Enantioselective H-atom transfer reaction: A strategy to synthesize formaldehyde aldol products

Article abstract of DOI:10.1021/ol047347h

(Chemical Equation Presented) Enantioselective radical alkylation of Baylis-Hillman adducts furnished aldol products in good yield and selectivity. The results illustrate that the selectivity in the hydrogen atom transfer is dependent on the size of the e

Full text of DOI:10.1021/ol047347h

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1453-1456
Enantioselective H-Atom Transfer
Reaction: A Strategy to Synthesize
Formaldehyde Aldol Products
Mukund P. Sibi* and Kalyani Patil
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
mukund.sibi@ndsu.edu
Received December 23, 2004 (Revised Manuscript Received February 22, 2005)
ABSTRACT
Enantioselective radical alkylation of Baylis−Hillman adducts furnished aldol products in good yield and selectivity. The results illustrate that
the selectivity in the hydrogen atom transfer is dependent on the size of the ester substituent, with smaller substituents providing better
enantioselectivity.
The aldol reaction constitutes one of the most important
carbon-carbon bond forming reactions.1 Enantiopure aldol
products can be synthesized in numerous ways,2 and can be
converted to substructures that are widely present in biologi-
cally interesting targets such as â-lactones,3 â-lactams, and
various other derivatives. The use of radical reactions4 for
generating sensitive aldol products is relatively underdevel-
oped,5 even though the mild, neutral conditions seem well
suited. Our group was the first to report enantioselective
intermolecular radical additions to synthesize acetate aldols,
in which the products are chiral at the â-carbon but not the
R-carbon.6 Stereochemistry was generated in the alkylation
step but not the ensuing hydrogen atom transfer step. While
a number of enantioselective alkylations have been devel-
oped, only a few enantioselective hydrogen atom transfer
reactions have been reported, with the controlling factors not
well understood. We recently described a highly efficient
tandem alkylation-hydrogen atom transfer reaction to
synthesize â2-amino acids (2) from N-protected R-aminom-
ethyl acrylate (1), where the stereodetermining step involves
enantioselective hydrogen atom transfer (eq 1).7 The reduc-
(1) Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
Germany, 2000; p 539. ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999. For
recent reviews, see: (a) Palamo, C.; Oiarbide, M.; Garcia, J. M. Chem.
Soc. ReV. 2004, 1, 135. (b) Alcaide, B.; Almendros, P. Eur. J. Org. Chem.
2002, 1595. (c) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed.
2000, 39, 1352. (d) Nelson, S. J. Tetrahedron: Asymmetry 1998, 9, 357.
(2) For some recent examples, see: (a) Trost, B. M.; Ito, H. J. Am. Chem.
Soc. 2000, 122, 12003. (b) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am.
Chem. Soc. 2000, 122, 2395. (c) Yamada, Y. M. A.; Yoshikawa, N.; Sasai,
H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (d) Singer,
R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360.
(3) For some applications of aldol products see: (a) Frampton, G. A.;
Hannah, D. R.; Henderson, N.; Katz, R. B.; Smith, I. H.; Tremayne, N.;
Watson, R. J.; Woollam, I. Org. Process Res. DeV. 2004, 8, 415. (b) Watson,
R. J.; Batty, D.; Baxter, A. D.; Hannah, D. R.; Owen, D. A.; Montana, J.
G. Tetrahedron Lett. 2002, 43, 683. (c) Jin, Y.; Kim, D. H. Synlett 1998,
1189. (d) Pommier, A.; Pons, J.-M. Synthesis 1995, 729.
(4) For recent reviews on enantioselective radical processes, see: (a)
Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. ReV. 2003, 103, 3263. (b)
Sibi, M. P.; Rheault, T. R. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, p 461.
(c) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163.
(5) (a) Garner, P.; Anderson, J. T.; Cox, P. B.; Klippenstein, S. J.; Leslie,
R.; Scardovi, N. J. Org. Chem. 2002, 67, 6195. (b) Garner, P.; Anderson,
J. T. Org. Lett. 1999, 1, 1057. (c) Evans, P. A.; Murthy, V. S.; Roseman,
J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. 1999, 38, 3175. (d) Lee, E.;
Choi, S. J. Org. Lett. 1999, 1, 1127. (e) Lee, E.; Yoo, S.-K.; Choo, H.;
Song, H. Y. Tetrahedron Lett. 1998, 39, 317. (f) Garner, P.; Leslie, R.;
Anderson, J. T. J. Org. Chem. 1996, 61, 6754. (g) Lee. E.; Tae. J. S.; Lee,
C.; Park, C. M. Tetrahedron Lett. 1993, 34, 4831.
(6) Sibi, M. P.; Zimmerman, J.; Rheault, T. Angew. Chem., Int. Ed. 2003,
42, 4521.
10.1021/ol047347h CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/18/2005

tion8 of such carbonyl-substituted radicals can be viewed as
being complementary to enantioselective protonation of
enolates.9 In this paper, we report related radical alkylation
of simple R-hydroxy acrylates (3), which are readily available
as Baylis-Hillman reaction adducts.10 Under radical condi-
tions, substrates 3 can react in their free alcohol form without
need for protection providing access to enantioenriched aldol
products 4 (eq 2).
Table 1. MgI2-Catalyzed H-Atom Transfer Reactionsa,b
entry
R
R1X
ethyl-I
i-Pr-I
cyclohexyl-I
t-Bu-I
ethyl-I
i-Pr-I
cyclohexyl-I
t-Bu-I
ethyl-I
compd
yield (%)c
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
t-Bu
t-Bu
t-Bu
t-Bu
Bn
8a
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
53
52
60
68
68
53
61
52
92
95
88
10
11
Bn
Bn
i-Pr-I
cyclohexyl-I
a Typical reaction conditions: For 1 equivalent of substrate, 10 equiva-
lents of radical precursor, 3.6 equivalents of Bu3SnH, and 3.6 equivalents
of Et3B were used. For more details see the Supporting Information. b 1
equiv of Lewis acid used. c Isolated yield after column purification.
Our experimental work began by investigating additions
to R-hydroxymethyl acrylates 5-711 under achiral conditions
(Table 1). The reactivity was high, and good yields were
obtained at -78 °C even in the absence of any Lewis acid.12
With MgI2 as the representative Lewis acid,13 moderate yields
were observed for methyl- and tert-butyl-substituted esters
5 and 6, irrespective of the size of radical added (entries
1-8). On the other hand, excellent yields were obtained
when benzyl ester 8 was used (entries 9-11). It appears that
some acrylate polymerization interferes when methyl and
tert-butyl esters 5 and 6 were used, but was less significant
with the benzyl ester 7.
(7) Sibi, M. P.; Patil, K. Angew. Chem., Int. Ed. 2004, 43, 1235.
(8) For examples of H-atom transfer reactions mediated by chiral Lewis
acids, see: (a) Sugimoto, H.; Nakamura, S.; Watanabe, Y.; Toru, T.
Tetrahedron: Asymmetry 2003, 14, 3043. (b) Sibi, M. P.; Sausker, J. B. J.
Am. Chem. Soc. 2002, 124, 984. (c) Sibi, M. P.; Asano, Y.; Sausker, J. B.
Angew. Chem., Int. Ed. 2001, 40, 1293. (d) Murakata, M.; Tsutsui, H.;
Takeuchi, N.; Hoshino, O. Tetrahedron 1999, 55, 10295. (e) Urabe, H.;
Yamashita, K.; Suzuki, K.; Kobayashi, K.; Sato, F. J. Org. Chem. 1995,
60, 3576. For selected examples of enantioselective reductions with chiral
H-atom transfer reagents, see: (f) Zeng, L.; Perchyonok, T.; Schiesser, C.
H. Tetrahedron: Asymmetry 2004, 15, 995. (g) Dakterniecks, D.; Perchy-
onok, V. T.; Schiesser, C. H. Tetrahedron: Asymmetry 2003, 14, 3057. (h)
Blumenstein, M.; Lemmler, M.; Hayen, A.; Metzger, J. O. Tetrahedron:
Asymmetry 2003, 14, 3069. (i) Dakternieks, D.; Dunn, K.; Perchyonok, V.
T.; Schiesser, C. H. Chem. Commun. 1999, 1665. (j) Blumenstein, M.;
Schwarzkopf, K.; Metzger, J. O. Angew. Chem., Int. Ed. Engl. 1997, 36,
235. (k) Nanni, D.; Curran, D. P. Tetrahedron: Asymmetry 1996, 7, 2417.
(9) For a review on enantioselective protonations see: Eames, J.;
Weerasooriya, N. Tetrahedron: Asymmetry 2001, 12, 1. For non free radical
methods involving reductive alkylation of acrylates with enantioselective
protonation see: (a) Reetz, M. T.; Moulin, D.; Gosburg, A. Org. Lett. 2001,
3, 4083. (b) Chapman, C. J.; Wadsworth, K. J.; Frost, C. G. J. Organomet.
Chem. 2003, 680, 206. (c) Chapman C. J.; Frost, C. G. AdV. Synth. Catal.
2003, 345, 353. (d) Huang, T.-S.; Li, C.-J. Org. Lett. 2001, 3, 2037. (e)
Moss, R. J.; Wadsworth, K. J.; Chapman, C. J.; Frost, C. G. Chem. Commun.
2004, 1984. For Co-mediated reduction/protonation, see: Ohtsuka, Y.;
Ikeno, T.; Yamada, T. Tetrahedron: Asymmetry 2003, 14, 967.
(10) For recent reviews on Baylis-Hillman reaction, see: (a) Basavaiah,
D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811. (b) Langer,
P. Angew. Chem., Int. Ed. 2000, 39, 3049. (c) Ciganek, E. Org. React.
1997, 51, 201.
Chiral Lewis acids were then screened14 for enantioselec-
tive alkylation-hydrogenation, using isopropyl iodide as rad-
Table 2. Effect of Chiral Lewis Acid on Enantioselectivitya
entry
Lewis acidb
ligandb
yield (%)c
ee (%)d
(11) For the synthesis of substrates, see the Supporting Information. For
benzyl substituent, see: O’Leary, B. M.; Szabo, T.; Svenstrup, N.; Schalley,
C. A.; Lutzen, A.; Schafer, M.; Rebek J., Jr. J. Am. Chem. Soc. 2001, 123,
11519.
(12) Reaction of 6 with different radicals at -78 °C in the absence of
any Lewis acid gave products in good yields; EtI (78%), i-Pr-I (51%),
cyclopentyl-I (79%), cyclohexyl-I (74%), t-Bu-I (62%). Compound 5
showed similar results.
(13) Other Lewis acids such as Yb(OTf)3, Mg(ClO4)2, and Sm(OTf)3
gave similar yields. Use of 30 mol % of the Lewis acid gave similar yields.
Since we had used MgI2 for synthesizing â-amino acids, the same Lewis
acid has been used for obtaining the aldol products.
1
2
3
4
5
6
MgI2
11
11
12
12
13
14
53
52
61
65
45
40
55
24
21
25
21
23
Zn(OTf)2
Sm(OTf)3
Yb(OTf)3
Al-Salen
Cr-Salen
a For reaction details see the Supporting Information. b 1 equiv of chiral
Lewis acid used. c Isolated yield after column purification. d Determined
with chiral GC.
1454
Org. Lett., Vol. 7, No. 8, 2005

ical precursor and tert-butyl ester 6 as substrate (Table 2).
Three different classes of ligands were tested, namely the
bisoxazoline, proline, and salen ligands (see 11-14). MgI2
with bisoxazoline ligand 11 showed the best enantioselec-
tivity (entry 1). With Zn(OTf)2 and the same ligand the
enantioselectivity deteriorated, although the chemical yield
was unaffected (entry 2). It has been reported by our group
that lanthanide Lewis acids with proline ligand 12 provide
good enantioselectivity in radical additions to oxazolidinone
cinnamates;15 however, only low enantioselectivity was
obtained upon alkylation-hydrogenation of substrate 6
(entries 3 and 4). Commercially available aluminum and
chromium salen Lewis acids provided moderate selectivity
for the H-atom transfer reaction (entries 5 and 6). Several
H-atom donors with size or reactivity differing from that of
tributyltin hydride were also screened but were not found to
be beneficial.16
(78-92% ee, entries 2-5). The medium sized benzyl ester
7 gave much inferior enantioselectivity (entries 11-14) with
all the radicals irrespective of their size, although the sense
of induction was the same as that with the methyl ester 5.
By contrast ester 6 with the bulky tert-butyl substituent gave
the opposite sense of stereoinduction (entries 6-10).17 The
absolute configuration of 8c was determined to be (S)
whereas for 9c it was (R), based on conversion to a known
compound.18 The stereochemistries of 8b and 9b were also
shown to be complementary, based on conversion to a
common compound. Thus a remarkable dependence on the
size of the ester substituent, with the small methyl ester
substituent leading to relatively high (S) configuration, the
bulky tert-butyl ester substituent leading to the reversed (R)
configuration, albeit with lesser selectivity, and the interme-
diate-sized benzyl substituent giving intermediate selectivity.
With free alcohols 5-7, Lewis-acid chelation should
Table 3 shows results for a series of enantioselective
additions to esters 5-7, using various acyclic and cyclic
radicals and using MgI2-ligand 11 as the chiral Lewis acid.
involve six-membered rings. In our protected â2
-amino acid
work (see eq 1), we had observed high enantioselectivity
when eight-membered-ring Lewis acid complexes were
involved. Thus the free alcohol 6 was converted to acetate
15,19 which seemed likewise capable of eight-membered-
ring chelation. Radical additions to the acetate 15 in the
absence of a Lewis acid gave the products in good yields
(Table 4, entries 1 and 3). However, when the same MgI2-
Table 3. Enantioselective H-Atom Transfer Reactions with
Various Radical Precursorsa,b
Table 4. Enantioselective H-Atom Transfer Reactions to
Acetatesa,b
entry
R
R1X
ethyl-I
compd
yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Me
Me
Me
Me
8a
8b
8e
8c
8d
9a
9b
9e
9c
9d
10a
10b
10e
10c
51
69
82
52
77
58
53
62
75
80
85
94
81
97
75e
88e
i-Pr-I
90e
entry
R1X
product
yield (%)c
ee (%)d
cyclopentyl-I
cyclohexyl-I
t-Bu-I
ethyl-I
i-Pr-I
cyclopentyl-I
cyclohexyl-I
t-Bu-I
ethyl-I
i-Pr-I
78e
1e
2
cyclohexyl-I
cyclohexyl-I
i-Pr-I
16
16
17
17
59
90
84
89
Me
92e
34f
36f
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Bn
Bn
Bn
Bn
-62e
-55e
-69e
-71e
-53e
40
3e
4
i-Pr-I
a For reaction details see the Supporting Information. b 1 equiv of chiral
Lewis acid used. c Isolated yield after column purification. d Determined
with chiral HPLC. e Reaction in the absence of a Lewis acid. f ee for the
products was determined by converting them to the corresponding benzoate
derivative.
44
48
41
cyclopentyl-I
cyclohexyl-I
a For reaction details see the Supporting Information. b 1 equiv of chiral
Lewis acid used. c Isolated yield after column purification. d Determined
with chiral HPLC. e ee determined for benzoate derivative.
11 catalyst that was successful with free alcohols 5 and 6
and in our â2-amino acid project was used, the enantiose-
lectivity of the hydrogen atom transfer was quite low (Table
4, entries 2 and 4).
Methyl ester 5 consistently gave the best enantioselectivity
(entries 1-5). While a primary radical gave moderate
enantioselectivity (entry 1), the addition of larger secondary
or tertiary alkyl groups resulted in good enantioselectivity
We do not have a definitive model to explain the surprising
reversal of enantioselectivity between methyl ester 5 and tert-
butyl ester 6. At least several possibilities may apply. One
(17) 30 mol % chiral Lewis acid-catalyzed reactions provided ee values
in the range of 20-25% for most of the substrates with the radical precursors
shown.
(18) Imogai, H.; Larcheveque, M. Tetrahedron: Asymmetry 1997, 8, 965.
Also see the Supporting Information.
(14) Various other chiral Lewis acids were investigated and the best
results are shown here. Chiral Lewis acid reactions were also performed
on methyl ester. Since the results were similar, they are not shown here.
(15) Sibi, M. P.; Manyem, S. Org. Lett. 2002, 4, 2929.
(16) Radical reactions with Ph3SnH and (TMS)3SiH (TMS ) trimeth-
ylsilyl) were not clean.
(19) Reactions of methyl ester substituted acetate provided polymerized
products.
Org. Lett., Vol. 7, No. 8, 2005
1455

is that the methyl ester 5 reacts via an octahedral magnesium
complex, while for steric reasons the bulkier tert-butyl ester
reduces the coordination number for magnesium such that
reaction proceeds via a tetrahedral complex instead. A second
more likely possibility is that all three substrates 5, 6, and 7
react via octahedral magnesium complexes, but that the
substrates can coordinate in either of two orientations,
depending on the size of the ester substituent. With a methyl
ester 5, Dreiding model analysis suggests that the ester
carbonyl coordinates trans to one of the ligand nitrogens
(Figure 1, complex A in the simplified conceptual diagram).
via orientation A must be fairly high. While the sense of
selectivity with tert-butyl substrate 6 is reversed, the level
of enantioselectivity is never as high (53-71% ee). It is
possible that while substrate 6 reacts primarily via complex
B, that stereochemical erosion results from significant
competing reaction via complex A. With the medium-sized
benzyl ester 7, presumably reaction occurs largely via
complex A, but with too much reaction via orientation B to
allow useful selectivity. A third possibility is that the reversal
of enantioselectivity between substrates 5 and 6 simply
reflects local conformational effects that result from the
differing sizes of the ester substituents. The presence of the
sp3-hybridized carbon in the substrate backbone provides
considerable flexibility in a six-membered-ring chelate with
the Lewis acid.
In summary, we have developed an interesting route to
R-substituted aldol products from simple Baylis-Hillman
R-hydroxymethyl acrylates. Under the mild radical conditions
the alkylation-hydrogenation reaction requires no protection
of the hydroxyl group. An unexpected reversal in enantio-
selectivity is observed between methyl and tert-butyl esters.
The results provide additional examples of enantioselective
hydrogen atom transfer reactions.
Figure 1. Models to explain stereochemistry
Acknowledgment. We thank the NIH (NIGMS-54656)
for financial support. We also thank Prof. Craig Jasperse for
helpful discussions.
With the bulky tert-butyl substituent, however, it appears
that the chiral cavity is not well suited for coordination of
substrate 6 in orientation A. We believe that the tert-butyl
ester 6 instead reverses its orientation and reacts via complex
B, in which the hydroxy group rather than the ester carbonyl
occupies the position trans to a ligand nitrogen. This reversal
of orientation would accommodate the observed reversal in
enantioselectivity. With methyl ester 5, enantioselectivities
as high as 92% were obtained, so the preference for reaction
Supporting Information Available: Characterization
data for all new compounds and experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL047347H
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Org. Lett., Vol. 7, No. 8, 2005