Multicomponent reaction design: a one-pot route to substituted di-O-acylglyceric acid amides from α-diazoketones

Article abstract of DOI:10.1016/j.tetlet.2008.07.167

A four-component assembly of substituted di-O-acylglyceric acid amides has been developed from α-diazoketones. The process involves copper-catalyzed reaction of the α-diazoketone with a carboxylic acid, and subsequent Passerini condensation of the in situ formed α-acyloxyketone.

Full text of DOI:10.1016/j.tetlet.2008.07.167

Tetrahedron Letters 49 (2008) 5983–5985
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Tetrahedron Letters
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Multicomponent reaction design: a one-pot route to substituted
di-O-acylglyceric acid amides from a-diazoketones
*
Lijun Fan, Ashley M. Adams, Bruce Ganem
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A four-component assembly of substituted di-O-acylglyceric acid amides has been developed from a-di-
Received 17 June 2008
Accepted 29 July 2008
Available online 3 August 2008
azoketones. The process involves copper-catalyzed reaction of the
a
-diazoketone with a carboxylic acid,
-acyloxyketone.
Ó 2008 Elsevier Ltd. All rights reserved.
and subsequent Passerini condensation of the in situ formed
a
O
Multicomponent reactions (MCRs) have attracted the attention
and interest of synthetic chemists as efficient processes for the
assembly of densely functionalized structures. MCRs are of special
interest in making compounds that exhibit pharmacological activ-
ity.1 As part of our laboratory’s effort to expand the repertoire of
useful MCRs, we have investigated the utility of functionalized car-
bonyl compounds such as acyl cyanides2 and acyltetrazoles3 in iso-
nitrile-based multicomponent condensations, whose scope has
traditionally been limited to simple aldehydes and ketones.4 Here,
we report a versatile, 4-component condensation of readily avail-
Ph
Cu(acac)2
HOAc
O
Ph
CHN2
t-BuNC
NH
t-Bu
HOAc
1a
AcO
AcO
5a
O
Ph
CH2OAc
6a
Scheme 2.
able a-diazoketones with (two) carboxylic acids and isonitriles to
afford a new family of structurally diverse, substituted di-O-acyl-
glyceramides 5 (Scheme 1).
By suitable manipulation of the glyceramide framework in 5,
the method can be used to create new families of synthetic amphi-
philic compounds having potential applications as surfactant-
active compounds and as carriers for drug encapsulation and
delivery.
We therefore investigated two-stage, one-pot MCRs of the
representative diazoketone 1a (Scheme 2) triggered by an initial
metal-catalyzed insertion into a typical carboxylic acid (e.g.,
HOAc),6,7 followed by an in situ Passerini condensation as shown.
With Rh2(OAc)4 as catalyst, complex product mixtures were
formed from which only minor quantities of the initial insertion
product 1-acetoxy-4-phenyl-2-butanone 6a could be isolated.
However, using Cu(acac)2 (10 mol %),7 the desired di-O-acyl-
glyceramide 5a was obtained in 68% yield, along with 6a (26%).
Optimization of this 4-component reaction led to several inter-
esting findings. To begin with, Shinada et al. used relatively large
quantities of Cu(acac)2 (10 mol %) for the initial diazoketone inser-
tion reaction, raising the concern that copper complexation of the
isonitrile component might cause a sequestering effect that would
interfere with the subsequent Passerini condensation leading to 5.
To investigate this question, a pure sample of 1-acetoxy-4-phenyl-
2-butanone 6a was subjected to the Passerini reaction leading to
5a with and without Cu(acac)2 (5 mol %), and the progress of the
condensation was monitored by following disappearance of the
ketoacetate, as shown in Figure 1.
Simple
tions of the Passerini or Ugi condensations, even when heated to
60–70 °C. However, -diazoketones and sulfonic acids spontane-
a-diazoketones proved refractory to the standard condi-
a
ously formed b-ketosulfonates, a family of reactive carbonyls that
were recently utilized in a new Ugi-based approach to substituted
2-oxazolines.5
O
O
R2-CO2H
R1
+
R1
R4CO2
R3
Cu(acac)2
N
1
2
N2
H
R4-CO2H
R3-NC
+
R2CO2
5
As the data in Figure 1 illustrate, Cu(acac)2 exerted a mild rate-
retarding effect on the formation of 5a. A similar effect was also
noted in Passerini reactions of the parent ketone, 4-phenyl-2-buta-
none, which suggested that complexation by Cu(acac)2 depleted
the reaction medium of the key of the isonitrile reactant. Besides
explaining the modest yield of 5a, isonitrile sequestration by
3
4
Scheme 1.
* Corresponding author. Tel.: +1 607 255 7360; fax: +1 607 255 6318.
E-mail address: bg18@cornell.edu (B. Ganem).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.167

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L. Fan et al. / Tetrahedron Letters 49 (2008) 5983–5985
by Andreana et al., reporting that certain a-substituted aldehydes
capable of bidentate binding underwent enantioselective Passerini
reactions using an indan (pybox) Cu(II) Lewis acid complex.8 Using
the synthesis of 5 h as a test case, diazoketone 1d was reacted with
isobutyric acid in the absence of Cu(acac)2 to form the correspond-
ing acyloxypropanone. The subsequent Passerini reaction was con-
ducted in the presence of indan (pybox) Cu(II) catalyst (20 mol %)
following the protocol of Andreana et al. and produced 5 h with
no measurable enantiomeric excess.
The new MCR represents a more selective and efficient alterna-
tive to the stepwise introduction of carboxylic ester groups into the
vic-diol backbone of glyceramides, since it avoids the potential for
ester interchange by competing O,O-acyl transfer side reactions. As
one illustration of its utility, we describe the synthesis of a ‘facially
amphiphilic’9 diester 5i containing one lipophilic and one hydro-
philic side chain, each derived from a carboxylic acid.
100
80
60
40
20
0
w/Cu ketoester
w/o Cu ketoester
Representative experimental procedure—synthesis of diester 5b—A
mixture of acetic acid (57 lL, 1.0 mmol) and Cu(acac)2 (2.6 mg,
0
5
10
15
20
0.01 mmol, 1 mol %) in toluene (2 mL) in a 10 mL round bottomed
flask was heated to 60 °C for 10 min under nitrogen. To it was
added dropwise a solution of diazoketone 1a (226 mg, 1.3 mmol,
1.3 equiv) in toluene (2 mL). Once gas evolution was judged com-
plete, the reaction mixture was stirred for an additional 5 min,
then cooled and concentrated in vacuo. The oily residue was blan-
keted in nitrogen, then treated with iso-butyric acid (140 L,
1.5 mmol, 1.5 equiv) and t-BuNC (170 L, 1.5 mmol, 1.5 equiv). The
resulting reaction mixture was stirred at rt under N2 for 20 h.
The product was purified by flash column chromatography (1:1
EtOAc/hexanes, Rf = 0.3) to afford 5b (338 mg, 90%) as a pale yellow
oil.10
Time (h)
Figure 1.
copper also accounted for the recovery of significant quantities of
unreacted ketoacetate 6a.
One successful solution to the problem involved using excess
isonitrile. However, to optimize the synthetic efficiency of the
process we investigated whether lower catalyst loads might also
improve the yields of 5. Dropwise addition of diazoketone 1a
(1.3 equiv) into a toluene solution (60 °C, 30 min) of acetic acid
and 1.0 mol % of Cu(acac)2 followed by in situ Passerini condensa-
tion afforded 5a in 94% yield. Upon further experimentation, we
observed that the diazoketone insertion reaction could be achieved
equally well in most cases without any metal catalyst, although the
somewhat higher temperatures required (100–110 °C) led us to
favor the use of 1 mol % Cu(acac)2 in most circumstances.
Table 1 summarizes the scope and versatility of the new four-
component synthesis of di-O-acylglyceric acid diamides depicted
in Scheme 1, which has been successfully implemented as a one-
pot process.
The initial insertion reactions were monitored by N2 evolution
and usually required heating for 30–60 min at 60–90 °C. In reac-
tions using diazoketones 1a–c, 1.3 equiv of diazoketone was used,
whereas insertions using diazoacetone 1d were optimally achieved
using 1.8 equiv of diazoketone. The scope of the new four-compo-
nent condensation appears to be limited to aliphatic diazoketones.
In the case of benzoyldiazomethane, the initial insertion was suc-
Acknowledgments
Financial support from Johnson & Johnson’s Focused Giving
Grant Program is gratefully acknowledged. One of us (LF) wishes
to thank the Sien Moo Tsang endowment for a graduate fellowship.
Support of the Cornell NMR Facility has been provided by NSF and
NIH.
References and notes
1. Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
2. Oaksmith, J. A.; Peters, U.; Ganem, B. J. Am. Chem. Soc. 2004, 125, 13606.
3. Clémençon, I. F.; Ganem, B. Tetrahedron 2007, 63, 8665.
4. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (b) Nair, V.; Rajesh,
C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem.
Res. 2003, 36, 899–907.
5. Fan, L.; Lobkovsky, E.; Ganem, B. Org. Lett. 2007, 9, 2015.
6. Noels, A. F.; Demonceau, A.; Petiniot, N.; Hubert, A. J.; Tessyié, Ph. Tetrahedron
1982, 38, 2733.
7. Shinada, T.; Kawakami, T.; Sakai, H.; Takada, I.; Ohfune, Y. Tetrahedron Lett.
1998, 39, 3757.
8. Andreana, P. R.; Liu, C. C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231.
9. Willham, K. A.; Laurent, B. A.; Grayson, S. M. Tetrahedron Lett. 2008, 49, 2091.
10. Spectroscopic data for representative new compounds: for 5b: 1H NMR (300 MHz,
CDCl3)TM 7.12–7.28 (m, 5H), 6.39 (s, 1H), 4.90 (d, 1H, J = 11.5 Hz), 4.42 (d, 1H,
J = 11.5 Hz), 2.46–2.61 (m, 4H), 2.28 (m, 1H), 2.02 (s, 3H), 1.41 (s, 9 H), 1.20 (dd,
6H, J = 7.0, 2.5 Hz); 13C NMR (125 MHz, CDCl3)TM 174.53, 170.15, 168.63, 140.86,
128.71, 128.67, 126.40, 85.74, 64.98, 51.64, 35.05, 33.35, 29.72, 28.93, 20.86,
19.35, 19.21; IR (neat) 3438(s), 2970(s), 1745(s), 1691(s); CIMS (methane) m/z:
378.3 (M+H), 308.2, 209.2.
cessful, but the a-acyloxyketone failed to undergo the subsequent
Passerini reaction.
The product glyceramides 5 were formed as racemic mixtures.
With respect to controlling the new stereogenic center formed in
the second step of the MCR, we were intrigued by a recent paper
Table 1
Cu(acac)2-catalyzed 4-Component Condensations of R1COCHN2, R2CO2H, R3NC, and
R4CO2H leading to 5
For 5c: 1H NMR (CDCl3)TM 7.97 (d, 2H), 7.12–7.58 (m, 8H), 5.24 (d, 1H,
J = 11.7 Hz), 4.64 (d, 1H, J = 11.7 Hz), 4.24 (q, 2H, J = 7.2 Hz), 4.10 (t, 2H,
J = 6.3 Hz), 2.61 (m, 2 H), 2.22–2.46 (m, 4H), 1.61 (m, 2H), 1.10–1.40 (m, 13H),
0.88 (t, 3H, J = 5.0 Hz); 13C NMR (CDCl3)TM 171.62, 170.22, 169.72, 165.72,
140.65, 133.36, 129.89, 129.81, 128.72, 128.62, 128.58, 126.33, 85.96, 65.27,
61.92, 41.62, 35.14, 34.09, 33.49, 31.83, 31.76, 29.72, 29.22, 29.11, 25.13, 24.90,
22.79, 22.78, 14.35, 14.27, 14.24; IR (neat) 3389(b), 2935(s), 2852(s), 1745(s),
1727(s), 1684(s); CIMS (methane) m/z: 526.3 (M+H), 400.2, 382.2.
For 5d: 1H NMR (CDCl3)TM 7.36 (s, 5 H), 6.31 (s, 1H), 5.26 (t, 1H, J = 5.0 Hz), 5.13
(s, 1H), 4.90 (d, 1H, J = 11.8 Hz), 4.37 (d, 1H, J = 11.8 Hz), 3.96 (t, 2H, J = 6.6 Hz),
2.52 (m, 1H), 2.19 (m, 1H), 1.95 (m, 1H), 1.58 (s, 2H), 1.37 (s, 9H), 1.24 (b, 10H),
1.13 (dd, 6H J = 7.0, 2.3 Hz), 0.86 (t, 3H, 6.3 Hz); 13C NMR (CDCl3)TM 176.60,
1 R1
=
2 R2
=
3 R3
=
4 R4
=
Product (yield) (%)
Ph(CH2)21a
1a
1a
C7H151b
CH3
CH3
Ph
(CH3)2CH
Ph
C7H15
NCCH2
(CH3)2CH
H(CH2O-CH2)3
t-Bu
t-Bu
EtO2CCH2
t-Bu
cyclo-C6H11
n-Bu
EtO2CCH2
n-Bu
CH3
(CH3)2CH
C7H15
CbzNHCH2
CH3
CH3
5a (94)
5b (90)
5c (72)
5d (70)
5e (80)
5f (70)
5g (76)
5h (71)
5i (58)
1b
cyclo-C6H111c
1c
CH31d
1d
Ph
CbzNHCH2
C7H15
t-Bu

L. Fan et al. / Tetrahedron Letters 49 (2008) 5983–5985
5985
168.22, 167.72, 156.54, 136.17, 128.80, 128.55, 128.31, 87.53, 67.48, 64.48,
51.73, 43.70, 34.11, 32.11, 31.87, 29.44, 29.19, 28.82, 22.99, 22.78, 19.20, 19.11,
14.29; IR (neat) 3422(m), 3339(b). 2961(s), 2927(s), 2857(s), 1735(s), 1672(s);
CIMS (methane) m/z: 521 (M+H), 413, 312.
J = 7.2 Hz), 4.12 (dd, 2H, J = 3.5, 1.5 Hz), 3.40 (s, 2H), 2.46 (m, 1H), 1.75–1.88 (m,
4H), 1.10–1.40 (m, 9H); 13C NMR (CDCl3)TM 169.97, 169.34, 165.11, 162.50,
134.18, 130.25, 130.09, 129.27, 113.12, 88.23, 66.17, 62.20, 42.39, 41.82,
27.95, 27.59, 26.74, 26.61, 26.37, 25.02, 14.59; IR (neat) 3426(s), 2930(s),
2854(s), 1757(s), 1726(s), 1683(s); CIMS (methane) m/z: 445 (M+H), 360,
323.
For 5g: 1H NMR (CDCl3)TM 8.05 (d, 2H, J = 5.0 Hz), 7.44–7.66 (m, 3H), 6.99 (t, 1H,
J = 5.0 Hz), 5.26 (d, 1H, J = 11.5 Hz), 5.00 (d, 1H, J = 11.5 Hz), 4.24 (q, 2H,