Enantioselective rhodium(I)-triethylamine catalyzed addition of potassium isopropenyl trifluoroborate to enones

Article abstract of DOI:10.1016/j.tetlet.2008.05.147

A general process is reported for the highly enantioselective 1,4-addition of isopropenyl trifluoroborate to cyclic enones under catalysis by a chiral Rh(I) complex and triethylamine at room temperature.

Full text of DOI:10.1016/j.tetlet.2008.05.147

Tetrahedron Letters 49 (2008) 4894–4896
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Tetrahedron Letters
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Enantioselective rhodium(I)-triethylamine catalyzed addition
of potassium isopropenyl trifluoroborate to enones
*
Gojko Lalic, E. J. Corey
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A general process is reported for the highly enantioselective 1,4-addition of isopropenyl trifluoroborate to
cyclic enones under catalysis by a chiral Rh(I) complex and triethylamine at room temperature.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 May 2008
Accepted 30 May 2008
Available online 5 June 2008
O
Recently, we reported a formal enantioselective synthesis of
platensimycin (1),1 in which the initial stereocenter was intro-
duced by the catalytic enantioselective 1,4-addition of an isopro-
penyl group to enone 2 (Scheme 1). Despite the existence of
numerous methods for enantioselective 1,4-addition to enones,2–4
no instances of such reactions with secondary alkenyl groups had
been described in the literature. We developed an approach that
appears to be uniquely effective in achieving this transformation
under special conditions with Rh(I) catalysis. The substrates used
in this key step were 2 and 3. In this Letter, we provide details of
the discovery and the scope of this transformation.
Our initial effort to achieve an enantioselective addition of
potassium isopropenyl trifluoroborate to enone 2, using standard
reaction conditions,5 resulted in the formation of a 1:1 mixture
of addition products 4 and 5, in only moderate yield because of
concurrent hydrolysis of the ethylene ketal (Scheme 2). The enan-
tiomeric purity of 4 was 96%. In order to suppress this hydrolysis,
the 1,4-addition reaction was performed in the presence of trieth-
ylamine, which allowed the isolation of the same isomeric mixture
of addition products in 95% yield.
[Rh(cod)2]BF4 (3.0 mol%)
OMe
(
S
)-BINAP (3.3 mol%)
BF3K
+
toluene,H2O
110 ˚C, 3 h
45% yield, 96% ee
Me
3
O
O
2
O
O
OMe
OMe
+
Me
O
O
O
O
Me
4
5
Scheme 2. Formation of the two isomeric products under standard reaction
conditions.
gate addition reaction. Consequently, higher temperatures are
unnecessary and the reaction can be carried out at room tempera-
ture. Such mild conditions lead to a wider utility and greater effi-
ciency of conjugate addition.
At lower temperature the desired 2-propenyl adduct 4 is
favored over the 1-propenyl adduct 5. At 110 °C the products are
formed in a 1:1 ratio, while at 80 °C 4 is favored by 1.2:1. At room
temperature, 4 was formed as the only product of the reaction and
was isolated in 96% yield and 94% ee. The exclusive formation of 4
at room temperature and the high enantioselectivity are notewor-
thy, especially since Genêt et al. have reported the formation of
racemic products in all rhodium-catalyzed 1,4-additions of potas-
sium trifluoroborates performed under 100 °C.5
Repeated experiments conducted without triethylamine con-
firmed that the amine base is responsible for both the reactivity
and enantioselectivity observed in the reaction performed at room
temperature.6 Specifically, as summarized in Scheme 3, the conju-
gate addition reaction with 2 was not only slow at 23 °C in the
absence of Et3N (only 7% yield after 36 h), but also gave racemic
product.
An important finding from experiments using triethylamine as
an additive was that this base not only inhibits Lewis acid-induced
hydrolysis of the substrate, but also greatly accelerates the conju-
O
Me
OMe
BF3K
O
Me
NHAr
+
Me
3
O
O
O
O
2
1, platensimycin
Scheme 1. 1,4-Addition as a key step in an enantioselective formal synthesis of
platensimycin.
* Corresponding author. Tel.: +1 617 495 4033; fax: +1 617 495 0376.
E-mail address: corey@chemistry.harvard.edu (E. J. Corey).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.147

G. Lalic, E. J. Corey / Tetrahedron Letters 49 (2008) 4894–4896
4895
selectivities were observed in reactions of potassium isopropenyl
trifluoroborate with several cyclic enones (see Table 1, entries
1–3).7,8 It is noteworthy that with an acyclic enone (entry 4) the
conjugate adduct was formed in good yield, but was racemic. It
O
O
3 (2.0 equiv)
OMe
OMe
[Rh(cod)2]BF4 (3.0 mol%)
(S)-BINAP (3.3 mol%)
toluene, H2O, Et3N
23 ˚C, 36 h
was also possible to effect conjugate addition to the acyclic
a,b-
O
O
2
O
O
Me
enal shown in entry 4 of Table 1, but here again the product was
racemic. The addition of Z alkyl-substituted terminal alkenyl
groups, which previously have not been used in enantioselective
rhodium-catalyzed 1,4 addition reactions, was also achieved. The
addition products of (E) and (Z)-1-hexenyl trifluoroborates and
2-cyclopenten-1-one were isolated in good yields and in 70% ee
(entries 6 and 7).
4
with Et3N
with out Et3N
96% yield, 94% ee
7% yield, 0% ee
Scheme 3. The effect of triethylamine on the reactivity and selectivity of the 1,4-
addition reaction.
We performed several experiments aimed at understanding the
underlying reasons for the beneficial effect of triethylamine on the
conjugate addition process. When triethylamine was added to a
solution of [Rh(BINAP)Cl]2 and isopropenyl trifluoroborate in tolu-
ene-d8-H2O mixture, new signals in the 31P NMR spectrum at
40.3 ppm (dd, JP–Rh = 198 Hz, JP–P = 30 Hz) and 44.4 ppm (dd,
JP–Rh = 194 Hz, JP–P = 30 Hz) replaced the signals of the starting rho-
dium dimer within 10 min, indicating complete conversion of the
dimer into transmetallation product [Rh(BINAP)(isopropenyl)L].
Further optimization of the reaction parameters led to toluene
and dioxane as optimal solvents for the reaction, whereas other
common solvents, such as ether, dichloromethane, THF, and aceto-
nitrile, led to significantly inferior yields and enantioselectivities.
Of the common amine bases, triethylamine and Hünig’s base were
most effective, with the best results achieved in the presence of
2 equiv of triethylamine relative to the trifluoroborate salt. Under
these optimized reaction conditions excellent yields and enantio-
Table 1
R2
R3
R1
[Rh(cod)2]BF4 (3.0 mol%)
R5
O
R1
R5
O
(S
)-BINAP (3.3 mol%)
BF3K
+
R2
R4
R6
Et3N (3 equiv),
toluene, H2O, 23 ˚C, 72 h
R6
R3
R4
a 2D2
ꢀ
ee (%)
93
a
Entry
1
Enone
Product
Yield (%)
80
½
O
O
ꢁ112
ꢁ74
Me
O
O
O
2
87
>98
Me
O
3
89
81
89
ꢁ79
0
>98
0
Me
Me
O
H
4b
C5H11
HO
Me
C5H11
Me
O
O
5
0
0
Me
C5H11
C5H11
O
O
O
6c
89
83
ꢁ63
70
70
C4H9
C4H9
O
7c
ꢁ101
a
c = 1 in CHCl3.
b
c
Alcohol isolated after NaBH4 reduction of the crude product.
Reaction time was 96 h.

4896
G. Lalic, E. J. Corey / Tetrahedron Letters 49 (2008) 4894–4896
lyst because it accelerates the B–Rh transmetallation reaction by
displacement of the original ligand on Rh (X, e.g., X@OH). This
would imply that the Et3N ligand on Rh is more readily displaced
than Xꢁ (i.e., that Rh is more electrophilic with Et3N as a ligand
than with Xꢁ).
In summary, we have described a highly efficient rhodium-
catalyzed 1,4-addition of potassium vinyl trifluoroborate salts to
cyclic enones in the presence of triethylamine. The low tempera-
ture at which reaction is conducted allows the use of vinyl trifluo-
roborate salts that are incompatible with the standard reaction
conditions. Most notably, it allows accelerated enantioselective
addition of an isopropenyl group to cyclic enones which could
not be achieved using previously described procedures. We also
provided evidence for the dramatic acceleration of the transmetal-
lation step by Et3N of the conjugate addition.
Scheme 4.
Under the same conditions, in the absence of triethylamine, the
formation of the transmetallation product was not observed even
after 2 h. These experiments indicate that triethylamine acceler-
ates the conjugate addition process by increasing the rate of the
boron–rhodium transmetallation step.
References and notes
One explanation for this dramatic effect could be that triethy-
amine facilitates the formation of rhodium hydroxo dimer. Hayashi
et al. have reported that hydroxodimer, usually formed from
[Rh(BINAP)Cl]2 in the presence of KOH, readily participates in
transmetallation reactions with boronic acids, and can serve as a
superior catalyst for 1,4-addition of boronic acids.9 In an attempt
to observe the formation of the hydroxodimer, triethylamine was
added to a solution of [Rh(BINAP)Cl]2 in toluene-d8–H2O mixture.
Over 4 h we observed a slow appearance of a new singlet in 31P
NMR at 27 ppm, indicating the loss of the original rhodium com-
plex. However, when KOH or tetrabutylammonium hydroxide
was used in place of Et3N (conditions for formation of Rh-hydroxo
dimer), the rate of the reaction was greatly decreased. (Scheme 4).
When triethylamine was used in the reaction together with KOH,
the rate of the reaction was not affected by the presence of KOH.
The results of these experiments strongly suggest that hydroxide
is not involved in the formation of the active catalyst.
1. Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921–4923.
2. Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171–196.
3. Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–3236.
4. Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844.
5. Pucheault, M.; Darses, S.; Genêt, J. P. Eur. J. Org. Chem. 2002, 3552–3557.
6. The beneficial effect of triethylamine on the rate of rhodium catalyzed 1,4-
additions to enones has been reported: Itooka, R.; Iguchi, Y.; Miyaura, N. J. Org.
Chem. 2003, 68, 6000–6004.
7. To a 15 mL Schlenk tube were added [Rh(cod)2]BF4 (0.030 equiv, 0.015 mmol),
(S)-BINAP (0.033 equiv, 0.016 mmol), and potassium vinyl trifluoroborate
(2.00 equiv, 1.00 mmol). The Schlenk tube was flushed with nitrogen several
times and degassed toluene (1.00 mL), triethylamine (3.00 equiv, 1.50 mmol),
and water (0.50 mL) were added. After stirring the resulting mixture for 10 min
at room temperature, freshly distilled enone (1.00 equiv, 0.50 mmol) was added.
The Schlenk tube was closed and the reaction mixture was stirred at room
temperature. After 72 h, the reaction mixture was diluted with CH2Cl2,
transferred to a separatory funnel, and washed with 0.1 M aqueous HCl and
brine. The organic fraction was dried over MgSO4 and filtered. Solvent was
removed under reduced pressure and the crude product was purified by silica
gel chromatography.
8. The absolute configuration of the products was assigned by analogy to the
assignment made for compound 4, which was elaborated into a product of a
known absolute stereochemistry (see Ref. 1 for details).
9. Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124,
5052.
An alternative explanation for the role of triethylamine, consis-
tent with the results of our experiments, is the formation of a
triethylamine rhodium complex, which serves as the active cata-