1,5-Asymmetric Induction in Methyl Ketone Aldol Addition Reactions

Full text of DOI:10.1021/jo962417m

7
88
J . Org. Chem. 1997, 62, 788-789
1
,5-Asym m etr ic In d u ction in Meth yl Keton e
Ta ble 1. 1,5-In d u ction w ith Va r iou s Meta l En ola tes
Ald ol Ad d ition Rea ction s
David A. Evans,* Paul J . Coleman, and Bernard C oˆ t e´
Department of Chemistry & Chemical Biology, Harvard
University, Cambridge, Massachusetts 02138
entry
M
T (°C) solvent yielda (%) anti/synb
Received December 30, 1996
Chx2Bc
1
2
3
4
5
6
7
-78 CH2Cl2
-78 CH2Cl2
-78 PhMe
-78 Et2O
85
80
81
83
85
85
79
82:18
87:13
94:06
94:06
98:02
50:50
40:60
Bu2Bd
The aldol reaction holds potential as a powerful method
for the convergent assembly of polyacetate-derived ster-
eochemical arrays (1,3-polyols). Two possible control
elements that might influence the stereochemical course
of these processes are illustrated below (eqs 1 and 2).
Bu2B
Bu2B
1
Bu2B
-115 Et2O
-78 CH2Cl2
-78 THF
TMS/BF3‚OEt2
e
Li
a
Yields determined by either isolation, HPLC, or NMR analysis
Abbreviations: PMB
with an internal standard.
)
b
1
p-(MeO)C6H4CH2. Ratios determined either by HPLC or H NMR
c
analysis of the unpurified product mixture. Enolization condi-
tions: Chx2BCl, Et3N, -78 °C, CH2Cl2. d Enolization conditions:
Bu2BOTf, i-Pr2NEt, -78 °C, solvent (ref. 5). e LDA enolization.
Ta ble 2. Ster eoselective Ald ol Rea ction s w ith
Rep r esen ta tive Keton es
In the addition of enol derivatives to â-alkoxy alde-
hydes, the influence of the â-heteroatom substituent may
be regulated by the nature of the aldol process selected
(eq 1). For example, good levels of 1,3-anti induction may
be realized in the Lewis acid-promoted addition with enol
silanes. In contrast, this same substituent possesses no
control over the analogous enol borinate nucleophilic
additions.2 We have speculated that the principal bias
exerted by the â-alkoxy substituent is electrostatic in
nature. Given the importance of these remote effects on
the π-facial selectivity of aldehyde electrophiles, we have
now probed the analogous polar effect of a â-heteroatom
substituent on the enolate facial bias in these acetate
aldol processes (eq 2).3 In this paper, methyl ketone
enolates that undergo highly 1,5-diastereoselective aldol
addition are identified, and the integration of this control
element into double-stereodifferentiating aldol reactions
is presented.
,4
This study was initiated with an examination of the
aldol reactions of unsubstituted ketone enolates 1 (M )
TMS, Li, BR
2
) that contain a â-alkoxy substituent (Table
1
). To isolate the contribution of electrostatic effects to
a
Major product (%, yield of aldol adducts). Abbreviations: PMB
the diastereoselectivity of these addition processes, eno-
lates 1 were selected bearing â-substituents of similar
)
)
p-(MeO)C6H4CH2; PMP ) p-(MeO)C6H5; TBS ) t-BuMe2Si; Tr
Ph3C. b Ratios determined by HPLC or 1H NMR analysis of the
steric size (-OCH
2
2 2
Ar vs -CH CH Ar) but different
unpurified product mixture.
electronic properties. Unlike our previous study on 1,3-
2
5
induction (eq 1), the dialkylboron enolates displayed
good levels of asymmetric induction with dihydrocinna-
maldehyde, consistently favoring the 1,5-anti diol product
(
1) For general approaches to the synthesis of 1,3-diol relationships
2
(Table 1, entries 1-5). Due to the similar steric
in conjunction with C-C bond formation see: (a) Rychnovsky, S. D.;
Hoye, R. C. J . Am. Chem. Soc. 1994, 116, 1753-1765. (b) Mora, Y.;
Asai, M.; Okumura, A.; Furukawa, H. Tetrahedron 1995, 51, 5299-
requirements of the â-substituents, electrostatic effects
might be at least partially responsible for enolate face
selectivity. The enolate facial bias may be further
enhanced by a decrease in reaction temperatures (Table
5
314. (c) Knochel, P.; Brieden, W.; Rozema, M. J .; Eisenberg, C.
Tetrahedron Lett. 1993, 34, 5881-5884.
2) (a) Evans, D. A.; Duffy, J . L.; Dart, M. J . Tetrahedron Lett. 1994,
5, 8537-8540. (b) Evans, D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G.
J . Am. Chem. Soc., 1996, 118, 4322-4343.
3) (a) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J .
C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J . Org. Chem. 1989,
4, 2817-2825. (b) Seebach, D.; Misslitz, U.; Uhlmann, P. Angew.
Chem., Int. Ed. Engl. 1989, 28, 472-473.
4) For 1,4-induction in acetate aldol reactions see: (a) Zibuck, R.;
Liverton, N. J .; Smith, A. B. J . Am. Chem. Soc. 1986, 108, 2451-2453.
b) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24-37. (c)
Paterson, I.; Goodman, J . M.; Isaka, M. Tetrahedreon Lett. 1989, 30,
(
1
, entry 5). In contrast to our previous study on 1,3-
3
2
induction (eq 1), the Lewis acid-mediated aldol reaction
in this system demonstrated no asymmetric induction
(
(
Table 1, entry 6).6 Similarly, the aldol reactions of metal
5
enolates capable of internal chelation with the â-het-
(
7
eroatom were also nonselective (Table 1, entry 7).
(
(5) Evans, D. A.; Nelson, J . V.; Vogel, E.; Taber, T. R. J . Am. Chem.
7
3
3
4
121-7124. (d) Trost, B. M.; Urabe, H. J . Org. Chem. 1990, 55, 3982-
983. (e) Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 33,
587-3590. (f) Lagu, B. R.; Liotta, D. C. Tetrahedron Lett. 1994, 35,
485-4488.
Soc. 1981, 103, 3099-3111. The regiochemistry (CH
3 2
vs CH ) of the
enolization process with Bu BOTf and Chx BCl with these methyl
2
2
ketone substrates is high (>95:5). In certain cases, 9-BBNOTf is
nonselective in this enolization process.
S0022-3263(96)02417-6 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 4, 1997 789
Ta ble 3. Dou ble Ster eod iffer en tia tin g Ald ol F r a gm en t Cou p lin g Rea ction sa
a
Reactions carried out at -78 °C, except where noted, in the indicated solvent. Abbreviations: PMB ) p-(MeO)C6H4CH2; TES )
Et3Si; TBS ) t-BuMe2Si; Np(â) â ) naphthyl; Tr ) Ph3C.
The generality of 1,5-enolate induction was probed in
the examples illustrated in Table 2. Dihydrocinnamal-
dehyde was selected as the common aldehyde for pur-
poses of comparison; however, it appears that these
tended these calculations to the more relevant reaction
of Me BOC(Me))CH + MeCH)O and find that the
twist-boat, while still favored, differs from the chair
geometry by only 0.4 kcal/mol.
2
2
8
results may be generalized to other aldehydes. Not
The double-stereodifferentiating reactions of these
enolates with chiral â-alkoxy aldehydes offer the pos-
sibility of controlling the absolute stereochemistry of the
aldol process from the proximal alkoxy substituent on
either the aldehyde (1,3-induction) or the enolate frag-
ment (1,5-induction) since face selectivity in either reac-
tion component can be regulated by the proper selection
of aldol reaction type. For example, the preceding data
suggest that selection of a boron enolate 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
surprisingly, the structure of the â-oxygen protecting
group plays an important role in reaction diastereose-
lectivity (Table 2, entry 2).9 Accordingly, silicon protect-
ing groups may be employed to neutralize this control
element. Finally, the aldol reactions of methyl ketones
3
d -f illustrate that the â-oxygen substituent may be
constrained within an oxygen heterocycle without a
significant alteration in reaction diastereoselection (Table
1
0 ,15
2
, entries 4-6).
Aldol reaction diastereoselectivity in this and related
reactions (cf. eq 3) is the product of both the degree of
enolate diastereoface selectivity and the integrity of the
transition state through which the reaction proceeds. For
the present reactions, the sense of asymmetric induction
enol silane addition will ensure dominant 1,3-induction
2a
from the aldehyde â-oxygen substituent (eq 1).
The
(1,5-anti) may be reconciled with our previous observa-
double-stereodifferentiating aldol processes illustrated in
Table 3 confirm this premise. The aldol reactions of
enantiomerically pure methyl ketone 5 with the il-
tions on the related addition reactions of substituted
enolates that exhibit exceptionally high levels of 1,5-syn
diastereoselection (eq 3)11 if the two reactions proceed
through different transition structures: (twist-boatf1,5-
anti vs chairf1,5-syn). The implication of a twist-boat-
13
lustrated enantiopure aldehydes illustrate the degree
of stereochemical control attainable in these double
stereodifferentiating processes. The application of this
methodology in the synthesis of polyol natural products
will be reported shortly.14
Ack n ow led gm en t. Support has been provided by
the NIH and NSF. The authors thank R. F. Kester for
the ab initio calculations on the aldol transition struc-
tures.
preferred transition structure in the reactions of the
methyl ketone-derived enolates was first suggested by
Houk, who has reported ab initio calculations at the
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for all reactions, product stereochemical proofs, and
characterization of all new compounds (16 pages).
3
-21G level that indicate the twist-boat is favored over
the chair transition structure by 1.4 kcal/mol for the
reaction of H BOCH)CH + CH
)O.12 We have ex-
J O962417M
2
2
2
(
12) Li, Y.; Padden-Row, M. N.; Houk, K. N. J . Org. Chem. 1990,
(
6) TiCl
4
, Ti(O-i-Pr)
2
Cl
2
, SnCl
4
, ZnCl
2
, TrCl/SnCl
2
, and TrClO
4
were
55, 481-493.
also found to give extremely low levels of stereochemical induction.
(13) Since submission of this manuscript, a related study has been
reported: Paterson, I; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett.
1996, 37, 8585-8588.
(
7) Mg(II), Ti(IV), and Sn(II) enolates were also nonselective.
(8) Selectivity and isolated yields for the 1,5-anti product with boron
enolate 1 was high regardless of the structure of the aldehyde:
isovaleraldehyde (90:10, 88%), isobutyraldehyde (94:6, 84%), pivalde-
hyde (95:5, 88%), and benzaldehyde (94:6, 88%).
(14) The author has deposited atomic coordinates for ketone 4f with
the Cambridge Crystallographic Date Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(15) (R)-6 amd (S)-6 were prepared in analogy to the Heathcock
procedure: (a) Theisen, P. D.; Heathcock, C. H. J . Org. Chem. 1988,
53, 2374-2378. (b) We have found that commerically available 2(R)-
and 2(S)-naphthylethanol work well in this esterification process:
Evans, D. A.; Black, W. C. J . Am. Chem. Soc. 1993, 115, 4497-4513.
(
9) This trend has also been noted in the addition of enolsilanes to
â-alkoxy aldehydes. See ref 2a.
10) The authors wish to thank Mr. Duke Fitch for carrying out the
reaction illustrated in entry 3, Table 2.
11) (a) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34,
871-6874. (b) Evans, D. A.; Fitch, D. J . Org. Chem. 1997, 62, in press.
(
(
6