Alkylation of chiral α-hydroxy ketones derived from (1R)-(+)-camphor. An asymmetric variant of the classical acetylene route to carbonyl compounds

Article abstract of DOI:10.1021/ol0163530

Equation presented The asymmetric version of the traditional route for transforming acetylene into α-branched carbonyl compounds is now feasible for the first time. The method involves the temporary attachment of camphor to acetylene and gives a remarkably high diastereo-and enantioselectivity.

Full text of DOI:10.1021/ol0163530

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3249-3252
Alkylation of Chiral r-Hydroxy Ketones
Derived from (1R)-(+)-Camphor. An
Asymmetric Variant of the Classical
Acetylene Route to Carbonyl
Compounds
,†
Claudio Palomo,* Mikel Oiarbide,† Antonia Mielgo,† Alberto Gonza´lez,‡
Jesu´s M. Garc´ıa,‡ Cristina Landa,‡ Ainara Lecumberri,‡ and Anthony Linden§
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, UniVersidad del Pa´ıs
Vasco, Apdo. 1072, 20080-San Sebastia´n, Spain, Departamento de Qu´ımica Aplicada,
UniVersidad Pu´blica de NaVarra, Campus de Arrosad´ıa, 31006-Pamplona, Spain,
and Organisch-Chemisches Institut der UniVersita¨t Zu¨rich, Winterthurerstrasse-190,
CH-8057, Zu¨rich, Switzerland
qoppanic@sc.ehu.es
Received June 26, 2001
ABSTRACT
The asymmetric version of the traditional route for transforming acetylene into r-branched carbonyl compounds is now feasible for the first
time. The method involves the temporary attachment of camphor to acetylene and gives a remarkably high diastereo- and enantioselectivity.
Over the past 30 years, asymmetric alkylation of enolates
has become one of the most popular methods for the
construction of carbon-carbon bonds.1 During this time
remarkable advances have been made in the development
of efficient processes that mainly rely upon the use of chiral
auxiliaries.2 A common feature of these processes is the use
as the starting material of a carboxylic acid to which the
chiral auxiliary is covalently bonded through the acyl
moiety.3 As a consequence, the problems of chemo- and
regioselectivity during enolate formation and alkylation are
not applicable. The hydration of terminal alkynes followed
by sequential alkylation of the resulting ketones is, on the
† Universidad del Pa´ıs Vasco.
‡ Universidad Pu´blica de Navarra.
§ Organisch-Chemisches Institut der Universita¨t Zu¨rich.
(1) (a) StereoselectiVe Synthesis (Houben-Weyl), E21 Vol. 2; Helmchen,
G., Hoffmann, R. W., Mulzer J., Shaumann, E., Eds.; Georg Thieme:
Stuttgart, New York, 1996. (b) Fey, P.; Hartwig, W. In ref 1a, pp 969-
972. (c) Enders, D. In Asymmetric Synthesis, Vol. 3B; Morrison, J. D., Ed.;
Academic Press: Orlando, 1984; p.275. (d) Enders, D.; Kipphardt, H.; Fey,
P. Organic Syntheses; Wiley: New York, 1993; Collect. Vol. VIII, pp 403-
414. (e) Enders, D.; Klatt, M. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; p 178. (f) Fey, P.
In ref 1a, pp 973-1015. For enantioselective enolate alkylations, see: (g)
O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439-1457. (h) Hughes,
D. L. In ComprehensiVe Asymmetric Catalysis III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Heidelberg, 1999; pp
1273-1294.
(2) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; John Wiley: New York, 1995; pp 166-187.
(3) For reviews, see: (a) Ru¨ck, K. Angew. Chem., Int. Ed. Engl. 1995,
34, 433-435. (b) Franklin, A. S. J. Chem. Soc., Perkin Trans. 1 1998,
2451-2465. (c) Regan, A. C. J. Chem. Soc., Perkin Trans. 1 1998, 1151-
1166. (d) Regan, A. C. J. Chem. Soc., Perkin Trans. 1 1999, 357-373. (e)
Fey, P. In ref 1a, pp 1016-1029. For a recent practical example, see: (f)
Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
10.1021/ol0163530 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/27/2001

other hand, the classical and most direct route for the
transformation of acetylene into R-branched carbonyl com-
pounds. The important advantages of this route are the
accessibility of the raw materials needed during the process
(only a diversity of alkyl halides would be required for
generality) and the minimum number of synthetic steps
required to convert commercially available chemicals into
somewhat complex small molecules on a large scale.
However, although acetylene is one of the least expensive
carbon sources, with a worldwide production exceeding
300 000 tons/year,4 this procedure is inherently nonselective
and therefore of limited practical use. Here we present the
first asymmetric variant of this process that demonstrates
how acetylene and alkyl halides can be transformed into
R-branched carbonyl compounds in a chemo-, regio-, and
stereoselective way.5
and facilitates the optional selective introduction of a third
alkyl group (R2). At the end, camphor is regenerated for
reuse, with concomi-tant liberation of the target R-branched
carboxylic acid and/or ketone.
To put this design into practice, we succeeded in carrying
out the alkylation of 2 under the conditions shown in Scheme
1. Namely, when the lithium enolate of 2 is treated with
Scheme 1. Monoalkylation of Ketone 2 and Methylation of
Ketones 4-7a
The synthetic concept of the approach is outlined in Figure
1 and arises from our earlier reports concerning the use of
a (a) Reference 6. (b) For reactive alkyl iodides: LDA (1.3 equiv),
THF, -78 °C, 2 h then R-I (1.3 equiv), -30 °C, 1.5 h. For less
reactive aliphatic iodides: LDA (1.3 equiv), THF, -78 °C, 2 h
then DMPU (20%), R-I (5-6 equiv), -50 °C, 4 h. (c) LDA (1.5-
2.0 equiv), THF, DMPU (20%), -50 °C, 4 h, MeI (1.5 equiv),
-30 °C, 1 h. (d) TBAF, THF, rt, 30 min. Yields in parentheses
refer to isolated pure compounds. Purity determined by GC analysis
and/or analytical HPLC.
Figure 1. Acetylene and alkyl halides as raw materials for the
preparation of carbonyls with an R-stereogenic center. Criteria for
working hypothesis: (a) exclusive formation of Z-enolates I; (b)
pronounced enolate diastereofacial bias; (c) clean release of the
auxiliary from II.
reactive alkyl halides, such as methyl iodide, allyl iodide,
and benzyl iodide, the reaction proceeds cleanly in THF as
solvent to give ketones 3, 4, and 5 in 90%, 81%, and 80%
isolated yields, respectively, as the exclusive products
formed. On the other hand, when primary aliphatic iodides,
such as ethyl iodide, propyl iodide, and hexyl iodide were
used, the reaction proceeded in the presence of DMPU (20
mol %) to give the monoalkylated products 6, 7, and 8 in
83%, 93%, and 73% isolated yields. Remarkably, overalky-
lation did not occur in any reaction.8 In line with the observed
diastereoface differentiation property of the lithium enolate
of 2 in aldol and Mannich reactions, it was found that the
alkylation of the alkaline metal enolates of this family of
ketones occurs with remarkable diastereoselectivity. For
example, the sterically undemanding methylations, which are
(1R)-(+)-camphor and acetylene in the “acetate” aldol6 and
Mannich reactions.7 In our design, acetylene is the elementary
source of acetyl that ends up incorporated into the final
products. During the alkylation process, (1R)-(+)-camphor,
in its turn, directs the chemo-, regio-, and diastereoselective
incorporation of the two alkyl units in a stepwise fashion
(4) For industrial applications of acetylene, see: (a) Weissermel, K.; Arpe,
H.-J. Industrial Organic Chemistry; VCH: Weinheim, 1997; pp 91-104.
(b) Szmant, H. H. Organic Building Blocks of the Chemical Industry; John
Wiley: New York, 1989; pp 188-264.
(5) For a recent innovative approach to transform alkynes into carbonyls
with an R stereogenic center, see: (a) Spino, C.; Beaulieu, C. J. Am. Chem.
Soc. 1998, 120, 11832-11833. (b) Spino, C.; Beaulieu, C.; Lafreniere, J.
J. Org. Chem. 2000, 65, 7091-7097.
(8) A small amount (2%-4%) of the starting unreacted methyl ketone 2
was isolated in some instances.
(6) (a) Palomo, C.; Gonza´lez, A.; Garc´ıa, J. M.; Landa, C.; Oiarbide,
M.; Rodr´ıguez, S.; Linden, A. Angew. Chem., Int. Ed. Engl. 1998, 37, 180-
182. (b) Palomo, C.; Oiarbide, M.; Aizpurua, J. M.; Gonza´lez, A.; Garc´ıa,
J. M.; Landa, C.; Odriozola, I.; Linden, A. J. Org. Chem. 1999, 64, 8193-
8200.
(7) Palomo, C.; Oiarbide, M.; Gonza´lez-Rego, M. C.; Sharma, A. K.;
Garc´ıa, J. M.; Gonza´lez, A.; Landa, C.; Linden, A. Angew. Chem., Int. Ed.
2000, 39, 1063-1065.
(9) For the problem of stereocontrol in enolate methylations, see, for
instance: (a) Evans, D. A.; Chapman, K. T.; Hung, D. T.; Kawaguchi, A.
T. Angew. Chem., Int. Ed. Engl. 1987, 26, 1184-1186. (b) Palomo, C.;
Berre´e, F.; Linden. A.; Villalgordo, J. M. J. Chem. Soc., Chem. Commun.
1994, 1861-1862. (c) Boyd, V. A.; Perales, J. B.; Negrete, G. R.
Tetrahedron Lett. 1997, 38, 6631-6634. (d) Abdel-Aziz, A. A.-M.; Okuno,
J.; Tanaka, S.; Ishizuka, T.; Matsunaga, H.; Kunieda, T. Tetrahedron Lett.
2000, 41, 8533-8537.
3250
Org. Lett., Vol. 3, No. 21, 2001

often difficult to control,9 proceeded with extremely high
efficiency. Thus, ketones 4-7 upon exposure to LDA in the
presence of DMPU (20 mol %) and subsequent treatment
with methyl iodide provided, after desilylation of the resulting
intermediates, compounds 9-12 in yields of 80-85% and
diastereomeric ratios of up to g98:2.
On the other hand, the alkylation reactions with other alkyl
halides were best accomplished by using the sterically less
demanding R′-hydroxy ketones 13-18, Scheme 2. In these
Table 1. Asymmetric Alkylation of Camphor-Based Ketone
Enolatesa
ketones
R
R1-X
productb yield, %c
4
5
6
7
13
CH2dCHCH2 MeI
9
10
11
12
81
85
78
80
92
80
87
85d
87d
75
85
84
70
84
85
80
86
74
PhCH2
CH3CH2
MeI
MeI
CH3CH2CH2 MeI
CH3
CH2dCHCH2Br
PhCH2Br
19a
19b
19c
19d
19e
19f
20b
21a
21g
21h
22i
23b
23d
24a
CH2dCMeCH2Br
CH3CH2I
CH3CH2CH2I
CH3(CH2)2CH2I
Scheme 2. Asymmetric Alkylations of Ketones 13-18a
14
15
CH2dCHCH2 PhCH2Br
PhCH2
CH2dCHCH2Br
CH3(CH2)4CH2I
2-Naphth-CH2Br
CHCCH2Br
16
17
CH3CH2
CH3CH2CH2 PhCH2Br
CH3CH2I
18
n-hexyl
CH2dCHCH2Br
a All reactions were carried out on a 1-2 mmol scale. For details, see
ref 10 and Supporting Information. b In all cases, dr g 98:2 as determined
by GC using a J&W DB-5 column, unless otherwise mentioned. The validity
of this assay is provided by comparison of the chromatograms of 10/19b,
11/19d, and 12/19e. Diastereomers 9/19a were hydrogenated to the
corresponding 12/19e for dr determinations. c All yields refer to isolated
pure products after column chromatography. d Traces (∼2%) of O-alkylation
at the tertiary hydroxyl group was detected by GC analysis of the reaction
mixture.
a (a) TBAF, THF, rt, 30-60 min. (b) For reactive alkyl halides:
KHMDS (0.5 M in toluene, 2.3-2.5 equiv), THF, -78 °C, 4 h
then R1-Br (2 equiv), THF, -78 f -50 °C, 0.5-1.5 h. For less
reactive aliphatic halides: KHMDS (0.5 M in toluene, 2.3-2.5
equiv), DMF, -78 °C, 4 h then R1-I (3 equiv), -78 °C, 2 h.
Table 1.10 In every case, good to excellent yields are attained,
and in each case, essentially only one diastereomer is
produced. It is also worth noting that, with few exceptions,
all of ketone compounds are crystalline, and analytically pure
solids of g99% de can therefore be isolated by direct
crystallization from the crude reaction mixture.
The elucidation of the configuration of the products was
achieved by cleavage of the acyloin moiety to afford the
corresponding carboxylic acids, along with the recovery of
the starting camphor. For example, treatment of 10, 19b, and
19d, Scheme 3, with cerium ammonium nitrate afforded
carboxylic acids 25, 26, and 27, respectively, in 90%, 95%,
and 90% isolated yields, and in each case the starting
camphor was recovered with yields in the range 85-90%.11
The observed optical rotations of these R-branched carboxylic
acids were then compared with published values.12 In
addition, a single-crystal X-ray structure analysis of the
alkylated products 19b and 19c further corroborated the
assigned configuration of the products.13
instances, the use of potassium as the counterion for enolates
was another requirement for optimum results. In this respect,
the alkylation of ketones 13-18 with reactive alkyl halides
proceeded efficiently in THF as solvent, while for less
reactive primary aliphatic halides DMF gave superior results,
(10) Alkylation of ketones 13-18 (for reactive alkyl halides): Potas-
sium bis(trimethylsilyl)amide (0.5 M in toluene, 4.6 mL, 2.3 mmol) was
added dropwise to a solution of the starting ketone (1.0 mmol) in dry THF
(4.0 mL) at -78 °C under a nitrogen atmosphere, and the mixture was
stirred for 4 h at the same temperature. The corresponding bromide (2.0
mmol) was added, and the reaction was allowed to reach -50 °C and was
stirred at this temperature until completion (0.5-1.5 h). The reaction was
quenched at -50 °C with 5 mL of saturated aqueous NH4Cl, and the mixture
was allowed to warm to room temperature. The layers were separated, and
the aqueous phase was extracted with CH2Cl2 (2 × 15 mL). The combined
organics were dried over MgSO4, and the solvent was removed under
reduced pressure. The alkylated compounds were obtained as white solids
or oils, and diastereomeric ratios were determined by gas chromatography
at this stage. Purification of the products was effected by flash column
chromatography (eluant: ethyl acetate/hexane 1:30). For less reactive
aliphatic alkyl halides: A solution of the starting ketone (1.0 mmol) in
dry DMF (3.0 mL) was added dropwise over a solution of potassium bis-
(trimethylsilyl)amide (0.5 M in toluene, 5.0 mL, 2.5 mmol) in dry DMF
(3.0 mL) at -78 °C, and the mixture was stirred for 4 h at the same
temperature. The corresponding iodide (3.0 mmol) was added, and the
mixture was stirred for 2 h at this temperature. The reaction was quenched
with 5 mL of saturated aqueous NH4Cl, and the mixture was allowed to
warm to room temperature. The layers were separated, and the aqueous
phase was extracted twice with Et2O (15 mL). The combined organic
extracts were washed with water (10 mL) and dried over MgSO4, and the
solvent was removed under reduced pressure. The alkylated products were
obtained as white solids or oils. Diatereomeric ratios were determined by
gas chromatography. Purification was effected by silica gel flash column
chromatography (eluant: ethyl acetate/hexane 1:30).
The excellent diastereoselectivity attained with these
camphor-based alkyl ketones is also of particular interest in
that the reaction provides, through carbonyl addition and
(11) (1R)-(+)-Camphor: Aldrich [R]25 ) +42.2 (c ) 1.0 in EtOH).
Recovered material, [R]25 ) +41.5 (c )D1.0 in EtOH).
D
(12) Observed values: 25 +29.0 (c ) 1.0 in CHCl3) [published value
+30.4 (c ) 1.0 in CHCl3), see: Davies, S. G.; Sanganee, H. J.
Tetrahedron: Asymmetry 1995, 6, 671-674]; 26 -29.5 (c ) 1.1 in CHCl3)
[published value -25.1 (neat), see: Evans, D. A.; Ennis, M. D.; Mathre,
D. J. J. Am. Chem. Soc. 1982, 104, 1737-1739]; 27 -16.0 (c ) 1.0 in
CH2Cl2) [published value for the (S)-isomer +19 (neat) [Aldrich catalog]].
Org. Lett., Vol. 3, No. 21, 2001
3251

ketones.15,16 Importantly, simply by changing the alkylation
sequence of the process, access to either one of the
enantiomeric forms of the final carbonyl compound (i.e. 25/
26, 28/29) would be possible by starting from just a single
chiral unit, the methyl ketone 2. Therefore, a wide variety
of R-branched carbonyl compounds with the desired R-con-
figuration can easily be prepared from acetylene and alkyl
halides, which are the only organic raw materials that are
consumed during the reaction.
Scheme 3. Enantioselective Synthesis of R-Branched
Carboxylic Acids and Ketonesa
Acknowledgment. This work was finantially supported
by Universidad del Pa´ıs Vasco, Gobierno Vasco, and by
MEC (PB 98-0549). Grants to A.S. and M.C.G. from
Gobierno Vasco, to C.L. from MEC, and to A. Lecumberri
from UPNA are acknowledged.
a (a) (NH4)2Ce(NO3)6 (3 equiv), CH3CN/H2O, 0 °C, 1 h. (b) RLi
(3 equiv), THF, -78 f 0 °C, 1 h.
Supporting Information Available: Experimental pro-
cedures for alkylation reactions, desilylation, and cleavage
to carboxylic acids and ketones; characterization data for
compounds 3, 10, 13, 19b, 19d, 23b; ORTEP diagrams of
subsequent diol cleavage, access to R-branched alkyl
ketones.1e,14 Under optimized conditions (-78 f 0 °C), the
reaction proceeds with 3 equiv of the respective alkyllithium
within about 1 h to give, after diol cleavage, ketones 28, 29,
and 30 in good yields and essentially without racemization
of the R-stereocenter. This transformation formally represents
a perfectly regiocontrolled alkylation of nearly symmetrical
1
19b and 19c; and representative H, 13C, and MS spectra
and GC and HPLC chromatograms of compounds 26, 27,
28, 29, and 30. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0163530
(13) Crystallographic data (excluding structure factors) for the structures
19b and 19c reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as suplemmentary publication numbers CCDC-
161732 and 161733, respectively. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax (+44) 1223 336-033; e-mail deposit@ccdc.cam.ac.uk).
(14) For a recent example, see: Oppolzer, W.; Darcel, C.; Rochet, P.;
Rosset, S.; deBrabander, J. HelV. Chim. Acta 1997, 80, 1319-1337.
(15) For the problems associated with the alkylation of open-chain
ketones, see: ref 2, p 168.
(16) The enantiomeric purity of carboxylic acids 25, 26, and 27 was
determined by HPLC analyses of their methyl esters using a ChiralCel OB-H
column and hexanes as the eluant (flow 0.5 mL/min). The same method
was applied for the determination of the enantiomeric purity of ketones 28,
29, and 30, and it was confirmed by comparison of the chromatograms
with those corresponding to racemic products.
3252
Org. Lett., Vol. 3, No. 21, 2001