Directed diastereoselectivity in the asymmetric Claisen/metathesis reaction sequence

Article abstract of DOI:10.1021/jo800496h

(Chemical Equation Presented) The Claisen/metathesis sequence is a versatile synthetic tool for the synthesis of quaternary hydroxy and amino acid carbocycles. By correctly choosing both the configuration of the allylic alcohol and the double bond geometry, specific access to any one of four possible stereoisomers is possible in good yield and excellent diastereoselectivity. The enantiomerically pure allylic alcohols are easily obtained by addition of terminal alkynes to aldehydes. Controlled reduction of the triple bond then gives the desired double bond geometry.

Full text of DOI:10.1021/jo800496h

including both carbo- and heterocycles in fair to good diaste-
reoselectivities.2 Burke et al. reported the synthesis of substituted
dihydropyran-2-carboxylates starting from several enantiopure
allylic alcohols and obtained selectivities of up to >20/1 for
the rearrangement step.3 Since then, several other groups have
described examples in which the reaction sequence is performed
with nonchiral substrates.4
In their total synthesis of Pancratistatin, Kim et al. used an
enantiopure substrate in an Ireland-Claisen/metathesis sequence
with only moderate diastereoselectivity (6/1) in the rearrange-
ment step.5 More recently, in the synthesis of (-)-Perrottetinene,
the key cis-disubstituted cyclohexene ring was obtained by a
highly diastereoselective (>20/1) Ireland-Claisen/metathesis
sequence.6 The absolute stereochemistry was derived from the
starting chiral γ-hydroxy vinylstannane building block.
It was recently shown that the asymmetric Ireland-Claisen/
metathesis sequence can be used to synthesize various cyclic
quaternary R-alkoxyacids/esters with excellent diastereoselec-
tivities from enantiomerically pure allylic alcohols and unsatur-
ated R-alkoxy acids (Scheme 1).7
Directed Diastereoselectivity in the Asymmetric
Claisen/Metathesis Reaction Sequence
Nicolas P. Probst, Arnaud Haudrechy, and Karen Ple´*
UniVersite´ de Reims, Institut de Chimie Mole´culaire de
Reims, CNRS 6229, IFR 53 Biomole´cules, UFR Sciences,
Baˆt 18, B.P. 1039, 51687 Reims Cedex 2, France
karen.ple@uniV-reims.fr
ReceiVed March 3, 2008
SCHEME 1. The Ireland-Claisen/Metathesis Sequence
The Claisen/metathesis sequence is a versatile synthetic tool
for the synthesis of quaternary hydroxy and amino acid
carbocycles. By correctly choosing both the configuration
of the allylic alcohol and the double bond geometry, specific
access to any one of four possible stereoisomers is possible
in good yield and excellent diastereoselectivity. The enan-
tiomerically pure allylic alcohols are easily obtained by
addition of terminal alkynes to aldehydes. Controlled reduc-
tion of the triple bond then gives the desired double bond
geometry.
This asymmetric sequence has been successfully used in both
the formal total synthesis of fumagillin8 and that of a spirotetr-
onate subunit of the quartromicins.9
While the Ireland-Claisen rearrangement is technically
limited to silyl ketene acetal intermediates, many variations have
been reported. For example, with allylic esters having R-het-
eroatoms, an enolate Claisen rearrangement is evoked, in the
presence or absence of trimethylsilyl chloride.10 The rearrange-
ment usually proceeds via a highly ordered six-member chairlike
transition state. The R-heteroatom stabilizes the enolate through
Since its introduction in 1972, the Ireland-Claisen rearrange-
ment has proven to be an invaluable tool for the stereoselective
formation of carbon-carbon bonds.1 This rearrangement has
been widely used in natural product synthesis, and has also been
shown to be extremely useful in the formation of quaternary
stereogenic centers. When esters are prepared from chiral allylic
alcohols and carboxylic acids, an efficient chirality transfer
occurs from the carbinol center to the newly formed stereo-
center(s) at C2 and/or C3 of the acid product.
When the Claisen rearrangement is associated with ring
closing metathesis, a powerful tandem reaction sequence can
be generated in which access to a large number of asymmetric
unsaturated carbocycles is possible, depending on the starting
substrate. In 1998, two groups simultaneously described this
sequence. Piscopio et al. reported the approach with nonchiral
substrates for the synthesis of a variety of cyclic systems,
(3) Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J. J. Org. Chem.
1998, 63, 3160–3161.
(4) (a) Srikrishna, A.; Khan, I. A.; Babu, R. R.; Sajjanshetty, A. Tetrahedron
2007, 63, 12616–12620. (b) Srikrishna, A.; Babu, R. R. Tetrahedron Lett. 2007,
48, 6916–6919. (c) Srikrishna, A.; Lakshmi, B. V.; Mathews, M. Tetrahedron
Lett. 2006, 47, 2103–2106. (d) Srikrishna, A.; Lakshmi, B. V. Tetrahedron Lett.
2005, 46, 7029–7031. (e) Srikrishna, A.; Lakshmi, B. V. Tetrahedron Lett. 2005,
46, 4879–4881. (f) Srikrishna, A.; Lakshmi, B. V. Synlett 2005, 1173–1175. (g)
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46, 3465–3468. (h) Beaulieu, P.; Ogilvie, W. W. Tetrahedron Lett. 2003, 44,
8883–8885. (i) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh, S. P. D.;
Braddock, D. C.; Procopiou, P. A.; White, A. J. P.; Williams, D. J. J. Org.
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(1) (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897–
5898. (b) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976,
98, 2868–2877. (c) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III J. Org. Chem.
1991, 56, 650–657. (d) Ireland, R. E.; Wipf, P.; Xiang, J. N. J. Org. Chem.
1991, 56, 3572–3582. (e) McFarland, C. M.; McIntosh, M. C. In The Claisen
Rearrangement; Hiersemann, M., Nubbemeyer, U., Eds.; Wiley-VCH Verlag
GmbH & Co. KgaA: Weinheim, Germany, 2007; pp 177-210.
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(7) Franc¸ais, A.; Bedel, O.; Picoul, W.; Meddour, A.; Courtieu, J.; Haudrechy,
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(8) (a) Picoul, W.; Urchegui, R.; Haudrechy, A.; Langlois, Y. Tetrahedron
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4338 J. Org. Chem. 2008, 73, 4338–4341
10.1021/jo800496h CCC: $40.75 2008 American Chemical Society
Published on Web 05/08/2008

a five-member chelate ring, and (Z)-enolates are almost exclu-
sively obtained (Scheme 2). The relative stereochemistry of the
newly formed centers can then be controlled by simply changing
the olefin geometry of the starting allylic alcohol.
optimize product yield. The unsaturated acid was prepared in 5
steps in 70% overall yield starting from bromoacetic acid 9
(Scheme 5). Intermediate esterification was performed solely
to facilitate purification.
SCHEME 2. Z-Enolate Formation
SCHEME 5. Synthesis of γ-Unsaturated r-Alkoxy Acid 11
If the starting ester is prepared from both a chiral allylic
alcohol and an unsaturated R-hydroxy or R-amino acid, excellent
diastereoselectivity can be expected in the Claisen rearrange-
ment. A sequential metathesis reaction would lead to a large
number of diverse unsaturated carbocycles with the stereose-
lective formation of a quaternary carbon center R to the carboxyl
group. Herein, we wish to report our results on the directed
diastereoselective synthesis of cyclic quaternary R-hydroxy and
R-amino acid derivatives.
Preparation of the unsaturated R-amino acid 12 was done in
a straightforward manner from DL-2-amino-4-pentenoic acid and
di-tert-butyl dicarbonate.13 Esterification was then carried out
with the four chiral allylic alcohols with use of standard DCC
coupling techniques, giving the desired compounds in good yield
(Table 1).
TABLE 1. Ester Preparation
For the purpose of our study, γ-unsaturated R-hydroxy or
R-amino acids were chosen for the acid moiety, which, after
ring closing metathesis, would lead to the formation of the
corresponding unsaturated cyclopentenes. To easily access
the desired chiral allylic alcohols in both configurations, we
chose to use the method developed by Carreira et al.11 for
the enantioselective synthesis of propargylic alcohols by the
addition of terminal alkynes to aldehydes (Scheme 3).
SCHEME 3. Propargylic Alcohol Synthesis
Isobutyraldehyde was chosen as the coupling partner with
alkyne 212 for strictly practical purposes as the coupling reaction
works best with secondary aldehydes, and the isopropyl moiety
is eliminated in the metathesis step.
The double bond configuration was then established through
partial reduction of the alkyne by either hydrogenation in the
presence of Lindlar’s catalyst (Z-olefins) or treatment with Red-
Al in THF (E-olefins) (Scheme 4).
When our model ester 17 was subjected to standard re-
arrangement conditions (1.5 equiv of KHMDS (commercial
solution), toluene, TMSCl -78 °C)7 the rearranged methyl ester
18 was obtained in 77% yield after treatment with diazomethane.
The presence of 10-15% of unreacted ester leads us to further
optimize reaction conditions. It was found that addition of the
ester to LiHMDS, generated in situ from n-BuLi and freshly
distilled 1,1,1,3,3,3-hexamethyldisilazane in toluene, increased
the reaction yield to 91% with no recovered starting material
(Scheme 6).
SCHEME 4. Alkyne Reduction
These conditions were then applied to esters 13a-16a to give
the rearranged products in excellent yield and diastereoselectivity
(Table 2).14 Ring closing metathesis was performed by using
Compared to our previously reported conditions,7 the syn-
thesis of the protected R-hydroxy acid 11 was modified to
(11) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M J. Am. Chem. Soc. 2000, 122,
(13) Kaptein, B.; Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.;
Veerman, J. J. N.; Kamphuis, J.; Peggion, C.; Formaggio, F.; Toniolo, C.
Tetrahedron 2001, 57, 6567–6577.
1806–1807.
(12) Bekele, T.; Brunette, S. R.; Lipton, M. A. J. Org. Chem. 2003, 68, 8471–
8479.
(14) Diastereoselectivities were calculated from 500 MHz 1H NMR spectra.
J. Org. Chem. Vol. 73, No. 11, 2008 4339

developed by Riguera et al.16 Unfortunately, but perhaps not
surprisingly, TBAF deprotection of the DPS group gave 74%
of lactone 29 instead of the expected alcohol 27 (Scheme 8).
SCHEME 6. Optimized Rearrangement Conditions
SCHEME 8. Alcohol Deprotection and Lactone Formation
TABLE 2. The Claisen/Methathesis Sequence with r-Alkoxy and
r-Amino Estersa
To avoid lactonization it was necessary to either “deactivate”
the methyl ester or to deprotect the alcohol in a situation where
cyclization was impossible. Two of the four cyclopentenes in
each series (22a, 22b, 26a, and 26b) were ideal candidates for
deprotection without cyclization. If the methyl ester and the
alcohol were in a trans configuration, lactone formation would
be difficult because of the strain involved in closing the fused
ring system. This would, of course, also confirm the relative
stereochemistry of the adjacent chiral centers. If lactonization
occurred, the cis relationship of the primary alcohol and the
methyl ester would thus be established. These results are
presented in Table 3.
a See the asterisk in the first column: series a: R ) OPMB; series b:
R ) NHBoc.
Grubb’s first generation catalyst, and the cyclized products were
obtained in excellent yields.
Chelate Claisen rearrangement of the chiral R-aminoesters
13b-16b was performed by slightly modifying the procedure
reported by Kazmaier et al. in the presence of zinc chloride
(Scheme 7).15
TABLE 3. Relative Configuration of the Adjacent Stereocentersa
SCHEME 7. Chelate Claisen Rearrangement of 13b
The corresponding methyl esters 19b, 21b, 23b, and 25b were
obtained in fair yield and excellent diastereoselectivity (Table
2). Ring closing metathesis then proceeded smoothly in the
presence of Grubb’s catalyst.
The relative and absolute stereochemistry depicted in Table
2 is based on our previous work in the (S)-OPMB series, in
which several six-member rings issued from the Ireland-Claisen/
metathesis sequence were analyzed by using deuterium NMR
in chiral liquid crystals.7 Although we felt confident about
predicting stereochemistry based on this and the highly ordered
transition states involved, we also felt that it was necessary to
unequivocally confirm the stereochemistry of all of the obtained
products. To do so, we used the chiral shift reagents (R)- or
(S)-9-anthrylmethoxyacetic acid (9-AMA) to determine the
absolute configuration of the ꢀ-chiral primary alcohol, a method
a See the asterisk in the last column: series a: R ) OPMB; series b:
R ) NHBoc.
The absolute configuration of the primary alcohols was then
determined as follows. Alcohols 31a, 31b, 33a, and 33b were
1
coupled to both the (R)- and (S)-9-AMA acids, and H NMR
spectra were recorded for the esters. This method is based on
the observation that the sign of ∆δRS is consistently positive or
negative depending on the spatial arrangement of the substituents
in relation to the anthryl ring of the chiral shift reagent. Figure
1 shows the ∆δRS values experimentally obtained for the NHBoc
(15) (a) Kazmaier, U.; Schneider, C. Synlett 1996, 975–977. (b) Kazmaier,
U.; Schneider, C. Synthesis 1998, 1321–1326. (c) Kazmaier, U.; Schneider, C.
Tetrahedron Lett. 1998, 39, 817–818. (d) Schneider, C.; Kazmaier, U. Eur. J.
Org. Chem. 1998, 1155–1159.
(16) Latypov, S. K.; Ferreiro, M. J.; Quin˜oa´, E.; Riguera, R J. Am. Chem.
Soc. 1998, 120, 4741–4751.
4340 J. Org. Chem. Vol. 73, No. 11, 2008

give the corresponding methyl ester, which was purified by flash
chromatography (petroleum ether/EtOAc 95:5). The methyl ester
(1 equiv) was then dissolved in CH2Cl2 (0.2 M solution). First
generation Grubbs catalyst (0.1 equiv) was added and the reaction
heated to 40 °C for 1 h. After cooling, the mixture was concentrated,
and the crude product was purified by flash chromatography to
afford the pure compound.
(E)-(2R,3S)-2-Allyl-3-(tert-butyldiphenylsilanyloxymethyl)-2-(4-
methoxybenzyloxy)-6-methylhept-4-enoic Acid Methyl Ester (19a).
Yield 75% (99% de), colorless oil. [R]20 -15.8 (c 0.69, CHCl3);
D
1H NMR (250 MHz, CDCl3) δ 1.00 (s, 6H), 1.02 (s, 9H), 2.33 (m,
1H), 2.70 (m, 3H), 3.61 (s, 3H), 3.70 (dd, J ) 7.9, 9.9 Hz, 1H),
3.79 (s, 3H), 4.06 (dd, J ) 3.8, 9.9 Hz, 1H), 4.41 (s, 2H), 5.08 (s,
1H), 5.14 (s, 1H), 5.34 (dd, J ) 9.5, 15.3 Hz, 1H), 5.55 (dd, J )
6.7, 15.3 Hz, 1H), 5.79 (m, 1H), 6.82 (d, J ) 8.6 Hz, 2H), 7.21 (d,
J ) 8.4 Hz, 2H), 7.30-7.43 (m, 6H), 7.64-7.67 (m, 4H); 13C NMR
(62.5 MHz, CDCl3) δ 19.2, 22.4, 22.6, 26.8, 31.4, 37.1, 51.5, 51.9,
55.2, 63.0, 66.1, 82.9, 113.5, 118.6, 124.1, 127.5, 128.6, 129.4,
130.8, 132.5, 133.8, 133.9, 135.6, 142.1, 158.8, 172.7; IR (neat)
FIGURE 1. Comparison of the ∆δRS values of the 9-AMA esters.
(R)- and (S)-9-AMA derivatives and clearly confirms the
absolute configuration of the chiral center.
In conclusion, we have shown that an enolate Claisen
metathesis sequence is a versatile synthetic tool for the synthesis
of quaternary hydroxy and amino acid carbocycles. The judi-
cious choice of both the configuration of the allylic alcohol and
the double bond geometry gives access to any one of four
stereoisomers in good yield and excellent diastereoselectivity.
The enantiomerically pure chiral allylic alcohols are easily
obtained by using the synthetic method developed by Carreira.
Controlled reduction of the triple bond then gives the desired
E or Z geometry. While this method has been exemplified for
five-member rings, it is clear that changing the position of the
unsaturation in the acid partner can give access to six, seven,
or higher member rings in a completely controlled manner.
Work is currently in progress to apply this sequence to the
synthesis of biologically active natural products.
ν
max 2956, 2931, 2858, 1737, 1514 cm-1; ESI-MS m/z 623.3 [M +
Na]+. Anal. Calcd for C37H48O5Si: C 73.96, H 8.05. Found: C 74.27,
H 8.07.
(1R,2S)-2-(tert-Butyldiphenylsilanyloxymethyl)-1-(4-methoxy-
benzyloxy)cyclopent-3-enecarboxylic Acid Methyl Ester (20a).
Yield 92% (colorless oil). [R]20 -95.5 (c 0.93, CHCl3); Rf 0.74
D
(petroleum ether/EtOAc 8:2); 1H NMR (250 MHz, CDCl3) δ 1.03
(s, 9H), 2.76 (d, J ) 17.6 Hz, 1H), 3.14 (d, J ) 17.6 Hz, 1H), 3.19
(br s, 1H), 3.65 (s, 3H), 3.66 (d, J ) 6.2 Hz, 2H), 3.77 (s, 3H),
4.43 (d, J ) 11.37 Hz, 1H), 4.52 (d, J ) 11.4 Hz, 1H), 5.61 (d, J
) 3.7 Hz, 1H), 5.78 (d, J ) 3.7 Hz, 1H), 6.85 (d, J ) 8.4 Hz, 2H),
7.27 (d, J ) 8.4 Hz, 2H), 7.34-7.42 (m, 6H), 7.64 (d, J ) 7.3 Hz,
4H); 13C NMR (62.5 MHz, CDCl3) δ 19.2, 26.8, 41.1, 51.9, 55.3,
59.0, 63.3, 66.9, 88.7, 113.7, 127.6, 128.9, 129.6, 135.6, 135.6,
159.1, 172.6; ESI HRMS m/z calcd for C32H38O5Si (M + Na)+
553.2386, found 553.2384.
Experimental Section
General Procedure for the Ireland-Claisen/Metathesis
Sequence (OPMB Esters). n-BuLi (3 equiv, 2.3 M solution in
hexanes) was added to a solution of HMDS (4 equiv) in dry toluene
cooled to 0 °C under argon and stirred for 15 min. The solution
was then further cooled to -78 °C. The starting ester (1 equiv)
dissolved in dry toluene (3 mL) was added dropwise via a canula
to the reaction vessel at -78 °C. The reaction mixture was stirred
for 45 min before freshly distilled TMSCl (3 equiv) was introduced
via syringe and maintained at this temperature for an extra 10 min
before gradually warming to rt. After 2 h, the reaction mixture was
quenched by a saturated aqueous solution of ammonium chloride
(10 mL). The aqueous layer was extracted with diethyl ether, dried
over MgSO4, filtered, and concentrated. The crude acid was
immediately treated with a solution of diazomethane in ether to
Acknowledgment. We would like to thank the University
of Reims Champagne-Ardenne and the Centre National de
Recherche Scientifique (CNRS) for their financial support. We
would especially like to thank AstraZeneca for their support
(Ph.D. scholarship to N.P.).
Supporting Information Available: General experimental
procedures and copies of NMR spectra (1H and 13C) of all of
the new compounds synthesized. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO800496H
J. Org. Chem. Vol. 73, No. 11, 2008 4341