Highly diastereoselective asymmetric thio-Claisen rearrangements

Full text of DOI:10.1021/ja992959w

190
J. Am. Chem. Soc. 2000, 122, 190-191
Highly Diastereoselective Asymmetric Thio-Claisen
Rearrangements
Shuwen He, Sergey A. Kozmin, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago
5735 South Ellis AVenue, Chicago, Illinois 60637
Figure 1.
Scheme 1
ReceiVed August 16, 1999
ReVised Manuscript ReceiVed December 1, 1999
The Claisen rearrangement has evolved into one of the most
powerful transformations for the stereoselective formation of
carbon-carbon bonds.1 Compared to the more familiar oxygen
version, the “thio-Claisen” rearrangement has been little inves-
tigated,2 particularly its asymmetric version, wherein the chirality
resides in the amino portion of the starting thioamide. The
asymmetric thio-Claisen rearrangements investigated to date suffer
from low diastereofacial selectivity as a consequence of free
rotation around the C-N bond in the N,S-ketene acetal intermedi-
ate (Scheme 1).3 The sole exception comes from the work of
Meyers et al., wherein the rigid bicyclic thiolactam framework
prevents rotation around the C-N bond of the N,S-ketene acetal
intermediate.4 Described below are the first examples of asym-
metric thio-Claisen rearrangements of systems containing C2-
symmetric amines, which proceed with good to exceptionally high
diastereoselectivities.5
Table 1. Thio-Claisen Rearrangements Giving One New
Stereogenic Center
The decision to use a C2-symmetric amine as the chiral auxiliary
for the thio-Claisen rearrangement was based on the following
considerations. First, deprotonation of a tertiary thioamide is
known to produce the Z-thioenolate with very high selectivity.2c
Second, there is a strong preference for the chairlike transition
state in the Claisen rearrangement.1 Finally, the use of a
C2-symmetric auxiliary was expected to preclude the rotomer issue
mentioned above, since both rotomers6 would be identical. Taken
together, these factors meant the thio-Claisen rearrangement using
a C2-symmetric amine would proceed primarily through only two
low-energy transition states, A and B, of which the former was
expected to be favored for steric reasons (Figure 1).
The required thioamide substrate, (-)-1, was readily prepared
via a two-step sequence from (+)-trans-2,5-diphenylpyrrolidine.7
Acylation of the amine with propionyl chloride (Et3N, CH2Cl2,
92%) followed by thionation with Lawesson’s reagent (PhMe,
reflux, 98%) afforded enantiopure thioamide (-)-1.8 Compound
a THF, n-BuLi, -78 °C; add allylic bromide, then warm to the
conditions indicated. b Isolated yield. c The diastereoselectivities (de)
were determined by HPLC.
(-)-1 was deprotonated with n-BuLi at -78 °C, and the resultant
Z-thioenolate was treated with the allyllic bromide.2c Rearrange-
ment of the N,S-ketal intermediate was carried out by warming
the reaction mixture to room temperature or, when necessary, to
reflux.
The first group of asymmetric thio-Claisen rearrangements to
be examined were selected so as to produce one new stereogenic
center (Table 1). Upon treatment of the enolate of 1 with allyl
bromide or methallyl bromide and allowing the reaction mixture
to warm to room temperature, the thio-Claisen rearrangements
took place readily and afforded the expected products, 5a and
5b, in nearly quantitative yields. The product from allyl bromide
was obtained as a 9.8:1 ratio of diastereomers (81% de), and that
from methallyl bromide was obtained in a 7.7:1 ratio (77% de).9
The absolute configuration of the newly created centers for both
rearrangement products was established by correlation with
authentic samples of the amides prepared via Evans’s chiral
oxazolidinone alkylation methodology.10 This correlation con-
firmed that the observed diastereoselectivity originated from the
facial bias imposed by the chiral auxiliary in 4, with the
rearrangement proceeding predominantly via transition state A
(Figure 1).
(1) (a) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 827. (b) Enders, D.; Knopp,
M.; Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847. (c) Ziegler, F. E.
Chem. ReV. 1988, 88, 1423. (d) Ito, H.; Taguchi, T. Chem. Soc. ReV. 1999,
28, 43.
(2) (a) Schuijl, P. J. W.; Brandsma, L. Recl. TraV. Chim. Pays-Bas 1968,
87, 929. (b) Takano, S.; Hirama, M.; Ogasawara, K. Tetrahedron Lett. 1982,
23, 881. (c) Tamaru, Y.; Furukawa, Y.; Mizutani, M.; Kitao, O.; Yoshida, Z.
J. Org. Chem. 1983, 48, 3631. (d) Metzner, P. Synthesis 1992, 1185.
(3) (a) Welch, J. T.; Eswarakrishnan, S. J. Am. Chem. Soc. 1987, 109, 6716.
(b) Reddy, K. V.; Rajappa, S. Tetrahedron Lett. 1992, 33, 7957. (c) Jain, S.;
Sinha, N.; Dikshit, D. K.; Anand, N. Tetrahedron Lett. 1995, 36, 8467.
(4) Lemieux, R. M.; Devine, P. N.; Mechelke, M. F.; Meyers, A. I. J. Org.
Chem. 1999, 64, 3585 and references therein.
(5) We had earlier found trans-2,5-diphenylpyrrolidine to be a superb chiral
auxiliary for dienes in Diels-Alder reactions. See: (a) Kozmin, S. A.; Rawal,
V. H. J. Am. Chem. Soc. 1997, 119, 7165. (b) Kozmin, S. A.; Rawal, V. H.
J. Am. Chem. Soc. 1999, 121, 9562.
(6) Of the infinite number of rotomers possible, only the two shown allow
optimum stabilizing delocalization between the sp2-hybridized nitrogen lone
pair and the enamine π-bond.
(7) Chong, J. M.; Clarke, I. S.; Koch, I.; Olbach, P. C.; Taylor, N. J.
Tetrahedron: Asymmetry 1995, 6, 409.
The results from the next two examples studied were striking.
After alkylation of the thioamide enolate with 4-bromo-2-methyl-
2-butene and warming the reaction mixture to room temperature,
the intermediate N,S-ketene acetal remained unrearranged. To
promote the rearrangement, the reaction mixture was heated to
reflux for 6-7 h. Despite the higher temperature, the rearrange-
(9) Determined by HPLC comparison with authentic samples. See Sup-
porting Information.
(10) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(11) The absolute configuration was assigned by analogy with the rear-
rangement products with allyl bromide and methallyl bromide (Table 1, entries
1 and 2).
(8) The enantiomeric excess of the thioamide was >99% based on chiral
HPLC comparison with (()-1. Reviews on Lawesson’s reagent: (a) Voss, J.
In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John
Wiley & Sons: New York, 1995; Vol. 1, p 530. (b) Cava, M. P.; Levinson,
M. I. Tetrahedron 1985, 41, 5061.
10.1021/ja992959w CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/21/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 1, 2000 191
Table 2. Rearrangements Producing Two New Stereogenic Centers
Scheme 2
, >
de
de
, >
analogously to that with the crotyl bromides. Gratifyingly, the
thio-Claisen rearrangement of the Z-cinnamyl bromide alkylation
product proceeded with exceedingly high syn:anti and facial
selectivities.12
The examples shown in entries 5 and 6 are most interesting:
two stereogenic centers, of which one is quaternary, are produced
with almost complete diastereocontrol. Indeed, the present
chemistry is particularly well suited for the synthesis of quaternary
stereogenic centers because the intermediate N,S-ketene acetal
would necessarily have a Z-oriented substituent.
a THF, n-BuLi, -78 °C; add allylic bromide, then warm to the
conditions indicated. b Isolated yield. c The diastereoselectivities (de)
were determined by HPLC.
Finally, the present thio-Claisen chemistry appears to have
considerable scope. We have examined the alkylative rearrange-
ment of two additional thioamides, 6a and 6b (Scheme 2). Both
rearrangements proceeded in high yields and afforded the thio-
Claisen products with excellent diastereoselectivity (>98% by
NMR).
In summary, we have investigated several thio-Claisen rear-
rangements using a C2-symmetric pyrrolidine13 as the removable
chiral auxiliary.14 The rearrangements proceed with high syn:anti
selectivities and good to excellent asymmetric induction. In
particular, the rearrangements of allylic units possessing a
substituent cis to the allylic sulfide take place with exceptionally
high diastereoselectivity, among the highest reported for any
Claisen rearrangement. A simple, predictive model is provided
to explain the extraordinary asymmetric inductions observed.
ment proceeded with excellent diastereoselectivity and afforded
thioamide 5c as a single diastereomer (by HPLC).9 Similarly high
selectivity was observed for the alkylative rearrangement using
(2-bromo-ethylidene)-cyclohexane.9
The observed high diastereoselectivity for entries 3 and 4, as
well as the difference in the level of selectivity between entries
1, 2 and entries 3, 4, can be understood by inspection of molecular
models (Figure 1). Of the two likely transition states, A and B,
the former is expected to be of lower energy because the allylic
group is positioned in the open face of the C2-symmetric chiral
auxiliary, on the side away from the proximal phenyl group on
the pyrrolidine ring. Transition state B is disfavored since it has
the allyllic group in close proximity to the pyrrolidine phenyl
group. The steric problem is particularly severe when there is a
“Z-oriented” substituent on the allylic sulfide (R1 in Figure 1).
The other two substituents, R2 and R3, are pointed away from
the phenyl group in the transition state and are not expected to
greatly affect the diastereoselectivity (e.g., entry 2).
Acknowledgment. This work was supported by the National Institutes
of Health. Partial support of this research by Pfizer Inc. is gratefully
acknowledged.
The above analysis brings out a novel and unique aspect of
the present work: It is the “Z-oriented” substituentsand it onlys
that is of paramount importance for realizing high diastereo-
selectiVity. To test this proposition, we examined the alkylative
rearrangement of E- and Z-crotyl bromides (Table 2). The
rearrangement with E-crotyl bromide took place upon warming
the reaction mixture to room temperature and gave a 97.6:2.4
ratio of anti and syn diastereomers, respectively (entry 1).9 The
asymmetric induction for the major (anti) diastereomer was 7.5:
1, very similar to that observed with allyl bromide.11 The
intermediate formed upon alkylation with Z-crotyl bromide
rearranged much more slowly than that with E-crotyl bromide
and required heating to reflux for 3 h. As predicted, the
diastereomeric excess (de) of the syn product was exceptionally
high (entry 2).12
Supporting Information Available: Details for preparations and
1
characterizations of all new compounds, including copies H NMR and
13C NMR spectra, along with HPLC analysis of diastereoselectivity (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA992959W
(13) We have also examined the thio-Claisen rearrangement using the
commercially available auxiliary, (R,R)-(-)-2,5-bis(methoxymethyl)pyrroli-
dine. Treatment of the enolate of the thioamide with HMPA (3 equiv), followed
by addition of 4-bromo-2-methyl-2-butene and heating the reaction mixture
to reflux, afforded the expected thio-Claisen product with excellent diaste-
reoselectivity (>99%). The product (92% total yield) contained about 6% of
the direct alkylation product, produced as a single diastereomer.
The results from the alkylation rearrangement using E- and
Z-cinnamyl bromides (Table 2, entries 3 and 4) paralleled those
with the crotyl bromides. As expected, the rearrangement with
E-cinnamyl bromide proceeded with high anti selectivity, but the
de of the anti diastereomer was only modest (4.9:1). The
stereochemistry of the rearrangement products was assigned
(14) The chiral auxiliary can be cleaved from the thio-Claisen products
under reductive hydrolysis conditions. For example, (-)-(2R,3S)-2-methyl-
3-phenyl-4-penten-1-ol was obtained in 64% overall yield from thioamide 5h
as shown below. The alcohol was obtained with >30:1 syn:anti ratio. Mosher
ester analysis (NMR) indicated the ee to be >97% (see Supporting Information
for details).
(12) The small amount of the anti diastereomers arises primarily from the
E-bromide (ca. 3% by NMR) present in the alkylating agent. If corrected for
the contamination by the E-isomer, the syn:anti selectivity for the rearrange-
ment is >99%.