An asymmetric nickel-chromium coupling toward the synthesis of Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2010.02.078

An asymmetric nickel-chromium coupling strategy has been employed in the generation of enantioenriched Baylis-Hillman adducts with selectivities reaching >90% ee and in fair to moderate yields (up to 65%) using a chiral sulfonamide ligand. The reaction conditions appear to show reasonable generality and are compatible with both aromatic and aliphatic aldehydes. Utilizing such a strategy not only allows for the preparation of products which contain substitution at the β-position on the olefin but also allows for the separation of olefin isomers in this transformation.

Full text of DOI:10.1016/j.tetlet.2010.02.078

Tetrahedron Letters 51 (2010) 2151–2153
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An asymmetric nickel–chromium coupling toward the synthesis
of Baylis–Hillman adducts
*
Francis G. Fang, Thomas E. Horstmann , Jonathan Therrien
Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric nickel–chromium coupling strategy has been employed in the generation of enantioen-
riched Baylis–Hillman adducts with selectivities reaching >90% ee and in fair to moderate yields (up to
65%) using a chiral sulfonamide ligand. The reaction conditions appear to show reasonable generality
and are compatible with both aromatic and aliphatic aldehydes. Utilizing such a strategy not only allows
for the preparation of products which contain substitution at the b-position on the olefin but also allows
for the separation of olefin isomers in this transformation.
Received 9 December 2009
Revised 8 February 2010
Accepted 12 February 2010
Available online 18 February 2010
Keywords:
Baylis–Hillman
Ó 2010 Elsevier Ltd. All rights reserved.
Nickel–chromium-mediated coupling
Asymmetric
Enantioselectivity
The Baylis–Hillman reaction represents one of many important
carbon–carbon bond-forming reactions whose utility can be found
in the synthesis of natural products and medicinally relevant com-
pounds.1 The significance of this transformation lies in the genera-
tion of densely functionalized carbon skeletons from the simple
co-workers have reported that chiral sulfonamide chromium com-
plex 1 under catalytic conditions in the presence of vinyl iodide 2
and aldehyde 3 affords allylic alcohol 4 in good yields and enanti-
oselectivity (Eq. 1).5 Inspired by these results, we were attracted to
the feasibility of applying these conditions to
a-halo-a,b-unsatu-
coupling of readily available
a,b-unsaturated carbonyl compounds
rated carbonyl compounds in an effort to furnish the desired
and aldehydes in the presence of a tertiary amine or phosphine cat-
alyst. Traditionally, however, this intriguing reaction is often hin-
dered by the lack of reactivity and scope of substrates efficient in
this process. Despite recent developments in the generation of
asymmetric catalysts which have resulted in some elegant exam-
ples of high yielding and highly enantioselective Baylis–Hillman
products, the need for alternative methods for the preparation of
these novel synthons is still of great interest.2 In the context of
the total synthesis of Luminacin D at Eisai Inc., the strategy toward
the synthesis of fragment A consisted of a Baylis–Hillman synthon
from which all stereocenters within this complex natural product
are established (Scheme 1).3 From these studies, we sought to
probe the generality of using a nickel–chromium process to create
these allylic alcohols. We report herein an asymmetric Nozaki–
Hiyama–Kishi coupling aimed at the synthesis of enantioenriched
Baylis–Hillman adducts of increased tolerance to substrate substi-
tution and functionality.
Baylis–Hillman adducts.
ð1Þ
Stimulated by the discovery of a catalytic nickel–chromium-
mediated coupling, several research groups have recently disclosed
a number of catalytic asymmetric protocols.4 Included among
those expanding the frontiers in this area of interest, Kishi and
In preliminary experiments, it was determined that under stoi-
chiometric conditions, coupling of methyl
a-bromoacrylate 5 and
aldehyde 6 using CrCl2, NiCl2, and sulfonamide ligand 7 in THF
afforded the desired product 8 in 30% yield and 87% enantiomeric
* Corresponding author. Tel.: +1 978 837 4679; fax: +1 978 794 4910.
E-mail address: thomas_horstmann@eisai.com (T.E. Horstmann).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.078

2152
F. G. Fang et al. / Tetrahedron Letters 51 (2010) 2151–2153
Scheme 1. Application of a Ni–Cr-mediated coupling to prepare a Baylis–Hillman intermediate in the synthesis of Luminacin D.
excess proving that the adjacent ester functionality does not im-
pede the reaction (Eq. 2).6,7 Interestingly, it was observed that
the (E)-olefin isomer of acrylate 5 was the predominant reactive
partner under the coupling conditions.8 Presumably, this discrimi-
nation could be due to the lower reactivity of the (Z)-isomer from a
more sterically encumbered nickel or chromium species with the
ethyl substituent. Encouraged by the reactivity and selectivity ob-
tained for this protocol, we proceeded to determine if other sol-
vents effected reaction reactivity or selectivity. In analogy to
reaction condition screening by Kishi and co-workers, acetonitrile
was used as an alternate solvent. It was found that for aldehyde
6, both THF and acetonitrile provided adduct 8 in comparable yield
and enantiomeric excess.
In conclusion, we have shown that substituted Baylis–Hillman
adducts can be generated via an asymmetric nickel–chromium
reaction with high enantiomeric excess (up to 94% ee). Both aro-
matic and aliphatic electrophiles are compatible with the reaction
conditions and afford products in fair to moderate yields. Using
such a strategy, it can be envisioned that substrates which would
not be compatible under a traditional Baylis–Hillman type mecha-
nism could also be made accessible by this methodology. Such
experiments and future optimization toward a catalytic process
are for future investigation.
Table 1
Substrate scope for coupling reactiona
Entry Electrophile
Product
Yieldb
(%)
eec
(%)
1
30
46
28
32
65
N.R.
87
90
94
55
88
2
ð2Þ
3
4d
5d
6
With these conditions in hand, we wanted to further explore
what scope of electrophiles would perform favorably in this reac-
tion. We were delighted to find that several aldehydes examined
afforded selectivity under the nickel–chromium conditions
(Table 1).9 Analagous to aldehyde 6 (entry 1), aromatic aldehydes
provided excellent selectivities in this reaction. p-Tolualdehyde 9
and benzaldehyde 11 (entries 2 and 3) furnished the desired Bay-
lis–Hillman adducts 10 and 12 in fair yields (46% and 28%, respec-
tively) and in excellent enantiomeric excess (90% and 94%,
respectively). While aromatic aldehydes furnished selectivities
>90%, we also discovered that other aliphatic aldehydes produced
fair to good selectivities as well. Cyclohexanecarboxaldehyde 13
(entry 4) and isobutyraldehyde 15 (entry 5) afforded the Baylis–
Hillman products 14 and 16 in 32% and 65% yield and 55% and
88% ee, respectively. In an attempt to generate tertiary alcohols,
acetophenone 17 was also screened. However, it was found that
this substrate was inert to the reaction conditions even under pro-
longed reaction times.
a
Reactions were carried out at rt in THF (0.20 M in aldehyde) using 5 (3.0 equiv
as a mixture of olefin isomers) and (1.0 equiv) in the presence of CrCl2 (3 equiv),
NiCl2 (3 equiv), and ligand 7 (3 equiv).
b
Isolated yield after silica gel chromatography.
Determined by HPLC using a chiral column.
Four equivalents of vinyl bromide 5 was used.
c
d

F. G. Fang et al. / Tetrahedron Letters 51 (2010) 2151–2153
2153
3. Fang, F.; Johannes, C.; Yao, Y.; Zhu, X. PCT Int. Appl. WO 2003057685, 2003.
Acknowledgments
4. Furstner, A.; Nongyuan, S. J. Am. Chem. Soc. 1996, 118, 12349–12357.
5. (a) Choi, H.-W.; Nakajima, K.; Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.;
Kishi, Y. Org. Lett. 2002, 4, 4435–4438; For non-catalytic processes, see: (b) Wan,
Z.-K.; Choi, H.-W.; Kang, F.-A.; Nakajima, K.; Demeke, D.; Kishi, Y. Org. Lett. 2002,
4, 4431–4434; (c) Chinpiao, C.; Katsuya, T.; Kishi, K. J. Org. Chem. 1995, 60, 5386–
5387; (d) Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7, 5417–5419.
6. Representative procedure for the synthesis of adduct 8 (note: all reagents were
weighed out in a glove box): In a clean dry flask was weighed chiral ligand 7
(3 equiv). The ligand was dissolved in THF (concentration 0.17 g ligand/mL). After
the ligand dissolved, CrCl2 (3 equiv) was added to the solution. To form the
chromium complex, Et3N (3 equiv) was then added dropwise to the reaction
mixture. To ensure complexation, the resulting solution requires a temperature of
>30 °C. Slight warming might be necessary. The solution was then stirred for one
hour turning dark green in color. Vinyl bromide 5 (3.0 equiv as mixture of olefin
isomers) and aldehyde 6 (1 equiv) were then added to this solution. Finally, NiCl2
(3 equiv) was added and the reaction mixture was diluted with THF (0.2 M in
aldehyde). The solution was stirred at rt for 12 h. The mixture was cooled to 0 °C
and ethylenediamine (10 equiv) was added dropwise andstirred for onehour. The
reaction mixture was then diluted with heptane and water and stirred for 15 min.
The reaction mixture was filtered over Celite, washed with heptane (50 mL) and
water (50 mL), and transferred to a separatory funnel. The aqueous layer was
extracted with heptane (3 ꢀ 10 mL) and the organic layer dried over MgSO4,
filtered, and concentrated in vacuo to afford a crude green oil. The crude oil was
then purified by silica gel chromatography eluting with heptane/CH2Cl2/MTBE (5/
5/1). The Baylis–Hillman product was isolated as colorless clear oil and analyzed
by chiral HPLC (Chiralcel OD for this particular substrate).
We thank Eisai Co., Ltd for their support. In addition, we also
thank Dr. Thomas Noland for analytical support and Drs. Charles
Chase, Atsushi Endo, Charlie Johannes and Gordon Wilkie for help-
ful discussions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.078.
References and notes
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7. (a) Characterization for compound 8: 1H NMR (400 MHz, CDCl3) d 7.33 (m, 5H,
OCH2C6H5), 6.21 (dt, 1H, J = 7.33 Hz, 0.88 Hz, HCCCO2Et), 4.55 (m, 1H,
CH2CHOH), 4.52 (s, 2H, OCH2Ar), 4.23 (q, 2H, J = 7.33 Hz, 7.03 Hz, CO2CH2CH3),
3.65 (m, 2H, CH2CH2OBn), 3.45 (d, 1H, J = 5.86 Hz, OH), 2.45 (apparent quintet,
2H, J = 7.6 Hz, CH3CH2CHCCO2Et), 1.95 (m, 2H, CH2CH2CHOH), 1.31 (t, 3H,
J = 7.33 Hz, OCH2CH3), 1.05 (t, 3H, J = 7.61 Hz, CH2CH3); 13C NMR (100 MHz,
CDCl3) d 167.7, 143.9, 138.2, 133.2, 128.7, 128.0, 127.9, 73.5, 72.3, 68.7, 60.5,
36.4, 23.0, 14.5, 14.0; HRMS (CI) exact mass calcd for [M+Na]+ (C17H24O4)
requires m/z 310.2018, found m/z 310.2015; ½a D23:8
¼ þ6:2 (c 0.30 g/mL, CH2Cl2)
ꢁ
(b) see Ref. 9.
8. We have not isolated any of the products related to coupling of the (Z)-
bromoacrylate.
9. The indicated stereochemical outcome is consistent with that observed in Refs.
5a,b since the transition state for this coupling process is expected to be the
same.