Enantioselective rhodium-catalyzed alkylative desymmetrization of 3,5-dimethylglutaric anhydride

Article abstract of DOI:10.1055/s-0028-1083275

A rhodium-catalyzed enantioselective cross-coupling of sp³ organozinc reagents and 3,5-dimethylglutaric anhydride has been developed to afford the corresponding products, syn-deoxypolypropionates, in excellent yields and enantioselectivities. T

Full text of DOI:10.1055/s-0028-1083275

PRACTICAL SYNTHETIC PROCEDURES
335
Enantioselective Rhodium-Catalyzed Alkylative Desymmetrization of
3,5-Dimethylglutaric Anhydride
Desymmetrization of
3
a
,5-Dimethy
t
lglutar
t
ic Anhy
h
dride ew J. Cook, Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Fax +1(970)4911801; E-mail: rovis@lamar.colostate.edu
PSP
Received 16 June 2008; revised 30 August 2008
No144
Abstract: A rhodium-catalyzed enantioselective cross-coupling of sp3 organozinc reagents and 3,5-dimethylglutaric anhydride has been
developed to afford the corresponding products, syn-deoxypolypropionates, in excellent yields and enantioselectivities. This reaction has
been developed so that both commercially available and in situ prepared organozinc reagents are competent coupling partners.
Key words: organozinc reagents, Grignard reagents, C–C bond formation, syn-deoxypolypropionates
Me
O
Me
Me
OH
O
Me
O
O
Me
O
I
Me
O
O
O
MeN
Me
HO
N
H
O
Me
OH
abyssomicin C
(–)-doliculide
H
O
H
Me
OH
O
O
Me
O
Me
Me
Me
OH
HO
Me
Me
Me
Me
Me
Me
Me
OH
Me
pectinatone
CO2H
OH
O
Me
Me
Me
Me
ionomycin
Figure 1 Examples of natural products containing syn-deoxypolypropionate motifs
The desymmetrization of achiral compounds into entities diphenylzinc.5 Although high enantioselectivities were
that bear one or more defined stereocenters is a powerful accomplished, this reaction was especially sensitive to the
transformation.1 Cyclic anhydrides are especially attrac- zinc reagent used with only diphenyl- and dimethylzinc
tive substrates for these reactions as they are readily avail- being applicable. In some previous work from our group,
able as single meso-diastereomers. The products of such this drawback was circumvented via the introduction of a
transformations are present in many fragments of natural rhodium-phosphoramidite complex for this reaction
products. The enantioselective desymmetrization of cy- which allowed, for the first time, the use of in situ pre-
clic anhydrides has been achieved with heteroatom nu- pared arylzinc triflates as the nucleophile.6
cleophiles with impressive results;2 however, the
corresponding reaction with carbon-based nucleophiles is
We sought to extend this strategy to glutaric anhydrides
and sp3 nucleophiles, the products of which are syn-deoxy-
less explored. Building on our success of nickel-catalyzed
polypropionates, a ubiquitous structure in many natural
cross couplings,3,4 we have further expanded this ap-
products (see Figure 1).7 Following a thorough catalyst
proach to enantioselective carbon–carbon bond forma-
and ligand screening, we discovered that the combination
tion. We demonstrated that palladium was an efficient
of chloronorbornadienylrhodium(I) dimer ([Rh(nbd)Cl]2)
catalyst for the cross-coupling of succinic anhydrides with
and tert-butylphosphinooxazoline (t-Bu-PHOX)8 was op-
timal. This catalyst system provides good yields and good
to excellent enantioselectivities with commercially avail-
able Me2Zn and Et2Zn; however, the reaction was less ef-
ficient with Ph2Zn and i-Pr2Zn (Scheme 1, Table 1).
SYNTHESIS 2009, No. 2, pp 0335–0338
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083275; Art ID: M03008SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

336
M. J. Cook, T. Rovis
PRACTICAL SYNTHETIC PROCEDURES
O
O
[Rh(nbd)Cl]2 (2.5 mol%)
(S)-t-Bu-PHOX (5 mol%)
O
O
O
PPh2
R
OH
R2Zn, THF, 25 °C
N
Me
Me
Me
Me
t-Bu
1
2
O
Me2Zn
87%, 86%ee
Et2Zn
95%, 95%ee
i-Pr2Zn
<20%
Ph2Zn
76%, 56% ee
(S)-t-Bu-PHOX
Scheme 1 Desymmetrization of 3,5-dimethylglutaric anhydride with commercially available zinc reagent
zylic nucleophile, which provides the optimal results.
Table 1 Desymmetrization of 3,5-Dimethylglutaric Anhydride
with In Situ Prepared Zinc Reagent
This reaction is tolerant of a wide range of substituents on
the benzene ring; however, electron-rich aromatics afford
slightly diminished enantioselectivities due to an uncata-
lyzed background reaction.
[Rh(nbd)Cl]2
(S)-t-Bu-PHOX
O
O
O
O
O
R
OH
RZnX, THF, 50 °C
Me
Me
Me
Me
Functionalized nucleophiles may be generated using
Knochel’s procedure10 and the reaction is tolerant of both
ester and halide functionalities.11
Entry RZnX
Y =
Yield (%) ee (%)
1
2
3
4
85
80
62
70
95
94
88
90
MeZnBr
This chemistry is also amenable to scale-up; the reaction
of dimethylglutaric anhydride and methylzinc bromide
proceeds in excellent yields and enantioselectivities
(Scheme 2). The catalyst loading may be reduced to 1.5
mol% rhodium dimer (3 mol% Rh atom) and 3 mol% of
the ligand with little effect on yields or enantioselectivi-
ties.
EtZnBr
n-PrZnBr
n-BuZnBr
ZnBr
5
62
92
6
7
8
9
H
87
75
74
78
90
85
88
90
[Rh(nbd)Cl]2 (1.5 mol%)
(S)-t-Bu-PHOX (3 mol%)
O
O
O
O
O
OMe
Me
F
Zn(OAc)
Me
OH
MeZnBr, THF, 25 °C
82%, 95% ee
Me
Me
Y
Me
Me
2a
1 (5 mmol)
Zn(OAc)
10
68
90
Scheme 2 Large-scale desymmetrization of 3,5-dimethylglutaric
anhydride with in situ prepared nucleophile
Zn
Zn
Zn
11
12
66
76
89
94
OAc
2
All reactions were carried out under argon in flame-dried glassware
with magnetic stirring. Column chromatography was performed on
EM Science silica gel 60 (230–400 mesh). TLC analyses were per-
formed on EM Science 0.25 mm silica gel 60-F plates. For spectral
and HPLC/GC data for all compounds described, see ref. 11.
Cl
2
13
78
95
CO2Et
2
In Situ Alkylzinc Reagent (0.15 M); General Procedure
A flame-dried 10 mL round-bottom flask was charged with ZnBr2
(225 mg, 1 mmol) under an inert atmosphere in a glove box. The
flask was sealed with a septum, removed from the glove box, and
placed under a positive pressure of argon. To this was added anhyd
THF (3 mL) and Et2O (3 mL) and cooled to 0 °C. The alkylmagne-
sium bromide9 (2 M in Et2O; 0.5 mL,1 mmol) was added dropwise,
then the resulting suspension was stirred at 0 °C for 30 min and at
25 °C for 1 h. The stirring was stopped and the precipitate was al-
lowed to settle over 1 h. The supernatant was decanted via syringe
and used directly.
As these are the only commercially available diorgano-
zinc reagents, this reaction was somewhat limited at this
point. Therefore, a protocol was developed for the use of
in situ prepared nucleophiles. Three distinct nucleophile
classes were examined: alkyl, benzylic, and functional-
ized.
Alkyl nucleophiles were prepared using a Grignard–
ZnBr2 transmetalation protocol whereby the majority of
the magnesium salts may be precipitated allowing for the
alkyl transfer to occur in excellent yields and enantiose-
lectivities. This sequence may be applied to a variety of
unfunctionalized alkyl nucleophiles generated from their
corresponding Grignard reagents.9
In Situ Benzylzinc Reagent (0.15 M)
A flame-dried 10 mL round-bottom flask was charged with
Zn(OAc)2 (183 mg, 1 mmol) under an inert atmosphere in a glove
box. The flask was sealed with a septum, removed from the glove
box, and placed under a positive pressure of argon. To this was add-
ed anhyd THF (3 mL) and Et2O (3 mL) and cooled to 0 °C. Benzyl-
magnesium chloride (2 M in Et2O; 0.5 mL, 1 mmol) was added
dropwise, then the resulting suspension was stirred at 0 °C for 30
min and at 25 °C for 1 h. The stirring was stopped and the precipi-
Benzylic nucleophiles can be generated from their Grig-
nard reagent also. It is important to use freshly prepared
Grignard reagent made from the corresponding benzyl
chloride. Transmetalation with Zn(OAc)2 affords the ben-
Synthesis 2009, No. 2, 335–338 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Desymmetrization of 3,5-Dimethylglutaric Anhydride
337
tate was allowed to settle over 1 h. The supernatant was decanted
via syringe and used directly.
with Et2O (3 × 50 mL). The combined organic layers were dried
(MgSO4, 20 g), filtered, and concentrated in vacuo to afford the title
compound (648 mg, 82%, 95% ee) as a colorless oil.11 Chiral GC
analysis (derived methyl ester) was performed using a Chiraldex
BDM-2 column at 110 °C rising to 140 °C (2 °C/min) at 1 mL/min;
peaks appeared at 13.15 (minor) and 13.33 min (major). The abso-
lute stereochemistry was determined by comparison of optical rota-
In Situ Functionalized Zinc Reagent (0.15 M);10 General Proce-
dure
An oven dried Schlenk flask was charged with alkyl iodide (0.6
mmol), then sealed and treated to four cycles of evacuation using ar-
gon to backfill. This was then cooled to 0 °C and neat Et2Zn (307
mL, 366 mg, 3 mmol) was added. Following 10 min at 0 °C, the mix-
ture was heated to 40 °C for 12 h. The excess Et2Zn and EtI were
removed under vacuum (Caution: evacuate using Schlenk tech-
niques and add MeOH to vacuum trap to quench the remaining
Et2Zn). Anhyd THF (1 mL) was added and the vessel evacuated
again and this sequence was repeated further two times. Finally the
mixture was allowed to cool to 25 °C, THF (2 mL) was added, and
used directly.
tion [a]D –11.0 (c = 7.6, CHCl3); {Lit.12 [a]D +14.7 (c = 7.6,
CHCl3) for the 2S,4R-enantiomer}. All other analytical data were
consistent with those reported by Sih and co-workers.12
23
25
Acknowledgment
M.J.C. acknowledges the American Heart Association for a post-
doctoral fellowship. T.R. thanks Johnson and Johnson, Merck, Eli
Lilly, and Boehringer Ingelheim for support. T.R. is a fellow of the
A. P. Sloan Foundation and thanks the Monfort Family Foundation
for a Monfort Professorship.
Rhodium-Catalyzed Desymmetrization; General Procedure
To a flame-dried 10 mL round-bottomed flask was added
[Rh(nbd)Cl]2 (4 mg, 0.0088 mmol) and t-Bu-PHOX (6.5 mg,
0.0176 mmol) in a glove box. The flask was sealed with a septum,
removed from the glove box, and purged with argon for 15 min. An-
hyd THF (2 mL) was added and then the nucleophile solution (0.3
mmol) was added via syringe. The solution was heated to 50 °C and
dimethylglutaric anhydride (1; 25 mg, 0.176 mmol) in THF (1 mL)
was added. The mixture was stirred overnight at 50 °C and then sub-
jected to either of the two workup procedures: To afford the free
acid, the mixture was partitioned between Et2O (5 mL) and HCl (1
M, 5 mL) and the aqueous phase was extracted with Et2O (3 × 5
mL). The combined organic washings were extracted with aq sat.
NaHCO3 (2 × 5 mL) and the combined aqueous phases were acidi-
fied (pH 1) and extracted with Et2O (3 × 10 mL). The combined or-
ganic phases were dried (MgSO4), filtered, and concentrated in
vacuo to afford the pure free acid. To afford the methyl ester, the
mixture was partitioned between Et2O (5 mL) and HCl (1 M, 5 mL)
and the aqueous phase was extracted with Et2O (3 × 5 mL). The
combined organics were dried (MgSO4), filtered, and concentrated
in vacuo. The residue was dissolved in toluene–MeOH (1:1, 5 mL)
and TMSCHN2 (2 M in Et2O, 0.5 mL) was added. After 10 min, the
solution was concentrated in vacuo and chromatographed directly
to afford the pure methyl ester.
References
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(–)-(2R,4S)-2,4-Dimethyl-5-oxohexanoic Acid (2a); Large-Scale
Procedure
A flame-dried 100 mL round-bottomed flak was charged with
ZnBr2 (2.25 g, 10 mmol) under an inert atmosphere in a glove box.
The flask was sealed with a septum, removed from the glove box,
and placed under a positive pressure of argon. To this was added an-
hyd THF (30 mL) and Et2O (30 mL) and cooled to 0 °C. MeMgBr
(3.3 mL, 3 M in THF, 10 mmol) was added dropwise, then the re-
sulting suspension was stirred at 0 °C for 30 min and at 25 °C for 1
h. The stirring was stopped and the precipitate was allowed to settle
over 1 h. To a separate 100 mL round-bottomed flask was added
[Rh(nbd)Cl]2 (35 mg, 0.0750 mmol) and (S)-tert-butylphosphino-
oxazoline (56 mg, 0.150 mmol) under an inert atmosphere in a
glove box. The flask was sealed with a septum, removed from the
glove box, and placed under a positive pressure of argon. To this
was added anhyd THF (10 mL) followed, 5 min later, by the meth-
ylzinc bromide solution (48 mL) prepared earlier (which was de-
canted from the precipitate via syringe) and a pre-prepared solution
of 3,5-dimethylglutaric anhydride (1; 710 mg, 5 mmol) in THF (5
mL). The mixture was allowed to stir at 25 °C for 36 h. The resulting
dark brown solution was partitioned between Et2O (50 mL) and aq
1 M HCl (50 mL) and the aqueous layer was extracted with Et2O
(2 × 50 mL). The combined organic layers were washed with aq sat.
NaHCO3 (2 × 25 mL). The aqueous layers were combined and acid-
ified to pH 1 using aq 1 M HCl and the acidified layer was extracted
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Synthesis 2009, No. 2, 335–338 © Thieme Stuttgart · New York

338
M. J. Cook, T. Rovis
PRACTICAL SYNTHETIC PROCEDURES
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(9) The reaction proceeds in a cleaner fashion if the Grignard is
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Synthesis 2009, No. 2, 335–338 © Thieme Stuttgart · New York