Direct carbinolamide synthesis

Article abstract of DOI:10.1016/j.tetlet.2007.08.077

Carbinolamides were prepared by treatment of aldehydes with carboxamides in the presence of dicyclohexylboron chloride and triethylamine. All carbinolamide products were stable to isolation, purification and routine handling.

Full text of DOI:10.1016/j.tetlet.2007.08.077

Tetrahedron Letters 48 (2007) 7456–7459
Direct carbinolamide synthesis
Sezgin Kiren, Ning Shangguan and Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey,
Piscataway, NJ 08854, United States
Received 28 July 2007; revised 3 August 2007; accepted 20 August 2007
Available online 24 August 2007
Abstract—Carbinolamides were prepared by treatment of aldehydes with carboxamides in the presence of dicyclohexylboron
chloride and triethylamine. All carbinolamide products were stable to isolation, purification and routine handling.
Ó 2007 Elsevier Ltd. All rights reserved.
A part of our program to advance new preparative
methods for complex amide synthesis has focused on
the problem of the carbinolamide.1 The carbinolamide
and the corresponding amido ether represent syntheti-
cally challenging structural motifs present in small
molecule natural products (e.g., 12), and constitute the
defining structural element of N-linked glycosylated
proteins and peptides (2, Fig. 1). Moreover, the reactive
nature of such functionality could be used in certain
substrates to leverage access to other nitrogen contain-
ing targets. Preliminary findings are presented here that
demonstrate that the carbinolamide is readily obtained
from amide and aldehyde.
O-alkylated carbinolamide constitutes the central
synthetic challenge of each active member of this natural
product class4 (e.g., 35 and 46, Fig. 2). Among the most
successful methods are those of Matsumoto,7 Roush,8
Hoffmann,9 and more recently, Huang.10
Our interest in carbinolamide synthesis was piqued by
the structure of psymberin (3). We reported an approach
to psymberin whereby 10 was prepared from pyran 6 by
way of 511 (Schemes 1 and 2). Stereochemical assign-
ments were made based on the correlation of 6 and 10
to the natural product. The structure of 5 was correlated
to the core of mycalamide A, as shown (5!8).12
Although direct addition of amides to electron deficient
aldehydes is known, most approaches to other carbin-
olamides require multi-step sequences.3 Several creative
approaches to this class of complex amides have been
developed in the context of the pederins, where an
Ideally, the carbinolamide of 3 would be prepared by
direct addition of 9 to 10 (Scheme 2). To investigate the
feasibility of this union, we examined the preparation
Me OMe O
OMe
8
OH
Me
O
Me
N
H
O
OH
OH
Me
O
O
O
3 psymberin
Me
N
H
Me
HO
RO
HO
HO
Me
H
N
O
R
O
OH
O
NHAc
Me
O
OH
O
O
OMe
O
O
Me
Me
O
2 N-linkage of
glycopeptides and proteins
OMe
Me
1 zampanolide
4
mycalamide A
N
H
OH
O
Figure 1. Carbinolamide and O-alkylated amides.
Me
HO
Keywords: Amide synthesis; Carbinolamide; Pederin; Mycalamide;
Psymberin.
OH
*
Figure 2. Two pederin-type natural products.
Corresponding author. E-mail: ljw@rutchem.rutgers.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.077

S. Kiren et al. / Tetrahedron Letters 48 (2007) 7456–7459
Me OMe
7457
O
OR OH
O
OR
Me OMe O
a-b
OH
Me
OH
Me
OH
NH2
OR
15 R = H
OR
O
ref 12
Me
Me
16 R = Bz
Me OMe
O
c-d
5
5
6
15
NH2
OR
17 R=TBS
OR OMOM
OMe
Me
Me
OR OMOM
OMe
Me
a,b
c,d
Scheme 4. Reagents and conditions: (a) BzCl, pyridine, 80%; (b)
(COCl)2, cat. DMF then NH3, 80%; (c) AcCl, MeOH, then NH3, 45%;
(d) TBSCl, Im, DMAP, 96%.
O
O
Me
7
8
Initially, we attempted to use aluminum imidates. Hoye
employed an aluminum imidate to give the carbinol-
amide of 1.14 The generality of this addition had not
been reported. One rationale for the success of this addi-
tion focused on possible stabilization of the product by a
hydrogen bond network.14a,15 To test this, we examined
the coupling of 18 to 19, which was accomplished by
treatment of the amide with 1 equiv of DIBAL, and then
addition of 1 equiv of the aldehyde (Scheme 5). The
reaction was conveniently run on a 2 g scale, and the
product was isolated after aqueous workup and purified
by column chromatography to give 20 as a white solid in
61% yield. DIBAL (13.0 mL, 1.0 M in hexane) was
added slowly at room temperature to a solution of hex-
anamide (1.35 g, 13 mmol) in THF (12 mL). The reac-
tion mixture was stirred at room temperature for 1 h,
and then cyclohexylcarboxaldehyde (1.5 g, 13.0 mmol)
was added slowly to the mixture. The reaction mixture
was stirred for 1 h, quenched with saturated Rochelle’s
salt solution, and then extracted with CH2Cl2. The com-
bined organic extracts were dried over Na2SO4 and con-
centrated under reduced pressure. The residue was
purified by FCC (silica gel, ethyl acetate/hexane 1:1.5)
to give 20 (1.80 g, 61%) (mp 99–101 °C uncorrected).
1H NMR (300 MHz, CDCl3) 6.28 (d, 1H, J = 7.8 Hz),
5.06 (dd, 1H, J = 7.8, 7.5 Hz), 4.27 (br, 1H) 2.16 (t,
1H, J = 7.5 Hz), 0.98–1.89 (m, 17H), 0.87 (t, 3H,
J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) 174.5, 77.7,
42.5, 37.1, 31.8, 28.5, 28.4, 26.6, 26.1, 26.0, 25.6, 22.7,
14.3; IR mmax (KBr pellet, cmꢀ1) 3246, 3068, 1645,
1553, 1026; m/z (ESIMS) calculated for C13H25NO2Na
[MNa]+ 250.18, found: 250.2. Unfortunately, this reac-
tion proved capricious. Boron imidates, which appar-
ently have not been the subject of study, were
investigated as an alternative and found to add reliably
to aldehydes.
R = TBDPS
Scheme 1. Reagents and conditions: (a) NaH, MOMCl, THF, 60%;
(b) NaH, CH3I, THF, 98%; (c) BH3ÆTHF, 2-methyl-2-butene, then
H2O2, NaOH, 82%; (d) Ph3PCH2, 75%.
Me+
Me OMe
O
O
OAc
Me
NH2
Me
OR
AcO
3
O
9
Me
Me
O
OAc
10
OAc
O
Scheme 2. Synthetic plan.
of carbinolamides from commercial and synthetic alde-
hydes and amides (e.g., 12, 14, 16 and 17). Aldehydes
12 and 14 were obtained as shown in Scheme 3. Amides
16 and 17 were prepared from 1513 as shown in Scheme 4.
The aldehydes and amides correspond to, in varying
degrees, the structural features of 3 and 4.
OR
OAc
Me
OHC
OAc
Me
a
b ,c
6
O
O
Me
Me
11
12
OR
OHC
OAc
Me
OAc
Me
d
e,f
11
O
O
Me
Me
O
OH
O
i.
DIBAL,THF
Me
Me
H3C(H2C)4
N
H
H3C(H2C)4
NH2
ii.
13
14
CHO
R = TBDPS
18
20
2g scale, 61% yield
Scheme 3. Reagents and conditions: (a) Ac2O, pyr 98%; (b) TBAF,
THF, 95%; (c) (COCl)2, DMSO, 80%; (d) Pd/C, H2, 98%; (e) TBAF,
THF; (f) DMP, 50% (two steps).
19
Scheme 5.

7458
S. Kiren et al. / Tetrahedron Letters 48 (2007) 7456–7459
The results are shown in Table 1. The reaction condi-
tions are based on the findings of Patterson et al.16 for
aldol addition of boron enolates. Thus, the amide
(1.2 equiv) was taken up in diethyl ether (0.2 M), NEt3
(2.0 equiv) was added, the mixture was cooled to 0 °C,
and to this boron chloride (1.3 equiv, 1.0 M in hexane)
was added dropwise. The heterogeneous mixture was
stirred for 15 min, and then the aldehyde (1.0 equiv)
was added. After 30 min the reaction was quenched with
a mixture of MeOH/phosphate buffer (pH = 7.40)/H2O2
(30%). Isolation and purification gave the carbinol-
amide. Presumably, the boron imidate is formed under
the reaction conditions and then adds to the aldehyde.
Protected amides 16 and 17 add to the simple aldehyde
of entry 5 as well as to pyran aldehydes related to 3
(entries 6–8). At present, there is no significant stereo-
selectivity in the addition reaction. Nevertheless, the
yield appears to be independent of silyl or ester protec-
tion, and the pyran side chain does not significantly
influence the efficiency of the reaction.
Table 1. Carbinolamide formation
O
O
O
OH
Cy2BCl
The boron imidate conditions proved ineffective for car-
binolamide formation for pyran aldehydes 21 and 22
(Scheme 6).17 In these instances, decomposition of the
aldehydes took place instead of addition, for example,
b-elimination (!23). These findings are similar to the
observations made by Rawal18 and likely reflect the side
reactions promoted by excess boron reagent.
R
NH2
H
R
NEt3, Et2O
R
N
H
R
Entry Amide
Aldeyhde Carbinolamide (yield)
OH
O
1
18
19
H3C(H2C)4
N
H
20 (88%)
OH
We find that carbinolamides are not as intrinsically
unstable as earlier reports suggest. Indeed in all cases,
the carbinolamides of this study were stable to the reac-
tion conditions, and accommodated aqueous workup,
flash column chromatography, routine handling, and
storage. It has been proposed that an appropriately
positioned heteroatom may serve as an intramolecular
hydrogen bond acceptor and that this interaction ac-
counts for unexpected stability of such carbinolamides
(e.g., 24).15a The presence of an interaction has experi-
mental support from related systems (25, Fig. 3).15b
However, in light of the results presented here, particu-
larly entries 1-4 of Table 1, the notion that carbinola-
mides are unstable in the absence of a hydrogen bond
network must be reevaluated. Although the extended
hydrogen bond networks interaction has been obser-
ved,15b it has not been established that such networks
are necessary to render a carbinolamide stable to isola-
tion without special precautions.19 Importantly, carbin-
olamide O-alkylation is a known transformation.20 Such
alkylation reduces potential hydrogen bonding interac-
tions, and yet, the products exhibit significant stability.
An additional example is shown in Scheme 7. Carbinola-
mide 20 was smoothly converted to the methyl deriva-
tive 26. The data suggest that carbinolamides are
intrinsically stable enough to be isolated, characterized,
and manipulated, even in the absence of an extended
hydrogen bond network.21
O
Me
2
3
4
5
18
i-PrCHO H3C(H2C)4
N
H
Me
(84%)
OH
O
Me
N
H
CyCONH2 i-PrCHO
Me
(70%)
O
OH
N
H
CyCONH2 19
(60%)
Me OMe
O
OH
N
H
16
16
19
12
OBz
(66%, dr 1:1)
Me OMe
O
OH
H
OAc
Me
N
H
O
OBz
6
7
8
Me
(40%, dr 1:1)
Me OMe
O
OH
H
OAc
Me
N
H
O
OTBS
i. Cy2BCl
17
12
16
no addition
Me
NEt3, Et2O
ii. 21 or 22
(39%, dr 1:1)
OAc
O
OHC
OHC
O
OHC
OAc
OR
Me
Me OMe
O
OH
H
OAc
Me
O
Me
Me
Me
Me
O
N
H
Me
O
OBz
16
14
Me
21
22
23 R = H, Ac
Me
(40%, dr; 2:1)
Scheme 6.

S. Kiren et al. / Tetrahedron Letters 48 (2007) 7456–7459
7459
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O
OH
O
OMe
Ag2O, MeI
CH2Cl2
H3C(H2C)4
N
H
H3C(H2C)4
N
H
58%
20
26
Scheme 7.
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H
H
O
O
O
O
R
R
Me
R
N
N
H
NH
H
O
R
O
O
OtBu
24
25
Figure 3. Previous proposed hydrogen bonded networks.
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Generous financial support from Merck & Co. and Rut-
gers, The State University of New Jersey is gratefully
acknowledged.
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19. This rationale has been invoked to account for the
stability of zampanolide (1); see Ref. 14a.
20. For an example relevant to zampanolide (1), see Smith, A.
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21. There is a twofold proviso, however. The reaction
conditions used to generate the carbinolamide must be
compatible with isolation, and the other functionality
must not facilitate decomposition.