Influence of β-substituents in aldol reactions of boron enolates of β-alkoxy methylketones

Article abstract of DOI:10.1021/ol102303p

Moderate to good levels of substrate-based 1,5-syn-stereocontrol could be achieved in the boron-mediated aldol reactions of β-tert-butyl methylketones with achiral aldehydes, independent of the nature of the β-alkoxy protecting group (P = PMB or TBS). The

Full text of DOI:10.1021/ol102303p

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5056-5059
Influence of ꢀ-Substituents in Aldol
Reactions of Boron Enolates of
ꢀ-Alkoxy Methylketones
Luiz C. Dias,* Em´ılio C. de Lucca, Jr., Marco A. B. Ferreira, Danilo C. Garcia, and
Cla´udio F. Tormena
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP, C.P. 6154,
13084-971, Campinas, SP, Brazil
ldias@iqm.unicamp.br
Received September 24, 2010
ABSTRACT
Moderate to good levels of substrate-based 1,5-syn-stereocontrol could be achieved in the boron-mediated aldol reactions of ꢀ-tert-butyl
methylketones with achiral aldehydes, independent of the nature of the ꢀ-alkoxy protecting group (P ) PMB or TBS). The analysis of the
relative energies of the transition structures by theoretical calculations using the density functional B3LYP shows relative energies favoring
the corresponding OUT-1,5-SYN transition structures, explaining the observed 1,5-syn stereoinduction.
The first evidence for 1,5-anti asymmetric induction in aldol
reactions of boron enolates generated from ꢀ-alkoxy meth-
ylketones was described in 1989 by Masamune and co-
workers in their approach to the synthesis of the AB fragment
[C1-C16] of bryostatin 1.1
Since then, numerous approaches from the research groups
of Paterson,2 Evans,3 Denmark,4 Dias,5 and others6 have
shown that the sense of induction in aldol reactions of boron
enolates of ꢀ-alkoxy methylketones with aldehydes favors
the formation of the 1,5-anti diastereoisomer. However, we
demonstrated that it is possible to obtain good levels of 1,5-
syn induction from ꢀ-trifluoromethyl and ꢀ-trichloromethyl-
ꢀ-alkoxy methylketones independent of the nature of the
ꢀ-alkoxy protecting group (Scheme 1).5c,d
(4) (a) Denmark, S. E.; Fujimori, S.; Pham, S. M. J. Org. Chem. 2005,
70, 10823. (b) Denmark, S. E.; Fujimori, S. Synlett 2001, 1024. (c) Denmark,
S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971.
(1) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.;
Somfai, P.; Whritenour, D. C.; Masamune, S.; Kageyama, M.; Tamura, T.
J. Org. Chem. 1989, 54, 2817.
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Org. Lett. 2002, 4, 4325. (b) Dias, L. C.; Aguilar, A. M. Org. Lett. 2006,
8, 4629. (c) Dias, L. C.; Marchi, A. A.; Ferreira, M. A. B.; Aguilar, A. M.
Org. Lett. 2007, 9, 4869. (d) Dias, L. C.; Marchi, A. A.; Ferreira, M. A. B.;
Aguilar, A. M. J. Org. Chem. 2008, 73, 6299. (e) Dias, L. C.; Pinheiro,
S. M.; Oliveira, V. M.; Ferreira, M. A. B.; Tormena, C. F.; Aguilar, A. M.;
Zukerman-Schpector, J.; Tiekink, E. R. Tetrahedron 2009, 65, 8714. (f)
Dias, L. C.; Aguilar, A. M. Chem. Soc. ReV. 2008, 37, 451. (g) Dias, L. C.;
Aguilar, A. M. Quim. NoVa 2007, 30, 2007.
(2) (a) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett.
1996, 37, 8581. (b) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron
Lett. 1996, 37, 8585. (c) Paterson, I.; Collet, L. A. Tetrahedron Lett. 2001,
42, 1187. (d) Paterson, I.; Di Francesco, M. E.; Kuhn, T. Org. Lett. 2003,
5, 599.
(3) (a) Evans, D. A.; Gage, J. R. Tetrahedron Lett. 1990, 31, 6129. (b)
Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788. (c)
Evans, D. A.; Coˆte´, B.; Coleman, P. J.; Connell, B. T. J. Am. Chem. Soc.
2003, 125, 10893. (d) Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003,
125, 10899. (e) Evans, D. A.; Nagorny, P.; McRae, K. J.; Sonntag, L.-S.;
Reynolds, D. J.; Vounatsos, F. Angew. Chem., Int. Ed. 2007, 46, 545. (f)
Evans, D. A.; Welch, D. E.; Speed, A. W. H.; Moniz, G. A.; Reichelt, A.;
Ho, S. J. Am. Chem. Soc. 2009, 131, 3840.
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P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am. Chem. Soc.
2006, 128, 2796. (c) Li, P.; Li, J.; Arikan, F.; Ahlbrecht, W.; Dieckmann,
M.; Menche, D. J. Am. Chem. Soc. 2009, 131, 11678. (d) Li, P.; Li, J.;
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75, 2429.
10.1021/ol102303p  2010 American Chemical Society
Published on Web 10/08/2010

Et3N in Et2O, providing the 1,5-syn and 1,5-anti aldol adducts
(Scheme 3, Table 1). These boron-mediated aldol reactions
Scheme 1. 1,5-syn Stereoinduction in Aldol Reactions of
ꢀ-Trifluoromethyl and ꢀ-Trichloromethyl-ꢀ-Alkoxy
Methylketones
Scheme 3. Aldol Reactions of 6 and 7 with R′CHO
More recently, Yamamoto and co-workers have described
that very useful levels of 1,5-syn selectivity could be obtained
in lithium-mediated aldol reactions employing ꢀ-alkoxy
methylketones with super silyl protecting groups at the
ꢀ-oxygen.7
Table 1. Aldol Reactions of 6 and 7 with R′CHO
aldehyde
dra
yield
(%)b
entry
P
(R′)
(1,5-syn:1,5-anti)
At this point, we decided to study the influence of bulky
substituents at the ꢀ-position in aldol reactions of kinetic
boron enolates generated from ꢀ-alkoxy methylketones.
Methylketones with either tert-butyldimethylsilyl (TBS) or
p-methoxybenzyl (PMB) protecting groups at the ꢀ-oxygen
were initially employed to evaluate the potential steric and
electronic impact of the ꢀ-alkoxy protecting group.
Our studies began with the preparation of the ꢀ-alkoxy-
ꢀ-tert-butyl methylketones 6 (P ) PMB) and 7 (P ) TBS)
starting with an aldol reaction between acetone and pivala-
ldehyde mediated by L-proline, providing 5 in 63% yield
and 90% ee, as determined by Mosher ester analysis (Scheme
2).8 Treatment of methylketone 5 with 4-methoxybenzyl
1
TBS (7)
TBS (7)
i-Pr, 8a
i-Pr, 8a
65:35
65:35
80:20
74:26
82:18
66:34
78:22
72:28
81:19
68:32
83:17
62:38
75:25
68:32
79:21
65:35
98
79
91
92
85
98
80
86
86
71
95
90
85
86
86
88
2c
3
PMB (6) i-Pr, 8a
TBS (7) Et, 8b
PMB (6) Et, 8b
TBS (7) t-Bu, 8c
PMB (6) t-Bu, 8c
TBS (7)
PMB (6) CH2dC(Me), 8d
TBS (7)
PMB (6) Ph, 8e
TBS (7)
PMB (6) p-NO2C6H4, 8f
TBS (7)
PMB (6) p-MeOC6H4, 8g
4
5
6
7
8
9
10
11
12
13
14
15
16
a
CH2dC(Me), 8d
Ph, 8e
p-NO2C6H4, 8f
p-MeOC6H4, 8g
TBS (7)
PhCH2CH2, 8h
Ratio was determined by H and 13C NMR analysis of the diastere-
oisomeric mixture of aldol adducts. b Isolated yields of both syn and anti
isomers after SiO2 gel flash column chromatography. c CH2Cl2 as solvent.
1
Scheme 2. Preparation of ꢀ-Alkoxy Methylketones 6 and 7
were found to proceed with good yields and good levels of
remote 1,5-syn stereoinduction for methylketone 6 (P )
PMB) providing 1,5-syn isomers 9a-g as the major products.
In the same way, the boron enolate reactions of methylketone
7 (P ) TBS) with aldehydes 8a-h resulted in a mixture of
aldol adducts 11a-h and 12a-h, favoring the 1,5-syn aldol
adducts 11a-h (Scheme 3, Table 1).
Notably, these reactions provided the 1,5-syn isomer,
opposite to 1,5-anti stereoinduction observed for boron-
mediated aldol reactions of simpler ꢀ-alkyl-ꢀ-alkoxy meth-
ylketones, indicating the overriding contribution, in this
special case, from the bulky substituent at the ꢀ-position.
More surprisingly, independent of the nature of the ꢀ-oxygen
protecting group, the 1,5-syn isomer is always obtained as
the major product. The stereoinduction observed in these
reactions shows that the volume of the substituent in
ꢀ-position is crucial for control of remote stereochemistry.
Thus, it is clear that the major contribution to the sense
of 1,5-syn induction observed in aldol reactions involving
boron enolates of methylketones 1-4 is due to the volume
of the substituent at the ꢀ-position and not to electronic
effects, as stated previously.5
2,2,2-trichloroacetimidate in the presence of catalytic amounts
of TfOH gave methylketone 6 in 90% yield.9 Protection of
the ꢀ-oxygen in 5 as its TBS ether was achieved by using
TBSCl and imidazole in DMF at room temperature for 48 h
providing 7 in 78% yield10 (Scheme 2).
The aldol reactions of methylketones 6 and 7 with
aldehydes 8a-h were investigated using (c-Hex)2BCl and
(7) Yamaoka, Y.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 5354.
(8) (a) List, B. Tetrahedron 2002, 58, 5573. (b) List, B.; Pojarliev, P.;
Castello, C. Org. Lett. 2001, 3, 573. (c) List, B.; Lerner, R. A.; Barbas,
C. F., III J. Am. Chem. Soc. 2000, 122, 2395. See Supporting Information
file for more details.
(9) Doi, T.; Numajiri, Y.; Munakata, A.; Takahashi, T. Org. Lett. 2006,
8, 531.
(10) Zou, B.; Wei, J.; Cai, G.; Ma., D. Org. Lett. 2003, 5, 3503.
Org. Lett., Vol. 12, No. 21, 2010
5057

The relative stereochemistry for aldol adducts 11a-h and
12a-h (obtained from methylketone 7) was unambiguously
established after removal of the TBS protecting group in 11c
(major product, obtained after purification by SiO2 gel flash
column chromatography) with HF in acetonitrile,11 affording
the meso 1,5-diol 13, as required by a 1,5-syn relationship
(Scheme 4). Removal of the TBS group in 12c (minor
Scheme 6. Preparation of ꢀ-Alkoxy Methylketones 16, 17, and
20
Scheme 4. Proof of Stereochemistry for Aldols 11c and 12c
ꢀ-OTr methylketones 16 and 17 (Scheme 6).12 The meth-
ylketone 20 (R ) Me) was obtained by monoprotection of
diol 18 with TrCl, AgOTf, and 2,6-lutidine in CH2Cl2
providing alcohol 19 followed by Swern oxidation.
The aldol reaction between the boron enolates generated
from methylketones 16, 17, and 20, applying the conditions
described in Table 1, was performed (Scheme 7, Table 2).
isomer) generated the C2-symmetric 1,5-diol 14, [R]D +50
(c ) 0.45, CH2Cl2), as required by a 1,5-anti relationship.
To assign the relative stereochemistry for aldol adducts
obtained from methylketone 6 (P ) PMB), we treated a 78:
22 mixture of adducts 9c and 10c (P ) PMB) with DDQ
providing a mixture of diols 13 and 14 in 78% yield, which
Scheme 7. Aldol Reactions of 16, 17, and 20 with R′CHO
1
had their H and 13C NMR spectra compared with those of
diols prepared in Scheme 4 from 11c and 12c (Scheme 5).
Scheme 5. Proof of Stereochemistry for Aldols 9c and 10c
Surprisingly, entries 1 and 7 (Table 2) revealed that when
the Tr protecting group is introduced in methylketone 17 (R
) t-Bu) the 1,5-syn selectivity previously observed is lost.
In the same way, methylketone 20 (R ) Me) (entries 2, 5,
and 8) led to a 50:50 ratio of diastereoisomers. These results
show that the combination of ꢀ-alkyl groups with a ꢀ-OTr
substituent gives rise to no selectivity, independent of the
nature of this R group. However, the aldol reactions of
methylketone 16 (R ) p-NO2C6H4) were found to proceed
with good yields and low levels of remote 1,5-anti stere-
oinduction providing aldol adducts 22a,b,d-f as the major
products.
This proved that the 1,5-syn isomer is the major product with
both TBS and PMB protecting groups.
At this point, we decided to investigate the impact of a
bulky protecting group like ꢀ-trityl (OTr) at the ꢀ-oxygen.
To accomplish this, we chose methylketones with different
stereoelectronic properties at the ꢀ-substituents (R ) Me,
p-NO2C6H4, and t-Bu). The preparation of the ꢀ-alkoxy-
methylketones 16 (R ) p-NO2C6H4) and 17 (R ) t-Bu)
began with known hydroxy methylketones 15 and 5,
respectively.5c,d Protection of the ꢀ-oxygen in 15 and 5 was
achieved by using TrCl, AgOTf, and 2,6-lutidine in CH2Cl2
at room temperature for 1 h, providing the corresponding
This is interesting because in our previous studies we
found that high degrees of 1,5-anti stereoinduction were
obtained in aldol reactions of ꢀ-aryl-ꢀ-p-methoxybenzyl
(12) (a) Burk, R. M.; Gac, T. S.; Roof, M. B. Tetrahedron Lett. 1994,
35, 8111. (b) Lundquist, J. T., IV; Satterfield, A. D.; Pelletier, J. C. Org.
Lett. 2006, 8, 3915.
(11) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.;
Roberts, S. M. Tetrahedron Lett. 1979, 41, 3981.
5058
Org. Lett., Vol. 12, No. 21, 2010

Table 2. Aldol Reactions of 16, 17, and 20 with R′CHO
R
aldehyde
dra
yield
entry
(MK)
(R′)
(1,5-syn:1,5-anti) (%)b
1
2
3
4
5
6
7
8
9
t-Bu (17)
Me (20)
p-NO2C6H4 (16) i-Pr, 8a
p-NO2C6H4 (16) Et, 8b
i-Pr, 8a
i-Pr, 8a
50:50
50:50
27:73
40:60
50:50
30:70
50:50
50:50
33:67
30:70
71
95
51
55
95
98
95
77
76
76
Me (20)
CH2dC(Me), 8d
p-NO2C6H4 (16) CH2dC(Me), 8d
t-Bu (17)
Me (20)
Ph, 8e
Ph, 8e
p-NO2C6H4 (16) Ph, 8e
10 p-NO2C6H4 (16) p-NO2C6H4, 8f
a
1
Ratio was determined by H and 13C NMR analysis of the diastere-
oisomeric mixture of aldol adducts. b Isolated yields of both syn and anti
isomers after SiO2 gel flash column chromatography.
methylketones.5c,d After introducing TBS and t-Bu protecting
groups, the aldol reactions proceeded with low levels of 1,5-
syn stereoinduction. In this context, methylketone 16 (R )
p-NO2C6H4) shows unexpected selectivities.
Figure 1. Relative energies for boat-like transition structures
obtained using B3LYP/6-31G(d,p). Single-point energy (CPCM-
auks) in B3LYP/6-31+G(d,p).
To assign the relative stereochemistry for aldol adducts
obtained from methylketone 16 (R ) p-NO2C6H4, P ) Tr), we
treated a 27:73 misture of syn and anti aldol adducts 21a and
22a with HF in acetonitrile, giving a mixture of diols 27 and
28, respectively (Scheme 8). After comparison of their 1H and
On the basis of the results described here, the 1,5-syn
selectivities observed in aldol reactions of ꢀ-bulky boron
enolates cannot be explained via Goodman’s proposed IN-
1,5-SYN transition state. We have performed theoretical
calculations using density functional theory (B3LYP) on the
competing transition structures leading to both 1,5-anti and
1,5-syn aldol adducts. We studied the simple aldol transition
structures for the dimethylboron enolates and acetaldehyde.
For R ) CCl3 and t-Bu, the competitive boat-like transition
states containing stabilizing hydrogen bonds are higher in
energy when compared with the corresponding OUT-1,5-
ANTI and OUT-1,5-SYN transition states, lacking the formyl
H-bond. The analysis of the relative energies of these
transition states shows relative energies favoring the corre-
sponding OUT-1,5-SYN transition structure, thus preventing
the steric interactions of bulky R groups and supporting the
formation of the 1,5-syn diastereoisomer. The results pre-
sented in Figure 1 are in agreement with our experimental
results. Further details about the theoretical studies will be
described in a full account of this work.
Scheme 8. Proof of Stereochemistry for Aldols 21a and 22a
13C NMR spectra with spectroscopic data previously
reported,5c,d we observed that the 1,5-anti isomer is the major
product (see Supporting Information for full details).
Recently, Paton and Goodman proposed that the aldol
reactions of boron enolates generated from ꢀ-alkoxy meth-
ylketones proceed via boat-like transition states involving a
hydrogen bonding interaction.13,14 This intriguing formyl
hydrogen bond stabilizes the transition state IN-1,5-ANTI,
leading to the 1,5-anti isomer, and shows steric interactions
between the ꢀ-alkyl R group and the boron ligands in the
boat-like transition state IN-1,5-SYN, leading to the 1,5-syn
isomer (Figure 1).
Acknowledgment. We are grateful to FAEP-UNICAMP,
FAPESP, CNPq, and INCT-INOFAR (Proc. CNPq 573.564/
2008-6) for financial support and to Prof. Carol H. Collins
(IQ-UNICAMP) for helpful suggestions about English gram-
mar and style.
Supporting Information Available: Experimental pro-
cedures and spectral data for the prepared compounds as well
as Cartesian coordinates of transition structures with gas-
phase and solution-phase SCF absolute energies. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Paton, R. S.; Goodman, J. M. Org. Lett. 2006, 8, 4299. (b)
Goodman, J. M.; Paton, R. S. Chem. Commun. 2007, 2124. (c) Paton, R. S.;
Goodman, J. M. J. Org. Chem. 2008, 73, 1253
.
(14) The theoretical calculations were performed with the corresponding
S enantiomer of the ꢀ-alkoxy methylketone. For similar theoretical
calculations performed in our group, see ref 5e.
OL102303P
Org. Lett., Vol. 12, No. 21, 2010
5059