Synthesis of propionate motifs: Diastereoselective tandem reactions involving anionic and free radical based processes

Article abstract of DOI:10.1021/ja010805m

Reported herein is a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer reaction for the elaboration of propionate motifs. The nature of the protecting groups on the chiral β-alkoxy aldehyde and the type of Lewis acid used are vari

Full text of DOI:10.1021/ja010805m

8496
J. Am. Chem. Soc. 2001, 123, 8496-8501
Synthesis of Propionate Motifs: Diastereoselective Tandem Reactions
Involving Anionic and Free Radical Based Processes
Yvan Guindon,* Karine Houde, Michel Pre´vost, Benoit Cardinal-David, Serge R. Landry,
Benoit Daoust, Mohammed Bencheqroun, and Brigitte Gue´rin
Contribution from the Institut de recherches cliniques de Montre´al (IRCM), Bioorganic Chemistry
Laboratory, 110 aVenue des Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7, and Department of
Chemistry and Department of Pharmacology, UniVersite´ de Montre´al, C.P. 6128, succursale CentreVille,
Montre´al, Que´bec, Canada H3C 3J7
ReceiVed March 28, 2001. ReVised Manuscript ReceiVed June 13, 2001
Abstract: Reported herein is a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer
reaction for the elaboration of propionate motifs. The nature of the protecting groups on the chiral â-alkoxy
aldehyde and the type of Lewis acid used are varied to modulate the stereochemical outcome of the tandem
reactions. The mode of complexation is thus controlled (monodentate or chelate) for the Mukaiyama reaction
to give access to either syn or anti aldol products, precursors of the free radical reduction reaction. The endocyclic
effect is subsequently capitalized upon to control the hydrogen transfer step so that the syn-reduced product
may be achieved. Proceeding with excellent yield and diastereoselectivity, the synthetic sequence proposed
gives access to syn-syn and syn-anti propionate motifs. Also considered is a complementary approach using
a chelation-controlled Mukaiyama reaction in tandem with a free radical allylation reaction under the control
of the endocyclic effect that leads to the anti-anti product.
The synthesis of propionate motifs,1 generally found in
oxygen of the stereogenic center R to the carbon-centered radical
and another neighboring heteroatom to form a temporary ring
adjacent to the radical center that contributes to an enhancement
of anti selectivity (the exocyclic effect, Scheme 1a).4b,c Alter-
natively, and central to this present study, some Lewis acids
chelate between the oxygen of the stereogenic center and the
carbonyl of the ester, leading to the syn product with high
stereocontrol (the endocyclic effect, Scheme 1b).5a,c,d Another
approach we have developed employs the control of the
endocyclic effect to arrive at the anti product in allylation
reactions with secondary or tertiary halides (Scheme 1c).5b,e
The efficiency of Lewis acid in controlling not only radical
reactions but also other types of reactions involving chelated
intermediates inspired us to consider the possibility of a tandem
process that would give access to propionate motifs. The
Mukaiyama reaction,6 a powerful variant of the classical aldol
reaction, seemed a plausible candidate for the tandem sequence
biologically important polyketide products, has been a topic of
considerable interest for organic chemists. Many approaches
have been developed for the elaboration of propionate motifs,
but few2 have offered all four motifs with good diastereocontrol.
To this end, we have been intrigued by the prospect of an
approach involving a free radical based hydrogen transfer
reaction as a key element of a tandem reaction sequence. Such
a strategy might have been considered a heresy just a decade
ago, prior to the advent of free radical intermediates being used
in reactions aimed at achieving the induction of stereogenic
centers on acyclic molecules.3
Our group has worked extensively with reactions involving
free radicals flanked by an ester moiety and a carbon center
bearing a heteroatom such as an oxygen,4 and we have recently
demonstrated that it is possible to predetermine the outcome of
a hydrogen transfer reaction by varying the type of Lewis acid
(L.A.) used.5 Indeed, some Lewis acids can coordinate with the
(3) (a) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24,
296. (b) Liotta, D. C.; Durkin, K. A.; Soria, J. J. Chemtracts 1992, 5, 197.
(c) Miracle, G. S.; Cannizzaro, S. M.; Porter, N. A. Chemtracts 1993, 6,
147. (d) Smadja, W. Synlett 1994, 1. (e) Giese, B.; Damm, W.; Batra, R.
Chemtracts 1994, 7, 355. (f) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions - Concepts, Guidelines and Synthetic
Applications; VCH: New York, 1996. (g) Renaud, P.; Gerster, M. Angew.
Chem., Int. Ed. 1998, 37, 2562.
(4) (a) Guindon, Y.; Yoakim, C.; Lemieux, R.; Boisvert, L.; Delorme,
D.; Lavalle´e, J.-F. Tetrahedron Lett. 1990, 31, 2845. (b) Guindon, Y.;
Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme, D.; Renaud, J.; Robinson,
G.; Lavalle´e, J.-F.; Slassi, A.; Jung, G.; Rancourt, J.; Durkin, K.; Liotta, D.
J. Org. Chem. 1994, 59, 1166. (c) Guindon, Y.; Faucher, A.-M.; Bourque,
EÄ .; Caron, V.; Jung, G.; Landry, S. R. J. Org. Chem. 1997, 62, 9276 and
references therein.
(5) (a) Guindon, Y.; Lavalle´e, J.-F.; Llinas-Brunet, M.; Horner, G.;
Rancourt, J. J. Am. Chem. Soc. 1991, 113, 9701. (b) Guindon, Y.; Gue´rin,
B.; Chabot, C.; Ogilvie, W. W. J. Am. Chem. Soc. 1996, 118, 12528. (c)
Guindon, Y.; Liu, Z.; Jung, G. J. Am. Chem. Soc. 1997, 119, 9289. (d)
Guindon, Y.; Rancourt, J. J. Org. Chem. 1998, 63, 6554. (e) Gue´rin, B.;
Chabot, C.; Mackintosh, N.; Ogilvie, W. W.; Guindon, Y. Can. J. Chem.
2000, 78, 852.
* Corresponding Author. Tel: (514) 987-5786; fax: (514) 987-5789;
e-mail: guindoy@ircm.qc.ca.
(1) Selected examples: (a) Iio, H.; Nagaoka, H.; Kishi, Y. J. Am. Chem.
Soc. 1980, 102, 7965 and preceding papers. (b) Still, W. C.; Barrish, J. C.
J. Am. Chem. Soc. 1983, 105, 2487. (c) Masamune, S.; Choy, W.; Petersen,
J. S.; Sita, L. R. Angew. Chem. 1985, 97, 1; Angew. Chem., Int. Ed. Engl.
1985, 24, 1. (d) Roush, W. R. J. Org. Chem. 1991, 56, 4151. (e) Paterson,
I.; Channon, J. A. Tetrahedron Lett. 1992, 33, 797. (f) Paterson, I.;
Cumming, J. G. Tetrahedron Lett. 1992, 33, 2847. (g) Paterson, I.; Tillyer,
R. D. Tetrahedron Lett. 1992, 33, 4233. (h) Harada, T.; Inoue, A.; Wada,
I.; Uchimura, J.; Tanaka, S.; Oku, A. J. Am. Chem. Soc. 1993, 115, 7665.
(i) Hoffmann, R. W.; Dahmann, G.; Anderson, M. W. Synthesis 1994, 629.
(j) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc.
1995, 117, 9073. (k) Hanessian, S.; Gai, Y.; Wang, W. Tetrahedron Lett.
1996, 37, 7473. (l) Roush, W. R.; Chemler, S. R. J. Org. Chem. 1998, 63,
3800.
(2) (a) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1987,
52, 3701. (b) Marshall, J. A.; Perkins, J. F.; Wolf, M. A. J. Org. Chem.
1995, 60, 5556. (c) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000, 65,
630.
10.1021/ja010805m CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/14/2001

Synthesis of Propionate Motifs
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8497
Scheme 1
Scheme 2
Scheme 3
in question for two reasons. First, the outcome of this carbon-
carbon bond-forming reaction can be dictated by the type of
Lewis acid used. With bidentate Lewis acid, the Mukaiyama
reaction has been shown to lead to the anti product through
Cram chelate control when an aldehyde with a stereogenic center
at the R position is involved (Scheme 2, path a).6 Alternatively,
the use of a monodentate Lewis acid in this reaction has been
shown to lead to the syn product, in which case an open Felkin-
Anh transition state (Scheme 2, path b) is proposed.6 Second,
the Mukaiyama reaction should be able to give access to the
chelated species illustrated in Scheme 1, which could then be
used in a subsequent radical reaction. Given this, a tandem
sequence that combines the Mukaiyama reaction, using either
Cram chelation or a Felkin-Anh pathway, with a radical
reduction proceeding through either the endocyclic or exocyclic
pathway should allow access to all four propionate motifs.
To be considered herein are tandem sequences that employ
the control of the endocyclic effect for the free radical step.
The Mukaiyama reaction is combined in tandem (i.e., one-pot
reaction) with a hydrogen transfer reaction for the elaboration
of 2,3-syn-3,4-anti and 2,3-syn-3,4-syn propionate motifs. This
strategy is then extended to a tandem Mukaiyama/free radical
based allylation reaction sequence to access a molecule bearing
stereocenters with a 2,3-anti-3,4-anti relative stereochemistry,
a motif that remains synthetically challenging despite recent
contributions within this field.7
As depicted in Scheme 3, a high anti selectivity between the
methyl group at the C-4 position and the newly formed alcohol
at C-3 is expected from the addition of a tetrasubstituted
enoxysilane bearing either a bromide or a phenylselenide on a
chelated R-methyl â-benzyloxy aldehyde (transition state D).8
On the resultant aldol product E, a Lewis acid that has been
chosen judiciously should migrate from the alkoxy group to
(7) Selected examples: (a) Hoffmann, R. W. Angew. Chem., Int. Ed.
Engl. 1987, 26, 489. (b) Hoffmann, R. W.; Dresely, S. Chem. Ber. 1989,
122, 903. (c) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.; Noda, T.; Filla, S.
A.; Masamune, S. Angew. Chem., Int. Ed. Engl. 1994, 33, 673. (d) Marshall,
J. A.; Perkins, J. F.; Wolf, M. A. J. Org. Chem. 1995, 60, 5556. (e) Jain,
N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 111, 6429. See
ref 1b, e, f, h, i, and l.
(8) Open or extended transition state models have provided the best
rationalization for the stereochemical results of the Mukaiyama reaction.
(a) Nakamura, E.; Yamago, S.; Machii, D.; Kuwajima, I. Tetrahedron Lett.
1988, 29, 2207. (b) Denmark, S. E.; Henke, B. R. J. Am. Chem. Soc. 1989,
111, 8032.
(6) (a) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, 1993; Vol. 2, Chapter 2.4. (b) Mahrwald,
R. Chem. ReV. 1999, 99, 1095.

8498 J. Am. Chem. Soc., Vol. 123, No. 35, 2001
Guindon et al.
the more basic oxygen on the carbonyl of the ester, allowing
for the formation of a new six-membered ring complex (chelate
F). The hydrogen transfer reaction should then be able to take
place via the endocyclic chelation mode and lead to a 2,3-syn-
3,4-anti propionate motif. A similar anti selectivity between the
methyl group at C-4 and the hydroxyl group at C-3 should be
expected from the chelation-controlled addition of a trisubsti-
tuted enoxysilane bearing a phenylselenide. Under the control
of the endocyclic effect, the addition of allyltributyltin should
give a 2,3-anti-3,4-anti motif.9
Alternatively, we envision the use of a substrate that prevents
chelation in order to reverse the facial selectivity of the
Mukaiyama reaction and thus favor the 3,4-syn product (Scheme
3b). An open Felkin-Anh transition state such as G5 is sought
for access to this stereochemical result. If the Lewis acid used
in the Mukaiyama step has the potential to form a chelate as
illustrated in I, then the subsequent radical reduction of the
phenylselenide should take place under endocyclic control
leading to the 2,3-syn isomer (Scheme 3).
The main advantage of the proposed sequences is that two
new stereogenic centers may be induced from a single chiral
center. Furthermore, the tandem sequence may be conveniently
carried out as a one-pot process, which offers an efficient new
approach to the preparation of propionate motifs. Complemen-
tary to previous approaches, such as the classical aldol reaction1j
and the crotylation reaction,1l,2 our strategy may offer an
alternative method for obtaining some of the more challenging
motifs. Our preliminary results of these tandem Mukaiyama/
free radical based reactions are described herein.
in a >20:1 ratio favoring 3,4-anti selectivity (Table 1, entry
12).14 Bromide compounds 9a and 9b were obtained in superior
yield, and no silylated side products were observed for this series
(Table 1, entry 13).
To obtain the syn aldol product, we used â-silyloxy aldehyde
1115 based on the presumption that a bulky silyl protecting group
would prevent the formation of the chelate.16 To this aldehyde
was added seleno-enoxysilane, and the resultant mixture was
tested with different Lewis acids at -78 °C. An excess of
MgBr2‚OEt2 performed poorly, and aldehyde 11 was recovered
even though the reaction mixture was warmed to -40 °C (Table
1, entry 14). The best results were achieved with BF3‚OEt2 and
Me2AlCl, a notable ratio of 1:11 having been obtained for both
in favor of 3,4-syn relative stereochemistry (Table 1, entries
15 and 16). The latter Lewis acid was able to form a chelate
between the hydroxyl and carbonyl groups of the Mukaiyama
product and was therefore retained for use in the tandem process.
The secondary phenylselenide required for the completion
of the anti-anti allylated motif was achieved through the addition
of a trisubstituted enoxysilane to aldehyde 1. The use of the
tert-butyldimethylsilyl enolate in the presence of MgBr2‚OEt2
led to an excellent anti ratio between the hydroxy group at C-3
and the methyl group at C-4.17 The yield of this reaction (53%,
see Table 1, entry 17) was increased significantly by using the
triethyl silyloxy (TES) analogue to give in excellent yield (90%)
selenides 14a and 14b (Table 1, entry 18) while maintaining
superior diastereoselectivity.18
The Free Radical Step. The second chemical step involving
the free radical reactions was then evaluated. As seen in Table
2 (entry 1), anti selenide 2a in the presence of a large excess of
MgBr2‚OEt2 was reduced at -78 °C with Bu3SnH and Et3B,
as the initiator, to give in good yield an excellent syn:anti ratio
>100:1.19 In the bromide series, the radical reduction of anti
isomer 4a gave higher selectivity than that noted for the
reduction of the syn counterpart 4b (Table 2, entries 2 and 3).20
Ratios of reduced products >30:1 were observed for selenides
7a and 7b as well as for bromides 9a and 9b (Table 2, entries
4 and 5). In each case, the major syn product 17a was obtained,
corroborating that chelate formation between the hydroxyl and
carbonyl groups of the substrate had taken place. Me2AlCl,
which had been efficient in the Mukaiyama reaction involving
a Felkin-Anh pathway, facilitated the formation of the chelate
with the â-hydroxy-R-seleno ester 13a, giving a ratio >20:1 in
favor of the 2,3-syn reduced product 18c (Table 2, entry 6).
The free radical based allylation reactions are summarized
in Table 3. As seen in entry 1, an excess of MgBr2‚OEt2 in the
presence of allyltributyltin was added to the solution of
phenylselenide 14a, which had been cooled to -40 °C. The
reaction was then allowed to warm to 0 °C. These conditions
Results and Discussion
The Mukaiyama Reaction. The first part of the two-step
process, the enoxysilane addition to the aldehyde, is reviewed
in Table 1. Different Lewis acids were added to a CH2Cl2
solution of â-benzyloxy-R-methylpropionaldehyde 110 and an
E:Z mixture of seleno-enoxysilane (4:1, 1.5 equiv) at -60 °C.
Attempts to achieve the 3,4-anti aldol product (Table 1, entries
1-5) using TiCl4, TiCl2(iOPr)2, Me2AlCl, and MeAlCl2 were
unsuccessful; however, MgBr2‚OEt2 in excess amounts (>5
equiv)11 gave excellent diastereoselectivity favoring the 3,4 anti
isomers 2a and 2b12 (Table 1, entries 6-10) in good yield. A
remarkable level of stereocontrol favoring anti-aldol products
(epimeric at C-2) was also obtained with bromo-enoxysilane
under optimized conditions (Table 1, entry 11). These results
were very encouraging for the planned tandem sequences
considering that MgBr2‚OEt2 had already proven to be success-
ful in chelation-controlled radical reduction reactions leading
to the syn product.5a,c,d
The optimized Mukaiyama conditions were applied to the
R-benzyloxy-aldehyde 613 to achieve carbon-carbon bond
formation with significant diastereoselectivity (Table 1, entries
12 and 13). For the selenide series, an additional 25% of aldol
products bearing a trimethylsilyl ether group at C-3 was isolated
(14) These aldol products could be easily converted into products 7a
and 7b by modifying the workup procedure.
(15) The preparation of aldehyde 11 has been reported previously in
Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112,
6348.
(16) Oxygen atoms of hindered silyl ethers are known to be less efficient
in complexation with Lewis acids; see Chen, X.; Hortelano, E. R.; Eliel, E.
L.; Frye, S. V. J. Am. Chem. Soc. 1992, 114, 1778 and references therein.
(17) The optimized Mukaiyama conditions offered a 7:1 (14a:14b) ratio.
(18) Me2AlCl, which had already performed poorly in our chelation-
controlled Mukaiyama reaction involving the quaternary enoxysilane (Table
1, entry 5), gave only a weak 1.1:1 ratio in favor of the 3,4-anti product
when used in combination with TES enolate.
(19) Compound 16b was derivatized in lactone, and the relative
configuration of the resultant product was established by NOE NMR
analysis.
(20) A similar observation has been made in chelation-controlled radical
reduction and allylation reactions of secondary R-iodoesters. See refs 4a,
b, and e.
(9) It has already been shown that R-phenylseleno-â-hydroxy esters can
give the anti allylated product under chelation-controlled conditions; see
Gerster, M.; Audergon, L.; Moufid, N.; Renaud, P. Tetrahedron Lett. 1996,
37, 6335.
(10) The preparation and characterization of aldehyde 1 have been
reported previously in Still, W. C.; Schneider, J. A. Tetrahedron Lett. 1980,
21, 1035.
(11) A similar observation has been made in chelation-controlled radical
reduction and allylation reactions (see ref 4b-e).
(12) The optimized Mukaiyama conditions offered a >20:1 (2a:2b) ratio.
(13) The preparation and characterization of aldehyde 6 have been
reported previously in Varelis, P.; Johnson, B. L. Austr. J. Chem. 1995,
48, 1775.

Synthesis of Propionate Motifs
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8499
Table 1. Mukaiyama Reactionsa
a When P ) Bn: aldehydes (0.05 M) in CH2Cl2 were treated at -60 °C with 1.5 equiv of enoxysilane and the appropriate L.A; when P )
1
TBDMS: the reaction was performed at -78 °C using a 0.1 M solution of aldehyde. b Ratios were determined by H NMR spectroscopy and/or
GC or HPLC. c Yields of isolated products. d 25% of isolated trimethylsilyl ether products were also obtained in a >20:1 anti:syn ratio. e At -40
°C, aldehyde 11 was recovered. f 1.75 equiv of enoxysilane was used. g The reaction was performed at -78 °C.
led to a ratio of >20:1 in favor of the anti allylated product
and to an intermediate yield (62%). The use of aluminum based
Lewis acids such as Me2AlCl (Table 3, entry 2) and AlMe3
(Table 3, entry 3) at -78 °C led to an improvement in yield,
gave high diastereoselectivity, and were the most efficient in
terms of reaction time. In these reactions, the stronger Lewis
acids rendered the carbonyl of the ester more electronegative
and in turn lowered the SOMO energy of the radical. Thus, the
free radical became even more electrophilic, and the rate of
addition to the electron rich double bond of the allylstannane
was increased.
The Tandem Reactions. With the significant results obtained
from the independent Mukaiyama and free radical reactions,
we were poised well to study the two-step sequences. First
attempts to realize the tandem reactions using aldehyde 1 and
MgBr2‚OEt2 proved to be difficult to reproduce. It was
determined that the length of the reaction in the first step, having
been performed under a N2 atmosphere, had resulted in a
dissipation of the oxygen that was needed to initiate and
maintain the chain of the free radical reaction. The process was
modified accordingly by exposing the reaction mixture to air
(O2) prior to initiation of the radical reduction step.
As seen in Table 4, two new stereogenic centers were
introduced with high diastereoselectivity in favor of the 2,3-
syn-3,4-anti propionate motif for both benzyloxy aldehydes 1
and 6 in the presence of MgBr2‚OEt2 (entries 1-4). A higher
ratio was achieved with aldehyde 1 when seleno-enoxysilane
was used in the one-pot process (Table 4, entry 1). Both seleno-
enoxysilane and bromo-enoxysilane reacted well with aldehyde
6 under chelation control, leading to the desired syn-anti motif
with excellent selectivity and in good yield (Table 4, entries
3-4).21 The hydrogen transfer study was completed with the
tandem reaction involving silyloxy aldehyde 11 in the presence
(21) For the selenide series, the crude mixture was subjected to flash
chromatography before being treated with TBAF in THF for the cleavage
of the trimethylsilyl ether group at C-3.

8500 J. Am. Chem. Soc., Vol. 123, No. 35, 2001
Table 2. Free Radical Hydrogen Transfer Reactionsa
Guindon et al.
Table 4. Tandem Mukaiyama and Free Radical Hydrogen Transfer
Reactionsa
enoxy-
silane
yieldc
(%)
entry aldehyde
products
ratiob
1
2
3
4
5
1
1
6
6
11
X ) SePh 16a:16b:16c:16d >30:1:0:0
70
68
65d
69
X ) Br
X ) SePh 17a:17b:17c:17d
X ) Br
X ) SePh 18a:18b:18c:18d
16a:16b:16c:16d
10:1:0:0
50:1:0:0
17a:17b:17c:17d 100:1:0:0
1:0:11:0.1 66
a Mukaiyama: aldehydes 1 and 6 (0.05 M) were treated in CH2Cl2
at -60 °C with enoxysilane (1.5 equiv) and MgBr2‚OEt2 (4 h); for
11: the reaction was performed at -78 °C using a 0.1 M solution of
aldehyde and 2 equiv of Me2AlCl (1 h). Reduction: the reaction mixture
was exposed to air 1 h before the addition of 4 equiv of Bu3SnH and
0.2 equiv of Et3B at -78 °C. b Ratios were determined by GC or HPLC.
c Yields of isolated products. d After flash chromatography, the mixture
was treated with TBAF in THF to cleave the trimethylsilyl ether group
at C-3.
a Substrates (0.1 M) were pretreated with Lewis acid, 2 equiv of
Bu3SnH, and 0.2 equiv of Et3B in CH2Cl2 at -78 °C. b Determined by
GC analysis of crude reaction isolates. c Isolated yields. d An inseparable
mixture of 13a and 12a (11%) was used for the radical reduction
Table 5. Tandem Mukaiyama and Allylation Reactionsa
1
reaction. e 2.0 equiv of iPr2NEt was added. f Determined by H NMR
spectroscopy of crude reaction isolates.
Table 3. Free Radical Allylation Reactionsa
yieldc
(%)
entry
additive (equiv)
products
ratiob
reaction
time (h)
temp
(°C)
ratiob
2,3-(syn:anti) (%)
yieldc
entry
L.A. (equiv)
1
2
3
none
Me2AlCl (3.5)
CH3COOH (1.2) 19a:19b:19c:19d 1:>20:0:0
Me2AlCl (3.5)
19a:19b:19c:19d 1:>20:0:0
19a:19b:19c:19d 1:>20:0:0
35
52
85
1
2
3
MgBr2‚OEt2 (5)
Me2AlCl (2.5)
Me3Al (2.5)
9
3.5
3.5
-40 to 0
-78
-78
1:>20
1:>20
1:>20
62
90
80
a Mukaiyama: aldehyde 1 (0.05 M) was treated in CH2Cl2 at -78
°C with enoxysilane (1.75 equiv) and MgBr2‚OEt2 (5 equiv, 1 h).
Allylation: the reaction mixture was warmed to -40 °C before the
addition of the additiVe with 4 equiv of allylSnBu3 and 0.2 equiv of
a Substrates (0.1 M) were pretreated with Lewis acid, 2 equiv of
allylSnBu3, and 0.2 equiv of Et3B in CH2Cl2 at -78 °C. b Determined
by H NMR spectroscopy of crude reaction isolates. c Isolated yields.
1
Et3B. b Ratios were determined by H NMR spectroscopy. c Yields of
1
of Me2AlCl, which gave as the major constituent the desired
compound 18c with a 2,3-syn-3,4-syn propionate motif (Table
4, entry 5).
isolated products.
Conclusion
Carrying out the Mukaiyama/radical allylation tandem se-
quence was more complicated considering that different Lewis
acids had given the best results for the reactions performed on
an individual basis: MgBr2‚OEt2 having worked well in the
Mukaiyama reaction,18 and Me2AlCl having provided the best
yield for the allylation. When MgBr2‚OEt2 was used for both
steps of the sequence, an excellent ratio of allylated products
was obtained in a 35% yield (Table 5, entry 1). Performing the
first step in the presence of MgBr2‚OEt2 followed by the addition
of Me2AlCl in the allylation reaction also led to high diaste-
reoselectivity of >20:1, but the yield was still low (Table 5,
entry 2). This suggested that the chelate formed by the
magnesium did not equilibrate with the Me2AlCl, which was
surprising given that the latter was stronger than the MgBr2‚
OEt2. The addition of an equimolar amount of acetic acid (CH3-
COOH) prior to the addition of Me2AlCl allowed for cleavage
of the O-Mg bond so that the aluminum could replace the
magnesium to form a chelate, resulting overall in a much
improved 85% yield of allylated products (Table 5, entry 3).
The two-step sequences offer an efficient and complementary
approach to the synthesis of propionate motifs and are conceptu-
ally exciting from the viewpoint that anionic and radical
processes are combined in the same reaction mixture. Further-
more, Lewis acid is used advantageously to activate and/or
control both the Mukaiyama reaction and the free radical
reaction. The endocyclic effect is capitalized upon for the free
radical step to give the 2,3-syn product in the case of the
hydrogen transfer reaction and the 2,3-anti product for the
allylation reaction. The formation of chelates R to the radical
center mimicking the exocyclic effect is a study that is presently
underway to gain access, using the hydrogen transfer reaction,
to other stereoisomers bearing a 2,3-anti relative diastereo-
selectivity. Through this work, we hope to establish a general
and versatile approach to the synthesis of all propionate motifs.
The scope and limitations of the two-step synthetic sequences
will be evaluated further, while Lewis acids will continue to be
explored and their potential tested in iterative processes.

Synthesis of Propionate Motifs
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8501
General Procedure for the Preparation of Benzyloxy Esters 16,
17, and 19 via in Situ Mukaiyama and Radical Reduction or
Allylation Reactions. To a cold (-60 °C) solution of aldehyde 1 or 6
(1 equiv) in dry CH2Cl2 (0.05 M) were added the appropriate silylketene
acetal (1.5 equiv of tetrasubstituted enoxysilane or 1.75 equiv of
trisubstituted enoxysilane) and the appropriate Lewis acid. The resulting
solution was stirred for 4 h at -60 °C (until the aldehyde was
completely consumed, as determined by TLC). The reaction mixture
was exposed to air (O2) for 1h at 0 °C before the addition of either
Bu3SnH or allylSnBu3 (4 equiv) and Et3B (0.2 equiv of a 1.0 M solution
in hexanes) at -78 °C. Et3B (0.2 equiv) was added each 30 min until
the reaction was judged complete by TLC. 1,3-Dinitrobenzene (0.2
equiv) was then added to the solution, and the mixture was stirred an
additional 15 min at -78 °C. The reaction mixture was poured into a
saturated NaHCO3 solution and extracted with EtOAc. The combined
organic extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure.
Preparation of Silyloxy Esters 18a-d via in Situ Mukaiyama
and Radical Reduction Reactions. To a cold (-78 °C) solution of
aldehyde 11 (100 mg, 0.31 mmol) in dry CH2Cl2 (0.1 M) were added
the silylketene acetal (193 mg, 0.61 mmol) and Me2AlCl (1.0 M in
hexane, 600 µL). The resulting solution was stirred for 10 min at -78
°C (until the aldehyde was completely consumed, as determined by
TLC). The reaction mixture was exposed to air (O2) for 5 min, and the
radical reduction reaction step was initiated as described above in the
general procedure for the preparation of benzyloxy esters 16 and 17.
Experimental Section
General Procedure for Radical Reduction or Allylation under
Chelation-Controlled Conditions. To a stirred solution of R-sele-
noester or R-bromoester (1 equiv) in dry CH2Cl2 (0.1 M) at -78 °C
was added the appropriate Lewis acid (with Me2AlCl, 2.0 equiv of
iPr2Net was added to the reaction mixture). The mixture was stirred
for 15 min at the same temperature before either Bu3SnH or allylSnBu3
(2 equiv) and Et3B (0.2 equiv of a 1.0 M solution in hexanes) was
added. The resulting suspension was stirred at -78 °C, and 0.2 equiv
of Et3B was added each 30 min until the reaction was judged complete
by TLC. 1,3-Dinitrobenzene (0.2 equiv) was then added to the solution,
and the mixture was stirred an additional 15 min at -78 °C. The
reaction mixture was poured into a saturated NaHCO3 solution and
extracted with EtOAc (3×). The combined organic extracts were
washed with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure.
5-Benzyloxy-3-hydroxy-2,4-dimethylpentanoic Acid Methyl Ester
(16a and 16b). The ratios for 16a and 16b were determined by GC
analysis of the crude isolate arising from the radical reductions of 2a
and 4a. The compounds were purified by flash chromatography on silica
gel using 100% hexane to 10% EtOAc-hexane (82%). Compound
16a (2R,3S,4S): colorless oil; R×a6 0.17 (hexane:EtOAc, 4:1); [R]25
D
) -1.3° (c 2.87, MeOH); IR (neat) υmax 3500, 2950, 2880, 1740, 1455,
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.23-7.39 (m, 5H), 4.51 (s, 2H),
3.87-3.93 (m, 1H), 3.69 (s, 3H), 3.61-3.69 (m, 2H), 3.55 (dd, J )
6.6, 2.4 Hz, 1H), 2.58-2.66 (m, 1H), 1.85-1.95 (m, 1H), 1.19 (d, J )
7.1 Hz, 3H), 0.91 (d, J ) 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 176.1, 137.7, 128.5, 127.8, 127.7, 76.0, 74.8, 73.6, 51.9, 42.5, 35.8,
13.9, 9.8; MS (FAB) m/z 267 (MH+, 49), 181 (7), 159 (12), 91 (100),
71 (8); HRMS calcd for C15H23O4 (MH): 267.1596, found: 267.1592
(1.6 ppm).
Acknowledgment. The authors wish to thank NSERC for
its financial support, as well as Ms. LaVonne Dlouhy for her
assistance in the preparation of this manuscript.
Supporting Information Available: Experimental proce-
dures and characterization data for compounds E,Z-silylketenes,
2-15, 17-19; determination of relative configuration for
compounds 2a, 4b, 7b, 9b, 13a, 13b, 14a, 16b, 17b, 18a, and
19b; experimental procedures and characterization data for
lactones 20-26; NMR spectra for compounds E,Z-silylketenes,
2b, 3a, 3b, 5a, 5b, 8b, 10b, 15a, 15b, 16b, 18b, 18d, 19a, 21,
23, and 25 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Compounds 16a and 16b (inseparable 1:1 mixture; ratio determined
by 1H NMR analysis) resulted from the radical reduction of 2a
performed at 0 °C in the absence of Lewis acid. Compound 16b
(2S,3S,4S): colorless oil; R×a6 0.17 (hexane:EtOAc, 4:1); IR (neat) υmax
3500, 2950, 2880, 1740, 1510, 1100, 740, 700 cm-1; H NMR (400
1
MHz, CDCl3) δ 7.23-7.39 (m, 5H), 4.52 (s, 2H), 3.70 (s, 3H), 3.61-
3.68 (m, 2H), 3.52-3.61 (m, 1H), 3.41 (d, J ) 7.0 Hz, 1H), 2.70-
2.79 (m, 1H), 1.84-2.00 (m, 1H), 1.22 (d, J ) 7.5 Hz, 3H), 1.02 (d,
J ) 6.9 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ_176.1, 138.0, 128.5,
128.4, 127.6, 73.6, 73.5, 73.3, 51.7, 43.1, 36.2, 14.9, 14.6.
JA010805M