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

Article abstract of DOI:10.1021/ol0269805

[reaction: see text] Via an X-ray analysis, the sulfonamide bearing R(1) = i-Pr, R(2) = Me, and R(3) = Me is shown to be a tridentate ligand to a Cr(III) salt. This class of ligands, represented by R(1) = t-Bu, R(2) = 2-naphthyl, and R(3) = Me, is effecti

Full text of DOI:10.1021/ol0269805

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4431-4434
Asymmetric Ni(II)/Cr(II)-Mediated
Coupling Reaction: Stoichiometric
Process
Zhao-Kui Wan, Hyeong-wook Choi, Fu-An Kang, Katsumasa Nakajima,
Damtew Demeke, 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
1
2
3
Via an X-ray analysis, the sulfonamide bearing R ) i-Pr, R ) Me, and R ) Me is shown to be a tridentate ligand to a Cr(III) salt. This class
1
2
3
of ligands, represented by R ) t-Bu, R ) 2-naphthyl, and R ) Me, is effective to achieve an asymmetric Ni/Cr-mediated coupling reaction
and, with the C14-C38 segment of halichondrins, its synthetic potential has been demonstrated. A possible mechanism is suggested for the
process.
As demonstrated in a number of examples, the Ni/Cr-
mediated coupling reaction has shown its unique potential
most when applied to a polyfunctional molecule.1,2 Thus, this
reaction shows its uniqueness particularly at a late stage in
a multiple-step synthesis where scalability and practicability
are not necessarily the priority. In connection with the
ongoing efforts for development of a practical synthesis of
halichondrins (Figure 1) and/or halichondrin analogues,3-6
we are specifically interested in the overall transformation
depicted in Scheme 1. Obviously, such a transformation can
be applied to a synthesis of the C17-C20 and C23-C27 ring
systems present in the halichondrins. However, to use the
Ni/Cr-mediated coupling reaction for practical purposes, two
specific issues must be addressed. First, since this coupling
reaction is typically carried out in the presence of 3∼4 equiv
(1) (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.
(2) 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.
(3) (a) Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka,
J.; Okumura, Y.; Hirata, Y. J. Am. Chem. Soc. 1985, 107, 4796. (b) Hirata,
Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701.
Figure 1. The structure of halichondrin B.
10.1021/ol0269805 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/09/2002

It was soon recognized that replacement of the o-hydrogen
indicated in 6 with a methyl group resulted in a major impact
on the asymmetric induction, cf. 7.10
Scheme 1
Being encouraged by this preliminary observation, we then
made extensive efforts on the optimization of 7, through
which several promising ligands have emerged, including
9∼11 (Figure 2).11,12
(4) For isolation of the halichondrins from different species of sponges,
see: (a) Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J. E.; Dufresne, C.;
Doubek, D. L.; Schmidt, J. M.; Cerny, R. L.; Hooper, J. N. A.; Ru¨tzler, K.
C. J. Med. Chem. 1991, 34, 3339. Pettit, G. R.; Tan, R.; Gao, F.; Williams,
M. D.; Doubek, D. L.; Boyd, M. R.; Schmidt, J. M.; Chapuis, J. C.; Hamel,
E.; Bai, R.; Hooper, J. N. A.; Tackett, L. P. J. Org. Chem. 1993, 58, 2538.
(b) Litaudon, M.; Hart, J. B.; Blunt, J. W.; Lake, R. J.; Munro, M. H. G.
Tetrahedron Lett. 1994, 35, 9435. Litaudon, M.; Hickford, S. J. H.; Lill, R.
E.; Lake, R. J.; Blunt, J. W.; Munro, M. H. G. J. Org. Chem. 1997, 62,
1868.
(5) For the synthetic work from this laboratory, see: (a) 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. (b) Stamos, D. P.; Chen, S. S.; Kishi, Y. J. Org. Chem. 1997,
62, 7552 and references therein.
(6) For the synthetic work by Salomon, Burke, and Yonemitsu, see: (a)
Kim, S.; Salomon, R. G. Tetrahedron Lett. 1989, 30, 6279. Cooper, A. J.;
Pan, W.; Salomon, R. G. Tetrahedron Lett. 1993, 34, 8193 and references
therein. (b) Burke, S. D.; Lee, K. C.; Santafianos, D. Tetrahedron Lett.
1991, 32, 3957. Austad, B. C.; Hart, A. C.; Burke, S. D. Tetrahedron 2002,
58, 2011 and references therein. (c) Horita, K.; Hachiya, S.; Nagasawa,
M.; Hikota, M.; Yonemitsu, O. Synlett. 1994, 38. Horita, K.; Nagasawa,
M.; Sakurai, Y.; Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1199 and
references therein.
of CrCl2, it is highly desirable to develop a method to reduce
the amount of Cr salt. Second, it is also desirable to develop
an asymmetric process to control the stereochemical course.
This analysis immediately calls for development of a
catalytic, asymmetric Ni/Cr-mediated coupling reaction.
Using dihydrocinnamaldehyde (1) and 2-iodo-1-hexene
(2), we searched for a suitable chiral ligand to realize the
Ni/Cr-mediated coupling in an enantioselective manner
(Scheme 2). In this connection, we first quote the example
Scheme 2
(7) Chen, C.; Tagami, K.; Kishi, Y. J. Org. Chem. 1995, 60, 5386.
(8) Sugimoto, K.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1997, 62,
2322.
(9) Fujisawa, T.; Ichiyanagi, T.; Shimizu, M. Tetrahedron Lett. 1995,
36, 5031.
(10) The ligand 7 was briefly tested with other nucleophiles under the
conditions of 7/CrCl2/NiCl2 (no NiCl2 for allyl chlorides)/Et3N/THF and
some representative examples are listed below.12
(11) The sulfonamide ligands were prepared by three different routes:
(a) (1) 3-methyl-2-nitrobenzoic acid/(COCl)2/DMF (cat.)/CH2Cl2, (2) L-
valinol/Et3N/CH2Cl2, (3) H2/Pd-on-C/MeOH, (4) MeSO2Cl/DMAP/py/rt;
(b) (1) 3-methylanthranilic acid/triphosgene/toluene-dioxane, (2) L-valinol/
DMF/100 °C, (3) MeSO2Cl/DMAP/py/rt; (c) (1) 3-methylanthranilic acid/
L-valinol/EDCI/MeCN, (2) MeSO2Cl/DMAP/py/rt. Among them, the first
route was found to be the most effective and to have a good applicability
for preparation of this class of sulfonamide ligands. For the experimental
details, see the Supporting Information.
(12) Three conditions, (1) Et3N/THF, (2) NaH/(Bn)(n-Bu)3NCl/THF, and
(3) NaH/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) or
1,1,3,3-tetramethylurea (TMU), were routinely used to screen a ligand (see
the Supporting Information for the experimental details). The ratios given
in Scheme 2 were obtained under condition 3, whereas the ratio given for
8 in Scheme 2 and the ratios given in Figure 2 were obtained under condition
1.
previously studied in this laboratory: the C29-C30 bond
of the halichondrins was asymmetrically formed in the
presence of chiral dipyridyl ligand 4.7 Disappointingly, 4 was
found not to give an enantiomeric excess for the current
system. Among numerous chiral ligands tested, the Kibayashi
ligand 58 gave a modest but definitive asymmetric induction.
With consideration of the pKa similarity between phenolic
and sulfonamido groups, the Fujisawa ligand 69 was then
tested, which gave a slightly improved asymmetric induction.
4432
Org. Lett., Vol. 4, No. 25, 2002

sulfonamide ligand complex 12 [7/Cr(III)(Cl)2(THF)] was
obtained, and its X-ray analysis ultimately demonstrated that
the sulfonamide 7 is a tridentate ligand (Figure 3).15 In
addition, the X-ray structure revealed several unique struc-
tural features, including the following: (1) 12 possesses an
almost perfect octahedral structure, (2) the isopropyl group
is cis to the sulfonamide chain, (3) one of the sulfonamide
oxygens is located above the phenyl ring, and (4) the
sulfonamide nitrogen is trans to one of the chlorides.
Naturally, we attempted to prepare a single crystal of alkenyl-
Cr(III)/sulfonamide ligand complexes but without much
success. However, a single crystal of the methyl-Cr(III)/
sulfonamide ligand complex 13 [7/Cr(III)(Me)(Cl)(THF)]
was obtained,15 whose structure was found to be amazingly
similar to that of 12 (Figure 3).16
Figure 2.
Curiously, the major enantiomer formed in the presence
These Cr(III)/sulfonamide ligand complexes do not neces-
sarily correspond to the organometallic species actually
involved in this chemical transformation. Nonetheless, it is
tempting to use the X-ray structures to speculate about
possible events (Panel A in Figure 4). At present, it is not
of these sulfonamide ligands was found to be opposite to
that formed in the presence of the phenol ligand 5 as well
as the C2-symmetric semicorrin ligand 8 (Scheme 2).13,14
These observations led to a speculation that the coordination
mode of a sulfonamide ligand is different from that of a
phenol or semicorrin ligand. A single crystal of the Cr(III)/
Figure 3. For clarity, only the oxygen of THF is shown. A
represents the X-ray structure of 12. Bond lengths: Cr-N1 ) 2.05
Å; Cr-N2 ) 2.03 Å; Cr-O (O of THF) ) 2.04 Å; Cr-Cl1 ) 2.30
Å, Cr-O (O of sulfonamide) ) 2.11 Å; Cr-Cl2 ) 2.27 Å. Bond
angles: N1-Cr-N2 ) 85.0°; N2-Cr-O (O of THF) ) 88.8°; O
(O of THF)-Cr-Cl1 ) 91.0°; Cl1-Cr-N1 ) 94.5°; N1-Cr-O
(O of sulfonamide) ) 89.6°; N2-Cr-O (O of sulfonamide) )
69.4°; O (O of THF)-Cr-O (O of sulfonamide) ) 85.5°; Cl1-
Cr-O (O of sulfonamide) ) 98.6°; N1-Cr-Cl2 ) 92.0°; N2-
Cr-Cl2 ) 94.4°; O (O of THF)-Cr-Cl2 ) 91.3°; Cl1-Cr-Cl2 )
97.7°. B represents the X-ray structure of 13. Bond lengths: Cr-
N1 ) 2.06 Å; Cr-N2 ) 2.05 Å; Cr-O (O of THF) ) 2.06 Å;
Cr-Cl1 ) 2.32 Å, Cr-O (O of sulfonamide) ) 2.28 Å; Cr-Me )
2.05 Å. Bond angles: N1-Cr-N2 ) 84.8°; N2-Cr-O (O of THF)
) 89.3°; O (O of THF)-Cr-Cl1 ) 91.0°; Cl1-Cr-N1 ) 94.3°;
N1-Cr-O (O of sulfonamide) ) 90.3°; N1-Cr-O (O of sulfon-
amide) ) 66.5°; O (O of THF)-Cr-O (O of sulfonamide) ) 84.6°;
Cl1-Cr-O (O of sulfonamide) ) 102.7°; N1-Cr-Me ) 91.5°;
N2-Cr-Me ) 94.7°; O (O of THF)-Cr-Me ) 91.9°; Cl1-Cr-
Me ) 96.2°.
Figure 4. A depicts the proposed two modes of coordination of
12 with an aldehyde, whereas B depicts the proposed two modes
of rotation of a coordinated aldehyde.
established whether the bond-forming step involves a mono-
or bimetallic species. However, we assume a four-centered
process involving one vinylchromium species.17 We further
(13) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett.
1990, 31, 6005. (b) Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993, 34,
4001.
(14) For a recent review, see: Braunstein, P.; Naud, F. Angew. Chem.,
Int. Ed. 2001, 40, 681.
(15) The X-ray crystals were obtained as follows: (1) 7/NaH/THF/rt/1
h, (2) CrCl3-(THF)3/rt/1 h (THF), (3) pentane dilution for 12 or (3) (Me)3Al/
toluene/-5 °C/1 h, rt/14 h, (4) pentane dilution for 13. The X-ray analysis
of 13 was conducted on the crystal obtained from the antipode of 7.
(16) Methyl-Cr(III)/sulfonamide complex 13 reacted smoothly with 1
to yield the expected product with the major enantiomer corresponding to
(R)-3.
Org. Lett., Vol. 4, No. 25, 2002
4433

assume the following: (1) the methyl-Cr(III)/sulfonamide
ligand complex 13 represents the alkenyl-Cr(III)/sulfonamide
ligand complex that participates in the bond-forming process,
(2) an aldehyde takes over the THF-ligation site, and (3)
the aldehyde coordinates to the metal center with an s-trans
conformation18-20 and, with progress of the reaction, the
aldehyde rotates toward the alkenyl group, cf., an arrow. With
these assumptions, only two coordination modes a and b
between 1 and 12 need to be considered. Interestingly, the
top-right quarter in complex 12 is sterically more congested
than the bottom-right quarter, and the 1/12 complex a, which
leads to the observed major enantiomer, is considered to be
favored over the 1/12 complex b.
Scheme 3. Ni/Cr-Mediated Couplinga
We assume that the bond-forming events in the presence
of the semicorrin ligand 8 are parallel to those in the presence
of the sulfonamide ligand, including the alkenyl group
occupying the axial ligation site. Because of the C2-
symmetric nature, the alkenyl-Cr(III)-semicorrin complexes
c and d are identical (Panel B in Figure 4). However, with
progress of the reaction, the aldehyde needs to rotate toward
the alkenyl group, resulting in desymmetrization of the two
complexes; namely, this operation leads to the two transition
states in which the isopropyl group in the ligand is either
trans or cis to the R2 group in the aldehyde moiety. For this
steric reason, the latter transition state, which leads to the
observed major enantiomer, is considered to be favored over
the former.
a The Ni/Cr-mediated coupling was carried out in a glove box
as follows: 7 (3 equiv) was treated with NaH (3.3 equiv) in THF
at rt for 30 min. To this solution were added CrCl2 (3 equiv) and
(Bn)(n-Bu)3NCl (1 equiv) and the mixture was stirred at rt for 1 h.
14 (1 equiv), 15 (2 equiv), and then NiCl2 (1 equiv) were added,
and the reaction mixture was stirred at rt for 8 h and diluted with
THF (ca. 0.01 M). This mixture was cooled down to -15 °C and
treated with t-BuOK at -15 °C. The overall stereoselectivity was
ca. 20:1 in the presence of 7, whereas ca. 3.5:1 in the absence of
7. For the details, see the Supporting Information.
In the following paper, we report an extension of this
stoichiometric process to the catalytic process.23
The explanations given are consistent with the currently
available experimental observations. However, with no direct
experimental evidence, it should be considered as a working
hypothesis. Nevertheless, it should serve us in designing and
developing the next generation of chiral ligands for the Cr-
mediated reactions.
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).
Having had some success in the development of asym-
metric Ni/Cr-mediated coupling under the stoichiometric
conditions, we then used the C14-C38 segment5 of the right
half of halichondrins as well as the C14-C35 segment of
ER-08652621 and ER-07634921 for demonstration of its
usefulness. The example shown in Scheme 3 is representa-
tive.22
Supporting Information Available: Experimental details
for Schemes 2 and 3, and for the synthesis of sulfonamide
ligand 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0269805
(21) (a) Towle, M. J.; Salvato, K. A.; Budrow, J.; Wels, B. F.; Kuznetsov,
G.; Aalfs, K. K.; Welch, S.; Zheng, W.; Seletsky, B. M.; Palme, M. H.;
Habgood, G. J.; Singer, L. A.; DiPietro, L. V.; Wang, Y.; Chen, J. J.; Quincy,
D. A.; Davis, A.; Yoshimatsu, K.; Kishi, Y.; Yu, M. J.; Littlefield, B. A.
Cancer Res. 2001, 61, 1013. (b) Wang, Y.; Habgood, G. J.; Christ, W. J.;
Kishi, Y.; Littlefield, B. A.; Yu, M. J. Bioorg. Med. Chem. Lett. 2000, 10,
1029. (c) Littlefield, B. A.; Palme, M. H.; Seletsky, B. M.; Towle, M. J.;
Yu, M. J.; Zheng, W. U.S. Patents 6214865, 6365759, and S/N 09/843,617.
(22) The C26-C27 bond formation was also demonstrated by using the
C20-C26 vinyl iodide, i.e., the mesylate of the vinyl iodide 3 reported in
the preceding paper: Xie, C.; Nowak, P.; Kishi, Y. Org. Lett. 2002, 4,
4427.
(17) A four-centered transition state involving one vinylchromium species
was suggested for an intramolecular Ni(II)/Cr(II)-mediated coupling:
MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2001, 123, 9033. MacMillan, D. W. C.; Overman, L. E.; Pennington,
L. D. J. Am. Chem. Soc. 1995, 117, 10391.
(18) For the structure of benzaldehyde/boron trifluoride adduct, see:
Reetz, M. T.; Hu¨llmann, M.; Massa, W.; Berger, S.; Rademacher, P.;
Heymanns, P. J. Am. Chem. Soc. 1986, 108, 2405.
(19) For the rotational barriers, see: LePage, T. J.; Wiberg, K. B. J.
Am. Chem. Soc. 1988, 110, 6642.
(20) For a review, see: Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
Angew. Chem., Int. Ed. 1990, 29, 256.
(23) Choi, H.; Nakajima, K.; Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan,
Z.-K.; Kishi, Y. Org. Lett. 2002, 4, 4435.
4434
Org. Lett., Vol. 4, No. 25, 2002