A practical chiral bicyclic thioglycolate lactam auxiliary for stereoselective quaternary carbon formation

Article abstract of DOI:10.1021/ol060106k

Chiral bicyclic thioglycolate lactams may be prepared in three steps from inexpensive commercial materials. The resulting lactams may be alkylated three times, twice using basic enolization and once using reductive enolization, to form α-quaternary carbox

Full text of DOI:10.1021/ol060106k

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1359-1362
A Practical Chiral Bicyclic Thioglycolate
Lactam Auxiliary for Stereoselective
Quaternary Carbon Formation
Aze´lie Arpin, Jeffrey M. Manthorpe, and James L. Gleason*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke St. West, Montreal, QC,
Canada H3A 2K6
jim.gleason@mcgill.ca
Received January 13, 2006
ABSTRACT
Chiral bicyclic thioglycolate lactams may be prepared in three steps from inexpensive commercial materials. The resulting lactams may be
alkylated three times, twice using basic enolization and once using reductive enolization, to form -quaternary carboxylic acid derivatives in
r
high yield and with high diastereoselectivity. The alkylation products may be cleaved under either acidic or reductive conditions to furnish
either carboxylic acids or primary alcohols, respectively.
The formation of all-carbon quaternary stereocenters is a
significant challenge in asymmetric synthesis.1 One approach
to this problem is by the alkylation of R,R-disubstituted
enolates. Although some progress has been made in achiev-
ing this goal using catalytic asymmetric methods,2 most
methods have involved chiral auxiliaries,3 particularly in
reactions with unactivated alkyl halides.4 As enolate stereo-
control, a key requirement in most methods, is difficult to
achieve in the formation of simple acyclic R,R-disubstituted
enolates, most enolates that have been employed in quater-
nary stereocenter formation have either been cyclic or
possessed chelating functionality, thus limiting the generality
of these methods.
Recently, we reported the stereoselective preparation of
acyclic R,R-disubstituted enolates by reduction of bicyclic
(3) For chiral auxiliary based methods for quaternary centers formation,
see: (a) Hanamoto, T.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1986,
27, 2463-2464. (b) Davies, S. G.; Walker, J. C. J. Chem. Soc., Chem.
Commun. 1986, 495-496. (c) Ihara, M.; Takahashi, M.; Niitsuma, H.;
Taniguchi, N.; Yasui, K.; Fukumoto, J. Org. Chem. 1989, 54, 5413-5414.
(d) Schultz, A. G. Acc. Chem. Res. 1990, 23, 207-213. (e) Groaning, M.
D.; Meyers, A. I. Tetrahedron 2000, 56, 9843-9873. (f) Frater, G. HelV.
Chim. Acta 1979, 62, 2825-2528. (g) Enders, D.; Zamponi, A.; Raabe,
G.; Runsink, J. Synthesis 1993, 725-728. (g) Hosokawa, S.; Sekiguchi,
K.; Enemoto, M.; Kobayashi, S. Tetrahedron Lett. 2000, 41, 6429-6433.
(h) Boeckman, R. K., Jr.; Boehmler, D. J.; Musselman, R. A. Org. Lett.
2001, 3, 3777-3780. (i) Enders, D.; Teschner, P.; Raabe, G.; Runsink, J.
Eur. J. Org. Chem. 2001, 4463-4466.
(4) For selected examples of quaternary carbon formation from enolates
via activation of allylic, aryl, and vinyl halides, see: (a) Trost, B. M.;
Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759-6760. (b) Spielvogel,
D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500-3501. (c) Chieffi,
A.; Kamikawa, K.; Ahman, J.; Fox, J. M.; Buchwald, S. L. Org. Lett. 2001,
3, 1897-1900. For recent organocatalytic aldol and imine additions, see:
(d) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10006-10007.
(e) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2004,
43, 2420-2423. For examples of enolate Michael additions, see reviews
in ref 1 and (e) Christoffers, J.; Baro, A. Angew. Chem. Int. Ed. 2003, 42,
1688-1690.
(1) For reviews, see: (a) Denissova, I.; Barriault, L. Tetrahedron 2003,
59, 10105-10146. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998, 37, 388-401. (c) Fuji, K. Chem. ReV. 1993, 93, 2037-2066. (d)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591-4597.
(e) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5363-5367.
(2) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
1984, 106, 446-447. (b) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe,
K.; Koga, K. J. Am. Chem. Soc. 1994, 116, 8829-8830. (c) Doyle, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62-63. For examples of
catalytic asymmetric alkylations to form R,R-dialkylated-R-amino acids,
see: (d) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013-3028. (e)
O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506-517.
10.1021/ol060106k CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/03/2006

thioglycolate lactams and subsequently demonstrated their
alkylation to form quaternary carbon centers with excellent
levels of stereocontrol (Scheme 1).5 The method can also
Scheme 2. Synthesis of Bicyclic Lactams
Scheme 1. Quaternary Carbon Formation via Bicyclic
Thioglycolate Lactams
be extended to aldol reactions if the lithium enolate is first
transmetalated to boron.6 The removal of the need for a cyclic
enolate held the potential for this to be a highly general
method. However, there were several limitations in-
cluding low selectivity in the alkylations of (E)-enolates, the
inability to directly hydrolyze the products to carboxylic
acids, and most importantly, a lengthy 10-step synthesis of
the starting lactam. Herein we report a significantly improved
second-generation bicyclic lactam that removes these short-
comings resulting in a general purpose auxiliary with wide
scope.
Incorporation of the first two alkyl groups of the R-
quaternary center could easily be achieved by sequential
alkylation of 5 using LDA and an alkyl halide in the presence
of LiCl.10 Both alkylation steps proceeded in high yield and
with excellent stereoselectivity (Table 1). In both cases, the
Table 1. Alkylation of Bicyclic Lactams
Our prior studies showed that a 5,7-bicylic thioglycolate
lactam was required to maintain the optimum O-C-C-S
dihedral angle necessary for high enolate stereocontrol.5a To
prepare such an auxiliary from proline, a one-carbon exten-
sion was required, resulting in a lengthy auxiliary synthesis.
We reasoned that the auxiliary preparation could be signifi-
cantly shortened by incorporating an oxygen in the five-
membered ring (e.g., 5).7 This was expected to enable a
modular synthesis from readily available starting materials
as well as to facilitate hydrolysis (and synthesis) of the
auxiliary through N T O acyl transfer chemistry. One
concern was that low yields and poor stereoselectivity have
been reported in closing related 5,7-bicyclic lactam acetals.8
In practice, however, we found that the desired acetals could
be formed efficiently and in high yield. S-Alkylation of
methyl thioglycolate with 2-(2-bromoethyl)-1,3-dioxolane
followed by transesterification/O f N acyl transfer with the
alkoxide of valinol produced lactam precursor 4 cleanly.
Transacetalization in 4 with BF3‚OEt2 afforded bicyclic
lactam 5 in excellent yield as a single stereoisomer (Scheme
2). The overall process could be carried out on large scale
without chromatographic purification of the intermediates;
the final product was isolated directly as a crystalline solid
(mp 138-139 °C).9
R1-X product yield [%] dr R2-X product yield [%] dra
Et-I
6a
95
98:1 Me-I
Pr-I
99:1 Et-I
99:1 Et-I
98:2 Me-I
Et-I
7a
7b
7c
7d
7e
7f
90
92
86
89
95
92
99:1
98:2
99:1
97:3
98:2
99:1
Me-I
Pr-I
Bn-Br
6b
6c
6d
90
89
88
a Determined by GC using a Chirasil Dex column.
alkyl halide approaches the convex face of the bicyclic lactam
enolate; as expected the isopropyl group plays no significant
role in facial discrimination. This result is consistent with
that observed in our first-generation auxiliary.
The reduction of the dialkylated bicyclic lactams to form
R,R-disubstituted enolates was easily carried out under
standard Birch conditions (Li/NH3, THF, -78 °C). Although
lithium di-tert-butylbiphenylide could also be used as a
reducing agent, reactions were generally cleaner, afforded
higher yields in the subsequent alkylations, and could be run
on larger scales using Li/NH3. In general, alkylations of the
(5) (a) Manthorpe, J. M.; Gleason, J. L. J. Am. Chem. Soc. 2001, 123,
2091-2092. (b) Manthorpe, J. M.; Gleason J. L. Angew. Chem., Int. Ed.
2002, 41, 2338-2341.
(6) Burke, E. D.; Gleason, J. L. Org. Lett. 2004, 6, 405-407.
(7) The derived bicyclic system bears a close resemblance to the bicyclic
lactams reported by Meyers that give excellent selectivity for quaternary
carbon formation via cyclic enolates. See ref 3e.
(9) Lactam 5 is the kinetic transacetalization product; extended treatment
with an excess of BF3‚OEt2 over 5 days affords the stereoisomeric aminal
as the major product (2:1 ratio).
(10) For the use of LiCl in alkylations of amides enolates, see: Myers,
A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. G.; Gleason J.
L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(8) Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001,
66, 1413-1419.
1360
Org. Lett., Vol. 8, No. 7, 2006

resulting R,R-disubstituted enolates were complete within a
few hours at -78 °C, and the products could be isolated in
high yield (Table 2). The reaction proved to be highly
stereoselectivity in the formation of stereorelated products
(compare entry 1 vs entry 6).16
Auxiliary cleavage was carried out under two sets of
conditions. First, direct hydrolysis to the carboxylic acid
occurs in excellent yield under acidic conditions (5 M H2SO4,
H2O, dioxane; Table 3). Monitoring this hydrolysis by NMR
Table 2. Reduction and Alkylation to Form Quaternary Carbon
Stereocenters
Table 3. Direct Hydrolysis to Carboxylic Acids
entry lactam R1 R2
R3-X
product yield [%] dra
(Z)-Enolates
1
2
3
4
5
6
7a
7a
7a
7a
7d
7e
Et Me Bn-Br
Et Me Pr-I
Et Me TBSO(CH2)3I
Et Me Cl(CH2)4I
Pr Et allyl-Br
Bn Me Et-I
9a
9b
9c
9d
9e
9f
92
88
86
79
91
87
93:7
99:1
96:4
95:5
95:5
97:3
entry
series
R1
R2
R3
yield [%]
1
2
4
4
5
6
a
b
d
g
h
j
Et
Et
Et
Me
Me
Me
Me
Me
Me
Et
Et
Et
Bn
Pr
81
79
80
60
82
81
Cl(CH2)4
Bn
(E)-Enolates
Me Et Bn-Br
Me Et Pr-I
Me Et Cl(CH2)4I
Me Et TBSO(CH2)3I
Et Pr allyl-Br
Pr
7
8
9
10
11
7c
7c
7c
7c
7b
9g
9h
9i
9j
9k
85
91
81
84
89
93:7
99:1
95:5
95:5
96:4
Cl(CH2)4
revealed, as expected, that the reaction occurs by acetal
cleavage to form a â-amido alcohol followed by N f O
acyl transfer to form a â-aminoester, which finally undergoes
acid hydrolysis to the carboxylic acid.17 Alternatively,
reductive cleavage to the primary alcohol could also be
carried out in excellent yield using lithium amidoborohydride
(Table 4) in THF.18
a Diastereoselectivities were determined by chiral HPLC and/or GC
analysis of products after auxiliary removal. See Supporting Information
for details.
stereoselective for both (Z)- and (E)-enolates.11,12 The
increased selectivity in the latter case, relative to the first-
generation auxiliary, presumably results from the pseudo-
C2-symmetric nature of the enolate, which compensates for
rotational isomerism about the N-C enolate bond.13 The
absolute configuration of the alkylation products is consistent
with that observed with true C2-symmetric enolates.14,15 The
reaction worked well with a variety of functionalized and
unfunctionalized alkyl halides. Significantly, the method is
not limited to products that contain methyl groups at the
quaternary carbon stereocenter, and the method can produce
a stereocenter with three groups of nearly identical size:
ethyl, propyl, and allyl (entries 5 and 11). Finally, in some
cases, altering the order of alkylation improved the dia-
Table 4. Reductive Cleavage to Primary Alcohols
entry
series
R1
R2
R3
yield [%]
1
2
2
3
4
a
e
f
g
k
Et
Pr
Bn
Me
Et
Me
Et
Me
Et
Bn
allyl
Et
Bn
allyl
85
84
87
85
84
(11) Enolate selectivities were estimated at >90:10 by reduction of 7a
(Z-enolate) and 7c (E-enolate) with LiDBB followed by trapping with
TMSCl.
Pr
(12) Because of rotational isomerism about the amide bond, it was not
possible to determine the stereoselectivity of the alkylation reactions directly
by NMR. Thermal instability prevented heating to coalesce rotational
isomers. Separation by GC and/or HPLC was also not possible. Thus
diastereoselectivity was inferred from the stereoisomer ratio of the auxiliary
cleavage products.
(13) Kim, Y.-J.; Streitwieser, A.; Chow, A.; Fraenkel, G. Org. Lett. 1999,
1, 2069-2071.
(14) Kawanami, Y.; Ito, Y.; Kitagawa, T.; Taniguchi, Y.; Katsuki, T.;
Yamaguchi, M. Tetrahedron Lett. 1984, 25, 857-860.
(15) The absolute configuration was determined by comparison of the
optical rotation of the hydrolysis products of 9b and 9h with literature values.
See Supporting Information for details.
In conclusion, we have developed a bicyclic lactam
auxiliary that may be readily prepared in a short sequence
(16) Products 9a and 9f are not true stereoisomers, as alkylation on sulfur
produces molecules with different molecular formulas. However, upon
cleavage of the auxiliary, the products are identical.
(17) For examples of N f O acyl transfer in the acceleration of amide
hydrolysis, see: Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21,
4233-4236 and ref 10.
(18) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996,
37, 3623-3626.
Org. Lett., Vol. 8, No. 7, 2006
1361

from inexpensive starting materials. The auxiliary produces
all-carbon quaternary stereocenters with excellent stereo-
selectivity via alkylation of R,R-disubstituted enolates, and
the products may be readily cleaved to afford R-quaternary
carboxylic acids and primary alcohols. Application of this
method to other types of enolate functionalizations as well
as to natural product synthesis is currently under study.
support from NSERC and FQRNT in the form of postgradu-
ate scholarships, and J.M.M. acknowledges support from
FCAR/FQRNT in the form of a postgraduate scholarship.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank NSERC and Merck
Frosst Inc. for funding of this research. A.A. acknowledges
OL060106K
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Org. Lett., Vol. 8, No. 7, 2006