Diastereoselective formation of β-hydroxyketones by the reduction of Ketene dimers

Article abstract of DOI:10.1016/j.tetlet.2012.12.011

A general method for the diastereoselective formation of β-hydroxyketones by the reduction of ketene dimers was developed. The reduction of ketene homodimers, derived from alkylarylketenes and dimethylketene, and ketene heterodimers, derived from methylketene and ethylphenylketene or diphenylketene, was investigated. Methylphenylketene dimer was reduced with optimal diastereoselectivity (dr = 6:1) using LiBH₄. However, more generally, LiAlH₄ was found to be the most effective reducing system with respect to diastereoselectivity (dr up to >99:1) and yield (62->99% for 10 examples).

Full text of DOI:10.1016/j.tetlet.2012.12.011

Tetrahedron Letters 54 (2013) 932–935
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective formation of b-hydroxyketones by the reduction of
Ketene dimers
Pei-Hsun Wei, Melanie A. Gary, Divya Nalla, Gero D. Harzmann, Ahmad A. Ibrahim, Kyle R. Dayak,
⇑
Nessan J. Kerrigan
Department of Chemistry, Oakland University, 2200 N. Squirrel Rd., Rochester, MI 48309-4477, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the diastereoselective formation of b-hydroxyketones by the reduction of ketene
dimers was developed. The reduction of ketene homodimers, derived from alkylarylketenes and dim-
ethylketene, and ketene heterodimers, derived from methylketene and ethylphenylketene or diphenylke-
tene, was investigated. Methylphenylketene dimer was reduced with optimal diastereoselectivity
(dr = 6:1) using LiBH4. However, more generally, LiAlH4 was found to be the most effective reducing sys-
tem with respect to diastereoselectivity (dr up to >99:1) and yield (62–>99% for 10 examples).
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 October 2012
Revised 2 December 2012
Accepted 5 December 2012
Available online 20 December 2012
Keywords:
Disubstituted ketenes
Ketoketenes
Ketene dimer
Ketene heterodimer
b-Lactones
Diastereoselective
Reduction
b-Hydroxyketones
Enolates
Chiral
Enantioenriched
Aldol reactions and their products are widely used in the syn-
thesis of complex molecules.1 While efficient routes exist for most
classes of aldol products, successful aldol reactions involving form-
aldehyde are rare.2 This is due to formaldehyde’s common avail-
ability as an aqueous solution which generally precludes the use
of moisture-sensitive metallating agents (e.g., TiCl4). We consid-
ered that the use of a conceptually different route that involved
sequential ketene dimerization-reduction would obviate the need
for formaldehyde itself and open the way to a general method
for the preparation of b-unsubstituted aldol products (Scheme 1).
A few years ago, both our group and Ye’s group reported sys-
tems for the dimerization of ketoketenes (disubstituted ketenes).3,4
In 2010, our group reported a versatile chiral phosphine catalytic
system (Josiphos) which provided a general method for the asym-
metric homodimerization of ketoketenes (Scheme 2).5
O
OH
O
O
Reducing Agent
R1
R1
R2
R1
R1 R2
R2
R2
Scheme 1. Reduction of ketene dimers to give b-hydroxyketones.
tion, followed by a stereoselective ketene dimer reduction, would
provide an efficient and diastereoselective route to aldol products
derived from formaldehyde.
In 1996 Calter showed that a nucleophilic catalyst system (TMS-
quinine or TMS-quinidine) could catalyze the homodimerization of
aldoketenes with high enantio-selectivity.7 While reduction of ald-
oketene dimer b-lactones provides access to aldol products pos-
sessing one chiral center in modest yield, both our group and
Ye’s group noted in preliminary communications that reduction
of ethylphenylketene dimer provides efficient access to an aldol
product possessing two chiral centers with high diastereoselectiv-
ity (dr >99:1).3–5 However, the scope of the reduction process had
been by no means established.3–5 In this Letter we describe our
studies on the development of a diastereoselective reduction of
methylphenylketene dimer, as well as a broader examination of
In addition, we recently described an alkaloid-catalyzed asym-
metric heterodimerization of ketenes that provided access to ke-
tene heterodimer b-lactone products in excellent enantiomeric
excess (Scheme 3).6 We believed that a ketene dimerization reac-
⇑
Corresponding author.
E-mail address: kerrigan@oakland.edu (N.J. Kerrigan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.011

P.-H. Wei et al. / Tetrahedron Letters 54 (2013) 932–935
933
Table 2
(c-hexyl)2P
Further optimization of reduction of methylphenylketene dimer 1a to form 2aa
Me
1. LiBH4
Solvent as per Table 2
Fe
Ar2P
O
OH
O
O
−78 °C
O
Ph
Me
O
•
Me
Ph
10 mol% Josiphos
CH2Cl2
Ph
O
2. Quenching Agent
Me Ph
R1
R2
R1
Me
R1
R2
R2
-25 °C
Entry
Solvent
Quench temp.
Quenching Agent
Conv
dr
up to 99% (10 examples)
1
2
3
4
THF
THF
THF
0 °C
Aq std. NH4Cl
Aq std. NH4Cl
H2O
69
76
64
16
6:1
5:1
2:1
nd
up to 96% ee
À78 °C
À78 °C
À78 °C
9 examples ≥85% ee
THF/Et2Ob
Aq std. NH4Cl
Scheme 2. Phosphine-catalyzed asymmetric homodimerization of ketenes.
a
All reactions were conducted at 0.25 M concentration of dimer in solvent.
Et2O from ethereal solution of LiBH4 (1.0 M in Et2O).
b
10 mol%
O
O
•
O
Me-Quinidine
O
Me
+
Table 3
Cl
Ph
Hünig's base
CH2Cl2
Substrate scope of the reduction of ketene dimers
Me
Ph
Et
Donor
Et
Ketene
-25 °C
Acceptor
Ketene
1. LiAlH4 or LiBH4
(S,Z)
98% ee
62%
precursor
O
THF
−78 °C
OH
O
O
R4
R1
R4
R2
Scheme 3. Catalytic asymmetric heterodimerization of ketenes.
2. Aq. std. NH4Cl
R1 R2
R3
R3
−78 °C
1a-1g
2a-2g
the substrate scope and diastereoselectivity of the reduction
method.
We began our investigations with a focus on the reduction of
methylphenylketene dimer, as we felt that the resulting aldol
Entry
R1
R2
R3
R4
Yielda (conv)
dr
Product
1b
2b
3
4
5
Me
Et
Et
Ph
Ph
Ph
4-ClPh
Ph
Me
Me
H
Me
Et
Et
Ph
Ph
Ph
4-ClPh
Ph
Me
Ph
Ph
62 (76)
0
>99
(93)
75
94
92
90
35 (69)
5:1
—
>99:1
7:1
7:1
—
—
—
2:1
2a
—
2b
2c
2d
2e
(À)-2f
(+)-2f
2g
Et
Et
product, bearing an a-quaternary stereogenic center with a methyl
substituent, would prove useful in synthetic activities (Table 1).8
Our initially favored reducing agent, LiAlH4, facilitated access to
the desired product in satisfactory yield (70%) but with moderate
diastereoselectivity (dr = 3:1).9 We then proceeded to evaluate a
range of common reducing agents (NaBH4, DIBAL, Zn(BH4)2, Li(t-
BuO)2AlH2, and LiBH4). A 2.0 M solution of LiBH4 in THF proved
to be the most effective reducing agent in terms of both diastere-
oselectivity (dr 6:1) and conversion (69%). Optimal reaction condi-
tions involved the use of 1 equiv of the LiBH4 reagent solution, with
the ketene dimer at a concentration of 0.25 M in THF, and with
reaction quenching performed at 0 °C using aqueous saturated
ammonium chloride (Table 1, entry 6).
n-Bu
Me
H
Me
Me
n-Bu
Me
Ph
Ph
Et
6
7c
8d
9
H
Ph
a
b
c
Yields are isolated yields.
LiBH4 was used.
For the (À)-enantiomer.
d
For the (+)-enantiomer.
Quenching the reaction at À78 °C (Table 2) led to no improve-
ment in dr with only a slight improvement in conversion observed
(76%). The selection of saturated aqueous ammonium chloride as
quenching agent, rather than water, was found to provide optimal
results in terms of both diastereoselectivity and yield (Table 2 en-
try 2 vs entry 3). The use of diethyl ether as co-solvent (when a
1.0 M ethereal solution of LiBH4 was used as reagent) had a dra-
matic deleterious effect on the reaction (entry 4). The use of less
than 1 equiv of LiBH4 (e.g., 0.5 equiv, 14% conv) or more dilute
reaction conditions (e.g., 0.15 M ketene dimer in THF, 60% conv)
led to lower conversions.
Table 1
Optimization of reduction of methylphenylketene dimer 1a to form b-hydroxyketone
2aa
O
OH
O
O
Reducing Agent and
Ph
Me
Me
Ph
Ph
Reaction Temp.
as per Table 1
Me Ph
Me
We then investigated the LiBH4 reducing system with ethyl-
phenylketene dimer. However, unfortunately it gave poor results
(Table 3, entry 2) and so we revisited LiAlH4 as a reducing agent
for all other substrates (Table 3, entries 3–9).10,11
Using the LiAlH4 reducing system, good yields and diastereose-
lectivities were obtained in the reduction of ketene homodimers
(entries 3–6) and also ketene heterodimers (entries 7–9). The ma-
jor diastereomer in each case was assigned to be the syn-diastereo-
mer by analogy with Ye’s work.4 Intermolecular proton quenching
(by added aqueous NH4Cl solution) of enolate 4, explains the ob-
served sense of diastereoselectivity (syn). A chelate of both oxy-
gens to aluminum or boron (M = Al or B) would hinder approach
of the proton source to the lower face of the enolate 4 in TS 1
Entry
Reducing agent
Yieldb (Conv)c
Solvent
Temp.(°C)
drd
1
2
3
LiAlH4
NaBH4
Li(t-BuO)2AlH2
DIBAL
Zn(BH4)2
LiBH4
70
0
0
(67)
(40)
(69)
THF
EtOH/H2O
THF
CH2Cl2
THF
THF
À78
r.t.
À78
À78
À78
À78
3:1
—
—
5:1
4:1
6:1
4
5e
6
a
Aqueous saturated ammonium chloride added as quenching agent in most
cases at 0 °C.
b
Yields are isolated yields.
c
d
e
Conversion (Conv) determined by GC–MS analysis of crudes.
Diastereomeric ratio (dr) was determined by 1H NMR analysis of crudes.
Quenched with HCl (1 M) solution.

934
P.-H. Wei et al. / Tetrahedron Letters 54 (2013) 932–935
Reducing
Agent (MHn)
O
OH
O
O
Ph
H
R1
Ph
H
R1
Ph
R1 Ph
R1
1
syn-2
MHn
H+
Intramolecular
hydride
H
M
H
O
H
M
M
O
O
transfer
H+
O
O
O
Ph
Ph
H
Ph
H
H
TS 1
via
H
R1 Ph
H
R1
R1 Ph
R1 Ph
R1
R1
3
4
5
Selectivity Model (TS 1):
H+
approach from above
is favored
R1
R1
Ph
O
O
Ph
M
approach from below is
disfavored
TS 1
Scheme 4. Possible mechanism for the formation of 2 as the syn-diastereomer (ligands on M in 5 and TS 1 omitted for clarity).
enriched 1a (94% ee), 1b (90% ee), (+)-1f, and (À)-1f were all
1. LiAlH4
reduced effectively and without significant loss of enantiomeric
integrity to give enantioenriched 2a (92% ee), 2b (91% ee), (+)-2f
(96% ee), and (À)-2f (96% ee), respectively (Scheme 5). Therefore
the present method provides a valuable route to enantioenriched
b-hydroxyketones from readily available ketene dimers.3–6
O
THF
−78 °C
OH
O
O
Ph
Me
Ph
Ph
Ph
2. Aq. std. NH4Cl
Me
Ph
Me
Me
1a
−78 °C
2a
66%
dr = 3:1
92% ee
In summary, we have evaluated reduction of ketene dimers as a
route to b-hydroxyketones and determined that lithium aluminum
hydride is the most general reducing agent with respect to sub-
strate scope and diastereoselectivity, although lithium borohy-
dride works best for the reduction of methylphenylketene dimer.
(94% ee)
O
O
OH
O
1. as above
2. as above
Ph
Ph
Et
Ph
Et
Et
Et
1b
2b 84%
dr >99:1
91% ee
Acknowledgments
(90% ee)
We thank the National Science Foundation (Grant Nos. CHE-
0911483 and CHE-1213638 to N.J.K., CHE-0821487 for NMR facil-
ities at Oakland University, and CHE-1048719 for LC-MS facilities
at Oakland University).
O
O
OH
O
1. as above
2. as above
Ph
Ph
Ph
Me
Me Ph
Ph
− 1f
( )-
(96% ee)
− 2f
( )- 92%
96% ee
Supplementary data
O
O
OH
O
Supplementary data (characterization data and procedures for
the preparation of b-hydroxyketones 2a–2g) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.12.011.
1. as above
2. as above
Ph
Me
Me Ph
Ph
(+)-1f
(96% ee)
+ 2f
( )- 90%
96% ee
References and notes
Scheme 5. Reduction of enantioenriched ketene dimers to give enantioenriched b-
hydroxyketones.
1. (a) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, p 111; (b) Evans, D. A.; Nelson, J. V.; Taber, T. R.
Top. Stereochem. 1982, 13, 1–115; (c) Mukaiyama, T. Org. React. 1982, 28, 203–
331; (d) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489–503; (e)
Calter, M. A.; Liao, W.; Struss, J. A. J. Org. Chem. 2001, 66, 7500–7504; (f) Calter,
M. A.; Liao, W. J. Am. Chem. Soc. 2002, 124, 13127–13129.
(Scheme 4). Therefore protonation of the upper face of the enolate
4 is favored. Lower diastereoselectivity obtained in entry 1, Table 1
and entry 9, Table 3 might be explained by non-selective proton-
ation of enolate 4 through competing transition states, in those
cases where a more reactive, less sterically hindered enolate (e.g.,
R1 = Me) presents itself.
2. Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590–3596. and references
cited therein.
3. (a) Ibrahim, A. A.; Harzmann, G. D.; Kerrigan, N. J. J. Org. Chem. 2009, 74, 1777–
1780; (b) Ibrahim, A. A.; Smith, S. M.; Henson, S.; Kerrigan, N. J. Tetrahedron Lett.
2009, 50, 6919–6922; (c) Wei, P.-H.; Ibrahim, A. A.; Mondal, M.; Nalla, D.;
Harzmann, G. D.; Tedeschi, F. A.; Wheeler, K. A.; Kerrigan, N. J. Tetrahedron Lett.
2010, 51, 6690–6694.
Retention of chirality during LiAlH4-reduction of our enantioen-
riched ketene dimers was also investigated (Scheme 5).5,6 Enantio-
4. Lv, H.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Adv. Synth. Catal. 2008, 350, 2715–2718.

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935
5. Ibrahim, A. A.; Wei, P.-H.; Harzmann, G. D.; Kerrigan, N. J. J. Org. Chem. 2010, 75,
7901–7904.
6. Ibrahim, A. A.; Nalla, D.; Van Raaphorst, M.; Kerrigan, N. J. J. Am. Chem. Soc.
2012, 134, 2942–2945.
7. (a) Calter, M. A. J. Org. Chem. 1996, 61, 8006–8007; (b) Calter, M. A.; Orr, R. K.
Org. Lett. 2003, 5, 4745–4748.
8. (a) Rasmussen, K.; Calligaro, D. O.; Czachura, J. F.; Dreshfield-Ahmad, L. J.;
Evans, D. C.; Hemrick-Luecke, S. K.; Kallman, M. J.; Kendrick, W. T.; Leander, J.
D.; Nelson, D. L.; Overshiner, C. D.; Wainscott, D. B.; Wolff, M. C.; Wong, D. T.;
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9. Experimental procedure using LiAlH4 for preparation of 2a: To methylphe-
nylketene dimer 1a (57 mg, 0.21 mmol) was added LiAlH4 (1 M in Et2O,
0.21 mL, 0.21 mmol) at À78 °C. The reaction was quenched with aqueous
saturated NH4Cl solution (5 mL) at À78 °C. The resulting crude product 2a had
a dr = 3:1 as determined by 1H NMR analysis. Crude 2a was purified by a flash
(iatrobeads). The solvent was removed under reduced pressure to afford ( )-2a
as a white solid (40 mg, 70%) and as a single diastereomer.
10. Selected characterization data for 2a: IR (thin film): 3428, 1720 cmÀ1 1H NMR
;
(200 MHz, CDCl3, TMS): d 7.40–7.11 (m, 10H), 4.02 (d, J = 11.6 Hz, 1H), 3.65 (q,
J = 10.3 Hz, 1H), 3.35 (d, J = 11.6 Hz, 1H), 2.35 (s, 1H), 1.35 (s, 3H), 1.16 (d,
J = 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3): d 215.3, 141.4, 139.2, 129.2, 128.9,
128.0, 127.8, 127.1, 127.1, 70.1, 59.1, 48.8, 22.1, 18.3; (M++Na)HRMS m/z Calcd
for C18H20O2Na: 291.1356; found: 291.1349.
11. Experimental procedure using LiBH4 for preparation of 2a: Methylphenylketene
dimer 1a (0.44 mmol) was dissolved in THF (1.8 mL) and the solution was cooled
to À78 °C. LiBH4 (2.0 M in THF, 0.22 mL, 0.44 mmol) was added to the cooled
solution at À78 °C. The reaction was allowed to warm to room temperature and
stirred until TLC showed complete consumption of starting material (ca. 80 min).
The reaction was then cooled to À78 °C and was quenched with aqueous
saturated NH4Cl solution (10 mL) at À78 °C. The aqueous phase was extracted
with CH2Cl2 (3 Â 5 mL), and the combined organic layers were dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure to afford b-
hydroxyketone 2a as a white solid (73 mg, 62%) with P94% purity and dr = 5:1 as
determined by 1H NMR and GC–MS analysis.
column chromatography over neutral silica (iatrobeads), eluting with
a
gradient solvent system (from hexane to 5% EtOAc/hexane) of neutral silica