The anti-selective boron-mediated asymmetric aldol reaction of carboxylic esters

Full text of DOI:10.1021/ja963754f

2586
J. Am. Chem. Soc. 1997, 119, 2586-2587
Scheme 1
The Anti-Selective Boron-Mediated Asymmetric
Aldol Reaction of Carboxylic Esters
Atsushi Abiko,*,† Ji-Feng Liu,† and Satoru Masamune*,‡
Institute for Fundamental Research, Kao Corporation
Ichikai-machi, Haga-gun, Tochigi 321-34, Japan
Department of Chemistry, Massachusetts Institute of
Technology, 77 Massachusetts AVenue
Scheme 2a
Cambridge, Massachusetts 02139
ReceiVed October 28, 1996
a (i) MesSO2Cl, Et3N, CH2Cl2, 100%; (ii) BnBr, K2CO3, MeCN,
reflux, 7 h, 95%; (iii) EtCOCl, py., CH2Cl2, 0 °C to room temperature,
100%.
Natural products of propionate origin such as macrolide
antibiotics often contain both anti- and syn-3-hydroxy-2-
methylcarbonyl units (1 and 2) in their structural framework.
While the efficient construction of the syn unit 2 can now be
readily achieved through an asymmetric aldol reaction,1 efforts
still continue to explore the synthetic method for the anti unit
1.2 Several methods for anti-aldols thus far recorded in the
literature include (1) the use of the boron, titanium, or tin(II)
enolate carrying chiral ligands,3 (2) an asymmetric version of
the Lewis acid catalyzed aldol reaction generally categorized
as the Mukaiyama aldol reaction,4 and (3) the use of the metal
enolate derived from a chiral carbonyl compound.5 In many
cases these methods provide anti-aldols with high enantiose-
lectivities but appear to present problems in terms of the
availability of reagents, the generality of reactions, or conditions
required for reactions. Because of its proven reliability,1 we
have focussed on the boron-mediated aldol reaction and disclose
herein the finding that the aldol reaction of the chiral ester 3
with a wide variety of aldehydes proceeds anti-selectively with
excellent diastereofacial selectivity.6
The design of ester 3 originates from our recent observations
that (1) carboxylic esters can be converted under the standard
conditions (dialkylboron triflate and amine) into the correspond-
ing boron enolates which react with aldehydes to yield aldol
products in high yield and (2) more importantly the syn- and
anti-stereochemistry of the aldol products can be controlled by
the proper choice of reagents and enolization conditions.7 Thus,
the reaction of an ester consisting of a sterically bulky alcohol
with dicyclohexylboron triflate and triethylamine led to the
predominant formation of the anti-aldols. After extensive
screening of the propionate esters of chiral (enantio-pure or
racemic) alcohols, the ester 3 was found to be a superb
stereocontrolling reagent in terms of both simple diastereo- and
diastereofacial selectivities. Both enantiomers of the propionate
3 were prepared from commercially available (+)- or (-)-
norephedrine in three steps: (1) selective sulfonylation of the
amino group with mesitylenesulfonyl chloride and triethyl-
amine,8 (2) selective N-alkylation with benzyl bromide in the
presence of base (K2CO3 in CH3CN),9 and (3) acylation with
propionyl chloride and pyridine. 3: mp 147 °C,10 [R]D 11.1 (c
2.24, CHCl3). Ent-3: mp 147 °C,10 [R]D -11.2 (c 2.38, CHCl3).
The stereoselectivity of the aldol reaction of ester 3 (with
isobutyraldehyde) was crucially influenced by the reaction
parameters involved in the generation of the enolates (Table
1). As expected from our earlier observation,7 the combination
of dibutylboron triflate and triethylamine failed to enolize 3
(entry 1). The use of diisopropylethylamine, instead of triethyl-
amine, effected the syn-selective aldol reaction (syn:anti ) 7:1;
ds for the syn-isomer >97:3) (entry 2). Dicyclopentylboron
triflate and triethylamine behaved similarly to the case of
dibutylboron triflate (entry 3), whereas the use of diisopropyl-
ethylamine afforded the anti-aldol product with high diastereo-
facial selectivity (entry 4). The use of dicyclohexylboron triflate
and triethylamine improved both reactivity and selectivity (entry
5), which indicated that this combination would represent a
synthetically useful method (see also Table 2 for the stereose-
lectivity). It should be noted that the E(O)-enolate, which
† Institute for Fundamental Research, Kao Corporation.
‡ Massachusetts Institute of Technology.
(1) For instance, see: (a) Kim, B.-M.; Williams, S. F.; Masamune, S.
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2 (Heathcock, C. H., Ed.), Chapter 1.7, p 239.
(b) Heathcock, C. H. Modern Synthetic Methods; Scheffold, R., Ed.; VCH:
New York, 1992; p 1.
(2) Braun, M.; Sacha, H. J. Prakt. Chem. 1993, 335, 653. Asymmetric
crotyl metalation could be used for the same transformation. Reviews of
allylmetal addition: Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489. Roush, W.
R.; In ComprehensiVe Organic Synthesis, Vol. 2; Heathcock, C. H., Ed.;
Pergamon Press: Oxford, 1991; pp 1-53. Fleming, I. In ComprehensiVe
Organic Synthesis, Vol. 2; Heathcock, C. H., Ed.; Pergamon Press: Oxford,
1991 pp 563-593. Panek, J. S. In ComprehensiVe Organic Synthesis, Vol.
1 Schreiber, S. L., Ed.; Pergamon Press: Oxford, 1991 pp 579-627.
(3) For Sn enolates, see: (a) Narasaka, K.; Miwa, T. Chem. Lett. 1985,
1217. For Ti enolates, see: (b) Duthaler, R. O.; Herold, P.; Wyler-Helfer,
S.; Riediker, M. HelV. Chim. Acta 1990, 73, 659. For B enolates, see: (c)
Meyers, A. I.; Yamamoto, Y. Tetrahedron 1984, 40, 2309. (d) Masamune,
S.; Sato, T.; Kim, B.-M.; Wollmann, T. A. J. Am. Chem. Soc. 1986, 108,
8279. (e) Reetz, M. T.; Rivaedeneira, E.; Niemeyer, C. Tetrahedron Lett.
1990, 27, 3863. (f) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112,
4976. (g) Gennari, C.; Hewkin, C. T.; Molinari, F.; Bernardi, A.; Comotti,
A.; Goodman, J. M.; Paterson, I. J. Org. Chem. 1992, 57, 5173. (h) Gennari,
C.; Moresca, D.; Vieth, S.; Vulpetti, A. Angew. Chem., Int. Ed. Engl. 1993,
32, 1618.
(4) For Si enolates, see: (a) Helmchen, G.; Leikauf, U.; Taufer-Knopfel,
I. Angew. Chem. Int. Ed. Engl. 1985, 24, 874. (b) Gennari, C.; Bernardi,
A.; Colombo, L.; Scolastico, C. J. Am. Chem. Soc. 1985, 107, 5812. (c)
Oppolzer, W.; Marco-Contelles, J. HelV. Chim. Acta 1986, 69, 1699. (d)
Oppolzer, W.; Starkemann, C.; Rodriguez, I.; Bernardinelli, G. Tetrahedron
Lett. 1991, 32, 61. (e) Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993,
34, 4321. For B enolates, see: (f) Danda, H.; Hansen, M. M.; Heathcock,
C. H. J. Org. Chem. 1990, 55, 173. (g) Walker, M. A.; Heathcock, C. H.
J. Org. Chem. 1991, 56, 5747. (h) Wang, Y.-C.; Hung, A.-W.; Chang, C.-
S.; Yan, T.-H. J. Org. Chem. 1996, 61, 2038. For Ti enolates, see: (i)
Ghosh, A. K.; Ohnishi, M. J. Am. Chem. Soc. 1996, 118, 2527.
(5) (a) Davies, S. G.; Dordor-Hedgecock, I. M.; Warner, P. Tetrahedron
Lett. 1985, 26, 2125. (b) Myers, A. G.; Widdowson, K. L. J. Am. Chem.
Soc. 1990, 112, 9672. (c) Van Draanen, N. A.; Arseniyadis, S.; Crimmins,
M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56, 2499. (d) Braun, M.;
Sacha, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 1318. (e) Paterson, I.;
Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett. 1994, 35, 9083.
(6) The titanium enolates derived from the propionates of two related
chiral sulfonamide-alcohols have been reported to undergo Lewis-acid
mediated aldol reactions. One set of aldol reactions proceeded syn-selectively
(Xiang, Y.-B.; Olivier, E.; Ouimet, N. Tetrahedron Lett. 1992, 33, 457)
and the other anti-selective (4i) even under similar conditions.
(7) Abiko, A.; Liu, J.-F.; Masamune, S. J. Org. Chem. 1996, 61, 2590.
(8) Reetz, M. T.; Ku¨kenho¨hner, T.; Weinig, P. Tetrahedron Lett. 1986,
27, 5711.
(9) Under other conditions such as Cs2CO3 in CH3CN (reflux, 0.5 h) or
KOt-Bu in DMF (room temperature, 3 h), the reaction also proceeded well.
(10) Compound 3 and ent-3 exist in polymorphic form: lower mp 124
°C.
S0002-7863(96)03754-7 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 10, 1997 2587
Table 1. Aldol Reaction of Ester 3a
Table 3. Aldol Reaction of Ester 3 and ent-3 with Representative
Aldehydea
yield
temp, time (%) 4cb 4′cb 5cb 5′cb
yieldc
(%)
ds for
anti(4:4′)
entry
R2BOTf
amine
Et3N
entry
RCHO
productb
1
2
3
4
5
6
7
Bu2BOTf
Bu2BOTf
-78 °C, 2 h <3
i-Pr2EtN -78 °C, 2 h
-78 °C, 2 h
c-Pen2BOTf i-Pr2EtN -78 °C, 2 h
c-Hex2BOTf Et3N -78 °C, 2 h
c-Hex2BOTf i-Pr2EtN -78 °C, 2 h
80 12
8
68 93
98 98
70 97
1
85
2
1
2
EtCHO
PrCHO
i-PrCHO
c-HexCHO
t-BuCHO
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
ent-4c
ent-4f
90
95
98
91
96
93
96
97
94
98
91
95
96.1:3.9
95.2:4.8
97.7:2.3
95.2:4.8
99.4:0.6
94.7:5.3
98.0:2.0
95.8:4.2
94.8:5.2
95.7:4.3
97.7:2.3
94.6:5.4
c-Pen2BOTf Et3N
3d
4
4
2
3
2
2
0
0
1
0
0
1
5
6
7
8
c-Hex2BOTf Et3N
-78 °C, 2 h; 97 66
0 °C, 1 h
31
PhCHO
(E)-MeCHdCHCHO
CH2dC(Me)CHO
BnOCH2CH2CHO
BnOCH2C(Me)2CHO
i-PrCHO
a Enolization: 3 (1 equiv) was treated with R2BOTf (2 equiv) and
amine (2.4 equiv) in CH2Cl2 under the conditions (temp. and time)
indicated in the table. Aldol reaction with i-PrCHO (1.2 equiv): at
-78 °C for 1 h and then 0 °C for 1 h. Yield and product ratio by
HPLC analysis. b 4c (R ) i-Pr; 2R,3R), 4′c (R ) i-Pr; 2S,3S), 5c (R )
i-Pr; 2R,3S), 5′c (R ) i-Pr; 2S,3R).
9
10
11e
12e
PhCHO
a After an enol borinate was formed at -78 °C, aldehyde (1.2 equiv)
was added at -78 °C. Aldol conditions: at -78 °C for 1 h and then
0 °C for 1 h. Yield and the isomer ratio by HPLC analysis. b 4a (R )
Et), 4b (R ) n-Pr), 4c (R ) i-Pr), 4d (R ) c-Hex), 4e (R ) t-Bu), 4f
(R ) Ph), 4g (R ) E-MeCHdCH-), 4h [R ) CH2dC(Me)], 4i (R )
BnOCH2CH2-), 4j [R ) BnOCH2C(Me)2-]. c Yields of syn isomers
(5 and 5′) < 2%. d See Table 1, entry 5. e ent-3 used.
Table 2. Enolization of Ester 3 with Dicyclohexylboron Triflatea
c-Hex2BOTf
(equiv)
Et3N
(equiv)
enolization
time
entry
yieldb ds (4c:4′c)
1
1.0
1.5
2.0
1.7
1.7
1.2
1.8
2.4
2.0
2.0
2 h
2
2
0.5
1
67
91
98
56
73
97.3:2.7
97.2:2.8
97.7:2.3
95.9:4.1
97.4:2.6
2
3c
4
examined. The diastereoselectivity of the reaction was measured
1
by HPLC and H NMR analyses. The purified aldol products
5
were converted to the corresponding alcohols (LiAlH4, THF, 0
°C, 1 h) and/or carboxylic acids (LiOH, THF-H2O, 3 days)4c
without loss of the stereochemical integrity.12 The absolute
stereochemistry of the major product was determined by
comparison of the optical rotation data of the corresponding
diols or methyl esters with the literature values. The chiral
auxiliary could be recovered by silica gel chromatography nearly
quantitatively and reused.
In conclusion, we have successfully devised a highly efficient,
reliable method for the stereoselective construction of the anti-
3-hydroxy-2-methylcarbonyl system, a task that has challenged
us for many years. It should be emphasized that the ready
availability of the auxiliary group, the ease of the operation,
and the mildness of the boron aldol reaction render this method
advantageous and practical.
a After the enol borinate was formed at -78 °C, i-PrCHO (1.2 equiv)
was added at -78 °C. Aldol conditions: at -78 °C for 1 h and then
0 °C for 1 h. Yield and isomer ratio by HPLC analysis. b Yields of syn
isomers (5c and 5′c) < 2%. c See Table 1, entry 5 .
formed at -78 °C, isomerized to a mixture of E(O)- and Z-
(O)-enolates (anti:syn ) ∼2:1) upon warming to 0 °C for 1 h
(entry 7). Rather unexpectedly, the absolute configuration of
the C-2 carbon of the major syn isomer 5c was the same as
that of the anti-isomer 4c. This shows that the E(O)- and Z-
(O)-enolates behave differently in the sense of facial selection
when they react with an aldehyde.11
The c-Hex2BOTf-Et3N combination was further investigated.
As shown in Table 2, entries 1-3, 2 equiv of the boron triflate
was necessary to complete enolization of 3 (1 equiv), and we
conclude that the optimal enolization condition is achieved with
the use of 2 equiv of c-Hex2BOTf and 2.4 equiv of Et3N in
CH2Cl2 at -78 °C for 2 h (entry 3). It is noted that the change
in the equivalent amount of the boron triflate (1-2 equiv) did
not affect the selectivity, and this fact rules out the possibility
that the formation of the anti-aldols proceeds through Lewis-
acid catalysis.
Acknowledgment. The work at M.I.T. was generously supported
by a grant (CA48175) from the National Institutes of Health awarded
to S.M.
Supporting Information Available: The general experimental
procedure for the preparation of 3, the general procedure for the aldol
reaction, general procedures for the hydrolysis of the aldol products,
and characterization of all new compounds (11 pages). See any current
masthead page for ordering and Internet access instructions.
The optimal conditions defined above for the aldol reaction
were used for representative aldehydes. As shown in Table 3,
the excellent anti-selectivity (anti:syn ) >98:2) and diastereo-
facial selectivity for anti-isomers (>95:5) were achieved for all
of the aliphatic, aromatic, and R,â-unsaturated aldehydes
JA963754F
(12) See Supporting Information for complete experimental details on
the hydrolysis of the aldol products.
(11) Corey, E. J.; Lee, D.-H. Tetrahedron Lett. 1993, 34, 1737.