has been successfully adopted by other groups for the
preparation of a number of natural products and medicinally
active compounds. However, this reagent is also limited in
terms of the range of compatible electrophilic trapping
agents, often requiring transmetalation to copper or the
addition of palladium-catalysts to enhance reactivity. This
low reactivity means reaction with simple aldehydes/ketones
is not possible.
In natural product syntheses under current investigation
in our laboratory,7 we required a highly reactive organo-
metallic reagent 6 capable of addition to hindered ketones.
Herein we describe the successful development and applica-
tion of reagents 6 (M ) Li).
Table 1. Metalation-Trapping of 10a-d and 9a
entry
precursor
productb
i
ii
iii
iv
vc
10a , P ) TBS
10b, P ) THP
10c, P ) MOM
10d , P ) SEM
9
12a , P ) TBS, 0%
12b, P ) THP, 57%
12c, P ) MOM, 82%
12d , P ) SEM, 82%
12e, P ) H, 0%
a THF, -78 °C; (i) n-BuLi (1.1 equiv), (ii) LiNp (2.5-3.0 equiv), (iii)
E+ (1.5-2.5 equiv). b Isolated yields. c Performed with 2.1 equiv of n-BuLi.
We were delighted to observe promising results with THP,
MOM, and SEM protection (entries ii-iv), indicating the
possibility that an additional coordinating site in the protect-
ing group might be advantageous. The unprotected alcohol
9 gave no product, and nor did the silyl ether 10a. No further
work was carried out with 10b in view of the diastereomeric
nature of the adducts. Deprotection studies showed that the
SEM ether 12d could be deprotected cleanly using 0.1 M
HCl in MeOH (3 h, rt) delivering 12e (P ) H) in 79% yield.
The SEM system was therefore chosen for further study,
and a range of electrophiles were employed to trap the
organolithium reagent 11d (Table 2). Thus, in addition
to cyclohexanone (entry i), cyclobutanone, benzaldehyde,
Weinreb amides, carbon dioxide, trimethylsilyl chloride, and
CD3OD were all successfully employed as electrophilic
trapping agents, giving adducts 12d, 14, 17, 20, 22, 24, 26,
and 29, respectively, in yields ranging from 75 to 98%
(entries ii-vii).
Following on from our earlier studies, we decided to
explore the preparation of reagents 6 commencing from a
proteinogenic R-amino acid (Scheme 1).8 Thus, standard
Scheme 1. Initial Studies
In most cases, removal of the SEM-protecting group
proceeded smoothly, giving alcohols 12e, 15, 18, 27, and
30 in unoptimized but reasonable yields (entries i-iii, vi and
vii). The main exceptions (entry iv) involved hydrolysis of
ketone adducts 20 and 22 where the only observed products
were the furans 21 and 23, respectively, resulting from a
cyclization-aromatization sequence. In addition (entry v),
the alcohol resulting from deprotection of ester 24 underwent
partial lactonization, and a second treatment of the crude
material with CSA in benzene completed lactonization,
giving γ-lactone 25.11
The alaninol derivatives obtained by deprotection were
then oxidized to the corresponding Boc-protected amino
acids, which were converted into their methyl esters using
trimethylsilyl diazomethane to aid isolation. In this manner,
fully protected amino acids 19,12 28, and 31 were obtained
in reasonable yields (entries iii, vi, and vii). Oxidation of
1°/3° diols 12e and 15 under these conditions gave the
spirocyclic lactones 13 and 16, respectively, by in situ
lactonization (entries i and ii). It should be noted that the
problems with hydrolyzing the ketone adducts such as 20
and 22 were overcome by double oxidation of the deprotected
benzaldehyde adduct 18, thus allowing the synthesis of
γ-keto-R-amino acid 19 (entry iii).12
conditions9 were employed to convert L-serine 7 via alcohol
8 into chloroalkane 9. Protection of alcohol 9 was undertaken
using a number of different groups giving the key lithiation
precursors 10a-d.
We were now in a position to investigate the generation
of organolithium reagents 11 (Scheme 1). It was obviously
crucial to generate a dianionic species to minimize the
possibility of â-elimination. We therefore employed the
butyllithium-lithium naphthalenide (LiNp) combination
developed by Yus et al. for chloroamide lithiation.10 This
protocol was employed with the unprotected alcohol 9 and
with the protected derivatives 10a-d, and the reaction
mixture was then quenched with cyclohexanone with the aim
of evaluating the procedure in terms of the yield of adducts
12a-e (Table 1).
(7) Runcie, K. A.; Taylor, R. J. K. Org. Lett. 2001, 3, 3237-3239.
McKillop, A.; McLaren, L.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. J.
Chem. Soc., Perkin Trans. 1 1996, 1385-1393.
(8) Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor,
R. J. K. J. Org. Chem. 2002, 67, 1802-1815. Collier, P. N.; Campbell, A.
D.; Patel, I.; Taylor, R. J. K. Tetrahedron 2002, 58, 6117-6125 and
references therein.
(9) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. Synthesis
1994, 31-33.
(10) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1996, 7, 2911-
2922. Review of functionalized organolithium reagents: Na´jera, C.; Yus,
M. Curr. Org. Chem. 2003, 7, 867-926.
(11) Yoda, H.; Nakagami, Y.; Takabe, K. Tetrahedron Lett. 1994, 35,
169-172.
(12) Jackson, R. F. W.; Turner, D.; Block, M. H. J. Chem. Soc., Perkin
Trans. 1 1997, 865-870.
20
Org. Lett., Vol. 6, No. 1, 2004