Further improvement on sulfonamide-based ligand for catalytic asymmetric 2-haloallylation and allylation

Article abstract of DOI:10.1021/ol801093p

(Chemical Equation Presented) The sulfonamide-based ligand B was found to exhibit an outstanding crystallinity and perform well as a ligand for Cr-mediated catalytic asymmetric 2-haloallylation and allylation. The new ligand has an appealing advantage ove

Full text of DOI:10.1021/ol801093p

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3073-3076
Further Improvement on
Sulfonamide-Based Ligand for Catalytic
Asymmetric 2-Haloallylation and
Allylation
Zhiyu Zhang, Jian Huang, Bin Ma, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received May 12, 2008
ABSTRACT
The sulfonamide-based ligand B was found to exhibit an outstanding crystallinity and perform well as a ligand for Cr-mediated catalytic
asymmetric 2-haloallylation and allylation. The new ligand has an appealing advantage over the first generation ligand; its high crystallinity
allows effective recovery of the ligand from a reaction in a pure form.
We have recently reported a Co/Cr-mediated catalytic
asymmetric 2-haloallylation of aldehydes with 2-haloallyl
halides.1–4 This method gives direct access to valuable
synthetic intermediates with a useful level of enantiomeric
excess. The value of this method can be seen from the
example shown in Scheme 1; the Co/Cr-mediated 2-iodoal-
lylation allows us to obtain the C14-C19 building block
for the synthesis of the marine natural product halichondrin
B and its analogues in a single step.5–8
sulfonamide-based ligand A (Scheme 1). In particular, A
exists as an amorphous solid thus far, but we recognized
that a crystalline ligand should offer appealing advantages,
Scheme 1
.
Cr-Mediated Catalytic Asymmetric 2-Iodoallylation
in the Presence of Ligand A1
Considering the synthetic utility of 3-halohomoallylic
alcohols,9 we wished to make further improvement on the
(1) Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126,
12248
.
(2) For reviews on Cr-mediated carbon-carbon bond-forming reactions,
see: (a) Fu¨rstner, A. Chem. ReV. 1999, 99, 991. (b) Wessjohann, L. A.;
Scheid, G. Synthesis 1999, 1. (c) Takai, K.; Nozaki, H. Proc. Japan Acad.
Ser. B 2000, 76, 123. (d) Saccomano, N. A. ComprehensiVe Organic
Synthesis, Trost, B. M.; Fleming, I. Eds. Pergamon, Oxford, 1991, Vol. 1,
173.
10.1021/ol801093p CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

including the purification and recovery of ligand and the
reproducibility and scalability of coupling reactions.
With this result in hand, we then conducted the study to
identify the optimum conditions for Cr-mediated catalytic
asymmetric 2-haloallylation, thereby revealing the following.
First, the complexation of CrBr3 with B is best achieved
under the condition of B/CrBr3/CoPc/Mn/Et3N/THF/42 °C/
1.5 h.1,12 Second, CoPc is a better activator than Fe(TMHD)3
(iron tris(2,2,6,6-tetramethyl-3,5-heptanedione)).1 Third, al-
though both Zr(Cp)2Cl2 and TMS-Cl are effective dissocia-
tion agents, a higher yield is generally observed in the
presence of the former.13,14 Fourth, the optimum concentra-
tion of reaction is 0.2 M. Fifth, 2-haloallylation is effectively
achieved in the presence of 5 mol % of CrBr3 and 5.5 mol
% of B.15
For this reason, we initiated a search for a crystalline
sulfonamide-based ligand, which should act as an effective
(i.e., equal to or better than A) catalyst for catalytic
asymmetric 2-haloallylation and allylation. We began with
a structure modification on the benzylsufonyl moiety.
Through this effort, sulfonamide ligand B and its enantiomer
ent-B (Figure 1), prepared from natural and unnatural tert-
Under the optimized conditions, 2-haloallylations were
conducted (Table 1). 2-Iodoallyl, 2-bromoallyl, and 2-chlo-
roallyl bromides were coupled with aldehydes 4a and 4b.
(6) For the synthetic work on the marine natural product halichondrins
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) Choi, H.-w.;
Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan, Z.-
K.; Xie, C Pure Appl. Chem. 2003, 75, 1. (c) Namba, K.; Jun, H.-S.; Kishi,
Y. J. Am. Chem. Soc. 2004, 126, 7770. (d) Namba, K.; Kishi, Y. J. Am.
Chem. Soc. 2005, 127, 15382. (e) Kaburagi, Y.; Kishi, Y Org. Lett. 2007,
Figure 1. New crystalline sulfonamide ligands B and ent-B.
9, 723, and references cited therein
.
(7) For synthetic work by Salomon, Burke, Yonemitsu, and Phillips,
see: (a) Kim, S.; Salomon, R. G. Tetrahedron Lett. 1989, 30, 6279. (b)
Cooper, A. J.; Pan, W.; Salomon, R. G. Tetrahedron Lett. 1993, 34, 8193,
and references cited therein. (c) Burke, S. D.; Lee, K. C.; Santafianos, D.
Tetrahedron Lett. 1991, 32, 3957. (d) Lambert, W. T.; Hanson, G. H.;
Benayoud, F.; Burke, S. D. J. Org. Chem. 2005, 70, 9382, and references
cited therein. (e) Horita, K.; Hachiya, S.; Nagasawa, M.; Hikota, M.;
Yonemitsu, O. Synlett 1994, 38. (f) Horita, K.; Nishibe, S.; Yonemitsu, O.
Phytochem. Phytopharm. 2000, 386, and references cited therein. (g)
leucinols, respectively, in 20-30 g,10 were found to exhibit
an outstanding crystallinity.11
Our next task was to demonstrate the effectiveness of B
for catalytic asymmetric 2-haloallylation. We were delighted
to observe that, under the previously used conditions (ligand/
CrBr3/cobalt phthalocyanine (CoPc)/Mn/ Et3N/THF/rt, fol-
lowed by addition of 2,6-lutidine, two coupling partners, and
TMS-Cl),1 the new ligand B performed at least as well as
the first-generation ligand A.
Henderson, J. A.; Jackson, K. L.; Phillips, A. L. Org. Lett. 2007, 9, 5299
.
(8) (a) Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singer,
L. A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay, L.;
Towle, M. J.; Salvato, K. A.; Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield,
B. A.; Yu, M. J. Bioorg. Med. Chem. Lett. 2004, 14, 5551. (b) Yu, M. J.;
Kishi, Y.; Littlefield, B. A. In Anticancer Agents from Natural Products,
Eds. Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds.; CRC Press:
Boca Raton, FL, 2005; pp 241-265. (c) Littlefield, B. A.; Palme, M. H.;
Seletsky, B. M.; Towle, M. J.; Yu, M. J.; Zheng, W. U.S. Patents 6214865
(3) For Cr-mediated enantioselective allylation, see: (a) Cazes, B.;
Vernière, C.; Gore´, J. Synth. Commun. 1983, 13, 73. (b) Chen, C.; Tagami,
K.; Kishi, Y J. Org. Chem. 1995, 60, 5386. (c) Namba, K.; Kishi, Y. Org.
Lett. 2004, 6, 5031, ref 1 and references cited therein. (d) Sugimoto, K.;
Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1997, 62, 2322. (e) Bandini, M.;
Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
1999, 38, 3357. (f) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Chem.
Commun. 2002, 919, and references cited therein. (g) Inoue, M.; Suzuki,
T.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 1140. (h) Inoue, M.; Nakada,
M. Angew. Chem., Int. Ed. 2006, 45, 252, and references cited therein. (i)
Berkessel, A.; Menche, D.; Sklo¨rtz, C. A.; Schroder, M.; Paterson, I. Angew.
Chem., Int. Ed. 2003, 42, 1032. (j) Lee, J.-Y.; Miller, J. J.; Hamilton, S. S.;
Sigman, M. S Org. Lett. 2005, 7, 1837. (k) Miller, J. J.; Sigman, M. S
J. Am. Chem. Soc. 2007, 129, 2752. (l) Xia, G.; Yamamoto, H. J. Am.
Chem. Soc. 2006, 128, 2554. (m) Xia, G.; Yamamoto, H. J. Am. Chem.
Soc. 2007, 129, 496.
and 6365759 and International Patent WO99/65894
(9) For the synthetic value of this functional group, for example, see
.
Scheme 1 in: (a) Corey, E. J.; Yu, C-M.; Kim, S. S. J. Am. Chem. Soc.
1989, 111, 5495
.
(10) This ligand was synthesized as depicted below. For the details, see
the Supporting Information.
(4) For reviews on metal-mediated enantioselective allylation, for
example, see: (a) Yamamoto, Y. Acc. Chem. Res. 1987, 20, 243. (b)
Marshall, J. A. Chem. ReV. 1996, 96, 31. (c) Denmark, S. E.; Fu, J. Chem.
ReV. 2003, 103, 2763.
(11) In addition to 2,6-dimethylbenzylsulfonamide B, 2-methylbenzyl-,
2,4-dimethylbenzyl-, and 2,5-dimethylbenzylsulfonamides were tested, but
all of them existed as oils. Using the procedure shown in ref,10 we attempted
(5) For the isolation of the halichondrins from a marine sponge
Halichondria okadai Kadota, see: (a) Uemura, D.; Takahashi, K.; Yama-
moto, 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. For isolation of the halichondrins from different species of sponges,
see: (c) 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.; Rutzler, K.
C J. Med. Chem. 1991, 34, 3339. (d) 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. (e) Litaudon, M.; Hart, J. B.; Blunt, J. W.; Lake, R. J.;
Munro, M. H; G, Tetrahedron Lett. 1994, 35, 9435. (f) 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.
to synthesize 2,4,6-trimethylbenzylsulfonyl chloride, but unsuccessfully.
(12) The tested conditions included: complexation at rt for 45 min, 1.5 h,
and 2.5 h; complexation at 42 °C for 45 min, 1.5 h, and 2.5 h. We attempted
to follow the complexation event by react IR spectroscopy, but the result
was not conclusive. Therefore, we relied on the overall performance
(asymmetric induction and yield) of 2-haloallylation to draw this conclusion.
We should note that, with this optimized complexation protocol, the
reproducibility of 2-haloallylation was also improved
(13) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349
(14) Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031
(15) The catalyst loading was tested for the case of 2 + 4a f 7a; the
following results were obtained: 10 mol % (yield ) 85%, ee ) 93%), 5
mol % (yield ) 76%, ee ) 92%), and 2.5 mol % (yield ) 60%, ee )
91%).
.
.
.
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Org. Lett., Vol. 10, No. 14, 2008

catalytic asymmetric allylation. Therefore, the effectiveness
of CrBr3 in the absence of the activator CoPc was tested for
allylation of (R)-(+)-citronellal (4b) with allyl bromide,
thereby demonstrating that CrBr3 is a chromium source
superior to CrCl3·3THF in terms of reaction rate, chemical
yield, asymmetric induction, and cost.20 Thus, both 2-ha-
loallylation and allylation are now conducted under the same
optimized condition, with one difference, i.e., with or without
the activator CoPc. Table 2 summarizes the Cr-mediated
catalytic asymmetric allylation of 4a and 4b with allyl, γ,γ-
dimethylallyl, and methallyl bromides in the presence of
ligand B or ent-B.18
Table 1. Cr-Mediated Catalytic Asymmetric 2-Haloallylationsa
The performance of new ligand B was excellent for
allylation of 4a; an excellent level of asymmetric induction
was achieved for its allylation with allyl bromide (97% ee)
and γ,γ-dimethylallyl bromide (98% ee), but a slightly lower
level was observed with methallyl bromide (91% ee).
Unlike 2-haloallylation, the effect from the methyl group at
the ꢀ-position was clearly detected for allylation of (R)-(+)-
citronellal (4b) with allyl and methallyl bromides, i.e., entry 2
(99% ee) vs entry 3 (75% ee) and entry 8 (99% ee) vs entry 9
(83% ee). Interestingly, however, the match/mismatch effect21
was negligibly small for allylation with γ,γ-dimethylally
bromide, i.e., entry 5 (95% ee) vs entry 6 (93% ee).
a All reactions were performed with CrBr3 (10 mol %), B, or ent-B
(11 mol %) and CoPc (0.2 mol %) at 0 °C. b Yields based on
chromatographically isolated products. c Yields based on chromato-
graphically isolated TMS ethers. d Enantiomeric excess (ee) was
estimated by 1H NMR analysis of its Mosher ester, whereas diastereo-
meric excess (de) was estimated directly from its 1H NMR spectrum.
For details, see the Supporting Information.
(22) A 30-g scale 2-iodoallylation was carried out as below.
Aldehyde 4a was chosen because the product 5a is a building
block in the halichondrin synthesis. On the other hand, (R)-
(+)-citronellal (4b)16 was selected to examine the effect on
the asymmetric induction from a substituent at the ꢀ-position.
As seen from entries 1, 4, and 7 in Table 1, new ligand B
gave an excellent result for 2-haloallylation of 4a; the level
of asymmetric induction with B was virtually the same as
that observed with A, whereas the chemical yields with B
were higher than those with A.17,18 With the study with (R)-
(+)-citronellal (4b), the methyl group at the ꢀ-position was
found to give no significant effect on the asymmetric
induction, i.e., entry 2 vs entry 3, entry 5 vs entry 6, and
entry 8 vs entry 9.
We then proceeded to allylation in the presence of ligand
B and its enantiomer ent-B. It is worthwhile to note that,
unlike 2-haloallyl halides, allyl halides are known to react
with aldehydes in the presence of only Cr(II) salt and also
that CrCl3·3THF, instead of CrBr3, was used as the chromium
source for catalytic asymmetric allylation in the previous
study.1,2,19 We were curious to examine if the condition
optimized for 2-haloallylation might also be effective for
A 2-L three-neck, round-bottomed flask equipped with a magnetic stir bar
was charged with CoPc (0.18 g, 0.296 mmol), ent-B (7.68 g, 18.0 mmol),
CrBr3 (Cerac, 5.08 g, 16.4 mmol), and Mn powder (Aldrich, 29.0 g, 523
mmol). The flask was capped with rubber septa. The inner atmosphere was
replaced with N2 via gentle evacuation (oil pump) and purged with N2 three
times. Anhydrous THF (Baker, ultra low water, no preservative, 700 mL)
and then a THF solution of Et3N (2.73 mL, 19.2 mmol; THF: 30 mL) were
cannulated into the flask. The reaction mixture was stirred at 42 °C for
1.5 h with a slight positive pressure of N2 and then cooled to rt. A THF
solution of 2,6-lutidine (2.50 mL, 20.9 mmol; THF: 30 mL) was cannulated
into the reaction flask. The reaction mixture was stirred at rt for 15 min
and cooled to 0 °C. A THF solution of 2-iodoallyl bromide (99.0 g, 401
mmol; THF: 40 mL) and a THF solution of aldehyde (30.0 g, 174 mmol;
THF: 40 mL) were cannulated into the reaction flask. Under a positive flow
of argon, the reaction flask was charged with Zr(Cp)2Cl2 (Alfa, 50.9 g, 174
mmol). The reaction flask was capped with rubber septa, placed in a 0 °C
bath, and stirred with a magnetic stirrer. Upon completion of the reaction
(15 h, monitored by TLC), the reaction mixture was diluted with EtOAc
(900 mL). After addition of Florisil (66 g), the mixture was stirred for 30
min and passed through a silica gel plug (130 g) with EtOAc (2.7 L). The
filtrate was washed with water (3 × 300 mL), and the aqueous layer was
extracted with EtOAc (3 × 100 mL). The combined organic layers were
washed with brine (400 mL), dried over Na2SO4 (250 g), and evaporated
to dryness under reduced pressure. The residue was applied on a silica gel
column (450 g), which was eluted with hexanes, hexanes/EtOAc (30:1),
and then hexanes/EtOAc (20 f 10:1). On evaporation of the eluent of
hexanes/EtOAc (30:1), the recovered ligand was obtained as a crystalline
solid, recrystallization (EtOAc/hexanes) of which gave recovered ligand
ent-B (6.02 g, 83% recovery) as colorless diamonds.23 An evaporation of
the eluent of hexanes/EtOAc (20 f 10:1) furnished the vinyl iodide (37.6
(16) The optical purity of 4b used was better than 99%.
(17) The difference in yields could, at least partly, be attributed to the
difference in the dissociating agent, i.e., Zr(Cp)2Cl2 vs TMS-Cl.14
(18) For the determination of absolute configuration, see Supporting
Information of reference 1.
(19) In the catalytic system, Cr(III) is reduced to Cr(II) by Mn in situ.
(20) For this combination of substrates, the time to completion, yield,
and de were 15 h, 81%, and 99%, respectively, with CrBr3, whereas they
were 40 h, 73%, and 92%, respectively, with CrCl3·3THF.
(21) For a review on this subject, see: (a) Masamune, S.; Choy, W.;
Peterson, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1.
1
g, 64% yield) as viscous oil. The purity of product was confirmed by H
NMR and TLC analyses. The enantiomeric excess (92%) was estimated
from 1H NMR analysis of its (+)-Mosher ester. Note: Large-scale
2-iodoallylation was carried out with the Pv- and TBDPS-protected
aldehydes. The observed asymmetric induction was practically identical in
the two series, but the yield in the TBDPS-series was 15∼20% higher than
that in the Pv series. In the TBDPS series, because of their similar polarity,
the product and ligand B were separated after the alcohol was transformed
into its 2,4,6-trimethylbenzenesulfonate. For the details, see the
Supporting Information.
Org. Lett., Vol. 10, No. 14, 2008
3075

In summary, the overall performance of new ligand B is
at least equal to that of the first generation ligand A. We
should point out the advantages that B offers. In our view,
the most significant advantage is the fact that B exhibits an
exceptional crystallinity. Therefore, it is practical to recover
the used ligand from a reaction in a pure form, thereby
allowing us to carry out a large-scale synthesis in an
economical manner. In order to illustrate this advantage, we
conducted 2-iodoallylation to prepare the C14-C19 segment
of halichondrins on a 30-g scale with the use of commonly
used laboratory glassware/equipment. From this coupling
reaction, the ligand B was recovered in 83% (after recrys-
tallization) for reuse.22
Table 2. Cr-Mediated Catalytic Asymmetric Allylationsa
Acknowledgment. Financial support from the National
Institutes of Health (CA 22215) and Eisai Research Institute
is gratefully acknowledged.
Supporting Information Available: Experimental details
and 1H NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
a All reactions were performed with CrBr3 (10 mol %) and B or ent-B
(11 mol %) at 0 °C. b Yields based on the chromatographically isolated
products. c Enantiomeric excess (ee) was estimated by 1H NMR analysis
of its Mosher ester, whereas diastereomeric excess (de) was estimated
directly from its 1H NMR spectrum. For the details, see the Supporting
Information.
OL801093P
(23) This recovered ligand was shown to be as effective (asymmetric
induction, yield, and reproducibility) as the original ligand.
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Org. Lett., Vol. 10, No. 14, 2008