Manganese η2-complexes as auxiliaries for stereoselective aldol synthesis of allenyl carbinols

Article abstract of DOI:10.1021/ol1021096

A convenient and robust manganese auxiliary was linked via an η²-bond to alkynyl esters and ketones using a mild complexation reaction with methylcyclopentadienyl manganese tricarbonyl. This complex readily underwent aldol reactions with exclusive α-substitution and in good diastereoselectivities especially with aryl ketone substrates. This selectivity has been rationalized using a cyclic transition state model in which the manganese auxiliary plays a critical role in promoting E(O)-geometry of the cumulenolate intermediate.

Full text of DOI:10.1021/ol1021096

ORGANIC
LETTERS
Manganese η2-Complexes as Auxiliaries
for Stereoselective Aldol Synthesis of
Allenyl Carbinols
2010
Vol. 12, No. 21
5078-5080
Manishabrata Bhowmick and Salvatore D. Lepore*
Department of Chemistry, Florida Atlantic UniVersity, Boca Raton,
Florida 33431, United States
slepore@fau.edu
Received September 3, 2010
ABSTRACT
A convenient and robust manganese auxiliary was linked via an η2-bond to alkynyl esters and ketones using a mild complexation reaction
with methylcyclopentadienyl manganese tricarbonyl. This complex readily underwent aldol reactions with exclusive r-substitution and in
good diastereoselectivities especially with aryl ketone substrates. This selectivity has been rationalized using a cyclic transition state model
in which the manganese auxiliary plays a critical role in promoting E(O)-geometry of the cumulenolate intermediate.
Neutral η2-complexed transition metals are virtually unknown
as auxiliaries for the mild and stereoselective formation of
carbon-carbon bonds. Certainly the use of allylmolybdenum
complexes by Liebeskind in 1,5-Michael-type additions
serves as a tantalizing and rare example of the potential for
unprecedented control in bond formation afforded by transi-
tion metal η3-auxiliaries.1 We are particularly interested in
developing mild and stereoselective methods for the prepara-
tion of allenyl esters from easily accessible alkynes. Allenyl
esters and ketones have taken on increased importance as
intermediates in organic synthesis.2 We have recently
exploited the potential of functionalized allenyl esters for a
highly abbreviated synthesis of [3.2.1] bridged bicyclic
compounds.3 In this regard, we required a regio- and
diastereoselective method for the preparation of R-carbinol
allenyl esters. Hammond4 and Miesch5 have recently reported
the synthesis of γ-carbinol allenoates from propargyl and
allenyl esters; however, these reported methods are not well-
suited to the preparation of the R-carbinol analogue. Others
have demonstrated that allenyl ketones can be further
functionalized at the R-position by condensation with alde-
hydes.6 These methods suffer from concomitant formation
of ꢀ-alkynyl ketones and dehydration products. In all reported
cases, the aldol reactions proceed with little or no diaste-
reoselectivity.
In our attempts to address this shortcoming, we turned to
a pioneering report by Franck-Neumann demonstrating that
alkynyl esters η2-complexed to methylcyclopentadienyl
manganese dicarbonyl (MMD) could be isomerized to the
corresponding allene in the presence of a stoichiometric
(4) (a) Xu, B.; Hammond, G. B. Angew. Chem., Int. Ed. 2008, 47, 689.
(b) Miesch, L.; Welsch, T.; Rietsch, V.; Miesch, M. Chem.sEur. J. 2009,
15, 4394. (c) Miesch, L.; Rietsch, V.; Welsch, T.; Miesch, M. Tetrahedron
Lett. 2008, 49, 5053.
(1) (a) Cheng, B.; Liebeskind, L. S. Org. Lett. 2009, 11, 3682. (b)
Coombs, T. C.; Zhang, Y.; Garnier-Amblard, E. C.; Liebeskind, L. S. J. Am.
Chem. Soc. 2009, 131, 876. (c) Zhang, Y.; Liebeskind, L. S. J. Am. Chem.
Soc. 2005, 127, 11258.
(5) (a) Miesch, L.; Welsch, T.; Rietsch, V.; Miesch, M. Chem.sEur. J.
2009, 15, 4394. (b) Miesch, L.; Rietsch, V.; Welsch, T.; Miesch, M.
Tetrahedron Lett. 2008, 49, 5053.
(2) For recent examples, see: (a) Shi, M.; Tang, X.-Y.; Yang, Y.-H. J.
Org. Chem. 2008, 73, 5311. (b) Huang, X.; Shen, R.; Zhang, T. J. Org.
Chem. 2007, 72, 1534. (c) Hopkins, C. D.; Guan, L.; Malinakova, H. C. J.
Org. Chem. 2005, 70, 6848. (d) Ma, S. Chem. ReV. 2005, 105, 2829.
(3) Maity, P.; Lepore, S. D. J. Am. Chem. Soc. 2009, 131, 4196.
(6) (a) Tsuboi, S.; Kuroda, H.; Takatsuka, S.; Fukawa, T.; Sakai, T.;
Utaka, M. J. Org. Chem. 1993, 58, 5952. (b) Petasis, N. A.; Teets, K. A.
J. Am. Chem. Soc. 1992, 114, 10328.
10.1021/ol1021096  2010 American Chemical Society
Published on Web 10/11/2010

amine base.7 The work of Franck-Neumann and others8 have
clearly established that MMD coordinates the more electron-
deficient R,ꢀ-bond of the allenyl carbonyl system. We have
previously hypothesized that MMD coordinates alkenes and
alkynes with an η2-bond that exhibits significant metallocy-
clic character leading to a preference for bonding with
carbon-carbon double bonds (metallocyclopropane) relative
to triple bonds (more strained metallocyclopropene) and thus
reversing thermodynamic preferences to shift equilibrium
toward allene formation.9 On the basis of this conception,
we reasoned that the preference of manganese for double
bonds could be used to solve the long-standing problem of
selective addition reactions to alkynyl esters and ketones.
Thus under very mild light activation, the MMD group is
introduced to an alkyne to give intermediate A (Scheme 1).
a very low energy UV lamp.12 Complex 1 was then treated
with a variety of bases to identify suitable conditions for the
aldol addition. We quickly noted that excess base (2.5 equiv)
generally led to improved yields. Among the various bases
examined (Table 1), tBuOK at 0 °C gave the best yield of aldol
Table 1. Optimization of MMD-Mediated Aldol Additions
T
(°C)
time ArCHO
%
yieldb
entry
base
LDA
(h)
(equiv)
2:3a
1
-55 to rt
0 to rt
-78 to rt
-78
20
48
24
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
5.0
10
100:0
0:100
50:50
0:100
50:50
100:0
50:50
0:100
50:50
60:40
70:30
84:16
80:20
82:18
20
2
TBAF
LiHMDS
KHMDS
DBU
10
3
25
4
65
5
-78 to rt
0 to rt
0 to rt
-78 to rt
-78
12
24
12
12
4
40
Scheme 1
.
Manganese as an R-Directing Group in Aldol
6
NaH
KH
10
Additions
7
68
8
tBuOLi
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
55
9
67
10
11
12
13
14
-55
3
55c
70c
74c
67c
67c
0
3
0
3
0
3
0
3
a Based on isolated yields of Mn-complexed products. b Combined
isolated yields. c Isolated yields of decomplexed 2.
product 2. Lower temperatures appeared to depress reaction
yields and lead to greater amounts of isomerization product 3.
We also examined the reaction using varying equivalents of an
aromatic aldehyde and found that 2.5 equiv led to optimal yields.
The use of aliphatic aldehydes in this reaction primarily led to
isomerized product 3. Although these complexed allenyl
R-carbinol products are rather stable toward silica gel chroma-
tography, a slight improvement in product yield was realized
when the crude products were first treated with a mild oxidant
to remove the MMD auxiliary prior to column purification
(Table 1, entries 10-14). Thus a variety of complexed al-
kynoates 4 were converted to allenoates 6 in good two-step
isolated yields (Table 2).
A subsequent deprotonation leads to cumulenolate D with
preferred addition of aldehyde at the R-position to give E
affording the more favorable manganese allene complex.
Importantly, similar reactions with noncomplexed alkynyl
esters lead to R-carbinol products often in low yields.10,11
A final mild oxidation of E then reveals desired allenyl R-
carbinol C. In this communication, we describe our validation
of this designed aldol addition reaction as a potentially gen-
eral solution to the stereoselective synthesis of R-substituted
allenes.
The reagent of choice for the oxidative removal of MMD
from crude products 5 was PhI(OAc)2. The use of 2 equiv
of this oxidant provided good overall yield of aldol product
within 1.5 h at room temperature. The aldol/oxidation
reaction of 4 also gave good yields with a variety of electron-
rich and electron-deficient aromatic aldehydes. Alkynyl
ketones are well-known for their propensity to act as Michael
acceptors; indeed, in previous alkylation studies, we have
observed dimerization products arising from unwanted
conjugate additions.10a By contrast, substrates 4 (R ) Ph)
were converted exclusively to aldol products in good two-
step yields (Table 2, entries 9-23). In this context, MMD
appears to act as an alkyne protecting group.
Our initial studies involved the addition of aldehyde MMD-
complex 1,which was conveniently generated in good yields
using inexpensive and commercially available methylcyclo-
pentadienyl manganese tricarbonyl (MMT) under the action of
(7) Frank-Neumann, M.; Brion, F. Angew. Chem., Int. Ed. 1979, 18, 688.
(8) (a) Giffard, M.; Gentric, E.; Touchard, D.; Dixneuf, P. J. Organomet.
Chem. 1977, 129, 371. (b) Giffard, M.; Dixneuf, P. J. Organomet. Chem.
1977, 85, C26.
(9) Lepore, S. D.; Khoram, A.; Bromfield, D. C.; Cohn, P.; Jairaj, V.;
Silvestri, M. A. J. Org. Chem. 2005, 70, 7443.
(10) Our early studies in this vein revealed that a direct alkylation of
an alkynyl ester to give allene product is usually not possible except in the
presence of multiple equivalents of strong amide bases leading to dianion
intermediates. Even under these forcing conditions, the method was limited
to the formation of allenyl esters with R-silyl, stannyl, and methyl
substitution: (a) Lepore, S. D.; He, Y. J.; Damisse, P. J. Org. Chem. 2004,
(12) The MMD complexes are air- and light-stable and amenable to
flash chromatography. The auxiliary is introduced by replacing a carbon
monoxide ligand on methylcyclopentadienyl manganese tricarbonyl (MMT)
with the alkynyl ketone or ester substrate. The MMT reagent is inexpensive
and widely available (e.g., Bosche Scientific, Inc. for less than $1/g).
69, 9171. (b) Lepore, S. D.; He, Y. J. J. Org. Chem. 2005, 70, 4546
.
(11) Our attempts to obtain R-substituted allenyl esters from ꢀ-keto esters
using an efficient dehydrative protocol also suffered similar limitations:
Maity, P.; Lepore, S. D. J. Org. Chem. 2009, 74, 158
.
Org. Lett., Vol. 12, No. 21, 2010
5079

The rel-(S,S) configuration of 8 can then be rationalized on the
basis of a metal chelated cyclic transition state (TS7) that
positions the aryl group of the aldehyde in a pseudoequatorial
orientation (Figure 1). In this mechanistic conception, large R
groups (e.g., R ) Ph), in addition to affording high E(O)
selectivity, promote the positioning of the aldehyde substituent
in TS7 to avoid 1,3-diaxial repulsions.
Table 2. Generality of One-Pot Aldol Addition/Oxidation
Reactions
The MMD auxiliary can also be used to induce a third
level of control (i.e., chemoselectivity). Thus, even in an aldol
reaction with alkynyl methyl ketone 9 (this class of substrate
is well-known to react primarily at the methyl position),13
R-carbinol allenoate 10 was the major product giving only
a small amount of condensation product 11 (Scheme 2). The
entry
R
R1
R2
Ar
C6H5
p-MeOC6H4
p-NO2C6H4
C6H5
p-CH3C6H4
p-MeOC6H4
p-NO2C6H4
p-ClC6H4
C6H5
p-CH3C6H4
p-MeOC6H4
p-NO2C6H4
p-ClC6H4
C6H5
p-CH3C6H4
p-MeOC6H4
p-NO2C6H4
p-ClC6H4
C6H5
p-CH3C6H4
p-MeOC6H4
p-NO2C6H4
p-ClC6H4
%Yield (dr)
1
2
3
4
5
6
7
8
tBuO
tBuO
tBuO
MeO
MeO
MeO
MeO
MeO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
PhC2H4
PhC2H4
PhC2H4
PhC2H4
PhC2H4
C5H10
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
84 (1.5:1)
72 (2.0:1)
88 (1.8:1)
88 (1.8:1)
76 (2.0:1)
72 (1.5:1)
70 (2.0:1)
90 (1.8:1)
76 (13:1)
80 (12.6:1)
81 (9.0:1)
83 (12.5:1)
73 (10:1)
79 (12:1)
82 (10.5:1)
76 (14:1)
78 (12:1)
92 (9.5:1)
60
Scheme 2. MMD Auxiliary Favors the R- over the R′-Position
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
H
C5H10
C5H10
C5H10
C5H10
C5H10
C5H10
C5H10
C5H10
C5H10
65
52
55
71
modest diastereoselectivity of product 10 (3:1) accords with
our transition state model as the small size of the ketone
methyl group would not be expected to exert selectivity in
cumulenolate formation.
Ph
Ph
a Isolated two-step yields; dr based on proton NMR.
In conclusion, we have introduced a new transition metal
auxiliary in aldol additions of alkynyl esters and ketones leading
to allene products with exclusive R-substitution. These alkyne
substrates have traditionally proven to be problematic in terms
of stereocontrol in bond formation. The key feature of this
method is the use of a convenient and inexpensive alkyne-
chelating reagent (MMT) that alters the thermodynamic prefer-
ence of the reaction in favor of allene formation and provides
a basis for diastereoselectivty especially with alkynyl ketones.
With a mechanistic framework in place for understanding the
observed regio- and diastereoselectivity in this system, efforts
are now being put forth for the development of a catalytic
asymmetric synthesis of allenes taking advantage of the
manganese auxiliary as a chelating center.
A crystal structure of product rac-8 (major diastereomer)
was obtained to determine its relative stereochemistry (Figure
1). We believe the relatively high diastereoselectivity of 8
Acknowledgment. We thank the National Institutes of
General Medical Science (073621-01) and NSF (0311369)
for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data of all new compounds;
Figure 1. Mechanistic rationale for diastereoselectivity with allenyl
ketones and crystallographic evidence.
1
copies of H and 13C NMR spectra; X-ray crystallographic
studies of 8. This material is available free of charge via the
Internet at http://pubs.acs.org.
(and those of entries 9-18 in Table 2) to be the result of
the selective formation of an E(O)-cumulenolate. Specifically,
the bulky MMD auxiliary is thought to lead to an intermediate
favoring an anti orientation with respect to the R and R1 groups.
OL1021096
(13) Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc. 2004,
126, 2660.
5080
Org. Lett., Vol. 12, No. 21, 2010