Stereoselective synthesis of secondary organozinc reagents and their reaction with heteroatomic electrophiles

Article abstract of DOI:10.1021/ol0068400

(equation presented) Various trisubstituted olefins were converted to configurationally stable diorganozinc compounds with high diastereoselectivity. Their reaction with various electrophiles centered on tin, sulfur, bromine, and phosphorus provided the d

Full text of DOI:10.1021/ol0068400

ORGANIC
LETTERS
2001
Vol. 3, No. 1
127-130
Stereoselective Synthesis of Secondary
Organozinc Reagents and Their
Reaction with Heteroatomic
Electrophiles
Eike Hupe and Paul Knochel*
Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Institut fu¨r Organische Chemie,
Butenandtstrasse 5-13, Haus F, 81377 Mu¨nchen, Germany
knoch@cup.uni-muenchen.de
Received November 8, 2000
ABSTRACT
Various trisubstituted olefins were converted to configurationally stable diorganozinc compounds with high diastereoselectivity. Their reaction
with various electrophiles centered on tin, sulfur, bromine, and phosphorus provided the desired substitution products with retention of
configuration. Novel, functionalized organocopper reagents such as 4 and chiral diphosphine 5 have been prepared.
The use of chiral organometallic reagents such as 1 in organic
synthesis has been limited by the availability of configura-
tionally stable organometallics.1 Whereas unstabilized sec-
ondary alkyllithiums and -magnesiums2 have moderate
configurational stability,3 secondary alkylzincs are configu-
rationally stable at temperatures up to 25 °C in the absence
of zinc halides.4 After transmetalation to the corresponding
copper reagent of type 2, reactions with electrophiles such
as allylic or propargylic bromides were found to proceed
with high retention of configuration (up to 99%), leading to
products of type 3; Scheme 1.
Scheme 1
(1) For the preparation of configurationally stable heteroatom-stabilized
organolithiums, see: (a) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc.
1980, 102, 1201. (b) Chong, J. M.; Mar, E. K. Tetrahedron 1989, 45, 7709.
(c) Matteson, D. S.; Tripathy, P. B.; Sarkar, A.; Sadhu, K. M. J. Am. Chem.
Soc. 1989, 111, 4399. (d) Pearson, W. H.; Lindbeck, A. C. J. Am. Chem.
Soc. 1991, 113, 8546. (e) Reich, H. J.; Medina, M. A.; Bowe, M. D. J. Am.
Chem. Soc. 1992, 114, 11003. (f) Hoppe, D.; Zschage, O. Angew. Chem.,
Int. Ed. Engl. 1989, 101, 67. (g) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc.
1991, 113, 9708. (h) Hoffmann, R. W.; Klute, W. Chem. Eur. J. 1996, 2,
694.
(2) (a) Whitesides, G. M.; Witanowski, M.; Roberts, J. D. J. Am. Chem.
Soc. 1965, 87, 2854. (b) Witanowski, M.; Roberts, J. D. J. Am. Chem. Soc.
1966, 88, 737. (c) Hoffmann, R. W.; Holzer, B.; Knopff, O.; Harms, K.
Angew. Chem., Int. Ed. 2000, 39, 3072.
(3) (a) Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, H. P.; Berger,
S.; Knochel, P. Tetrahedron 1994, 50, 2415. (b) Micouin, L.; Knochel, P.
Synlett 1997, 327. (c) Darcel, C.; Flachsmann, F.; Knochel, P. J. Chem.
Soc., Chem. Commun. 1998, 205. (d) Boudier, A.; Flachsmann, F.; Knochel,
P. Synlett 1998, 1438. (e) Boudier, A.; Knochel, P. Tetrahedron Lett. 1999,
40, 687. (f) Boudier, A.; Darcel, C.; Flachsmann, F.; Micouin, L.; Oestreich,
M.; Knochel, P. Chem. Eur. J. 2000, 6, 2748. (g) Boudier, A.; Hupe, E.;
Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2294.
Herein, we wish to report a significant extension of the
scope of this reaction. We have found that several hetero-
atomic electrophiles centered on tin, sulfur, bromine, and
phosphorus react with high stereoselectivity with diastereo-
merically enriched cyclic and acyclic secondary organozinc
10.1021/ol0068400 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/13/2000

reagents. Remarkably, all reactions occur with retention of
configuration.5 These results have been applied to the
synthesis of new functionalized copper reagent 4 and the
new chiral diphosphine 5.
Chlorotrialkylstannanes react more readily (-40 °C, 12 h),
furnishing the expected stannanes (9a-d) with excellent
trans selectivities (95-99% trans; see entries 2-5 of Table
1).
Thus, the hydroboration of trisubstituted cyclic olefins of
type 6 with Et2BH6 (50 °C, 12-16 h) furnishes an interme-
diate organoborane which undergoes a smooth boron-zinc
exchange upon reaction with Zni-Pr2 at room temperature.
The resulting mixed diorganozinc species were further
transmetalated to the corresponding copper reagents. These
organometallics react with various heteroatomic electrophiles,
leading to products 9-11 (Scheme 2). The reaction with
Interestingly, the alkenylsilane 6d is hydroborated with
excellent regioselectivity (only 1-2% of the other regioi-
somer was observed). After the usual transmetalation se-
quence (B-Zn-Cu), the resulting copper â-silyl bimetallic
reagent reacts with Bu3SnCl, providing the 1,2-bimetallic
product 9c (entry 4) in 50% yield (97% trans). Also, the
fully diastereoselective hydroboration of the allylic ether 6e
(dr(1,2) ) 99:1) affords, after stannylation with Me3SnCl, the
tin derivative 9d (97% trans) in 58% overall yield (entry
5). A similar level of stereoselectivity has also been achieved
in open-chain systems. Thus, the reaction of the Z- and
E-styrenes Z-12 and E-12 furnishes, after the hydroboration-
transmetalation sequence using (-)-IpcBH2,7 respectively,
the anti-copper species anti-13 and the syn-copper species
syn-13. After reaction with Me3SnCl, the diastereomeric
stannane products anti-14 (anti:syn ratio ) 92:8) and syn-
14 (syn:anti ratio ) 90:10) confirm the excellent stereose-
lectivity in the conversion of olefins to organostannanes: a
process formally equivalent to a stereo- and regioselective
alkene hydrostannation (Scheme 3). The enantioselectivity
Scheme 2a
Scheme 3a
a (a) Et2BH (3 equiv), 50 °C, 16 h; (b) Zni-Pr2 (3 equiv), 25 °C,
5 h; (c) CuCN‚2LiCl (1 equiv), -78 °C, 0.5 h; (d) ClPPh2 (4 equiv),
25 °C, 4 d, then 30% H2O2; (e) R3SnCl (3 equiv), -40 °C, 16 h;
(f) MeSSO2Me (3 equiv), -40 °C, 16 h; (g) BrCl2CCCl2Br (3
equiv), -40 °C, 16 h.
a (a) (-)-IpcBH2 (1 equiv), -35 °C, 48 h; (b) Et2BH (5 equiv),
50 °C, 16 h; (c) Zni-Pr2 (5 equiv), 25 °C, 5 h; (d) CuCN‚2LiCl (1
equiv), -78 °C, 0.5 h; (e) Me3SnCl (5 equiv), -40 °C, 16 h.
ClPPh2 followed by oxidation with H2O2 provides phosphine
oxide 8 (entry 1 of Table 1) directly from the zinc reagent
without the need of further transmetalation to copper.
Although the reaction requires 4 d at 25 °C for completion,
it affords 8 exclusively as the trans isomer (> 99%), showing
that the reaction of the intermediate diorganozinc of type 7
proceeds with complete retention of configuration. The
intermediate phosphine was oxidized directly with 30%
aqueous H2O2 before workup (Scheme 2 and Table 1).
of the hydroboration of Z-12 and E-12 with (-)-IpcBH2 lies
between 46 and 74% ee.3f
The conversion of the copper reagent derived from 7 to
thioethers of type 10 can be achieved with MeSSO2Me (-40
°C, 12 h); entries 6-9 of Table 1. The diastereoselectivities
of the thioethers range from 94 to 99%. Furthermore, a
diastereoselective bromination can be performed with 1,2-
dibromotetrachlorethane (-40 °C, 12 h), leading to the trans-
bromide 11 in 51% yield (95% trans) (Scheme 2; entry 10
of Table 1). This methodology can also be applied to
functionalized olefins such as the unsaturated acetal 15. For
example, following the usual procedure, the functionalized
(4) (a) Klein, S.; Marek, I.; Normant, J.-F. J. Org. Chem. 1994, 59, 2925.
(b) Houkawa, T.; Ueda, T.; Sakami, S.; Asaoka, M.; Takei, H. Tetrahedron
Lett. 1996, 37, 1045. (d) Matsubara, S.; Toda, N.; Kobata, M.; Utimoto, K.
Synlett 2000, 987. (e) Matsubara, S.; Yamamoto, H.; Arioka, D.; Utimoto,
K.; Oshima, K. Synlett 2000, 1202.
(5) The relative configuration was determined by NOE experiments and
1
by evaluation of the coupling constants in H NMR experiments.
(6) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel,
P. J. Org. Chem. 1996, 61, 8229.
(7) Brown, H. C.; Mandal, A. K.; Yoon, N. M.; Singaram, B.; Schwier,
J. R.; Jadhav, P. K. J. Org. Chem. 1982, 47, 5069.
128
Org. Lett., Vol. 3, No. 1, 2001

Table 1. Generation of Intermediate Chiral Zinc and Copper Reagents and Their Stereoselective Reaction with Heteroatomic
Electrophiles Leading to Phosphine Oxide 8, Stannanes 9a-d, Thioethers 10a-d, and Bromide 11
a The crude phosphine was oxidized to the corresponding phosphine oxide by aqueous 30% H2O2. b Diastereomeric ratio between centers C(1) and C(2).
c Overall yield of analytically pure product.
organocopper species 4 is formed. Its stannylation with Me3-
SnCl gives the trans-tin derivative 16 (71%, 95% trans),8
whereas its reaction with MeSO2SMe furnishes the thioether
17 (61%; 99% trans), Scheme 4.
Finally, the hydroboration of olefin 6b, using (-)-IpcBH2
as the hydroborating agent, allows the preparation of
(8) Typical procedure: preparation of 16. A flame-dried 25 mL flask
equipped with a magnetic stirring bar, an argon inlet, and a septum was
charged with alkene 15 (154 mg, 1 mmol). Et2BH (0.4 mL, 7.3 M in Me2S,
3 equiv) was added, and the resulting mixture was stirred for 16 h at 50
°C. After pumping off the volatiles (0.1 mmHg, 25 °C, 2 h), Zni-Pr2 (0.6
mL, 5 M in Et2O, 3 equiv) was added and the mixture was stirred for 5 h
at 25 °C. The boron-zinc exchange was ca. 85% as monitored by GC
analysis of oxidized aliquots (aqueous 3 M NaOH/aqueous 30% H2O2).
The volatiles were pumped off (0.1 mmHg, 25 °C, 0.5 h), and the gray-
black residue was diluted with THF (2 mL) and cooled to -78 °C. A freshly
prepared solution of CuCN‚2LiCl (1 mL, 1 M in THF, 1 equiv) was added
over 30 min and the mixture was stirred for 30 min at -78 °C. Then, Me3-
SnCl (3 mL, 1 M in THF, 3 mmol, 3 equiv) was slowly added (30 min).
After stirring for 30 min at -78 °C, the mixture was allowed to warm to
-40 °C and stirred at this temperature for 16 h. The reaction mixture was
then poured into an aqueous saturated KF solution (100 mL). After extraction
with Et2O and normal workup, column chromatography (SiO2, hexanes:
Et2O ) 24:1) afforded 227 mg (71%) of 16 as a colorless oil.
Org. Lett., Vol. 3, No. 1, 2001
129

Scheme 4a
Scheme 5a
a (a) Et2BH (3 equiv), 50 °C, 16 h; (b) Zni-Pr2 (3 equiv), 25 °C,
5 h; (c) CuCN‚2LiCl (1 equiv), -78 °C, 0.5 h; (d) Me3SnCl (3
equiv), -40 °C, 16 h; (e) MeSSO2Me (3 equiv), -40 °C, 16 h.
chiral phosphine oxide 8 in 45% yield, 82% ee, and > 99%
trans selectivity. Compound 8 has been converted to the
borane-protected diphosphine 5 as indicated in Scheme 5.9
In summary, we have prepared a range of new diastereo-
merically well-defined zinc-copper secondary alkyl organo-
metallics and have demonstrated that they react with retention
of configuration with various heteroatomic electrophiles. The
new chiral diphosphine 5 has been prepared by this method.
Further applications of secondary chiral alkylzinc reagents
in asymmetric catalysis and natural product synthesis are
currently underway.
a (a) (-)-IpcBH2 (1 equiv), -35 °C, 48 h; (b) Et2BH (5 equiv),
50 °C, 16 h; (c) Zni-Pr2 (5 equiv), 25 °C, 5 h; (d) ClPPh2 (5 equiv),
25 °C, 4 d, then 30% H2O2; (e) Cl3SiH (5 equiv), 120 °C, 12 h; (f)
n-BuLi, (1.2 equiv), -78 °C, 2 h; (g) PPh2Cl (1.2 equiv), -78 °C
to 25 °C, 7 h; (h) BH3‚DMS (5 equiv), 25 °C, 12 h.
thank also the BASF AG (Ludwigshafen), Chemetall GmbH
(Frankfurt), Aventis (Frankfurt), and DEGUSSA-HU¨ LS AG
(Hanau) for the generous gift of chemicals.
Acknowledgment. We thank the DFG (Leibniz program)
and the Fonds der Chemischen Industrie (Kekule´ scholarship
for E.H.) for generous support. We thank Dr. Yasunari
Monguchi for the preparation of some starting materials. We
Supporting Information Available: All analytical data
for compounds of Table 1 and Schemes 3, 4, and 5 and
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) Hupe, E.; Knochel, P. Patent application with Aventis Research &
Technologies GmbH & Co KG.
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Org. Lett., Vol. 3, No. 1, 2001