C for 10 min (1:2 THF/3m aqueous HCl). [c] Yield of
product isolated after chromatography. [d] Determined by 500 MHz
1H NMR spectroscopy. [e] Decomposition.
The current model for diastereoselection involves the
addition of the Z enolate of the amide to the acylsilane
(Scheme 2). A subsequent 1,2-Brook rearrangement could
in excellent yields with retention of stereochemistry (Table 2,
entries 1–4). The highest yields for the cyclization of 2-furyl
amide 5 can be obtained (Table 2, entries 5 and 6) by
decreasing the reaction temperature (condition B). The a-
methyl substituted g-amino-b-hydroxy amide 6 provides the
desired g-lactam in high yield with the higher temperature
conditions (condition A), but with inversion of stereochem-
istry at the a-position (Table 2, entry 7). Fortunately, the
lower temperature of condition B provides the corresponding
b-hydroxy-a-methyl-g-lactams in excellent yield with reten-
tion of stereochemistry (Table 2, entries 8–10).
With an efficient route towards the diastereoselective
formation of highly substituted b-hydroxy-g-lactams, we
turned our attention towards controlling the absolute stereo-
chemistry of the process. Towards this end, the use of (L)-
phenylalaninol derived acetamide 17[45] in the reaction
described above provides g-amino-b-hydroxy amide 18 in
good yield and excellent diastereoselectivity (Scheme 3). Our
Scheme 2. Model for diastereoselection.
potentially afford internally coordinated anionic species I.
The interaction of this anion with the imine to yield, in this
example, amide 6 could occur by an open arrangement such as
II to minimize the nonbonding interactions between the
diphenylphosphoryl group of the imine and the silyloxy and
amide groups of the homoenolate. This overall process
generates up to three contiguous stereogenic centers with a
high degree of control in a convergent, single flask operation.
The success of our multicomponent reaction with imines
provided the impetus for us to develop a general g-lactam
synthesis. Notably, the hydrolysis of the diphenylphosphoryl
amide and resulting cyclization of the amine to form the b-
hydroxy-g-lactams can be combined in a single operation.
Aqueous acid and microwave irradiation leads to the
concomitant deprotection and lactam formation in under
10 minutes (Table 2).[43,44] Surprisingly, the elimination of the
b-hydroxy substituent to provide unsaturated products was
not observed under these reaction conditions. The dimethy-
lacetamide derived g-amino-b-hydroxy amides (R1 = H)
undergo cyclization in 5 minutes at 1508C (condition A) to
afford the corresponding g-substituted b-hydroxy-g-lactams
Scheme 3. Asymmetric g-lactam formation.
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Communications
microwave (200 W), and stirred at this temperature for an additional
5 min. The resulting mixture was cooled to ambient temperature,
slowly neutralized with solid NaHCO3 (until evolution of gas ceases),
and extracted with CH2Cl2. The organic layers were combined, dried
over anhydrous Na2SO4, filtered, and concentrated by evaporation.
The residue was purified by flash chromatography (10–30% acetone/
CH2Cl2) to afford 50 mg (98%) of 9 as a white solid. Analytical data
for 9: mp = 198–2008C; IR (film): n˜ = 3303, 3188, 1701, 1668, 1443,
optimized amine deprotection and cyclization conditions
smoothly generates optically active g-lactam 19 in 92%
yield and 87% ee.[46]
In summary, we have developed a modular strategy for
the stereoselective synthesis of highly substituted b-hydroxy-
g-lactams by using b-silyloxy homoenolates that can be
accessed from amide enolates and acylsilanes. These uncon-
ventional nucleophilic species undergo addition to imines to
provide the g-amino-b-hydroxy amides in a single flask with
good yields and excellent levels of diastereoselectivity.
Exposure of the linear amide products to microwave irradi-
ation and acidic conditions promotes a cyclization to form the
corresponding g-lactams in excellent yields with retention of
stereochemistry. The use of a chiral acetamide in the initial
step affords g-lactams in high enantiomeric excess. Our
investigations will continue to explore the unique potential of
acylsilanes when combined with enolates to generate unusual
nucleophiles for use in synthesis.
1
1337, 1214, 1071, 1031, 732, 691 cmÀ1; H NMR (500 MHz, CDCl3):
d = 7.42–7.35 (m, 8H), 7.10 (d, 2H), 6.07 (s, 1H), 5.19 (s, 1H), 3.06 (d,
1H, J = 21.5 Hz), 2.83 (d, 1H, J = 21.5 Hz), 1.78 ppm (s, 1H);
13C NMR (125 MHz, CDCl3): d = 175.5, 142.5, 133.7, 129.4, 128.8,
128.0, 127.4, 125.4, 79.6, 69.4, 47.6 ppm; LRMS (ESI): Mass calculated
for C16H15NO2 [M+H]+, 254. Found [M+H]+, 254.
Procedure for the synthesis of b-hydroxy-g-lactams (condition B):
A Biotage microwave flask (0.5–2.0 mL) was equipped with a stirbar
and charged with g-amino-b-hydroxy amide 6 (0.20 mmol), THF
(1.0 mL), and 3m aqueous HCl (1.0 mL). The resulting mixture was
stirred for 2 min, heated to 708C in the microwave, and stirred at this
temperature for an additional 10 min. The resulting mixture was
cooled to ambient temperature, slowly neutralized with solid
NaHCO3 (until evolution of gas ceases) and extracted with CH2Cl2
(3 times). The organic layers were combined, dried over anhydrous
Na2SO4, filtered, and concentrated by evaporation. The residue was
purified by flash chromatography (10–30% acetone/CH2Cl2) to
afford 51 mg (96%) of 14 as white solid. Analytical data for 14:
mp = 144–1468C; IR (film): n˜ = 3263, 3060, 2926, 1699, 1491, 1446,
Experimental Section
Procedure for the synthesis of g-amino-b-hydroxy amides: THF
(2 mL) and diisopropylamine (0.54 mmol) were added to a flame-
dried, round-bottom flask equipped with a magnetic stirring bar and
purged with nitrogen. The solution was cooled to À788C and n-
butyllithium (1.6m in hexanes, 0.54 mmol) was added by syringe. The
reaction mixture was warmed to 08C and stirred for 30 min.
Dimethylacetamide (0.54 mmol) was added to the LDA solution
and the reaction mixture was stirred for 1 h. The reaction mixture was
cooled to À788C, and a À788C solution of benzoyltrimethylsilane
(0.59 mmol) in THF (0.5 mL) was added by cannula. The acylsilane
delivery flask was rinsed with an additional portion of THF (0.5 mL),
cooled to À788C, and transferred to the reaction flask. The resulting
homogeneous solution was stirred for 20 min and then a solution of
(E)-N-benzylidene-P,P-diphenylphosphinic amide (0.65 mmol) in
THF (2.0 mL) was added by cannula, again with rinsing of the
delivery flask with an additional portion of THF (0.4 mL). The
resulting reaction mixture was stirred at À788C for 15 h. The reaction
was quenched by the addition of saturated aqueous ammonium
chloride (2 mL), warmed to ambient temperature, stirred for 30 min,
and extracted with ethyl acetate (3 times). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concentrated
by evaporation. The unpurified silyl ether product was dissolved in
THF (2 mL). Tetrabutylammonium fluoride (1.0m in THF, 1.1 mmol)
was added to this solution and the mixture was stirred at room
temperature for 30 min. The reaction was quenched by the addition of
water, extracted with CH2Cl2, dried over anhydrous MgSO4, filtered,
and concentrated by evaporation. The residue was purified by flash
chromatography (20–40% acetone/CH2Cl2) to afford 192 mg (74%)
of 1 as a white solid. Analytical data for 1: mp = 1708C dec; IR (film):
1337, 1119, 1019, 697 cmÀ1 1H NMR (500 MHz, CDCl3): d = 7.59–
;
7.57 (d, 2H), 7.42–7.31 (m, 8H), 6.46 (s, 1H), 5.37 (s, 1H), 2.70 (q, 1H,
J = 7.5 Hz), 1.85 (s, 1H), 0.91 ppm (d, 3H, J = 7.5 Hz); 13C NMR
(125 MHz, CDCl3): d = 178.8, 141.1, 135.2, 129.3, 129.2, 128.7, 128.2,
128.0, 126.3, 100.0, 82.2, 64.6, 49.6, 12.9 ppm; LRMS (ESI): Mass
calculated for C17H17NO2 [M+H]+, 268. Found [M+H]+, 268.
Received: November 14, 2007
Published online: February 12, 2008
Keywords: g-lactams · acylsilanes · chiral auxiliaries ·
.
homoenolates · synthetic methods
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;
1H NMR (500 MHz, CDCl3): d = 7.85 (dd, 2H), 7.55–7.43 (m, 4H),
7.33 (t, 1H), 7.17–7.12 (m, 4H), 7.07–6.95 (m, 6H), 6.89 (s, 1H), 6.79
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J = 16.5 Hz), 3.36 (d, 1H, J = 16.5 Hz), 3.07 (s, 3H), 2.76 ppm (s, 3H);
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a
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