Chiral boron enolate aldol additions to chiral aldehydes

Article abstract of DOI:10.1021/ol0618712

We have examined the double-diastereodifferentiating aldol addition reactions of chiral enolborinate 1a with chiral aldehydes leading to the corresponding aldol adducts with excellent levels of 1,5-anti diastereoselection.

Full text of DOI:10.1021/ol0618712

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4629-4632
Chiral Boron Enolate Aldol Additions to
Chiral Aldehydes†
Luiz C. Dias* and Andrea M. Aguilar
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP,
C.P. 6154, CEP 13084-971, Campinas SP, Brazil
ldias@iqm.unicamp.br
Received July 28, 2006
ABSTRACT
We have examined the double-diastereodifferentiating aldol addition reactions of chiral enolborinate 1a with chiral aldehydes leading to the
corresponding aldol adducts with excellent levels of 1,5-anti diastereoselection.
The aldol reaction is one of the most powerful transforma-
tions for the creation of the 1,3-dioxygen relationships in
organic molecules.1 As the resulting aldol adducts resemble
the 1,3-polyol fragments, this reaction has been applied for
the synthesis of a wide variety of natural products with
biological and pharmacological significance.
The incorporation of convergence into the construction of
complex polyketides requires that large fragments must be
joined together at some point in the synthesis. The aldol
reaction provides an attractive method for such a convergent
assembly.2 The key aldol assemblage reactions that join large
fragments with high and predictable levels of stereocontrol
still lack the guidance of refined models and reaction
methodology.3 The use of boron enolates derived from
R-methyl and R-methyl-â-alkoxy methyl ketones for asym-
metric aldol reactions usually give low levels of diastereo-
selectivity when compared with the high selectivities ob-
served with the use of boron enolates prepared from ethyl
ketones.4,5 Usually, reagent control using chiral ligands on
boron is required to obtain useful levels of asymmetric
induction in the addition of boron enolates of R-methyl
ketones to achiral aldehydes.4-6 To gain insight into the
principles that dictate diastereoselectivity in double-stereo-
differentiating7,8 aldol reactions, we have investigated the use
of chiral methyl ketone 1 in boron-mediated aldol reactions
with chiral aldehydes 2-12 (Scheme 1).9 These substrates
were chosen to be representative of the complex fragments
that might be coupled in polyacetate and polypropionate-
(3) Denmark, S. E.; Fujimori, S.; Pham, S. M. J. Org. Chem. 2005, 70,
10823.
(4) (a) Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997.
(b) Paterson, I.; Florence, G. J. Tetrahedron Lett. 2000, 41, 6935.
(5) An exception is the aldol reaction of â-alkoxy methyl ketones which
proceed with high 1,5-stereoinduction under substrate control: (a) Evans,
D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788. (b) Evans, D.
A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.;
Tyler, A. N. Tetrahedron 1999, 29, 8671. (c) Tanimoto, N.; Gerritz, S. W.;
Sawabe, A.; Noda, T.; Filla, S. A.; Masamune, S. Angew Chem., Int. Ed.
Engl. 1994, 33, 673. (d) Roush, W. R.; Bannister, T. D.; Wendt, M. D.;
Jablonowski, J. A.; Scheidt, K. A. J. Org. Chem. 2002, 67, 4275. (e)
Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37, 8585.
(f) Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187.
(6) For aldol reactions of chiral methyl ketone trichlorosilyl enolates
under base catalysis see: Denmark, S. E.; Fujimori, S. Synlett 2001, 1024.
(7) (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1. (b) Kolodiazhnyi, O. I. Tetrahedron 2003,
59, 5953. (c) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 10. (d)
Seebach, D.; Prelog, V. Angew. Chem. 1982, 21, 654.
* To whom correspondence should be addressed. Fax: +55-019-3788-
3023.
† This paper is dedicated to Prof. Angelo da Cunha Pinto (UFRJ) for his
outstanding contributions to the field of organic synthesis in Brazil.
(1) Reviews of the aldol reaction: (a) Cowden, C. J.; Paterson, I. Org.
React. 1997, 51, 1. (b) Franklin, A. S.; Paterson, I. Contemp. Org. Synth.
1994, 1, 317. (c) Heathcock, C. H. In Comprehensive Organic Synthesis;
Heathcock, C. H., Ed.; Pergamon Press: New York, 1991; Vol. 2, p 181.
(d) Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe Organic
Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New York, 1991; Vol.
2, p 239. (e) Paterson, I. In Comprehensive Organic Synthesis; Heathcock,
C. H., Ed.; Pergamon Press: New York, 1991; Vol. 2, p 301. (f) Evans, D.
A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(2) (a) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett.
1996, 37, 8581. (b) Evans, D. A.; Cote, B.; Coleman, P. J.; Connell, B. T.
J. Am. Chem. Soc. 2003, 125, 10893.
(8) (a) Izumi, Y.; Tai, A. in Stereodifferentiating Reactions, Academic
Press: New York, 1977. (b) Masamune, S.; Hirama, M.; Mori, S.; Ali, S.
K.; Garvey, D. S. J. Am. Chem. Soc. 1981, 103, 1568.
10.1021/ol0618712 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/29/2006

product, indicating that there is a mild inherent selectivity
toward the 1,2-anti product by the resident R-stereogenic
center, especially with a PMB protecting group at the
aldehyde â-oxygen.13-16
Scheme 1
The boron enolate 13 reacted with chiral â-alkoxy alde-
hyde (R)-7 in Et2O at -78 °C to give a mixture of aldol
adducts 18/19 in a 64:36 ratio, respectively (Scheme 2).13a
We next examined the stereochemical impact of both R and
â-aldehyde substituents with chiral syn-disubstituted R-meth-
yl-â-alkoxy aldehyde 11. Boron enolate 13 reacted with
chiral syn-R,â-disubstituted aldehyde 11 to give the corre-
sponding 1,2-syn-1,3-syn product 20 in 86% yield, with a
small stereoinduction (67:33 diastereoselectivity) resulting
from the stereogenic centers (Scheme 2).13-16 This example
shows that under these conditions a 1,2-syn aldehyde has a
small preference to give the product of Felkin addition as
well as 1,3-syn addition. The reactions of 13 with both 7
and 11 show that 1,3-asymmetric induction imposes an
intrinsic facial bias on the carbonyl that results in the for-
mation of a 1,3-syn-dioxygen relationship.13a The results ob-
served with 1,2-syn aldehyde are in accordance with previous
observations made by Roush et al. (see 18:19, Scheme 2).16
The intrinsic facial selectivity of the boron enolate 1a
generated from methyl ketone 1 has been investigated before
in our laboratories.9 For this purpose, we reacted 1a with
achiral aromatic, olefinic, and aliphatic aldehydes.
derived aldol-type reactions. Aldehydes with tert-butyldi-
methylsilyl (TBS), benzyl (Bn) and p-methoxybenzyl (PMB)
protecting groups were employed to evaluate the potential
steric and electronic impact of the protecting group.2d,10
Aldehydes 2-6 were prepared from (2S)- and (2R)-methyl
3-hydroxymethylpropionate and aldehydes 7 and 8 were
prepared from (3S)- and (3R)-1,3-butanediol.11 The 1,2-syn
(9-12) aldehydes were easily prepared by using syn-selective
aldol reactions as the key steps.12
To successfully predict the viability of double stereodif-
ferentiating reactions, the key stereocontrol elements in each
of the chiral reacting partners must be identified.13 To check
the facial selectivities of aldehydes 2, 3, 7, and 11, we reacted
them with achiral boron enolate 13 in Et2O at low temper-
atures (Scheme 2).13
We were delighted to find that this reaction led to the for-
mation of 1,5-anti products 22 as the major isomers (up to
>95:5 diastereoselectivity) (Scheme 3).9 These studies
Scheme 2
Scheme 3
showed a remarkable influence of the resident â-alkoxy
stereocenter on the stereochemical course of the aldol
reactions.9,17
(9) Dias, L. C.; Bau´, R. Z.; de Sousa, M. A.; Zuckerman-Schpector, J.
Org. Lett. 2002, 4, 4325.
(10) For a discussion of the coordinating abilities of various ether
substituents, see: (a) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462. (b) Chen,
X. N.; Hortellano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1990,
112, 6130. (c) Mori, S.; Nakamura, M.; Nakamura, E.; Koga, N.; Morokuma,
K. J. Am. Chem. Soc. 1995, 117, 5055. (d) Schreiber, S. L.; Shambayati,
S.; Blake, J. F.; Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem. Soc.
1990, 112, 697.
(11) (a) Dias, L. C.; Steil, L. J. Tetrahedron Lett. 2004, 45, 8835. (b)
Dias, L. C.; dos Santos, D. R.; Steil, L. J. Tetrahedron Lett. 2003, 44, 6861.
(12) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83. (b) Evans,
D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. (c)
Evans, D. A.; Taber, T. R. Tetrahedron Lett. 1980, 21, 4675. (d) Evans, D.
A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103,
3099.
(13) For similar investigations, see: (a) Evans, D. A.; Dart, M. J.; Duffy,
J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322. (b) Gustin, D. J.;
VanNieuwenhze, M. D.; Roush, W. R. Tetrahedron Lett. 1995, 36, 3443.
(14) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
18, 2199. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61. (c)
We use the “Felkin” descriptor to refer to the diastereomer predicted by
the Felkin-Ahn paradigm. The “anti-Felkin” descriptor refers to diastere-
omers not predicted by this transition state model.
These reactions were characterized by poor levels of
diastereoselectivity. The achiral boron enolate 13 reacted with
chiral R-methyl aldehyde (S)-2 in Et2O at -78 °C to give
the corresponding 1,2-anti product 14 as the major product
in good yield but with only 58:42 diastereoselectivity
(Scheme 2).13,16
The boron enolate addition to aldehyde (S)-3 containing
a PMB protecting group gave a mixture of aldol adducts 16
and 17 in a 74:26 ratio favoring the anti-Felkin aldol adduct
16.13-16 The stereoinduction observed in these reactions
shows that the reaction weakly favored the anti-Felkin
4630
Org. Lett., Vol. 8, No. 20, 2006

At this point we initiated a double-stereodifferentiating
study.7,8 Boron enolate 1a reacted with aldehyde (S)-3 (R )
PMB) to give anti-Felkin product 23 as the major product,
with excellent diastereoselectivities (ds >95:5) (Scheme 4).
With enantiomeric aldehydes 2 and 5 we observed the
same trend and the overall diastereoselection of the process
was again controlled by the strong facial bias of the boron
enolate to give the 1,5-anti product (Scheme 5).
Scheme 4
Scheme 5
Reaction of aldehyde (S)-4 (R ) Bn) led to similar results
in terms of yields and diastereoselectivities.15,16 The facial
bias of chiral boron enolate 1a is dominated by the â-alkoxy
stereocenter and tends to give the 1,5-anti isomer.9 As the
facial bias of these particular aldehydes is for the anti-Felkin
product, there is an enhancement of the 1,5-anti selectivity
because the sense of stereoinduction by the boron enolate
and that of the aldehyde are the same. These two examples
represent “matched cases” of double stereodifferentiation.7,8
The aldol adducts 23 and 24 appeared ideally suited for
stereochemical analysis by using the very simple method for
assigning the relative stereochemistry of â-hydroxy ketones
reported in 2002 by Roush and co-workers.16,18 Recently,
we reported a refinement of Roush’s model, in which we
Addition of the chiral boron enolate 1a to aldehyde (S)-2
led to aldol adduct 28 as the major isomer, with >95:05
diastereoselectivity (Scheme 5). As the facial bias of the
aldehyde 2 was to give the 1,2-anti product, we expected a
matched case and high levels of diastereoselectivity in the
reaction of 1a with (S)-2, which was in fact observed. The
relative stereochemistry for aldol adduct 28 was determined
after conversion to the corresponding acetal 29 (63%) by
treatment of 28 with HF‚pyr in THF (Scheme 5). Analysis
1
of the H NMR coupling constants, specifically JHa-Hc
)
)
2.7 Hz, JHb-Hc ) 2.4 Hz, JHd-He ) 5.1 Hz, and JHd-Hf
11.7 Hz, proved that Ha, Hd, and Hf were all axial in 29.
This indicated that acetal 29 derived from a 1,5-anti-Felkin
aldol product.
1
show that H HMR ABX pattern analysis is not applicable
Addition of the boron enolate 1a to the enantiomeric
aldehyde (R)-5 led to the formation of aldol adduct 30 as
the major isomer with 86:14 diastereoselectivity (Felkin
product). Again, this represents a “partially matched case”
of double stereodifferentiation, as aldehyde 5 has a small
preference for anti-Felkin addition. The relative stereochem-
istry for aldol adduct 30 was established after conversion to
acetal 31 (68%, two steps) by treatment of 30 with HF‚pyr
followed by PPTS in MeOH (Scheme 5). Analysis of the
to â-hydroxy ketones (e.g., aldols) derived from aldehydes
lacking â-branches.19 The relative stereochemistry for aldol
adduct 23 was then unambiguously established after conver-
sion to the corresponding benzylidene acetal 25 by treatment
of 23 with DDQ in CH2Cl2 (Scheme 4).20 Analysis of the
1H NMR coupling constants, specifically J ) 9.9 Hz, proved
that Ha and Hb were both axial in 25 (Scheme 4). This
indicated that benzylidene acetal 25 derived from an anti-
Felkin aldol product. On the other hand, the use of enan-
tiomeric aldehyde 6 led to the formation of aldol adduct 26
as the major isomer with 90:10 diastereoselectivity (Felkin
addition). This aldehyde gives rise to lower selectivity
because the stereoinduction caused by the aldehyde is
opposite to the effect of the â-alkoxy stereocenter in the
boron enolate 1a. Apparently, this represents a “partially
matched case” of double stereodifferentiation, as aldehyde
6 has a small preference for anti-Felkin addition. The relative
stereochemistry of aldol 26 was determined after conversion
to the p-methoxybenzylidene acetal 27 by DDQ oxidation
of the PMB ether.21 The coupling constant measured between
Ha-Hb (J ) 2.1 Hz) in 27 confirmed the Felkin stereo-
chemistry for aldol 26.
(15) (a) The ratios were determined by 1H and 13C NMR spectroscopic
analysis of the unpurified product mixture; (b) All of the percentage values
represent data obtained from at least three individual trials.
(16) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwenhze,
M. S.; Gustin, D. J.; Dilley, G. J.; Lane, G. C.; Scheidt, K. A.; Smith, W.
J., III. J. Org. Chem. 2002, 67, 4284.
(17) Arefolov, A.; Panek. J. S. Org. Lett. 2002, 4, 2397.
(18) Liu, C. M.; Smith, W. J., III; Gustin, D. J.; Roush, W. R. J. Am.
Chem. Soc. 2005, 127, 5770.
(19) Dias, L. C.; Aguilar, A. M.; Salles, A. G., Jr.; Steil. L. J.; Roush,
W. R. J. Org. Chem. 2005, 70, 10461.
(20) Having confirmed the relative relationship between boron enolate-
derived stereogenic centers, the absolute stereochemistry of the newly
formed hydroxyl substituent was determined by ascertaining its relationship
to the known stereocenter originating from the aldehydes.
(21) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889.
Org. Lett., Vol. 8, No. 20, 2006
4631

1H NMR coupling constants, specifically JHa-Hc ) 11.1 Hz,
JHb-Hc ) 4.8 Hz, JHc-Hd ) 10.2 Hz, JHd-He ) 4.8 Hz, and
JHd-Hf ) 10.2 Hz, proved that acetal 31 derives from a Felkin
aldol product.
The next step involved the use of aldehyde (R)-7, and the
addition of boron enolate 1a proceeded smoothly providing
aldol 32 with 82:18 diastereoselectivity. Chiral boron enolate
1a reacted with aldehyde (S)-8 to give â-hydroxy ketone 33
with >95:05 diastereoselectivity (Scheme 6).
ties. Indeed, this was found to be the case. The reaction of
chiral boron enolate 1a with aldehyde 11 gave aldol 36 as
the major isomer (Felkin addition, matched case) (Scheme
7). Under the same conditions as described before, chiral
boron enolate 1a reacted with aldehyde 12 to give isomer
37 with >95:05 diastereoselectivity (Scheme 7). The stereo-
chemical assignment of compounds 34-37 was determined
by their 1H NMR analysis, according to Roush’s model.16,18,19
This method involves analysis of the ABX system for the
1
methylene unit R to the carbonyl group in the H NMR
spectra of the â-hydroxy ketones.16,18,19 The 1H NMR spectra
(measured in C6D6) of aldol adduct 34 (or anti-Felkin) exhibit
a characteristic doublet of doublet for Ha (2.78 ppm) with a
small Ja,x (2.6 Hz) downfield of the resonance for Hb (2.58
ppm), which shows a large Jb,x (8.6 Hz). Similar results were
observed for aldol adduct 35. For Felkin aldol adduct 36 (R
Scheme 6
1
) TBS), the H NMR displays a downfield resonance for
Ha (2.71 ppm) with a large Ja,x (9.2 Hz), and a higher
resonance for Hb (2.53 ppm), with a small Jb,x (2.9 Hz).
1
For Felkin aldol adduct 37 (R ) PMB), the H NMR
displays a downfield resonance for Ha (2.80 ppm) with a
large Ja,x (8.6 Hz), and a higher resonance for Hb (2.55 ppm),
with a small Jb,x (3.3 Hz). These results are consistent with
the aldols adopting internally hydrogen bonded conforma-
tions, as proposed by Roush and co-workers.16,18,19
The stereochemical outcome of these reactions seems to
be controlled mainly by the resident â-alkoxy stereogenic
center of boron enolate, although the result with aldehyde 7
was interesting as it shows a mismatched situation. We next
examined the addition of chiral boron enolate 1a to chiral
syn-disubstituted R-methyl-â-alkoxy aldehydes 9-12 (Scheme
7). Chiral boron enolate 1a reacted with aldehydes 9 and 10
We have described here that high levels of substrate-based,
1,5-anti-stereocontrol could be achieved in the boron-medi-
ated aldol reactions of R-methyl-â-alkoxy methyl ketones
with chiral aldehydes, leading to both Felkin and anti-Felkin
aldol addition products. The examples presented in this work
show that the levels of facial selection are independent of
the absolute stereochemistries of the aldehydes although
dependent on the absolute stereochemistry of the chiral boron
enolate. The strong internal stereoinduction of chiral enolate
1a dominated the overall stereochemical outcome of these
aldol addition reactions. These stereoselective aldol reactions
should prove valuable in polyketide synthesis and we believe
they will allow synthetic chemists to confidently pursue more
aggressive convergent approaches toward assembling com-
plex polyacetate arrays in the synthesis of natural products.
Further studies in this direction are underway to explore their
generality and origin and will be described in due course.22,23
Scheme 7
Acknowledgment. We are grateful to FAPESP and CNPq
for financial support. We thank also Prof. Carol H. Collins
(Institute of Chemistry, UNICAMP) for helpful suggestions
about English grammar and style.
Supporting Information Available: Product character-
ization for the prepared compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
to give a >95:05 ratio favoring the anti-Felkin isomers 34
and 35, respectively (Scheme 7). In this latter case, the
â-alkoxy stereocenter in the boron enolate (propensity for
1,5-anti addition) exerts a dominant influence on aldehyde
facial selectivity, by overriding the low intrinsic bias imposed
by the R and â-stereocenters in the aldehyde, to give the
1,2-syn-1,3-syn products. Chiral aldehydes 11 and 12 were
next employed in anticipation that their preference for
forming adducts 36 and 37, combined with the same intrinsic
preference of the substrate 1a, would lead to high selectivi-
OL0618712
(22) Several computational studies indicate that chairlike and boatlike
transiton states in methyl ketone aldol reactions are relatively close in
energy: (a) Li, Y.; Paddow-Row: M. N.; Houk, K. N. J. Org. Chem. 1990,
55, 1535. (b) Bernardi, F.; Robb, M. A.; Suzzi-Vall, G.; Tagliavini, E.;
Trombin, C.; Umani-Ronchi, A. J. Org. Chem. 1991, 56, 6472.
(23) For papers dealing with the origins of remote asymmetric induction
in these reactions, see: (a) Paton, R. S.; Goodman, J. M. Org. Lett. 2006,
8, 4299-4302. (b) Stocker, B. L.; Teesdale-Spittle, P.; Hoberg, J. O. Eur.
J. Org. Chem. 2004, 330.
4632
Org. Lett., Vol. 8, No. 20, 2006