The preparation of nonracemic secondary α-(carbamoyloxy)alkylzinc and copper reagents. A versatile approach to enantioenriched alcohols

Article abstract of DOI:10.1021/ol016986e

(matrix presented) Chiral α-(carbamoyloxy)alkyllithium reagents, prepared using Hoppe's sBuLi/(-)-sparteine methodology, were transmetalated with ZnCl₂. Further transmetalation with CuCN with overall retention of configuration gave chiral species that reacted with various electrophiles to give enantiomerically pure alcohols after deprotection. A short, highly efficient synthesis of an industrially relevant pheromone, japonilure, illustrates the value of the methodology.

Full text of DOI:10.1021/ol016986e

ORGANIC
LETTERS
2002
Vol. 4, No. 1
119-122
The Preparation of Nonracemic
Secondary r-(Carbamoyloxy)alkylzinc
and Copper Reagents. A Versatile
Approach to Enantioenriched Alcohols
Julien P. N. Papillon and Richard J. K. Taylor*
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K.
rjkt1@york.ac.uk
Received November 1, 2001
ABSTRACT
Chiral r-(carbamoyloxy)alkyllithium reagents, prepared using Hoppe’s sBuLi/(−)-sparteine methodology, were transmetalated with ZnCl2. Further
transmetalation with CuCN with overall retention of configuration gave chiral species that reacted with various electrophiles to give
enantiomerically pure alcohols after deprotection. A short, highly efficient synthesis of an industrially relevant pheromone, japonilure, illustrates
the value of the methodology.
Efforts to design asymmetric routes to secondary alcohols
have been considerable as a result of their usefulness as
building blocks and their widespread occurrence in natural
products. Nucleophilic addition to aldehydes and hydrogena-
tion or hydride addition to ketones are routine procedures
to prepare secondary alcohols, and a number of efficient
asymmetric variants have been developed. Enantioenriched
epoxides also make attractive precursors to secondary
alcohols, particularly given recent progress made in their
preparation. An alternative process, which has been much
less studied, is the reaction between a nucleophilic R-alkoxy-
alkylmetal reagent and an electrophile. The first convenient
preparation of R-alkoxyalkyllithium species, using R-alkoxy-
alkylstannane precursors, was reported by Still.1 Later, the
groups of Linderman2 and Fuchs3 reported the conjugate
addition of R-alkoxyorganocopper reagents. Importantly, Still
and Sreekumar also showed that enantioenriched R-alkoxy-
alkylstannanes could be transmetalated with n-butyllithium
with retention of configuration. The R-alkoxyalkyllithium
reagents thus formed were shown to be configurationally
stable below -40 °C in ethereal solvents.4 McGarvey et al.
demonstrated the stabilizing influence of oxygen upon the
carbanionic center5 and provided examples of the utility of
these anions in stereoselective synthesis.6 These findings
prompted several other groups to study the synthesis of the
R-alkoxyorganostannane precursors in enantioenriched form.7
Falck and co-workers have reported the successful stereo-
selective cross-couplings of R-alkoxytributylstannanes with
organohalides, using copper8 or copper/palladium9 catalysis.
(4) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201-
1202.
(5) Sawyer, J. J.; McDonald, T. L.; McGarvey, G. J. J. Am. Chem. Soc.
1984, 106, 3376-3377.
(6) (a) McGarvey, G. J.; Kimura, M. J. Org. Chem. 1982, 47, 5422-
5424. (b) McGarvey, G. J.; Bajiva, J. S. J. Org. Chem. 1984, 49, 4091-
4092. (c) McGarvey, G. J.; Kimura, M.; Kucervoy, A. Tetrahedron Lett.
1985, 26, 1419-1422.
(7) (a) Marshall, J. A.; Gung, W. Y. Tetrahedron Lett. 1989, 30, 2183-
2186. (b) Jephcote, V. J.; Pratt, A. J.; Thomas, E. J. J. Chem Soc., Perkin
Trans. 1 1989, 1529-1535. (c) Matteson, D. S.; Tripathy, P. B.; Sarkur,
A.; Sadhu, K. N. J. Am. Chem. Soc. 1989, 111, 4399-4402. (d) Chan, P.
C.-M.; Chong, C. J. M. J. Org. Chem. 1988, 53, 5584-5586.
(8) Falck, J. R.; Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995, 117, 5973-
5982.
(1) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481-1487.
(2) Linderman, R. J.; Godfrey, A.; Horne, K. Tetrahedron Lett. 1987,
28, 3911-3914.
(3) Hutchinson, D. K.; Fuchs, P. L. J. Am. Chem. Soc. 1987, 109, 4930-
4939.
(9) (a) Ye, J.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett. 1993, 34, 8007-
8010. (b) Ye, J.; Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc. 1994, 116,
1-5.
10.1021/ol016986e CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/12/2001

Calter and Bi recently reported a successful stereoselective
conjugate addition of a chiral mixed higher-order R-alkoxy-
cuprate reagent.10
Scheme 1a
A spectacular development in this field was achieved by
Hoppe et al., who demonstrated that the complex sBuLi/
(-)-sparteine could induce the enantioselective deprotonation
of achiral alkyl carbamates.11,12 The chiral lithium species
thus formed can be alkylated with retention of configuration
to give the protected secondary alcohols in high ee's. The
use of these lithium species has so far been limited as a result
of their configurational lability above -70 °C, although
Hoppe13 and others14 have reported various applications of
this methodology.
a (a) (i) sBuLi (1.5 equiv), (-)-sparteine (1.5 equiv), Et2O, -78
°C, 5 h, (ii) ZnCl2 (0.8 M in THF, 1.3 equiv), -78 °C to rt, (iii)
CuCN‚2LiCl (1.0 equiv) in THF, -40 to 0 °C, (iv) electrophile
3-13, -40 to 0 °C.
However, examples of the utilization of chiral nonracemic
R-alkoxyorganometallic compounds in synthesis have been
scarce. It seemed to us that transmetalation of Hoppe’s
species could lead to thermally and configurationally stable
compounds and thus open up interesting synthetic possibili-
ties. As far as we were aware when we commenced this
study, the only examples of transmetalation of the lithiated
carbamate prepared using Hoppe’s methodology had been
reported by Hoppe himself.11,15 His group prepared R-(car-
bamoyloxy)alkyl tin and silicon derivatives, although no
attempt at utilizing these species in cross-coupling reactions
has been reported. We were hopeful that the transmetalation
from the chiral lithium reagents to the alkylzinc derivatives
would be stereoselective.16 A handful of reports have shown
that chiral alkylzinc halides are configurationally stable, even
at room temperature.16,17 Moreover, Knochel has demon-
strated that the transmetalation of alkylzinc reagents with
copper cyanide gives reagents that react with a broad range
of electrophiles while showing excellent chemoselectivity.18
His group has also prepared racemic R-alkoxyalkylzinc
cuprates and showed that they are efficient nucleophiles.19
Our synthetic strategy is illustrated in Scheme 1. The
carbamate 1, prepared using the literature procedure,11b was
deprotonated at -78 °C for 4-5 h using 1.5 equiv of (-)-
sparteine and 1.5 equiv of sBuLi. A 0.8 M solution of ZnCl2
in THF20 was then added, followed by CuCN‚2LiCl in THF
and finally the electrophile.21 The results are summarized in
Table 1 (all yields are unoptimized).
The coupling of the chiral organometallic species 2c22
derived from 1 with allyl bromides proceeded in good yields
(entries 1-3). In the case of 1-bromocyclohex-2-ene the
reaction gave a 1:1 mixture of diastereomers (entry 2). The
reagent 2c also displayed excellent reactivity toward alkynyl
bromide 6 and gave the protected propargylic alcohol 17 in
72% yield (entry 4). The propargylic mesylate 7 reacted
exclusively in an SN2′ fashion to give the allene 18 in 75%
yield (entry 5). Activated vinyl iodide 8 (entry 6) and vinyl
triflate 9 (entry 7) reacted in modest yields and provided
further examples of the chemoselectvity of these types of
organometallic species.
(10) Calter, M. A.; Bi, F. C. Org. Lett. 2000, 2, 1529-1531.
(11) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl.
1990, 29, 1422-1424. (b) Hintze, F.; Hoppe, D. Synthesis 1992, 1216-
1218. (c) For a review, see: Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2282-2316.
The reactivity of 2c toward Michael acceptors was very
poor, and reaction with cyclohexenone or methyl acrylate
(12) For use of sBuLi/(-)-sparteine in the enantioselective deprotonation
of N-Boc pyrrolidines, see: Beak, P.; Basu, A.; Gallagher, J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552-560 and references
therein.
(13) (a) Laqua, H.; Fro¨hlich, R.; Wibbeling, B.; Hoppe, D. J. Organomet.
Chem. 2001, 624, 96-104. (b) Oestreich, M.; Fro¨hlich, R.; Hoppe, D. J.
Org. Chem. 1999, 64, 8616-8626. (c) Kleinfeld, S. H.; Wegelius, E.; Hoppe,
D. HelV. Chim. Acta 1999, 82, 2413-2421. (d) Hoppe, D.; Woltering, M.
J.; Oestreich, M.; Fro¨hlich, R. HelV. Chim. Acta 1999, 82, 1860-1868. (e)
Bebber, J. V.; Ahrens, H.; Fro¨hlich, R.; Hoppe, D. Chem. Eur. J. 1999,
1905-1911. (f) Schwerdtfeger, J.; Kolczewski, S.; Weber, B.; Fro¨hlich,
R.; Hoppe, D. Synthesis 1999, 1573-1592.
(14) (a) Tomooka, K.; Komine, M.; Sasaki, T.; Shimizu, H.; Nakai, T.
Tetrahedron Lett. 1998, 39, 9715-9718. (b) Menges, M.; Bru¨ckner, R. Eur.
J. Org. Chem. 1998, 1023-1030.
(15) (a) Shortly after completion of this work, a study of the reactivity
of nonracemic pyrrolidinylcuprates prepared from R-lithiated-N-Boc-
pyrrolidine was disclosed: Dieter, R. K.; Topping, C. M.; Chandupatla, K.
R.; Lu, K. J. Am. Chem. Soc. 2001, 123, 5132-5133. (b) see also:
Tomooka, K.; Shimizu, H.; Nakai, T. J. Organomet. Chem. 2001, 624, 364-
366.
(16) (a) Klein, S.; Marek, I.; Normant, J.-F. J. Org. Chem. 1994, 59,
2925-2926. (b) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J.-F.; Normant,
J.-F. Chem. Eur. J. 1999, 5, 2055-2068.
(17) (a) Houkawa, T.; Ueda, T.; Sakami, S.; Asaoka, M.; Takei, H.
Tetrahedron Lett. 1996, 37, 1045-1048. (b) Sakami, S.; Houkawa, T.;
Asaoka, M.; Takei, H. J. Chem. Soc., Perkin Trans. 1 1995, 37, 285-286.
(c) Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, P.; Berger, S.; Knochel,
P. Tetrahedron 1994, 50, 2415-2432.
(18) (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390-2392. For reviews, see: (b) Knochel, P.; Singer, R. D.
Chem. ReV. 1993, 93, 2117-2188. (c) Knochel, P.; Almena Perea, J. J.
Tetrahedron 1998, 54, 8275-8319.
(19) Chou, T.-S.; Knochel, P. J. Org. Chem. 1990, 55, 4791-4793.
(20) We found it convenient to quench the lithiated carbamate 2a with
a freshly prepared solution of anhydrous ZnCl2 in THF. Using ZnCl2 in
Et2O gave a heterogeneous mixture that was difficult to stir.
(21) Representative Experimental Procedure. sBuLi (2.0 mL, 1.32 M
in hexane, 2.64 mmol) was added dropwise to a stirred solution of 1 (0.40
g, 1.78 mmol) and (-)-sparteine (0.62 g, 2.65 mmol) in anhydrous ether
(5 cm3) at -78 °C. After 4 h at -78 °C, zinc chloride (0.8 M in THF, 2.9
mL, 2.32 mmol) was added dropwise at -78 °C over 10 min, and the
mixture was stirred for a further 20 min at this temperature. The mixture
was warmed to room temperature over 15 min and recooled to -40 °C,
and a solution of copper cyanide (99%, 0.16 g, 1.78 mmol) and lithium
chloride (dried at 150 °C under 0.2 mmHg for 4 h, 0.15 g, 3.56 mmol) in
anhydrous THF (3 cm3) was added rapidly. The yellow slurry was warmed
to 0 °C over 15 min and recooled to -40 °C. The electrophile (1.78 mmol)
was added dropwise, either neat if liquid or in a minimum volume of
anhydrous THF if solid. The mixture was allowed to warm to 0 °C over
1.5 h, whereupon it was quenched with dropwise addition of a 10% solution
of NH4OH in saturated aqueous NH4Cl. Ether was added, and the mixture
was vigorously stirred for 20 min and filtered through Celite. The organic
layer was washed with saturated aqueous Na2CO3, water, and brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified by column
chromatography to give the carbamates as colourless oils.
(22) The formula RCu(CN)ZnCl merely represents the stoechiometry of
the reagent; see ref 18.
120
Org. Lett., Vol. 4, No. 1, 2002

Table 1. Electrophilic Trapping of 2c
a The yield refers to isolated product. b The figure in brackets gives the yield based on recovered starting carbamate. c The ee’s were measured by HPLC
analysis; see Supporting Information. d The carbamate was hydrolyzed using: (i) cat. MeSO3H, MeOH, reflux, overnight, (ii) Ba(OH)2, MeOH, reflux, 2 h.
e The product was obtained as a 1:1 mixture of inseparable diastereomers. f The carbamate was hydrolyzed using: (i) cat. MeSO3H, MeOH, reflux, 24 h, (ii)
HSiCl3, Et3N, THF, reflux, 3 h. g Despite extensive efforts to measure the ee, we were unsuccessful using HPLC chiral columns Chiralcel OD, OJ, OJ-R and
Chiralpak AD; [R]20 + 18.4 (c 4.45, CHCl3). h Complete racemization occurred upon deprotection. i Only one diastereomer was detected by 1H NMR
D
spectroscopy. j The starting carbamate was recovered quantitatively. Abbreviations: n.d. ) not determined, n.a. ) not applicable, Ms ) methylsulfonyl, Tf
) trifluoromethylsulfonyl, Cby ) 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carbonyl.
gave at best traces of product (entries 8 and 9). An attempted
carbometalation with 1-heptyne was also unsuccessful (entry
11).
The hydrolysis of the carbamates was carried out using
the conditions described by Hoppe (Table 1, entries 1-7).11b
The carbamates 14, 15, and 17 afforded the corresponding
alcohols in very good yields, whereas 19 racemized and 16
and 20 decomposed upon treatment with Ba(OH)2 in reflux-
ing methanol. However, after opening the tetramethyl ox-
azolidine group of 20 under standard conditions, we found
that the carbamate could be cleaved with trichlorosilane (6
equiv) in the presence of triethylamine (6 equiv) in refluxing
THF25 to give the alcohol 30 in 69% yield (Scheme 2). This
new method for the deprotection of Hoppe’s carbamate was
ineffective with 16.
The alkylated carbamates were obtained in excellent ee's,
similar to those described by Hoppe in the case of the simple
alkylation of 2a, indicating that the transmetalation to the
mixed copper-zinc species 2c is stereoselective. The alky-
lation takes place with overall retention of configuration, as
shown by comparison between the optical rotation of (R)-
1-hepten-4-ol obtained by deprotection of 14 {[R]20D +13.2
(c 2.4, CHCl3)} with the value described in the literature
{[R]20 +12.7 (c 0.54, CHCl3)}.23 Attempts to directly
D
transmetalate the lithium species 2a with CuCN and subse-
quent reaction with allyl bromide afforded 14 in only 38%
yield and 88% ee,24 which is in sharp contrast with the results
obtained from similar experiments carried out with N-Boc-
2-lithiopyrrolidine.15
We have applied this methodology to the synthesis of the
Japanese beetle sex pheromone, japonilure. The Japanese
beetle, Papillia Japonica, is a pest causing damage to crops,
and japonilure has been used in traps to attract the males.26
It is particularly important that the synthetic pheromone is
(23) Kang. S.-K.; Park, D.-C.; Rho, H.-S.; Yu, C.-M.; Hong, J.-H. Synth.
Commun. 1995, 25, 203-214.
(24) The temperature was maintained under -70 °C throughout the
reaction and warmed only after the aqueous NH4Cl quench.
(25) Pirkle, J. W. H.; Hauske, J. R. J. Org. Chem. 1977, 41, 2781-
2783.
(26) Tumlinson, J. H.; Klein, M G.; Doolittle, R. E.; Proveaux, A. T.
Science 1977, 197, 789-792.
Org. Lett., Vol. 4, No. 1, 2002
121

Scheme 2a
Scheme 3a
a (a) MeSO3H cat., MeOH, reflux, 24 h; (b) HSiCl3 (6.0 equiv),
Et3N (6.0 equiv), anhydrous THF, reflux, 3 h.
a (a) (i) NaH, Et2O, rt, 30 min, (ii) CbyCl, Et2O, rt, 3 days; (b)
(i) sBuLi (1.5 equiv), (-)-sparteine (1.5 equiv), Et2O, -78 °C, 5
h, (ii) ZnCl2 (0.8 M in THF), -78 °C to rt, (iii) CuCN‚2LiCl in
THF, -40 to 0 °C, (iv) decynyl bromide,28 -40 to 0 °C; (c) (i)
MeSO3H cat., MeOH, reflux, 15 h, (ii) Ba(OH)2‚8H2O, MeOH,
reflux, 2 h; (d) (i) O3, DCM, -78 °C, (ii) PPh3 (1.2 equiv), DCM,
-78 °C to rt, 2 h; (e) N-iodosuccinimide (5.0 equiv), nBu4NI (1.0
equiv), rt, 15 min; (f) Lindlar catalyst, H2, quinoline, pentane, 0
°C, 4 h.
enantiomerically pure, since as little as 0.5% of the unnatural
(S)-enantiomer reduces the male response to the pheromone
by a third.26 Given the industrial importance of japonilure,
a large number of syntheses have been reported.27 Our
synthesis starts from 4-pentenol, which is converted into the
carbamate 33 in 95% yield (Scheme 3). The derived chiral
zinc cuprate is reacted with decynyl bromide28 to give the
alkyne 34 in 90% yield. Standard hydrolysis of the carbamate
and careful ozonolysis followed by triphenylphosphine
workup gave the lactol, which was immediately oxidized to
the lactone 36 using nBu4NI/NIS29 in 86% overall yield. The
enantiomeric excess of 36 was found to be superior to 99%.30
Reduction of 36 over Lindlar catalyst27b afforded japonilure
37 in 94% yield {[R]21D-69.4°, (c 0.74, CHCl3); lit.27b
[R]21D-70.4°, (c 1.08, CHCl3); lit.27a [R]21D-69.7 (c 1.0,
CHCl3)}. This constitutes a particularly efficient synthesis
of japonilure (6 steps, 61% overall yield, and ee > 99%).
In conclusion, we have demonstrated that Hoppe’s lithiated
alkyl carbamates can be transmetalated with zinc chloride
and further reacted with copper cyanide without loss of
chirality. These species react with various electrophiles to
afford, after hydrolysis of the carbamate, chiral alcohols of
enantiomeric purity superior to 96%.
Acknowledgment. We thank Pharmacia-Upjohn (Bio-
vitrum) for financial support and Drs. R. Crossley, E.
Desarbre, and C. Hedgecock for their encouragement. We
are also grateful to Dr J. Herbert (Sanofi) for his help with
the HPLC assays.
(27) (a) Baker, R.; Rao, V. B. J. Chem Soc., Perkin Trans. 1 1982, 69-
71. (b) Kuwahara, S.; Mori, K. Agric. Biol. Chem. 1983, 47, 2599-2606.
(c) Ramaswamy, S.; Oehschlager, A. C. Tetrahedron 1991, 47, 1145-1156.
(d) Fukusaki, E.; Senda, S.; Nakazono, Y.; Omata, T. Tetrahedron 1991,
47, 6223-6230. (e) Taylor, S. K.; Atkinson, R. F.; Almli, E. P.; Carr, M.
D.; Van Huis, T. J.; Whittaker, M. R. Tetrahedron: Asymmetry 1995, 6,
157-164 and references therein.
(28) Decynyl bromide was prepared in 91% yield from decyne using
AgNO3/NBS.
(29) Hanessian, S.; Wong, D. H.; Therien, M. Synthesis 1981, 394-
396.
Supporting Information Available: Analytical data for
compounds 14-20, 25, 26, 28-30, and 33-37 and experi-
mental procedures for compounds 30 and 33-37. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(30) The ee of 36 was determined by HPLC analysis (Chiralcel OD
column, hexane/2-propanol 99:1, 1 mL/min, 215 nm); see ref 27d.
OL016986E
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