Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: catalytic process.

Article abstract of DOI:10.1021/ol026981x

[reaction: see text] The stable, crystalline Cr(III)/sulfonamide complex 1a is shown to be an effective catalyst for the Ni/Cr-mediated coupling reaction. A possible mechanism is suggested for the process. 1a is also effective for other Cr-mediated coupli

Full text of DOI:10.1021/ol026981x

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4435-4438
Asymmetric Ni(II)/Cr(II)-Mediated
Coupling Reaction: Catalytic Process
Hyeong-wook Choi, Katsumasa Nakajima, Damtew Demeke, Fu-An Kang,
Hyuk-Sang Jun, Zhao-Kui Wan, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received September 27, 2002
ABSTRACT
The stable, crystalline Cr(III)/sulfonamide complex 1a is shown to be an effective catalyst for the Ni/Cr-mediated coupling reaction. A possible
mechanism is suggested for the process. 1a is also effective for other Cr-mediated coupling reactions. With this catalyst, a concise and
efficient synthesis of the C14−C26 segment of halichondrins has been developed.
As pointed out in the preceding paper,1 the Ni/Cr-mediated
coupling reaction has shown its unique power, particularly
when applied to a polyfunctional substrate. Thus, this reaction
has successfully been used at a late stage in a multiple-step
synthesis where scalability and practicability are not neces-
sarily the priority.2,3 For application of this process for a
practical synthesis, however, it is highly desirable to develop
a catalytic process for the Ni/Cr-mediated reactions. In 1996,
Fu¨rstner and Shi reported seminal work on a catalytic process
of the Ni/Cr-mediated coupling reaction, in which TMSCl
and Mn(0) are used as a dissociating agent of chromium-
alkoxides and a reducing agent of chromium, respectively.4
Electrochemically driven Cr(II)-mediated couplings were also
reported.5
We were curious to know whether the crystalline Cr(III)/
sulfonamide ligand complex 1a reported in the preceding
paper1 works as a catalyst for the Ni/Cr-mediated coupling.
Under the Fu¨rstner conditions in THF at rt, instead of DME/
DMF at 50 °C,4 the Ni/Cr-mediated coupling of 2 with 3
was found to proceed smoothly in the presence of 10 mol
% of 1a with 10 mol % of NiCl2, to give the expected product
in an excellent chemical yield with encouraging enantiomeric
excess. With the same substrates and catalysts 1a,b, opti-
mization studies were conducted, revealing the following:
(1) both 1a and b function as effective catalysts, (2) TMSCl
is the best agent to dissociate chromium-alkoxides,6 (3)
Mn(0) is the most effective reducing agent,6 (4) addition of
(4) (a) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533. (b)
Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
(5) (a) Grigg, R.; Putnikovic, B.; Urch, C. J. Tetrahedron Lett. 1997,
38, 6307. (b) Kuroboshi, M.; Tanaka, M.; Kishimoto, S.; Goto, K.; Tanaka,
H.; Torii, S. Tetrahedron Lett. 1999, 40, 2785. Kuroboshi, M.; Tanaka,
M.; Kishimoto, S.; Tanaka, H.; Torii, S. Synlett. 1999, 69. (c) Durandetti,
M.; Ne´de´lec, J.-Y.; Pe´richon, J. Org. Lett. 2001, 3, 2073.
(6) Dissociating and reducing reagents tested include (a) dissociating
agents TMS-Cl, TMS-Im, TMS-OTf, TES-Cl, and MeOCOCl and (b)
reducing agents Mn, Zn, Al, and Fe.
(1) Wan, Z.-K.; Choi, H.; Kang, F.-A.; Nakajima, K.; Demeke, D.; Kishi,
Y. Org. Lett. 2002, 4, 4431.
(2) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.;
Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.
(3) For recent reviews on Cr-mediated reactions, see: (a) Fu¨rstner, A.
Chem. ReV. 1999, 99, 991. (b) Wessjohann, L. A.; Scheid, G. Synthesis
1999, 1. (c) Saccomano, N. A. ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 1, p 173.
10.1021/ol026981x CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/09/2002

(Bn)(n-Bu)3NCl or Et3N‚HCl enhances the coupling ef-
ficiency,7 (5) addition of LiCl enhances the coupling rate,
(6) EtCN and THF are good solvents,8 (7) 10 mol % of 1a,b
is sufficient to complete the coupling within 24 h at rt, (8)
the optimal temperature is around rt but the reaction proceeds
at 0 °C, and (9) the optimal range of concentration is 0.5-
0.1 M.
process are the same as those proposed for the stoichiometric
process (Scheme 2a). Taking into account the relative rate
Scheme 2
The enantiomeric excess observed for the catalytic process
in THF was found to be lower than that in the stoichiometric
process. With the progress of coupling, a Lewis acid MnX2
is formed which might have an effect of lowering the
enantiomeric excess. However, addition of MnCl2 did not
appreciably affect the enantiomeric excess. In addition, a
rough time-course study indicated no noticeable change in
the enantiomeric excess throughout the coupling reaction.
Ultimately, the catalytic reaction in EtCN was found to
proceed as efficiently as in THF and give the product in
almost quantitative yield. Importantly, the enantiomeric
excess obtained in the catalytic process in EtCN was found
to be roughly comparable with that obtained in the stoichio-
metric process (Scheme 1).8
Scheme 1a
of ligand exchange on Cr(II) vs Cr(III) species,3 we assume
that the transmetalation takes place at the Cr(II)-oxidation
state, which is formed through chemical reduction of 1 by
Mn(0). The structural information on the proposed Cr(II)/
sulfonamide ligand complex is not available at this time, but
an X-ray structure was obtained on Cr(II)(Cl)2(4-tert-
butylpyridine)3 (9) (Figure 1).9 This Cr(II) complex 9
posseses an unusual square-pyrimidal geometry.10 Interest-
ingly, this structure can be viewed as an octahedral structure
with one vacant ligation site. It is tempting to suggest that
a Reagents and conditions: (a) 2 (1 equiv), 3 (2 equiv), 1 (10
mol %), NiCl2 (10 mol %), Mn (2 equiv), TMSCl (2 equiv),
Et3N‚HCl or (Bn)(n-Bu)3NCl (20 mol %), LiCl (2 equiv), EtCN or
THF, rt.
All these results indicate that the asymmetric reaction
developed in the stoichiometric process is translated well
into the catalytic, asymmetric process, and we speculate that
the critical bond-forming steps involved in the catalytic
(9) Stamos, D.; Kishi, Y. Unpublished result. Bond lengths: Cr-N(1)
) 2.14 Å; Cr-N(2) ) 2.15 Å; Cr-N(3) ) 2.36 Å; Cr-Cl(1) ) 2.37 Å;
Cr-Cl(2) ) 2.37 Å. Bond angles: N(1)-Cr-N(2) ) 173.9°; N(1)-Cr-
N(3) ) 95.4°; N(2)-Cr-N(3) ) 90.7°; N(1)-Cr-Cl(1) ) 89.5°; N(2)-
Cr-Cl(1) ) 90.2°; N(3)-Cr-Cl(1) ) 96.4°; N(1)-Cr-Cl(2) ) 88.6°;
N(2)-Cr-Cl(2) ) 90.1°; N(3)-Cr-Cl(2) ) 98.2°; Cl(1)-Cr-Cl(2) )
165.3°.
(7) (Bn)(n-Bu)3NCl and Et3N‚HCl are equally effective in EtCN, whereas
(Bn)(n-Bu)3NCl is slightly more effective in THF.
(8) The rate of coupling was found significantly faster in MeCN than in
EtCN. However, the enantioselectivity was significantly lower in MeCN
than in EtCN.
(10) (η1-C4H4N)2Cr(Py)3 is known to possess an unusual square-
pyramidal geometry similar to 9: Edema, J. J. H.; Gambarotta, S.; Meetsma,
A.; van Bolhuis, F.; Spek, A. L.; Smeets, W. J. J. Inorg. Chem. 1990, 29,
2147.
4436
Org. Lett., Vol. 4, No. 25, 2002

Scheme 3
Figure 1.
subgroups (Scheme 3): allyl halides are activated by Cr(II)
species alone,13 whereas alkenyl halides and alkyl halides
are activated through Ni(0) and Co(I) species, respectively.1,14
Gratifyingly, the ligand-Cr(III) complex shows good ap-
plicability for all three subgroups of Cr-mediated coupling
reactions, which certainly expands the scope of Cr-mediated
reactions.
The synthesis of the C14-C26 segment of halichondrins15
illustrates this point further (Scheme 4). The first bond
formation was achieved via a catalytic, asymmetric Ni/Cr-
mediated coupling reaction; in the presence of 10 mol % of
the proposed Cr(II)/sulfonamide ligand complex adopts a
similar structure and that the vacant ligation site is involved
in the transmetalation with the alkenyl-Ni(II) complex. The
Cr(III)/ligand complex thus formed proceeds through the
steps suggested for the stoichiometric series, to furnish
Cr(III)/ligand alkoxide. As suggested by Fu¨rstner,4 TMS-Cl
dissociates the Cr-alkoxide to give the TMS ether of 4 and
regenerates the ligand-Cr(III) complex 1. Thus, all the
chemistry takes place only at the two ligation sites of 1.
In addition, this process contains a catalytic cycle centered
on the Ni salt, which is coupled with the Cr-catalytic cycle
and hence with the Mn-redox cycle (Scheme 2b). Lastly,
the effect of LiCl on the overall reaction rate may be
attributed to formation of the Ni-ate complex from the
alkenyl-Ni(II) complex, enhancing the rate of transmetalation.
Overall, the catalytic Ni/Cr-mediated coupling reaction
relies on the two catalytic cycles. Therefore, to achieve this
bond-forming process economically in terms of the Cr(III)/
sulfonamide ligand complex 1, it is important to realize an
efficient catalytic cycle not only for Cr salt but also for Ni
salt. It appeared that the efficiency for the Cr-catalytic cycle
is sufficiently good but that of the Ni-catalytic cycle,
especially in EtCN, needs improvement. In practice, the
catalytic reaction in the presence of 10 mol % of 1 with
either 20-40 mol % of NiCl2 or 4-6 mol % Ni(COD)2 gave
a significantly improved reproducibility.11,12 Considering the
fact that the stoichiometric coupling is routinely performed
in the presence of 3-4 equiv of CrCl2, the current catalytic
process represents a reduction of Cr use by a factor of 30-
40.
Scheme 4a
We would like to point out the possibility that the Cr(III)/
sulfonamide complexes 1a,b can be potentially applied to
any chemistry associated with a Cr species, and we are
currently studying the scope that these complexes may offer.
Somewhat related to this issue, it should be noted that the
Cr-mediated coupling reactions are grouped into three
a Reagents and conditions: (a) (1) 10 (2 equiv), 11 (1 equiv),
the antipode of 1a (10 mol %), NiCl2 (40 mol %) or Ni(COD)2 (3
× 1 mol %), Mn (2 equiv), TMSCl (2 equiv), Et3N‚HCl or (Bn)(n-
Bu)3NCl (20 mol %), LiCl (2 equiv), EtCN or THF, rt. (2) PPTS/
Py/i-PrOH/RT. (3) K2CO3/MeOH, followed by separation via silica
gel chromatography (Biotage medium-pressure unit). The overall
yield of 12 from 11 was 70-80%. (b) (1) Dess-Martin oxidation
of 12 (90% yield). (2) The aldehyde (1 equiv), 13 (2 equiv), 1a
(50 mol %), Co-phthalocyanine (10 mol %), Mn (2 equiv), TMSCl
(2 equiv), Et3N‚HCl (20 mol %), LiCl (2 equiv), DME. (2) aq oxalic
acid/THF/rt, followed by silica gel column chromatography. The
overall yield of 14 from the aldehyde was 73%, with the 5.3:1.0
stereoselectivity
(11) In the presence of 20∼40 mol % of NiCl2, the coupling reaction
with 5 mol % of 1a gave a satisfactory result, except for the sluggish rate
of reaction.
(12) With addition of Ni(COD)2 in several portions (3-4 × 1 mol %),
the homocoupling of 11 can be avoided.
(13) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
Soc. 1977, 99, 3179. (b) Okude, Y.; Hiyama, T.; Nozaki, H. Tetrahedron
Lett. 1977, 43, 3829. (c) Kuroboshi, M.; Tanaka, M.; Kishimoto, S.; Tanaka,
H.; Torii, S. Synlett. 1999, 69.
Org. Lett., Vol. 4, No. 25, 2002
4437

the antipode of 1a with either 40 mol % of NiCl2 or 5 mol
% of Ni(COD)2, the coupling of 10 with 1116 furnished the
desired product.17 Treatment of the crude coupled product
with PPTS/Py/i-PrOH not only removed the resultant C20
TMS-silyl ether but also effected the cyclization.18 After
debenzoylation, the stereochemically homogeneous 12 was
isolated by silica gel chromatography19 in 70-80% overall
yield from 11 with ca. 9:1 overall stereoselectivity.
It is worthwhile noting the observation made on the C17
leaving group; in the coupling reaction with the substrate
with X ) I and Y ) Ts in 11, the C17 tosyl group was
reductively cleaved in THF slowly.20 However, this side
reaction was not significant in EtCN or could be eliminated
by replacing the tosyl group with the corresponding mesyl
group even in THF.21
with aldehydes in the presence of CrCl2 and a catalytic
amount of vitamin B12 or cobalt phthalocyanine. Using a
model system,22 we have first established that 1a acts as a
catalyst for the Co/Cr-mediated coupling reaction. Under the
condition established in the model system, selective activa-
tion of the alkyl iodide over the vinyl iodide present in 13
was indeed possible, but the coupling reaction was ac-
companied by a significant amount of byproducts. Screening
solvents, Co-sources, additives, and the amount of 1a, the
condition specified in Scheme 4 is most effective to date. In
this manner, the desired, stereochemically homogeneous
coupling product 1423 was isolated in 73% yield, with a 5.3:1
stereoselectivity, and the structure of 14 was confirmed on
comparison with the sample available from the previous
synthesis.15
A catalytic, asymmetric Co/Cr-mediated coupling reaction
was used for the C23-C24 bond formation. Takai and
Uchimoto showed that alkyl halides and tosylates are coupled
In summary, we have shown that the stable, crystalline
Cr(III)/sulfonamide complex 1 acts as an effective catalyst
for the Cr-mediated coupling reactions. We are currently
engaged with further improvements on the catalyst, particu-
larly in terms of the degree of asymmetric induction and the
catalyst loading.
(14) Takai, K.; Nitta, K.; Fujimura, O.; Utimoto. K. J. Org. Chem. 1989,
54, 4732.
(15) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S.
H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J.
Am. Chem. Soc. 1992, 114, 3162.
(16) 11 was prepared from the (R)-5-[(tert-butyldiphenylsilyl)oxy]-1,2-
epoxypentane obtained by catalytic, kinetic hydrolytic resolution of the
corresponding racemic epoxide, in three steps, (1) TMSCtCH/n-BuLi/BF3‚
Et2O/THF/-78 °C, (2) TsCl or MsCl/Py, and (3) NaI/TMSCl/H2O/MeCN.
13 was prepared from (R)-HCtCCH(Me)CH2OBn in three steps, (1) B-iodo-
9-BBN, (2) TsCl/Py, and (3) LiI/acetone.
(17) The C14-C26 segment 14 of halichondrins could be synthesized
by consecutive use of all the three subgrouped reactions (Scheme 3).
However, an attempted coupling of 2,3-dibromopropene with the TBDPS
silyl ether of 4-hydroxybutyraldehyde under the current protocol did not
give the satisfactory level of chemical yield nor asymmetric induction for
practical application.
Acknowledgment. We are grateful to the National
Institutes of Health (CA 22215) and Eisai Research Institute
for generous financial support. D.D. thanks the National
Institutes of Health for a postdoctoral fellowship (1 F32
AI50373-01).
Supporting Information Available: Experimental details
for the syntheses outlined in Schemes 1 and 4 and spectro-
scopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) C20-TMS deprotection and subsequent cyclization were effected
under various conditions, including (1) aq oxalic acid, followed by silica
gel treatment/EtOH or hexanes/CHCl3, (2) Montmorillonite clay/i-PrOH,
(3) PPTS/i-PrOH, and (4) Amberlite 15/i-PrOH.
OL026981X
(19) Separation of 12 from its C20-diastereomer was carried out in 1-2
g scales by a Biotage medium-pressure chromatographic unit.
(20) This side-product formation was found significantly slower than
the Ni/Cr-mediated coupling itself. Nonetheless, when the substrate with
X ) I and Y ) Ts in 11 was completely consumed, this side-product was
isolated in ca. 30% yield as a ca. 8:1 mixture of the C20 diastereomers.
(21) Two additional substrates with X ) I/Y ) Ts and X ) Br/Y ) Ts
in 11 were used for the coupling. In EtCN, both substrates gave the results
comparable to 11. For the details, see the Supporting Information.
(22) The catalytic Co/Cr-mediated coupling of dihydrocinnamaldehyde
(2) with isobutyl iodide was effected in EtCN (0.3 M), containing 1a (10
mol %), Co-phthalocyanine (5 mol %), Mn (2 equiv), TMSCl (2 equiv),
LiCl (2 equiv), and Et3N‚HCl (20 mol %), at rt for 40 h, to give the expected
product in g90% yield. The enantioselectivity found was 2.3:1, with the
major enantiomer corresponding to (R)-4.
(23) Separation of 14 from its C23-diastereomer was carried out by
gravity column chromatography on silica gel.
4438
Org. Lett., Vol. 4, No. 25, 2002