Dimethylzinc-mediated addition of alkenylzirconocenes to α-keto and α-imino esters

Article abstract of DOI:10.1021/ol0347141

(Matrix presented) Hydrozirconation of alkynes followed by in situ transmetalation to dimethylzinc and 1,2-addition to activated ketones and N-diphenylphosphinoylimines leads to tertiary allylic alcohols and amines in high overall yield. With 8-phenylmenthol as the chiral auxiliary, si-face attack proceeds in good to excellent diastereoselectivities.

Full text of DOI:10.1021/ol0347141

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2449-2452
Dimethylzinc-Mediated Addition of
Alkenylzirconocenes to r-Keto and
r-Imino Esters
Peter Wipf* and Corey R. J. Stephenson
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf+@pitt.edu
Received April 29, 2003
ABSTRACT
Hydrozirconation of alkynes followed by in situ transmetalation to dimethylzinc and 1,2-addition to activated ketones and N-diphenylphos-
phinoylimines leads to tertiary allylic alcohols and amines in high overall yield. With 8-phenylmenthol as the chiral auxiliary, si-face attack
proceeds in good to excellent diastereoselectivities.
The addition of organometallic reagents to R-keto esters1
provides access to 1,2-dioxygenated building blocks for
organic synthesis.2,3 The resulting tertiary R-hydroxy car-
boxylates serve as substructures for natural products and
medicinal agents.4 This approach is particularly valuable if
the organometallic reagent is readily obtained from storable
precursors and tolerates other commonly used functional
groups. In contrast to the use of Grignard and lithium
reagents, hydrozirconation of alkynes is relatively insensitive
to the presence of many electrophilic functions, and the
resulting organozirconocenes have been added to enones,5,6
aldehydes,7 epoxides,8 esters,9 isocyanates,10 nitrones,11 and
imines.12 As a continuation of our work on ZrfZn trans-
metalations of alkenylzirconocenes and in situ additions to
(5) For reviews, see: (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853.
(b) Lipshutz, B. H.; Pfeiffer, S. S.; Tomioka, T.; Noson, K. In Titanium
and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Wein-
heim, 2002; pp 110-148.
(6) (a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115. (b)
Loots, M. J.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 8045. (c) Lipshutz,
B. H.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112, 7440. (d) Wipf, P.;
Smitrovich, J. H. J. Org. Chem. 1991, 56, 6494. (e) Wipf, P.; Xu, W.;
Smitrovich, J. H.; Lehmann, R.; Venanzi, L. M. Tetrahedron 1994, 50,
1935.
(7) (a) Wipf, P.; Xu, W. Tetrahdron Lett. 1994, 35, 5197. (b) Wipf, P.;
Xu, W. Org. Synth. 1996, 74, 205. (c) Wipf, P.; Ribe, S. J. Org. Chem.
1998, 63, 6454. (d) Wipf, P.; Jayasuriya, N.; Ribe, S. Chirality 2003, 15,
208. (e) Maeta, H.; Hashimoto, T.; Hasegawa, T.; Suzuki, K. Tetrahedron
Lett. 1992, 33, 5965.
(1) Kovacs, L. Recl. TraV. Chim. Pays-Bas 1993, 112, 471.
(2) (a) Akiyama, T.; Nishimoto, H.; Ishikawa, K.; Ozaki, S. Chem. Lett.
1992, 447. (b) Fuji, K.; Tanaka, K.; Ahn, M.; Mizuchi, M. Chem. Pharm.
Bull. 1994, 42, 957. (c) Huang, D.-L.; Draper, R. W.; Lih, D. Tetrahedron
Lett. 1994, 35, 661. (d) Tamai, Y.; Nakano, T.; Miyano, S. J. Chem. Soc.,
Perkin Trans. 1 1994, 439 and references therein.
(3) For lead references on the tactically related addition of enolates to
R-keto esters, see: (a) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R.
J. Am. Chem. Soc. 1997, 119, 10859-10860. (b) Kobayashi, S.; Fujishita,
Y.; Mukaiyama, T. Chem. Lett. 1989, 2069.
(4) See, for example: (a) Comins, D. L.; Hong, H.; Saha, J. K.; Jianhua,
G. J. Org. Chem. 1994, 59, 5120-5121. (b) Senanayake, C. H.; Fang, Q.
K.; Grover, P.; Bakale, R. P.; Vandenbossche, C. P.; Wald, S. A.
Tetrahedron Lett. 1999, 40, 819.
(8) Wipf, P.; Xu, W. J. Org. Chem. 1993, 58, 825.
(9) (a) Wipf, P.; Xu, W. J. J. Org. Chem. 1993, 58, 5880. (b) Wipf, P.;
Xu, W.; Takahashi, H.; Jahn, H.; Coish, P. D. G. Pure Appl. Chem. 1997,
69, 639.
(10) Negishi, E.; Swanson, D. R.; Miller, S. R. Tetrahedron Lett. 1988,
29, 1631.
(11) Pandya, S. U.; Garcon, C.; Chavant, P. Y.; Py, S.; Valle´e, Y. Chem.
Commun. 2001, 1806.
(12) (a) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2003, 125, 761. (b) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem.
Soc. 2001, 123, 5122. (c) Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773.
(d) Kakuuchi, A.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 2003, 44,
923.
10.1021/ol0347141 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/10/2003

organic electrophiles,13 we have now extended this meth-
odology to the formation of functionalized tertiary allylic
alcohols via addition to R-keto esters (Scheme 1).14-16
Table 1. Preparation of Tertiary Allylic Alcohols and Amines
from Alkynes and R-Keto or R-Imino Esters
Scheme 1. Addition of Organozirconocenes to R-Keto Esters
Mediated by Transmetalation to Dimethylzinc
(E)-Alkenylzirconocenes 2 were readily obtained by hy-
drozirconation of alkynes 1 with Cp2ZrHCl in CH2Cl2 at
room temperature and, upon addition of a dimethylzinc
solution in toluene, converted to the more nucleophilic
alkenylzinc species 3. After addition of R-keto esters 4 at 0
°C to the reaction mixture, tertiary allylic alcohols 5 were
formed in 75-96% yield in 1-2 h upon warming to room
temperature (Table 1).17,18 In the absence of dimethylzinc,
only traces of addition products were observed.
Ester functionalities were tolerated both in the substrate
as well as in the alkyne component (entry 4). Silyl ethers
(entries 3 and 8) and Lewis basic benzyl ethers (entry 5),
internal alkynes (entry 2), and enynes (entry 6) all proceeded
successfully through the 1,2-addition and afforded the
expected R-hydroxy esters in high overall yields.
Since our initial attempts to affect an asymmetric addition
to ketoester 6 in the presence of chiral ligands7c,d,19 did not
yield enantiomerically enriched products, we turned our
attention to the readily available menthol derived R-keto
esters 26 and 27. There is encouraging literature precedent
(13) Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778.
(14) For representative examples for the addition of alkylzinc chloride,
dialkylzinc, or trialkylzincate reagents to activated ketones, see: (a) Pu,
L.; Yu, H.-B. Chem. ReV. 2001, 101, 757. (b) Basavaiah, D.; Krishna, P.
R. Tetrahedron 1995, 51, 12169. (c) Sugimura, H.; Watanabe, T. Synlett
1994, 175.
(15) For recent examples of asymmetric additions of alkylzinc reagents
to R-keto esters, see: (a) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem.
Soc. 2002, 124, 12668. (b) DiMauro, E. F.; Kozlowski, M. C. Org. Lett.
2002, 4, 3781.
(16) For reports on the alkenylalane addition to activated carbonyl
compounds and imines, see: (a) Ramachandran, P. V.; Reddy, M. V. R.;
Rudd, M. T. Tetrahedron Lett. 1999, 40, 627. (b) Wipf, P.; Nunes, R. L.;
Ribe, S. HelV. Chim. Acta 2002, 85, 3478.
a Yields of isolated product based on R-keto/imino ester.
(17) General Protocol. To a suspension of Cp2ZrHCl (0.24 g, 0.91
mmol) in dry CH2Cl2 (4.0 mL) was added 7 (0.11 mL, 0.91 mmol). The
reaction mixture was stirred for 10 min at rt and evaporated in vacuo. A
solution of the residue in dry toluene (4.0 mL) was cooled to -78 °C,
treated with Me2Zn (0.46 mL, 0.91 mmol), and warmed to 0 °C. After
addition of 6 (87 µL, 0.61 mmol), the reaction mixture was warmed to rt,
stirred for 2 h, quenched with saturated NH4Cl, diluted with EtOAc, and
filtered through Celite. The aqueous layer was extracted with EtOAc, and
the combined organic layers were washed with brine, dried (MgSO4), and
concentrated. The residue was purified by chromatography on SiO2 (19:1,
hexanes/EtOAc) to give 8 (0.14 g, 93%) as a colorless oil.
(18) Nonactivated ketones react only sluggishly under these reaction
conditions.
for the diastereoselective addition of organometallic reagents
to chiral R-keto esters20 and amides.21 Treatment of ben-
zoylformic acid 22 with R,R-dichloromethyl methyl ether22
afforded 70% of acid chloride 23, which could be converted
in the presence of DMAP in CH2Cl2 to the menthyl ester 26
(20) (a) Whitesell, J. K.; Bhattacharya, A.; Henke, K. J. Chem. Soc.,
Chem. Commun. 1982, 988. (b) Basavaiah, D.; Bharathi, T. K. Tetrahedron
Lett. 1991, 32, 3417. (c) Whitesell, J. K. Chem. ReV. 1992, 92, 953.
(21) Kiegiel, K.; Jurczak, J. Tetrahedron Lett. 1999, 40, 1009.
(22) Ottenheijm, H. C. J.; de Man, J. H. M. Synthesis 1975, 163.
(19) Wipf, P.; Wang, X. Org. Lett. 2002, 4, 1197.
2450
Org. Lett., Vol. 5, No. 14, 2003

and the 8-phenylmenthyl23 ester 27 in excellent yields
(Scheme 2).
Scheme 2. Use of Chiral Esters in the 1,2-Addition Process
and Assignment of Absolute Configuration by Conversion to the
Known Diol 31
Figure 1. Stereoview of the lowest-energy Me2Zn-chelated R-keto
ester complex that can be used to rationalize the si-face selectivity
of nucleophilic addition. The geometry was optimized at the
Hartree-Fock 6-31G* level using the Spartan program.
with the dipole-minimizing anti orientation of the carbonyl
groups. The conformational rigidity rationalizes the outstand-
ing facial selectivity observed in the nucleophilic addition
to the 8-phenylmenthol ester, and this analysis is also in good
agreement with Whitesell’s π-stacking model for nucleophilic
additions to esters with aryl auxiliaries.20
As a further extension of the scope of this methodology
toward the preparation of R,R-disubstituted R-amino acid
derivatives and 1,2-amino alcohols, we added alkenyl orga-
nometallics to R-N-diphenylphosphinoylimino esters (Scheme
3).26 While the analogous N-tosylimines have been utilized
previously,27 this work represents the first report of nucleo-
philic additions to R-N-diphenylphosphinoylimino esters,
which benefit from mild acidic deprotection conditions.12
Treatment of 26 and 27 at -20 °C with 1.5 equiv of the
organometallic reagent derived from 7 afforded 28 and 29,
respectively. While the menthyl ester 26 provided 28 only
in modest diastereoselectivity (3.3:1 by 500 MHz 1H NMR),
a single diastereoisomer was observed by 1H NMR analysis
in the formation of 29. To quantify the diastereoselectivity
of the addition process, the crude reaction mixture was
subjected to LiAlH4 reduction to afford diol 30 in 87% yield
along with 92% of recovered 25. Racemic diol 30 was readily
separated by chiral HPLC (Chiralcel OD) and compared to
material obtained from reduction of the 8-phenylmenthyl
ester. Furthermore, hydrogenation of the allylic alcohol using
H2/Rh/Al2O3 gave the known24 diol 31 in 97% yield (Scheme
2).25
According to the sign of the optical rotation of 31, the
addition proceeded with si-face attack via a π-stacked,
chelated complex20,21 to give the R-hydroxyester 29 in the
(R)-configuration. On the basis of HF-6-31G* ab initio
energy minimization, the chelated conformation shown in
Figure 1 is at least 1.7 kcal/mol lower in energy than any
alternative conformer, including monocoordinated structures
Condensation of phosphonamide 32 with keto esters 6 and
27 in the presence of TiCl4 and TEA afforded imino-esters
33 (40%) and 34 (69%), respectively.28 Addition of 1.5 equiv
of alkenylorganometallic reagent derived from alkynes 7 and
11 to imine 33 afforded allylic amides 35 (92%) and 36
(93%), respectively (Table 1). The analogous conversion of
the chiral imino ester 34 at -20 °C afforded allylic amide
37 with modest diastereoselection (77%, dr ) 5:1 by 600
1
MHz H NMR). We envisioned that the stereoselectivity
could be improved by precomplexing 34 with a Lewis acid.
Indeed, after a quick survey of Lewis acids, precomplexation
of 34 with 1 equiv of TiCl(O-i-Pr)3 at -40 °C and treatment
with 2 equiv of the alkenylorganometallics derived from
alkynes 7 and 11 gave allylic amides 37 (70%; dr ) 7.8:1)
and 38 (84%; dr ) 7.4:1), respectively. Saponification of
the major isomer of 37 followed by methylation with
TMSCHN2 led to methyl ester (+)-35 (84%). Hydrogenation
(PtO2, MeOH, quant), N-deprotection (HCl/MeOH), and
Cbz-protection afforded (-)-40 (73%). The configuration of
this R,R-disubstituted R-amino acid derivative was assigned
by comparison of the optical rotation of (-)-40 with an
(23) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
(24) Vanhessche, K. P. M.; Sharpless, K. B. J. Org. Chem. 1996, 61,
7978.
(25) Optical rotation [R]D +2.15 (c 1.07, EtOH) was measured for 31,
which indicated an ee of >89% compared to the literature value24 reported
for this compound.
(26) Tye, H. J. Chem. Soc., Perkin Trans. 1 2000, 275.
(27) Kulesza, A.; Jurczak, J. Chirality 2001, 13, 634.
(28) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561.
Org. Lett., Vol. 5, No. 14, 2003
2451

extended to the 1,2-addition of vinyl organometallics to
R-keto and R-imino esters. Functionalized tertiary allylic
alcohols and amines are formed in good to excellent yields.
The utility of this method has been further broadened by a
highly diastereoselective variant using 8-phenylmenthol as
a chiral auxiliary to afford chiral tertiary alcohols and R,R-
disubstituted R-amino acids. The chiral auxiliary can be
recovered and recycled in high yield. Further investigations
into catalytic asymmetric additions to R-keto and R-imino
esters will be reported in due course.
Scheme 3. Formation of R,R-Disubstituted R-Amino Acids by
Nucleophilic Addition to R-Imino Esters
Acknowledgment. This work has been supported by a
grant from the National Science Foundation (CHE-0078944).
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
copies of 1H and 13C NMR for 8, 10, 12, 14, 16, 18, 20, 21,
29, 30, 31, and 33-40. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0347141
(29) (a) Seebach, D.; Sting, A. R.; Hoffman, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708. (b) O’Donnell, M. J.; Fang, Z.; Ma, X.; Huffman, J.
C. Heterocycles 1997, 46, 617. (c) Ma, D.; Zhu, W. J. Org. Chem. 2001,
66, 348.
(30) Oxazolidinone 41 was alkylated with hexyl triflate at -78 °C
followed by saponification with NaOMe/MeOH to give (+)-40.
authentic sample of (+)-40 prepared independently using
Seebach’s methodology.29,30
In conclusion, the experimentally convenient protocol of
in situ hydrozirconation-transmetalation to zinc can be
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Org. Lett., Vol. 5, No. 14, 2003