A general method for the highly diastereoselective, kinetically controlled alkylation of ( )-nopinone

Article abstract of DOI:10.1016/S0040-4039(02)01589-7

A general method for the monoalkylation of (+)-nopinone was developed for a variety of carbon and heteroatom electrophiles to afford the kinetically controlled product 2 with high diastereoselectivity (98% d.e.) and excellent yield (75-90%).

Full text of DOI:10.1016/S0040-4039(02)01589-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6957–6959
A general method for the highly diastereoselective, kinetically
controlled alkylation of (+)-nopinone
Kevin R. Campos,* Sandra Lee, Michel Journet, Jason J. Kowal, Dongwei Cai, Robert D. Larsen
and Paul J. Reider
Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 22 July 2002; accepted 31 July 2002
Abstract—A general method for the monoalkylation of (+)-nopinone was developed for a variety of carbon and heteroatom
electrophiles to afford the kinetically controlled product 2 with high diastereoselectivity (98% d.e.) and excellent yield (75–90%).
© 2002 Published by Elsevier Science Ltd.
Although (+)-nopinone 11 is readily available from
b-pinene, its use as a chiral scaffold in natural products
synthesis is limited. This may be due in part because the
monoalkylation of the enolate of (+)-nopinone with
alkyl halides affords a mixture of diastereomers 2 and
3, usually favoring the thermodynamically preferred
product 3 (Scheme 1).2 In contrast, alkylation of the
subsequent mixture of diastereomers with a different
electrophile affords the dialkylated product 4 as a single
diastereomer. Products such as 4 have been applied to
several natural products syntheses;3 however, due to the
lack of a general diastereoselective method to access 2,
the 3-monosubstituted nopinones have remained
unused. We herein wish to report a highly diastereose-
lective monoalkylation of (+)-nopinone with a variety
of carbon and heteroatom electrophiles to afford the
kinetically preferred product 2 with no epimerization to
its thermodynamically favored counterpart 3.
Our initial efforts were focused on the alkylation of the
enolate of (+)-nopinone, generated from lithium diiso-
propylamide (LDA), with propargyl bromide 5a. We
quickly discovered that the temperature of the reaction
had a dramatic effect on the yield and selectivity of the
alkylation (Table 1). At higher temperatures, the yields
were respectable, but the diastereoselectivity was poor
(72:28), favoring the kinetically preferred product 2a.4
Conversely, as the temperature was decreased,
diastereomeric ratios as high as 99:1 favoring 2a were
observed, but the yields dropped to as low as 15%.
These results indicate a highly diastereoselective, kineti-
cally controlled alkylation to afford 2a at low tempera-
ture, which is competitive with epimerization to the
Table 1. Nopinone alkylation: dependence of diastereose-
lectivity and yield on temperaturea
Temperature (°C)
Conversion (%)b
2a:3ac
0
−25
−35
−45
−55
85
68
50
30
15
72:28
90:10
96:4
99:1
99:1
Scheme 1.
a All reactions were carried out in THF (1.2 M in substrate) using
1.05 equiv. LDA and 1.05 equiv. 5a.
b Conversion was determined 1.5 h after addition of 5a (HPLC).
c Diastereoselectivity was determined by HPLC.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01589-7

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K. R. Campos et al. / Tetrahedron Letters 43 (2002) 6957–6959
Having demonstrated the highly diastereoselective alkyl-
ation of the enolate of (+)-nopinone with a variety of
carbon electrophiles, we sought to apply this method to
some heteroatom electrophiles. Sulfenylation of the
enolate of (+)-nopinone at −78°C afforded good
diastereoselectivity (96:4, 2k:3k) and good yield (80%)
of the kinetically preferred diastereomer 2k (Table 3).7
The bromination of the lithium enolate of (+)-nopinone
with N-bromosuccinimide (NBS) was quite unselective,
even at −78°C (42% yield, 75:25, 2l:3l). In contrast, the
bromination of the enolsilane of (+)-nopinone with
NBS afforded the kinetically favored diastereomer 2l in
excellent yield and high diastereoselectivity (98:2, 2l:3l
at −78°C).8 In fact, the diastereoselectivity was still high
when run at room temperature (94:6, 2l:3l).
thermodynamically favored product 3a at higher tem-
peratures. In order to access 2a in good yield, the
reactivity of the enolate or the electrophile must be
increased such that the alkylation would occur at
−45°C. When the alkylation with 5a was performed
with 1 equivalent of 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone (DMPU) at −45°C, a high yield
and high diastereoselectivity were observed (90% yield,
99:1 2a:3a).5 Alternatively, when the more reactive
propargyl iodide 5b (Table 2) was used in the alkylation
in the absence of DMPU, a similarly high yield and
diastereoselectivity were observed (90% yield, 99:1
2a:3a). In every case, the reaction was quenched at low
temperature (see general procedure) in order to avoid
epimerization to the thermodynamically favored
product.6
The high diastereoselectivity of the bromination of the
enolsilane of (+)-nopinone at elevated temperatures
encouraged us to investigate the oxidation of the silyl
enol ether of (+)-nopinone, a reaction that is typically
run at 0°C.9 Following the literature procedure
(mCPBA/NaHCO3), the oxidation afforded clean con-
version to hydroxyketone 2m with high diastereoselec-
tivity (98:2, 2m:3m) and good yield (60%).10 This
method was also applied to the azidation of the enolsi-
lane of (+)-nopinone via the oxidative addition of azide
anion using ceric ammonium nitrate.11 Treatment of the
TIPS enol ether of (+)-nopinone under azidation condi-
tions published in the literature afforded the a-azidoke-
tone 2n with high diastereoselectivity (97:3, 2n:3n) and
good yield (73%).
With optimized reaction conditions in hand, a variety
of carbon electrophiles were investigated to demon-
strate scope and practicality (Table 2). Many of the
electrophiles investigated displayed similar yields and
selectivities to that of the original propargyl halide
system; however, more reactive electrophiles 5e,f
required lower reaction temperatures to afford high
diastereoselectivities. Less reactive electrophiles such as
5g–i afforded good diastereoselectivities but only mod-
erate yields (30%) of the alkylated adducts even with
DMPU as an additive. In order to obtain good yields
for these substrates, it was necessary to premix the
electrophile with NaI in DMPU/THF to generate the
iodide in situ.
In conclusion, a general procedure for the highly
diastereoselective alkylation of the enolate of (+)-
nopinone has been developed to afford the kinetically
Table 2. Diastereoselective nopinone alkylation with car-
bon electrophilesa
Table 3. Diastereoselective nopinone sulfenylation, bromi-
nation, hydroxylation, and azidation
El+
R
Yield (%)e El
2:3f
p-TolSSO2p-Tol
Lia
80 Sp-Tol 96:4 (2k:3k)
NBS
TMSb 80
Br
98:2 (2l:3l)
mCPBA/NaHCO3 TMSc 60
OH
N3
98:2 (2m:3m)
97:3 (2n:3n)
NaN3/CAN
TIPSd 73
a Reaction was carried out in THF (1.2 M in substrate) using 1.05
equiv. LDA and 1.05 equiv. thiosulfonate at −78°C for 1.5 h.
b Trimethylsilyl enol ether was formed in situ (1.05 equiv. LDA, 1.05
equiv. TMSCl) before addition to a THF solution of the heteroatom
electrophile (1.05 equiv., 1.25 M) at −78°C.
c Trimethylsilyl enol ether was isolated prior to addition to a solution
of mCPBA (1.05 equiv.) and NaHCO3 (4.4 equiv.) in CH2Cl2 at
0°C.
d Triisopropylsilyl enol ether was isolated prior to mixing with NaN3
(4.5 equiv.) in MeCN followed by addition of CAN (3 equiv., 0.4 M
in MeCN) at −20°C.
e Assay yield was determined by HPLC.
f Diastereoselectivity was determined by GC.

K. R. Campos et al. / Tetrahedron Letters 43 (2002) 6957–6959
6959
controlled product. This versatile method affords no
epimerization to the thermodynamically favored
product, is applicable to wide range of carbon and
heteroatom electrophiles, and provides access to an
underutilized natural product scaffold containing
diverse functionality.
of 2 (R=Me). See: Konopelski, J. P.; Djerassi, C. J. Org.
Chem. 1980, 45, 2297–2301.
3. (a) Kato, M.; Watanabe, M.; Vogler, B.; Tooyama, Y.;
Yoshikoshi, A. J. Chem. Soc., Chem. Commun. 1990,
1706–1707; (b) Inokuchi, T.; Asanuma, G.; Torii, S. J.
Org. Chem. 1982, 47, 4622–4626; (c) Yanami, T.;
Miyashita, M.; Yoshikoshi, A. J. Org. Chem. 1980, 45,
607–612; (d) Van Der Gen, A.; Van Der Linde, L. M.;
Witteveen, J. G.; Boelens, H. Recl. Trav. Chim. Pay-Bas.
1971, 90, 1034–1044.
General experimental procedure: To a solution of diiso-
propylamine (0.8 M in THF; 10 mL, 8 mmol) was
added n-BuLi (2.41 M in hexane; 3.2 mL, 7.7 mmol) at
−10°C under N2 with stirring. The LDA solution was
aged for 15 min before (+)-nopinone (1.0 mL, 7.24
mmol) was added dropwise with the temperature main-
tained between −10 and −15°C. After 10 min, the
mixture was cooled to −50°C and DMPU (0.88 mL,
7.24 mmol) was added to the solution. The appropriate
electrophile (7.7 mmol) was then added dropwise with
the temperature strictly maintained between −47 and
−45°C and stirred for 1.5 h after the addition was
complete. Trifluoroacetic acid (0.86 mL, 10.9 mmol)
was then added while keeping the reaction temperature
lower than −45°C. Upon complete addition of TFA,
the solution was allowed to warm up to −10°C after
4. Diastereomer 2a (stereochemistry determined by 1H
NMR) was treated under thermodynamic equilibration
with NaOEt in EtOH to yield 3a (stereochemistry confi-
rmed by 1H NMR) as the major product. The
diastereomeric ratio of 2a:3a was determined to be 15:85
by HPLC.
5. Other additives (HMPA, TMEDA) were also investigated
but none were as effective as DMPU. Alkylation is
complete within 1.5 h at −45°C. Lower temperatures
afforded sluggish reactions.
6. When the reaction was quenched by direct addition of
aqueous acid, some epimerization to the thermodynami-
cally favored product was always observed. In contrast,
the reaction can be quenched by direct addition of tri-
fluoroacetic acid (TFA) to the reaction solution at −45°C
or by reverse quench of the reaction solution at −45°C
into a 1:1 mixture of MTBE:satd NH4Cl (aq) with no
epimerization.
7. Goodridge, R. J.; Hambley, T. W.; Haynes, R. K.;
Ridley, D. D. J. Org. Chem. 1988, 53, 2881–2889.
8. The bromination of (+)-nopinone has been reported
albeit in lower yield and unreported diastereoselectivity.
See: Grimshaw, J.; Grimshaw, J. T.; Juneja, H. R. J.
Chem. Soc., Perkin Trans. 1 1972, 50–52 and references
cited therein.
which the mixture was partitioned between 3%
L-tar-
taric acid solution (20 mL) and EtOAc (20 mL). The
layers were separated and the organic layer was evapo-
rated under reduced pressure to yield the crude product
in 80–90% assay yield and purified by flash chromatog-
raphy using silica and AcOEt/Hex or MTBE/Hex as
the eluent.
Acknowledgements
9. Jauch, J. Tetrahedron 1994, 50, 12903–12912 and refer-
ences cited therein.
The authors gratefully acknowledge Robert B. Reamer
and Lisa DiMichele for their assistance in the stereo-
chemical assignment of 2 and 3 by H NMR.
1
10. The main impurity was unreacted starting material. The
actual product of the oxidation is the TMS-protected
hydroxyketone, which is deprotected with Na2CO3. If the
deprotection was allowed to stir for prolonged periods of
time, isomerization from 2m to 6 was observed.
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