Catalytic enantioselective and diastereoselective addition of aldehyde-derived enecarbamates to αoxo aldehydes

Article abstract of DOI:10.1002/anie.200600471

(Chemical Equation Presented) Added benefits: Catalytic enantio- and diastereoselective addition of aldehyde-derived enecarbamates to aldehydes is reported (see scheme). A copper(I)-diimine complex works well as the catalyst and the catalyst loading is no

Full text of DOI:10.1002/anie.200600471

Communications
Asymmetric Catalysis
DOI: 10.1002/anie.200600471
Catalytic Enantioselective and Diastereoselective
Addition of Aldehyde-Derived Enecarbamates to
a-Oxo Aldehydes**
Ryosuke Matsubara, Nobuyuki Kawai, and
Shu¯ Kobayashi*
Catalytic enantioselective aldol reactions have been widely
investigated and many successful syntheses have been
reported.[1] While most of the studies employed ketones and
esters (or their derivatives) as nucleophilic donors, the use of
aldehydes as nucleophiles is a challenging topic because side
reactions such as self-condensation and further reactions of
products take place.[2] Quite recently, Denmark and Ghosh
reported the first catalytic diastereo-and enantioselective
crossed aldol reactions of aldehydes with trichlorosilyl
enolates which are activated by a chiral phosphoramide
catalyst.[3] Additionally Northrup and MacMillan have
reported proline-catalyzed direct enantioselective crossed
aldol reactions between aldehydes, a method which was
applied to the facile synthesis of carbohydrates.[4]
In previous publications, we have shown that enamides
and enecarbamates may be used as nucleophiles in addition
reactions with imines, aldehydes, and ketones.[5] It is espe-
cially noteworthy that reactions of enecarbamates afford
imine products bearing carbamate N-protecting groups, such
as tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz),
which may be readily removed to convert those products into
other nitrogen-containing compounds. Herein we report
asymmetric catalytic addition reactions of aldehyde-derived
enecarbamates with aldehydes. The products, in which the
aldehyde oxidation level is conserved, were obtained in good
yields with high enantioselectivities in the presence of less
than 1 mol% of copper(I) catalysts in most cases.
Scheme 1. Reaction of ethyl glyoxylate with aldehyde-derived enecarba-
mate 2a to identify the optimal conditions. Compound 4a is a putative
intermediate, compound 5 the overreaction product.
ously, but a complex mixture was obtained and none of the
expected products, that is, the aldimine-or aldehydet-ype
1
derivatives, were observed after hydrolysis. H NMR spec-
troscopy suggested that the product was a polymeric or
oligomeric material. Treatment of this crude material with
scandium trifluoromethanesulfonate (Sc(OTf)3) in EtOH/
CH3CN afforded the desired product 3a in a moderate yield
with an excellent ee value (see Scheme 1). This result
indicates that the crude material obtained in the first reaction
includes compounds with the structure of 4a. However,
careful analysis of the products revealed that overreaction
had occurred to give compound 5. In an attempt to suppress
the formation of 5, EtOH was used as a trapping reagent for
the initial reactive acylimine product. Under these conditions,
product 3a was obtained without the Sc(OTf)3 treatment, but
only in moderate yield (see Scheme 1).[7] The best yield
(80%) was observed when iPrOH (1 equiv) was employed
along with the copper catalyst and the crude product was
treated with Sc(OTf)3.
Once the optimal conditions were established, the scope
of the reaction was explored (Table 1). Unexpectedly, prod-
ucts of overreaction were not observed even in the absence of
alcohol when mono-or disubstituted enecarbamates were
used, so in all reactions other than that of entry 1, the alcohol
was omitted. It was found that even catalyst loading as low as
0.1 mol% was enough to bring the reaction to completion
within 1 h, and the product was obtained with high enantio-
selectivity (Table 1, entry 1). Phenylglyoxal also performed
well in the reaction, with the desired N,O-acetal being
obtained in moderate yield and with an acceptable ee value
(Table 1, entry 2). The enecarbamate bearing an allyloxycar-
bonyl protective group on the nitrogen atom was also found
to be applicable to this reaction (Table 1, entries 3 and 4).
Substituted enecarbamates 2c–e[8] were also acceptable sub-
strates and afforded the corresponding products with good
We set about the investigation of this project with
enecarbamate 2a (Scheme 1).[6] Enecarbamates that are
derived from aldehydes are rather stable in water and air
and they are readily prepared from the corresponding
aldehydes (2 steps) or a,b-unsaturated carboxylic acids
(1 pot, 4 steps). When the copper(I) catalyst from referen-
ce [5b] was employed, 2a was consumed almost instantane-
[*] R. Matsubara, N. Kawai, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences
The University of Tokyo
The HFRE Division, ERATO
Japan Science Technology Agency (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society of the Promotion of Sciences
(JSPS).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
Table 1: CuI-catalyzed addition of enecarbamates 2 to aldehydes.
The products obtained have a
broad range of applications. The
1,3-amino alcohol motif is present
in a number of natural products,
and herein we present a catalytic,
highly stereoregulated approach to
(2S,3S,4S)-3-hydroxy-4-methylpro-
line (HMP, 11; Scheme 2), which is
Entry
R
2
R1, R2, R3, R4
H, Cbz, H, H
x
t [h]
Yield [%][a]
syn/anti[b]
ee [%][c]
1[d]
2[e]
3
OEt
Ph
OEt
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
2a
2a
2b
2b
(E)-2c
(Z)-2c
(E)-2d
(Z)-2d
(E)-2e
(Z)-2e
2 f
0.1
1
0.1
1
1
1
1
1
1
1
1.5
1
80
54
50[f]
58
84
79
87
79
50[g]
0
–
–
–
–
92
88
96
91
97
95
98
94
96
a
nonproteinogenic amino acid
known to be a constituent of the
elastase inhibitors known as nosto-
peptins.[10] The reaction of ethyl
glyoxylate with (E)-2c was per-
formed on a 5-mmol scale with
1 mol% of the catalyst. After the
reaction mixture was stirred for
3.5 h,followed by treatment with
Sc(OTf)5, the resulting product 3c
was isolated in 95% yield (syn/
anti = 12/88, 97% ee (anti)). The
N,O-acetal 3c was reduced in high
yield by treatment with an excess
amount of TESH in the presence of
TMSOTf. The resulting alcohol was
H, CO2All, H, H
4[e]
5
1.5
5.5
28
5.5
28
24
24
18
28
24
H, Cbz, H, Me
H, Cbz, Me, H
H, Cbz, H, Et
H, Cbz, Et, H
H, Cbz, H, Cl
H, Cbz, Cl, H
H, Cbz, Me, Me
12/88
92/8
9/91
82/18
5/95
–
–
–
–
6
7
8
9
10
11
12
13
5
1
5
81
39
0
70
78
2 f
2g
Me, Cbz, H, H
[a] Yield of isolated compound 3 unless otherwise noted. [b] The diastereomeric ratio was determined
after reduction of 3; see Supporting Information. [c] ee Value of the major diastereomer. [d] iPrOH
(1 equiv) was added in the copper-catalyzed reaction. [e] 2 was slowly added over 2 h. [f] Yield of
toluoylated compound 6; see Supporting Information. [g] Yield of reduced compound 7; see Supporting
Information. All=allyl group.
yields and high enantioselectivities (Table 1, entries 5–9). It is
noteworthy that anti and syn products were formed stereo-
specifically from the E and Z enecarbamates, respectively.
Disubstituted enecarbamate 2 f was employed to afford N,O-
acetal 3 f in good yield with modest enantioselectivity
(Table 1, entries 11 and 12). The enecarbamate 2g, which
has a tertiary nitrogen atom, did not react with the aldehyde
at all, as expected from the results reported previously.[5b,c]
In all cases, the initial products were oligomeric or
polymeric (4); however, these products could be employed
directly in reactions that are typical of N,O-acetals. For
example, allylation proceeded smoothly in the presence of
trimethylsilyl trifluoromethanesulfonate (TMSOTf) to give
highly functionalized compound 8 in good yield [Eq. (1)].[9]
Compound 4c, prepared from 2c, was reduced by a combi-
nation of triethylsilane (TESH) and TMSOTf to afford
aminohydroxy ester 9 in good yield with high selectivity
[Eq. (2)].
Scheme 2. Total synthesis of HMP (11). Reaction Conditions: a) TESH,
TMSOTf, 98%; b) TBSOTf, 2,6-lutidine, 93%; c) Pd/C, H2, AcOH, 87%;
d) BnBr, KOH, 18[crown]-6, 86%; e) DIBALH, KCN, 78%; f) cHCl; Pd/
C, H2, H2O, 88%. TBS=tert-butyldimethylsilyl, DIBALH=diisobutyl-
aluminum hydride, cHCl=concentrated hydrochloric acid.
protected as the TBS ether, and after removal of the Cbz
group, cyclization and benzylation gave the desired product
10.[11] Reductive cyanation of 10 was successfully accom-
plished according to a reported method[12] and was followed
by hydration and deprotection to afford 11.
In summary, we have demonstrated that enecarbamates
derived from aldehydes can react with ethyl glyoxylate in the
presence of a chiral catalyst prepared from CuI and a diimine
ligand to give a polymeric structure, which can be converted
into the corresponding monomer by treatment with a catalytic
amount of Sc(OTf)3 in EtOH. In most cases, less than 1 mol%
of the catalyst was enough to complete the reactions and
afford the desired products in good yields with high enantio-
selectivities. Use of E-enecarbamates gave anti products and
Z-enecarbamates stereospecifically produced syn products.
Additionally, the reaction was successfully applied to an
Angew. Chem. Int. Ed. 2006, 45, 3814 –3816
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3815

Communications
efficient synthesis of HMP (11). Further studies on catalytic
asymmetric reactions of aldehyde-derived enecarbamates
with less reactive aldehydes are now in progress.
Received: February 4, 2006
Published online: May 3, 2006
Keywords: aldol reaction · asymmetric catalysis ·
.
aza-ene reaction · copper · N ligands
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