1,5-Asymmetric induction in boron-mediated β-alkoxy methyl ketone aldol addition reactions

Article abstract of DOI:10.1021/ja027640h

This article presents studies that illustrate β-alkoxy methyl ketone-derived boron enolates undergo diastereoselective aldol addition to afford the 1,5-anti diol relationship. The stereochemical outcome of this reaction is documented to be general for a v

Full text of DOI:10.1021/ja027640h

Published on Web 08/14/2003
1,5-Asymmetric Induction in Boron-Mediated â-Alkoxy Methyl
Ketone Aldol Addition Reactions
David A. Evans,* Bernard Coˆte´, Paul J. Coleman, and Brian T. Connell
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
Received July 10, 2002; E-mail: Evans@chemistry.harvard.edu
Abstract: This article presents studies that illustrate â-alkoxy methyl ketone-derived boron enolates undergo
diastereoselective aldol addition to afford the 1,5-anti diol relationship. The stereochemical outcome of this
reaction is documented to be general for a variety of â-alkoxy methyl ketone analogues and aldehyde
partners. The double stereodifferentiating reactions of these enolates with chiral â-alkoxy aldehydes have
also been investigated in conjunction with the possibility of controlling the absolute stereochemistry of the
aldol process. With the proper selection of reaction conditions, the proximal alkoxy substituent on either
the aldehyde (1,3-induction) or the enolate fragment (1,5-induction) can be employed to control facial
selectivity of the aldol addition. Selection of a boron enolate ensures dominant 1,5-anti induction from the
â-alkoxy methyl ketone-derived enolate partner while negating any influence of the â-alkoxy aldehyde
substituent. Conversely, if stereochemical control from the â-alkoxy aldehyde is desired, a Lewis acid-
catalyzed enolsilane addition ensures dominant 1,3-induction from the aldehyde â-oxygen substituent.
Introduction
Early evidence that remote induction in enolborane aldol
additions might be possible may be found in the bryostatin
studies of Masamune (eq 3).4 While the sense of 1,5-asymmetric
induction was low in this complex case, this study remains
significant in that remote induction is a possibility.
The aldol reaction is widely employed in the convergent
assembly of polyacetate-derived stereochemical arrays (1,3-
polyols).1 Two control elements that might influence the
stereochemical course of these processes are illustrated below
(eqs 1 and 2).
During the course of our synthesis of altohyrtin, we,5 and
Paterson,6 evaluated a related set of diastereoselective aldol
additions that were quite diastereoselective. In this article, we
present our studies that document the scope and limitations of
these selective methyl ketone-derived enolborinate aldol reac-
tions (eq 2).
In the addition of enol derivatives to â-alkoxyaldehydes, the
influence of the â-heteroatom substituent may influence the
stereochemical outcome of the aldol process selected (eq 1). It
is well-known that good levels of 1,3-anti induction may be
realized in the Lewis acid-promoted addition with enolsilanes
through either chelate2 or electrostatic control.3 In contrast, this
same â-substituent imparts no control over the analogous
enolborinate additions.
(2) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468 and references therein.
(3) (a) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35,
8537-8540. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J.
Am. Chem. Soc. 1996, 118, 4322-4343.
(4) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.; Somfai,
P.; Whritenour, D. C.; Masamune, S. J. Org. Chem. 1989, 54, 2817-2825.
(5) Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788-789.
(6) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37, 8585-
8588.
(1) For general approaches to the synthesis of 1,3-diol relationships in
conjunction with C-C bond formation, see: (a) Rychnovsky, S. D.; Hoye,
R. C. J. Am. Chem. Soc. 1994, 116, 1753-1765. (b) Mori, Y.; Asai, M.;
Okumura, A.; Furukawa, H. Tetrahedron 1995, 51, 5299-5314. (c)
Knochel, P.; Brieden, W.; Rozema, M. J.; Eisenberg, C. Tetrahedron Lett.
1993, 34, 5881-5884.
9
10.1021/ja027640h CCC: $25.00 © 2003 American Chemical Society
J. AM. CHEM. SOC. 2003, 125, 10893-10898
10893

A R T I C L E S
Evans et al.
Table 1. 1,5-Induction with Various Metal Enolates
Discussion
Initial Studies. Remote induction in the methyl ketone aldol
addition was first observed by us during the addition of the
9-BBN enolborinate of methyl ketone 1 to dihydrocinnamal-
dehyde. Two aldol adducts were identified from this reaction
(eq 4a). The major product 2 was isolated as a single diaste-
reomer derived from the less-substituted boron enolate. The
minor product 3 was also formed as a single stereoisomer. The
â-heteroatom substituent on the enolate component is clearly
exerting a powerful effect on the stereochemical course of this
reaction.7 Utilization of the more sterically discriminating
dibutylboron triflate8 enforced exclusive generation of the less-
substituted enolborinate, which afforded a single aldol adduct
with the same high level of diastereoselectivity (eq 4b). The
stereochemical relationship of the newly generated stereo-
center in the aldol product was determined to be anti with re-
spect to the resident â-heteroatom on the parent methyl ke-
tone 1.9
a
entry
M
T, °C
solvent
yield, %
anti/synb
1
2
3
4
5
6
7
Chx2Bc
-78
-78
-78
-78
-115
-78
-78
CH2Cl2
CH2Cl2
PhMe
Et2O
Et2O
CH2Cl2
THF
85
80
81
83
85
85
79
82:18
87:13
94:06
94:06
98:02
50:50
40:60
Bu2Bd
Bu2B
Bu2B
Bu2B
TMS/BF3‚OEt2
Lie
a Yields determined by isolation, HPLC, or NMR analysis with an internal
standard. b Ratios determined by either HPLC or H NMR analysis of the
1
unpurified product mixture. c Enolization conditions: Chx2BCl, Et3N, -78
°C, CH2Cl2. d Enolization conditions: Bu2BOTf, i-Pr2NEt, -78 °C, solvent
(ref 5). e LDA enolization.
The enolate facial bias may be further enhanced by a decrease
in reaction temperature (Table 1, entry 5). Again, in contrast to
our previous study on 1,3-induction (eq 1), the Lewis acid-
mediated aldol reaction in this system demonstrated no asym-
metric induction (Table 1, entry 6).3b Similarly, the aldol
reactions of metal enolates capable of internal chelation with
the â-heteroatom were also found to be nonselective (Table 1,
entry 7).11
Reaction Scope. The generality of 1,5-enolate induction was
probed in the examples illustrated in Table 2. Not surprisingly,
the structure of the â-oxygen protecting group plays an important
role in reaction diastereoselectivity.12 Accordingly, silicon
protecting groups may be used to neutralize this â-alkoxy control
element (Table 2, entry 2). The aldol reactions of methyl ketones
6d, 6e, and 6f, highlight the fact that the â-oxygen substituent
may be constrained within a ring without a significant alteration
in reaction diastereoselection (Table 2, entries 4-6).
Table 3 demonstrates the variety of aldehydes that participate
in this reaction. Hindered alkyl and aromatic aldehydes provide
aldol adducts in good yield and stereoselectivity, even when
the reaction temperature is not lowered below -78 °C.
In view of the relevance of this reaction to the synthesis of
polyacetate natural products, we decided to explore the scope
of this reaction. This study was initiated with an examination
of the aldol reactions of methyl ketone enolates 4 (M ) TMS,
Li, BR2) that contain a â-alkoxy substituent (Table 1). To isolate
the contribution of electrostatic effects to the diastereoselectivity
in these addition processes, enolates 4 were selected bearing
â-substituents of similar steric size but different electronic
properties (-OCH2Ar vs -CH2CH2Ar). In contrast to previous
observations on 1,3-induction (eq 1),3 the dibutyl enolborinates
displayed good levels of asymmetric induction in aldol reactions
with dihydrocinnamaldehyde, consistently favoring the 1,5-anti
diol product anti-5 (Table 1, entries 1-5). Due to the similar
steric requirements of the â-substituents, we speculate that
electronic rather than steric effects are responsible for enolate
face selectivity.
Temperature Effects. Diastereoselectivity in this and related
aldol reactions is the product of both the degree of enolate
diastereoface selectivity and the integrity of the transition state
through which the reaction proceeds. A significant temperature
effect was noted in this reaction (Table 4). Reaction diastereo-
selectivity drops significantly when the temperature is increased.
Examination of an Eyring plot clearly shows a nonlinear
relationship between reaction temperature and selectivity. This
suggests the intermediacy of more than one set of competing
diastereomeric transition states contributing to the observed
product ratios.13 If the reaction is run in CH2Cl2 for the purposes
of maintaining a fully homogeneous solution, this nonlinear
effect is still observed.14
The observation of a modest solvent effect (Table 1, entries
2-4) that documents a trend toward higher selectivity with a
decrease in solvent polarity is consistent with this postulate.10
(10) Based on dielectric constants, it is not clear why the more polar diethyl
ether (e ) 4.3) is a better solvent than toluene (e ) 2.4). However, ether
was typically used because it provided the cleanest reaction mixtures.
(11) TiCl4, Ti(Oi-Pr)2Cl2, SnCl4, ZnCl2, TrCl/SnCl2, and TrClO4 were also found
to give extremely low levels of stereochemical induction.
(12) This observation has also been noted in the addition of enolsilanes to
â-alkoxyaldehydes. See ref 3.
(13) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 477-515.
(14) The optimal solvent for these reactions is diethyl ether. However, the
reaction mixture is heterogeneous from the point of enolization until the
quench.
(7) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871-6874
(8) Evans, D. A.; Nelson, J. V.; Taber, T. R. J. Am. Chem. Soc. 1981, 103,
3099-3111. The regiochemistry (CH3 vs CH2) of the enolization process
with Bu2BOTf and Chx2BCl with these methyl ketone substrates is high
(>95:5). In certain cases, 9-BBNOTf is nonselective in this enolization
process.
(9) A detailed discussion of the procedures that were followed for the
assignment of the aldol-related stereochemical relationships is contained
in the Supporting Information.
9
10894 J. AM. CHEM. SOC. VOL. 125, NO. 36, 2003

B-Mediated â-Alkoxy Methyl Ketone Aldol Addition Reactions
Table 2. 1,5-Induction with Various Methyl Ketones
A R T I C L E S
Table 4. Temperature Profile
enolate â-stereocenter was observed under Mukaiyama (enol-
silane/Lewis acid) conditions (Table 1, entry 6). Since facial
selectivity in either reaction component can be regulated by the
proper selection of aldol reaction type (enolborinate or enolsi-
lane), the double stereodifferentiating reactions of these enolates
with chiral â-alkoxy aldehydes offer the possibility of controlling
the absolute stereochemistry of the aldol process from the
proximal alkoxy substituent on either the aldehyde (1,3-
induction) or the enolate fragment (1,5-induction). For example,
the preceding data suggest that selection of a enolborinate will
ensure 1,5-anti induction from the enolate partner while negating
the influence of the â-oxygen aldehyde substituent. Conversely,
if stereochemical control from the chiral aldehyde is desired,
selection of a Lewis acid-catalyzed enolsilane addition will
ensure dominant 1,3-induction from the aldehyde â-oxygen
substituent (eq 1).3 These double stereodifferentiating aldol
processes (Table 5) of enantiomerically pure enolborinate 9 with
the illustrated enantiopure aldehydes document the degree of
stereochemical control attainable in these double stereodiffer-
entiating processes. In summary, it is rather remarkable that
1,5-induction from the enolate component is more pronounced
(eq 5-7) than than 1,3-induction from the aldehyde component
(eq 8).
a Major product (% yield of aldol adducts). b Ratios determined by either
HPLC or H NMR analysis of the unpurified product mixture.
1
Table 3. Diastereoselective Aldol Additions to Representative
Aldehydes
Synthetic Utility. We first applied this boron-mediated aldol
reaction to a total synthesis of the marine natural product
Altohyrtin C (Spongistatin 2), where we carried out the aldol
bond construction illustrated in eq 6 (Table 5).15 The ability of
this methodology to mediate related complex fragment couplings
is illustrated in Table 6. In studies directed toward a total
a Yields determined by isolation, HPLC, or NMR analysis with an internal
1
standard. b Ratios determined by either HPLC or H NMR analysis of the
unpurified product mixture.
Double Stereodifferentiation. Although high levels of 1,5-
induction may be obtained with dibutyl enolborinate in these
methyl ketone aldol reactions (Table 3), no induction from the
(15) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.;
Rajapakse, H.; Tyler, A. N. Tetrahedron 1999, 55, 8671-8726.
9
J. AM. CHEM. SOC. VOL. 125, NO. 36, 2003 10895

A R T I C L E S
Evans et al.
Table 5. Double Diastereoselective Aldol Reactions
Table 6. Complex Aldol Fragment Aldol Couplings
synthesis of the antifungal macrolide roxaticin,16 the ketones
illustrated in eqs 9-12 were successfully coupled to the
indicated aldehyde in good yield and high (>95:5) diastereo-
selectivity. In each of these cases, the aldehyde was employed
as a 5-9:1 mixture of diastereomers at the â-position. It is
interesting to note that a kinetic resolution took place over the
course of these reactions, affording the desired product in
preference to the adduct derived from reaction of the undesired
aldehyde epimer. The observed product contained both the 1,5-
anti and the 1,3-anti stereochemistry in the polyol array. An
excess of the aldehydic isomers was employed in the reaction
and was typically recovered from the reaction as a 1:1 epimeric
ratio at the â-position.
A kinetic resolution was also observed in the reaction depicted
in eq 13. An excess of ketone 29, as an 89:11 diastereomeric
mixture at C9, was transformed into the derived boron enolate
and treated with aldehyde 30 (>99% ee) to deliver 31 as a 92:8
mixture favoring the desired C9 isomer. No evidence of a C13
(16) Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003, 125, preceding article.
9
10896 J. AM. CHEM. SOC. VOL. 125, NO. 36, 2003

B-Mediated â-Alkoxy Methyl Ketone Aldol Addition Reactions
Table 7. Other Examples of Complex 1,5-Induction
A R T I C L E S
diastereomer was observed. Recovered ketone 29 was shown
to be an 80:20 mixture of diastereomers at the â-stereocenter.
The product â-hydroxy ketone 31 has been elaborated to the
antitumor macrolide phorboxazole B.17 Finally, eq 14 illustrates
a complex aldol cross-coupling reaction recently carried out in
our laboratory.18 In this reaction, the aldehyde R-methyl and
â-OR substituents individually contribute to the aldehyde face
selectivity with the syn diastereomeric relationship for the
substituents being nonreinforcing.3b,19 In this double stereodif-
ferentiating reaction, dominant stereochemical control from the
enolate substituent affords the anti-Felkin aldol adduct. Subor-
dinate reinforcing stereocontrol is being provided by the
â-alkoxy substituent to override the facial bias of the methyl
substituent.
Table 7 illustrates the reactions and selectivities obtained
utilizing this aldol reaction that have been reported from other
laboratories.20 The yields are all good, and in most cases, the
selectivities are good to excellent. However, when steric bulk
is added to the vicinity of the â-heteroatom, selectivities often
diminish. In fact, in extreme cases (eq 21), the selectivity is
inverted to favor the 1,5-syn aldol product. This point has been
previously highlighted in Table 2 (entry 2).
A number of new applications of this boron aldol reaction
have recently appeared. For example, this reaction has been
recently incorporated into recent syntheses of leucascandrolide
A.21 In addition, the continued application of this fragment
coupling process directed toward the synthesis of peloruside
has just appeared.22 Finally, Leighton has employed a compli-
mentary double stereodifferentiating Mukaiyama aldol variant
(Table 5, eq 8) in his synthesis of mycoticin A.23
Conclusion
In summary, diastereoselective aldol addition reactions of
chiral â-alkoxy methyl ketones have been documented. Eno-
(20) (a) Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187-1191. (b)
Kozmin, S. A. Org. Lett. 2001, 3, 755-758. (c) Trieselmann, T.; Hoffman,
R. W. Org. Lett. 2000, 2, 1209-1212. (d) Bhattacharjee, A.; Soltani, O.;
De Brabander, J. K. Org. Lett. 2002, 4, 481-484. (e) Paterson, I.; Chen,
D. Y. K.; Coster, M. J.; Acena, J. L.; Bach, J.; Gibson, K. R.; Keown, L.
E.; Oballa, R. M.; Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.;
Norcross, R. D. Angew. Chem., Int. Ed. 2001, 40, 4055-4060.
(21) (a) Kozmin, S. A. Org. Lett. 2001, 3, 755-758. Wang, Y.; Janjic, J.;
Kozmin, S. A. J. Am. Chem. Soc. 2002, 124, 13670-13671. (b) Fettes,
A.; Carreira, E. Angew. Chem., Int. Ed. 2002, 41, 4098-4101. (c) Paterson,
I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343-347.
(22) Paterson, I.; Di Fransesco, M. E.; Kuhn, T. Org. Lett. 2003, 5, 599-602.
(23) Dreher, S. D.; Leighton, J. L. J. Am. Chem. Soc. 2001, 123, 341-342.
(17) Evans, D. A.; Fitch D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc.
2000, 122, 10033-10046.
(18) This reaction has been carried out by Dr. Kenneth J. McRae (Harvard
University).
(19) Evans, D. A.; Gage, J. R. Tetrahedron Lett. 1990, 31, 6129-6132.
9
J. AM. CHEM. SOC. VOL. 125, NO. 36, 2003 10897

A R T I C L E S
Evans et al.
lization with either n-Bu2BOTf or c-Hex2BCl6 allows exclusive
formation of the less-substituted enolborinate that participates
in highly distereoselective 1,5-anti aldol addition reactions to a
variety of aldehydes under mild conditions. This diastereocontrol
element can be eliminated, if so desired, by choice of a metal
counterion other than boron. This strategy allows other stereo-
control elements to dominate, such as the 1,3-anti induction
derived from addition of an enolsilane to a â-alkoxy aldehyde.
In the analysis of more complex methyl ketone aldol reactions
such as those illustrated below (eqs 22 and 23),24,25 it is tempting
to speculate that the â-alkoxy substituent could also be playing
a dominant role in directing the stereochemical course of the
indicated transformations. Indeed, Dias has drawn this conclu-
sion on the basis of the cited examples.24,26 A systematic study
that firmly documents this point would be a valuable contribu-
tion.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Support has been provided by the NIH
and NSF. The authors also thank the Merck Research Labora-
tories for student support.
JA027640H
(25) Arefolov, A.; Panek, J. S. Org. Lett. 2002, 4, 2397-2400.
(26) In the aldol reaction reported by Panek (eq 23), the indicated configurations
of the acetal centers in both reactant and product are currently in question.
This reaction has been reinvestigated by Professor L. C. Dias (Universidade
Estadual de Campinas, Instituto De Quimica-UNICAMP, Caixa Postal 6154
Campinas SPBRAZIL) who has kindly informed me of his results and of
the indicated configuration reassignment.
Supporting Information Available: Full experimental details,
characterization data, and product stereochemical assignments.
(24) Dias, L. C.; Bau, R. Z.; de Sousa, M. A.; Zukerman-Schpector, J. Org.
Lett. 2002, 4, 4325-4327.
9
10898 J. AM. CHEM. SOC. VOL. 125, NO. 36, 2003