Stereoselective construction of adjacent quaternary chiral centers by the Ireland-Claisen rearrangement: Stereoselection with esters of cyclic alcohols

Article abstract of DOI:10.1055/s-0029-1219965

This work describes a study of the Ireland-Claisen rearrangement of α,α-disubstituted enolates derived from esters of cyclic alcohols. Highly stereoselective enolizaitions could be generally achieved using N-benzyl Koga-type bases by matching chirality of the ester and the base. The [3,3]-sigmatropic rearrangement took place in good yields and moderate diastereoselectivity forming two adjacent quaternary stereogenic centers, and generally proceeding through a chairlike transition state. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219965

CLUSTER
1717
Stereoselective Construction of Adjacent Quaternary Chiral Centers by the
Ireland–Claisen Rearrangement: Stereoselection with Esters of Cyclic
Alcohols
Stereoselective
h
C
onstruction
e
of
A
djace
n
n
t
Q
uaternary
h
Chiral Cent
u
ers a Gu, Aaron T. Herrmann, Craig E. Stivala, Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
Fax +1(805)8934241; E-mail: zakarian@chem.ucsb.edu
Received 7 May 2010
defined quaternary stereogenic centers at the a-position to
Abstract: This work describes a study of the Ireland–Claisen rear-
rangement of a,a-disubstituted enolates derived from esters of cy-
clic alcohols. Highly stereoselective enolizaitions could be
generally achieved using N-benzyl Koga-type bases by matching
chirality of the ester and the base. The [3,3]-sigmatropic rearrange-
ment took place in good yields and moderate diastereoselectivity
forming two adjacent quaternary stereogenic centers, and generally
proceeding through a chairlike transition state.
the carboxyl group in the products.
Recently, we described a new approach to stereoselective
enolization of a-branched esters based on an unusual
chirality match between a Koga-type base and an enolate
precursor.3 Although this method requires an investment
in the synthesis of the chiral ester and chiral base counter-
parts, it provides direct and straightforward access to a,a-
disubstituted enolates that are difficult to prepare other-
wise. On the other hand, the starting materials can be
readily prepared by well-established methods.4,5 We have
previously demonstrated that the enolization method can
be effectively applied in the context of the Ireland–
Claisen rearrangement. With esters of acyclic alcohols,
high diastereoselectivities can be obtained for the assem-
bly of adjacent stereogenic all-carbon quaternary centers
(Scheme 1).3 The utility and efficiency of the method has
been demonstrated with a complex substrate on multi-
gram scale during the course of the total synthesis of
(+)-pinnatoxin A.6 The goal of the study reported in this
communication is to define the diastereoselectivity of the
reaction with esters of chiral cyclic alcohols.
Key words: diastereoselectivity, rearrangement, esters, sigmatrop-
ic, chirality, stereoselective synthesis
The widespread application of the Ireland–Claisen rear-
rangement in organic synthesis can be attributed to pre-
dictable relay of chirality in acyclic systems based on
well-understood chairlike transition structures, generally
high yields and stereoselectivities, and ready access to the
starting materials by esterification.1 Application of this
powerful approach for the formation of adjacent quaterna-
ry stereogenic centers in acyclic systems has been pre-
cluded by the lack of methods for stereocontrolled
formation of a,a-disubstituted enolates.2 For the same rea-
son, the rearrangement could not be reliably used to form
via stereoselective enolization:
CF3
NLi
Ph
N
O
Me3SiCl, THF
–78 to 25 °C
O
CO2H
85%, dr 5:1
CF3
NLi
N
O
Ph
Me3SiCl, THF
–78 to 25 °C
O
CO2H
90%, dr >10:1
R
available in multi-kilogram scale, no chromatography
two steps from styrene oxide
NH
Ph
N
Scheme 1 Examples of the acyclic diastereoselective Ireland–Claisen rearrangement forming adjacent chiral quaternary centers
SYNLETT 2010, No. 11, pp 1717–1722
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.06.2010
DOI: 10.1055/s-0029-1219965; Art ID: Y00610ST
© Georg Thieme Verlag Stuttgart · New York

1718
Z. Gu et al.
CLUSTER
[3,3]-sigmatropic rearrangement of carbohydrate-derived
pyranoid or furanoid substrates typically takes place
through a boatlike transition state.8 On the other hand, the
rearrangement of other types of cyclic esters can be stereo-
chemically more complex. As illustrated in Scheme 2, the
major product in the transposition of both E- and Z-silyl
enol ethers (E)-2 and (Z)-2 produced from 2-cyclohexen-
1-yl propionate is diastereomer 3, indicating that the E-
isomer favors the chairlike transition state, while the boat-
like transition state is preferred with the Z-isomer.9
Table 1 Enolization of (S)-5 with Koga Bases
OSiMe3
OSiMe3
O
R2NLi, THF, –78 °C;
Me3SiCl
+
RO
RO
RO
Z
E
(S)-5
R = PhCH2CH2CH2
Z/E ratiob
Entry
1
Base R2NLia
i-Pr2NLi
67:33
a,a-Disubstituted enolates have E and Z substituents at the
same time with unexplored preference for a chair or boat
transition state in the Ireland–Claisen rearrangement of
cyclic substrates, making them intriguing substrates for
the [3,3]-sigmatropic process.
NLi
2
3
56:44
83:17
N
Ph
NLi
For the purposes of this study we carried out a screening
of chiral Koga-type bases to investigate the effect of their
structure on the stereoselectivity of enolization. The re-
sults are summarized in Table 1.
N
Ph
4
89:11
NLi
The base with a benzyl group as the achiral substituent on
the nitrogen atom proved to have the highest stereodirect-
ing power (entries 10 and 11). Perhaps the biggest surprise
was that the achiral substituent on the nitrogen atom had a
profound effect on the direction of E/Z selectivity. N-Eth-
yl base showed virtually no stereoselection (entry 2). The
a-branched substituents in the S series, isopropyl and tert-
butyl, favored the Z-enolate formation with up to 89% se-
lectivity (entries 3 and 4). In the same S enantiomeric se-
ries, the b-branched achiral substituents on the nitrogen
reversed selectivity now favoring the formation of the E-
enolate, with the benzyl group giving the highest selectiv-
ity of 98% (entries 5, 7, and 10). As expected, opposite
enantiomers favored different geometric isomers in the
enolization process (cf. entries 6, 8, and 11). Replacement
of the piperidine with pyrrolidine reduced stereoselection
(entry 9). Introduction of an additional chiral center, as
shown in entries 12 and 13, did not have a positive effect
on selectivity, and in the mismatched case resulted in no
deprotonation of the substrate.
N
Ph
NLi
5
6
23:77
90:10
10:90
92:8
N
Ph
NLi
N
Ph
F3C
F3C
F3C
Ph
NLi
NLi
NLi
NLi
NLi
7
N
N
N
Ph
Ph
Ph
8
9
17:83
2:98
10
11
N
Ph
Ph
Ph
Ph
96:4
For an initial study of the Ireland–Claisen rearrangement
we selected ester 6 prepared from (S)-3-methyl-2-cyclo-
hexenol-1 and commercially available (S)-2-methylbuty-
ric acid (Scheme 3).10,11 Enolization with the lithium
amides derived from N-benzyl amines (S)- and (R)-7,
which showed the highest selectivity in the preceding
study, followed by silylation with TMSCl, thermal rear-
rangement at 70 °C, and mild hydrolysis of the silyl esters
afforded a mixture of 9 and 10 in good yields and moder-
ate diastereocontrol in favor of 9.12,13 Analysis of the prod-
ucts indicates that both (E)- and (Z)-8 undergo the [3,3]-
sigmatropic rearrangement through the chairlike transi-
tion state preferentially, although for (Z)-8 this preference
appears to be less pronounced. Surprisingly, the corre-
sponding t-BuMe2Si (TBS) ketene acetals could not be
formed when the lithium amide of amine 7 was used for
enolization even under forcing conditions. Remarkably,
when TBSOSO2CF3 was employed, only C-silylation
N
N
N
Ph
12
13
83:17
NLi
NLi
Ph
no reaction
Ph
a The lithium dialkylamides were generated by the treatment of a
solution of corresponding amines in dry THF with n-BuLi (1 equiv,
–78 °C to 0 °C, 1 h).
b Determined by 500 MHz NMR of the crude mixture of products.
In contrast to acyclic esters, it has been demonstrated pre-
viously that esters of medium-size cyclic alcohols can
preferentially undergo the Ireland–Claisen rearrangement
through a boatlike transition state.1,7 For example, the
Synlett 2010, No. 11, 1717–1722 © Thieme Stuttgart · New York

CLUSTER
Stereoselective Construction of Adjacent Quaternary Chiral Centers
1719
boat TS; 36%; dr 75:25
LDA, THF
TBSCl, HMPA
OTBS
favoring 3
O
O
(Z)-2
O
O
+
O
OTBS
OTBS
H
1
H
LDA, THF;
TBSCl
4
3
OTBS
chair TS; 47%; dr 85:15
O
favoring 3
(E)-2
Scheme 2 Influence of the substrate on the boat/chair transition-state preference
forming a hindered silane was observed. This problem The Ireland–Claisen rearrangement of ester 16 displayed
could be readily overcome by switching to (R)-bis[(R)-1- increased diastereoselectivity in favor of the chairlike
phenylethyl]amine (R,R)-11 or (S)-bis[(S)-1-phenyleth- transition state. Analysis of the transition structures pre-
yl]amine (S,S)-11, which also induce highly selective eno- sented in Scheme 5 reveals a gauche interaction between
lizations. This is an indication that the lithium enolates both substituents of the enolate and the R group in the
generated from ester 6 and bases 7 exist as a congested ag- chair transition states, while in the boat transition states
gregate that prevents O-silylation with TBSCl or there is an eclipsing interaction between R and only the Z-
TBSOSO2CF3.14 With the TBS ketene acetals, a slight re- substituent. When R = Me, the chair transition state expe-
duction in selectivity was noted [88% yield, dr 68% for riences higher destabilization compared to when R = H,
TBS-(E)-8; 80% yield, dr 55% for TBS-(Z)-8], but the thus decreasing selectivity favoring products resulting
preference for the chairlike transition state was main- from the chairlike transition state.
tained.
Additional examples of the diastereoselective Ireland–
Stereocontrol in both enolization and the [3,3]-sigmatrop- Claisen rearrangement performed within the scope of this
ic rearrangement with diastereomeric ester 12 was nearly study are enunciated in Scheme 6. With cyclic esters of a
identical, as expected (Scheme 4). An important conclu- number of a,a-disubstituted esters, the yields are general-
sion in this case is that the stereochemistry of the allylic ly very good, and the stereoselectivities are comparable to
alcohol exerts no influence on the enolization process, our previous examples in the range of about 70%. Diaste-
which appears to be controlled entirely by chirality of the reoselectivity in the rearrangement of ester 24, derived
ester and the base.
from 3-methylcyclopenten-1-ol, was nearly identical to
the previous examples.
O
O
OSiMe3
(S)-7, n-BuLi, THF;
Me3SiCl, –78 °C, 20 min
then 0 °C, 10 min
O
70 °C, 3 h, THF; aq HCl, THF
yield 85%; dr 70% (favoring 9)
dr 92%
chair TS preferred
(E)-8
6
O
O
+
OH
OH
O
O
OSiMe3
9
10
O
(R)-7, n-BuLi, THF;
Me3SiCl, –78 °C, 20 min
then 0 °C, 10 min
chair TS preferred
dr >90%
70 °C, 3 h, THF; aq HCl, THF
yield 76%; dr 60% (favoring 10)
(Z)-8
6
Ph
NH
Ph
Ph
NH
Ph
N
H
Ph
Ph
N
Ph
N
N
H
Ph
(R,R)-11
(S)-7
(R)-7
(S,S)-11
Scheme 3
Synlett 2010, No. 11, 1717–1722 © Thieme Stuttgart · New York

1720
Z. Gu et al.
CLUSTER
O
O
OSiMe3
O
(S)-7, n-BuLi, THF;
Me3SiCl, –78 °C, 20 min
then 0 °C, 10 min
70 °C, 3 h, THF; aq HCl, THF
yield 72%; dr 70% (favoring 14)
dr >90%
chair TS preferred
(E)-13
12
O
+
O
OH
OH
O
O
OSiMe3
15
14
O
(R)-7, n-BuLi, THF;
Me3SiCl, –78 °C, 20 min
then 0 °C, 10 min
chair TS preferred
dr >90%
70 °C, 3 h, THF; aq HCl, THF
yield 50%; dr 60% (favoring 15)
12
(Z)-13
OSiMe3
O
O
O
(S)-7, n-BuLi, THF;
Me3SiCl, –78 °C, 20 min
then 0 °C, 10 min
70 °C, 3 h, THF; aq HCl, THF
yield 70%; dr 80% (favoring 18)
chair TS preferred
dr >90%
(E)-17
16
O
O
+
OH
OH
H
H
OSiMe3
O
O
19
18
O
(R)-7, n-BuLi, THF;
Me3SiCl, –78 °C, 20 min
then 0 °C, 10 min
chair TS preferred
70 °C, 3 h, THF; aq HCl, THF
yield 68%; dr 75% (favoring 19)
dr >90%
(Z)-17
16
Scheme 4
OSiR3
The relative stereochemistry of carboxylic acids 9 and 10
was established by a series of experiments shown in
Scheme 7. Iodolactonization followed by deiodination
under radical conditions provided a mixture of lactones 26
and 27. NOE enhancements observed with 26 and 27 con-
firmed the assigned configuration. The assignment of 25
was confirmed by conversion of known acid 28 to methyl
ester 29 in two steps involving esterification and ring-
closing metathesis. After methyl ester formation, the
NMR data for the major product of the Ireland–Claisen re-
arrangement of 24 performed with (S)-7 correlated to
those of 29.
R3SiO
O
O
O
R
R
OSiR3
R
Z-chair TS
E-boat TS
O
OSiR3
R3SiO
O
O
R
R
OSiR3
R
E-chair TS
Z-boat TS
In conclusion, the Ireland–Claisen rearrangement of a,a-
disubstituted esters of carbocyclic alcohols can be carried
out with moderate diastereoselectivity using highly stereo-
selective enolizations with Koga-type bases, and the prod-
ucts resulting from chairlike transitions states are
generally preferred. This observation is in contrast with
the rearrangements of unbranched cyclic esters, where the
Scheme 5
boat versus chair selectivity demonstrates a higher depen-
dence on the enolate geometry.
Synlett 2010, No. 11, 1717–1722 © Thieme Stuttgart · New York

CLUSTER
Stereoselective Construction of Adjacent Quaternary Chiral Centers
(4) Selected methods: (a) Schmierer, R.; Grotemeier, G.;
1721
O
O
Helmchen, G.; Selim, A. Angew. Chem., Int. Ed. Engl. 1981,
20, 207. (b) Helmchen, G.; Selim, A.; Dorsch, D.; Taufer, I.
Tetrahedron Lett. 1983, 24, 3213. (c) Oppolzer, W.;
Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 5603.
(d) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem.
Soc. 1982, 104, 1737.
Ph
(S)-7, n-BuLi, THF; Me3SiCl, –78 °C;
O
then 70 °C, 3 h; aq HCl, THF
OH
yield 86%, dr 70%
Ph
21
20
(5) (a) Shirai, R.; Tanaka, M.; Koga, K. J. Am. Chem. Soc. 1986,
108, 543. (b) For a detailed, large-scale synthesis of Koga
bases, see: Frizzle, M. J.; Caille, S.; Marshall, T. L.; McRae,
K.; Nadeau, K.; Guo, G.; Wu, S.; Martinelli, M. J.; Moniz,
G. A. Org. Process Res. Dev. 2007, 11, 215.
O
O
O
(S)-7, n-BuLi, THF; Me3SiCl, –78 °C;
then 70 °C, 3 h; aq HCl, THF
(6) (a) Stivala, C.; Zakarian, A. J. Am. Chem. Soc. 2008, 130,
3774. (b) Lu, C.-D.; Zakarian, A. Org. Lett. 2007, 9, 3161.
(c) Stivala, C. E.; Zakarian, A. Tetrahedron Lett. 2007, 48,
6845. (d) Pelc, M. J.; Zakarian, A. Tetrahedron Lett. 2006,
47, 7519. (e) Pelc, M. J.; Zakarian, A. Org. Lett. 2005, 7,
1629. (f) Recent application toward the synthesis of
spirolide C: Stivala, C. E.; Zakarian, A. Org. Lett. 2009, 11,
839.
OH
yield 88%, dr 72%
22
23
O
O
O
(S)-7, n-BuLi, THF; Me3SiCl, –78 °C;
(7) (a) Chen, C.; Namba, K.; Kishi, Y. Org. Lett. 2009, 11, 409.
(b) Gul, S.; Schoenebeck, F.; Aviyente Houk, K. N. J. Org.
Chem. 2010, 75, 2115.
then 70 °C, 3 h; aq HCl, THF
OH
yield 77%, dr 71%
(8) Examples: (a) Wallace, G. A.; Scott, R. W.; Heathcock,
C. H. J. Org. Chem. 2000, 65, 4145. (b) Ireland, R. E.;
Vevert, J.-P. J. Org. Chem. 1980, 45, 4259.
24
25
Scheme 6
(9) (a) Bartlett, P. A.; Pizzo, C. h. F. J. Org. Chem. 1981, 46,
3896. (b) For a comprehensive study, see: Ireland, R. E.;
Wipf, P.; Xiang, J.-N. J. Org. Chem. 1991, 56, 3572.
(10) (a) Wang, Y.-F.; Lalonde, J. J.; Momongan, M.; Bergbreiter,
D. E.; Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200.
(b) Carea, G.; Danieli, B.; Palmisano, G.; Riva, S.;
Santagostina, M. Tetrahedron: Asymmetry 1992, 3, 775.
(11) General Procedure for Esterification – Synthesis of
(S)-[(S)-3-Methylcyclohex-2-enyl] 2-Methyl-
Acknowledgment
This research project was supported by the NSF CAREER Award
(CHE-0836757) and generous gifts from Eli Lilly and Amgen.
C.E.S. is a recipient of the Tobacco-Related Disease Research Pro-
gram (18DT-0002) and a UCSB Dean’s Fellowship.
butanoate (6)
EDCI (0.345 g, 1.80 mmol) was added to a mixture of (S)-3-
methyl-2-cyclohexen-1-ol (0.100 g, 0.89 mmol), (S)-2-
methylbutyric acid (0.153 g, 1.50 mmol) in CH2Cl2 (4.0
mL), and the resultant mixture was stirred at r.t. for 2 h.
After evaporation, the residue was purified by column
chromatography (3% EtOAc–hexanes) to give the ester 6
(0.143 g, 82%); [a]D22 –112 (c 1.0, CHCl3). 1H NMR (400
MHz, CDCl3): d = 5.44 (s, 1 H), 5.25 (s, 1 H), 2.40–2.28 (m,
1 H), 2.06–1.84 (m, 2 H), 1.82–1.58 (m, 8 H), 1.52–1.39 (m,
1 H), 1.13 (d, J = 6.8 Hz, 3 H), 0.90 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): d = 176.5, 140.7, 120.2, 68.3,
41.2, 29.9, 28.0, 26.8, 23.7, 19.1, 16.7, 11.6 ppm. HRMS
(FI): m/z calcd for C12H20O2 [M+]: 196.1463; found:
196.1455.
References and Notes
(1) (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94,
5897. For recent reviews, see: (b) Ilardi, E. A.; Stivala, C.
E.; Zakarian, A. Chem. Soc. Rev. 2009, 38, 3133.
(c) Martin Castro, A. M. Chem. Rev. 2004, 104, 2939.
(d) Chai, Y.; Hong, S.; Lindsay, H. A.; McFarland, C.;
McIntosh, M. C. Tetrahedron 2002, 58, 2905.
(2) A creative alternative approach to the formation of
stereodefined a,a-disubstituted enolates from cyclic
precursors has been described: (a) Manthorpe, J. M.;
Gleason, J. L. J. Am. Chem. Soc. 2001, 123, 2091.
(b) Tiong, E. A.; Gleason, J. L. Org. Lett. 2009, 11, 1725.
(3) Qin, Y.; Stivala, C. E.; Zakarian, A. Angew. Chem. Int. Ed.
2007, 46, 7466.
NOE
1. I2, NaHCO3, THF
2. n-Bu3SnH, Et3B, O2, THF
H
H
10
+
9
+
85%
O
O
NOE
70:30
O
O
27
26
70:30
1. Me3SiCHN2, CH2Cl2–MeOH
2. Grubbs II cat. (5 mol%), CH2Cl2, reflux, 6 h
O
HO
OMe
90%
O
28
29
Scheme 7
Synlett 2010, No. 11, 1717–1722 © Thieme Stuttgart · New York

1722
Z. Gu et al.
CLUSTER
(12) General Procedure for the Ireland–Claisen
Rearrangement – (S)-2-Methyl-2-[(R)-1-
monitored by TLC. After dilution with CH2Cl2 and H2O, the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The
organic layers were dried with Na2SO4, concentrated, and
the residue was purified by column chromatography (silica,
10% EtOAc–hexanes w/0.1% AcOH then 40% EtOAc–
hexanes w/0.1% AcOH) delivering a 70:30 mixture of
carboxylic acids 9 and 10 (16.7 mg, 85 mmol, 85%),
respectively. 1H NMR (300 MHz, CDCl3): d (major isomer)
= 5.66 (dd, J1 = 10.8 Hz, J2 = 0.8 Hz, 1 H), 5.61 (ddd,
J1 = 10.4 Hz, J2 = J3 = 3.2 Hz, 1 H), 2.10–2.10 (m, 1 H),
1.75–1.68 (m, 3 H), 1.51–1.40 (m, 3 H), 1.34–1.27 (m, 1 H),
1.14 (s, 3 H), 1.09 (s, 3 H), 0.87 (dd, J1 = J2 = 7.6 Hz, 3 H)
ppm.
Methylcyclohex-2-enyl]butanoic acid (9)
n-BuLi (1.96 M in hexanes, 0.105 mL, 0.20 mmol) was
added to a solution of (S)-7 (60 mg, 0.20 mmol) in THF (0.25
mL) at –78 °C. After 5 min, the flask was removed from the
ice bath and stirring was continued at r.t. The solution was
allowed to stir for 20 min before being cooled down to
–78 °C, at which point a solution of 6 (19.6 mg, 0.10 mmol)
in THF (0.50 mL) was added dropwise to the reaction vessel.
After 1.5 h, TMSCl (25 mL, 0.20 mmol) was added. The
mixture was stirred at –78 °C for 20 min, then at 0 °C for 10
min. The reaction mixture was diluted with hexanes (20
mL). The organic layer was washed with 1 M HCl (2 × 2
mL), followed immediately by sat. aq NaHCO3 (10 mL),
dried with Na2SO4, and concentrated. The residue was
dissolved in THF (1.0 mL) and heated in a sealed flask at
70 °C. After 3 h, the reaction vessel was cooled to r.t. and
THF (2.0 mL) was added followed by the addition of 1 M
HCl (3.0 mL). The progress of the silyl ester hydrolysis was
(13) Lithium diisopropylamide gives an equimolar ration of 9 and
10.
(14) For recent structural studies on lithium enolate aggregates,
see: (a) Li, D.; Sun, C.; Williard, P. G. J. Am. Chem. Soc.
2008, 130, 11726. (b) Godenschwager, P. F.; Collum, D. B.
J. Am. Chem. Soc. 2008, 129, 12023.
Synlett 2010, No. 11, 1717–1722 © Thieme Stuttgart · New York