Toward the development of a general chiral auxiliary. 9. Highly diastereoselective alkylations and acylations to form tertiary and quaternary centers.

Article abstract of DOI:10.1021/ol016738i

[reaction--see text] Enolates of a new camphor-derived lactam auxiliary are shown to monoalkylate with very high diastereoselectivity. A second alkylation occurs with reactive alkylating agents to afford quaternary centers also with high diastereoselectiv

Full text of DOI:10.1021/ol016738i

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3777-3780
Toward the Development of a General
Chiral Auxiliary. 9. Highly
Diastereoselective Alkylations and
Acylations to Form Tertiary and
Quaternary Centers
Robert K. Boeckman, Jr.,* Debra J. Boehmler, and Rhonda A. Musselman
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627-0216
rkb@rkbmac.chem.rochester.edu
Received September 10, 2001
ABSTRACT
Enolates of a new camphor-derived lactam auxiliary are shown to monoalkylate with very high diastereoselectivity. A second alkylation occurs
with reactive alkylating agents to afford quaternary centers also with high diastereoselectivity. In accord with a proposed model for
diastereoselection, lithium and sodium enolates provide products with an opposite sense of asymmetric induction.
Chiral auxiliary based alkylation methodologies have cen-
tered on forming tertiary centers with enolates of sterically
constrained amides or imides,1 esters,2 and N-acylsultams.3
Some examples exist of the successful formation of chiral
quaternary carbon centers. However, highly substituted
enolates, particularly those derived from acyclic imide and
N-acylsultams, are generally too unstable to allow creation
of quaternary carbon centers, readily undergoing elimination
to ketenes.4 Recent advances have also been made in catalytic
asymmetric alkylation, particularly as applied to R-amino
acid synthesis.5
The class of camphor lactam auxiliaries 1-3 (Figure 1)
developed in our laboratories have shown considerable utility
in asymmetric Diels-Alder and aldol reactions, particularly
(1) (a) Evans, D. A.; Ennis, M. D., Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737-1739. (b) Kawanami, Y.; Ito, Y.; Kitagawa, T.; Taniguchi,
Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1984, 25, 857-860. (c)
Jeong, K. S.; Parris, K.; Ballester, P.; Rebek, J., Jr. Angew. Chem. 1990,
102, 550-551. (d) Yan, T. H.; Chu, V. V.; Lin, T. C.; Wu, C. H.; Liu, L.
H. Tetrahedron Lett. 1991, 32, 4959-4962. (e) Rueck, K. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 433-435. (f) Crimmins, M. T.; Emmitte, K. A.;
Katz, J. D. Org. Lett. 2000, 2, 2165-2167.
(2) (a) Schmierer, R.; Grotemeier, G.; Helmchen, G.; Selim, A. Angew.
Chem. 1981, 93, 209-211. (b) Helmchen, G.; Wierzchowski, R. Angew.
Chem. 1984, 96, 59-60. (c) Duhamel, P.; Eddine, J.; Valnot, J. Y.
Tetrahedron Lett. 1984, 25, 2355-2358. (d) Alvarez-Ibarra, C.; Csakye,
A. G.; Maroto, R.; Quiroga, M. L. J. Org. Chem. 1995, 60, 7934-7940.
(3) (a) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989,
30, 5603-5606. (a) Martin, N.; Martinez-Grau, A.; Seoane, C.; Marco, J.
L. Tetrahedron Lett. 1993, 34, 5627-5630. (b) Lin, J.; Chan, W. H.; Lee,
A. W. M.; Wong, W. Y. Tetrahedron 1999, 55, 13983-13998.
(4) (a) Schoellkopf, U.; Lonsky, R. Synthesis 1983, 675-676. (b)
Tomioka, K.; Ando, K.; Takemasa, Y.; Koga, K. J. Am. Chem. Soc. 1984,
106, 2718-2719. (c) Ando, K.; Takemasa, Y.; Tomioka, K.; Koga, K.
Tetrahedron 1993, 49, 1579-1588. (d) Enders, D.; Eichenauer, H.; Baus,
U.; Schubert, H.; Kremer, K. A. M. Tetrahedron 1984, 40, 1345-1359.
(e) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933-2960. (f)
Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F. J. Am. Chem.
Soc. 1997, 119, 4565-4566. (g) Meyers, A. I.; Seefeld, M. A.; Lefker, B.
A.; Blake, J. F.; Williard, P. G. J. Am. Chem. Soc. 1998, 120, 7429-7438.
(5) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414-
12415. (b) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K.
Tetrahedron 1999, 56, 179-185. (c) Matsuo, J.-i.; Odashima, K.; Kobayashi,
S. Org. Lett. 1999, 1, 345-347. (d) Ooi, T.; Takeuchi, M.; Kameda, M.;
Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228-5229.
10.1021/ol016738i CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/13/2001

Table 1. Alkylations and Acylations To Give Tertiary Centers
Figure 1. The camphor-derived chiral auxiliaries.
4 R1
R2X
dra
yield (%) product
for the creation of quaternary carbon centers.6 Key to
extending the scope of these auxiliaries to include construc-
tion of tertiary and quaternary centers by alkylation and
acylation will be the stability of imide enolates derived from
1 and 2, relative to those derived from N-acyloxazolidinones
and sultams.1,3
a CH3
a CH3
a CH3
a CH3
b C2H5 CH3I
c iC3H7 CH3I
d allyl
a CH3
b C2H5 C2H5COCl
CH2dCHCH2Br
PhCH2Br
PMBOCH2CHdCHCH2I
49:1
99:1
99:1
90
7
8
9
10
11
12
13
14
15
89b
70
85
50
92c
73c
82
tBuCHdCHCHdCHCH2I 99:1
99:1
49:1
49:1
20:1
50:1
CH3I
PhCOCl
The lithium salts of 1 and 2 (n-BuLi/THF) are readily
acylated with a variety of acid chlorides and mixed pivaloyl
anhydrides to afford the imides 4 and 5.6 Subsequent
deprotonation of imides 4 with LDA affords exclusively the
Z enolates 6 as demonstrated by the NOE exhibited by the
TBS N,O-keteneacetals derived by trapping with tert-
butyldimethylsilyl (TBS) chloride.7 Treatment of 6 with a
variety of alkyl halides, including methyl, allylic, and
benzylic bromides and iodides cleanly affords 50-92%
yields of monoalkylation products having diastereomeric
ratios >49:1 (Table 1). The sense of asymmetric induction
found for the resulting monoalkylation products 7-15 is
consistent with approach of the electrophile to the face of
the enolate 6 opposite to the bulky gem-dimethyl bridge,
resulting from a combination of steric factors and restricted
rotation about the C-Naux bond in 6 owing to chelation.
The more reactive benzoyl and propionyl chlorides af-
forded selectivities of 20-50:1. Success with benzoyl
chloride is especially noteworthy given the ease of epimer-
ization in this case (Table 1). The nearly enantiomerically
pure R-substituted acyl groups could be cleaved from the
auxiliary by hydrolysis or alcoholysis (LiOOH, LiOBn),1,6
reductively (LAH, LiBH4),1,3,6 or by conversion to the
Weinreb amide (EtAlClN(OCH3)CH3) or thio ester (LiSEt).
The latter are particularly versatile undergoing direct conver-
sion to esters and amides and by reduction with DIBAl-H
to aldehydes.
68d,e
a Diastereomeric ratio was determined by 1H NMR. b Configuration was
proven by cleaving the auxiliary with LAH and comparing the optical
rotation to the known alcohol.1a c Absolute configuration was verified by
cleaving the auxiliary to the carboxylic acid with LiOH and comparing the
optical rotation to known compounds.8 d Also, 28% of O-acylation product
was observed. e Absolute configuration was determined by reducing the
ketone with ZnBH4, cleaving the auxiliary with LAH, and comparing the
optical rotation to a known diol.9
permit facile, highly diastereoselective monoalkylation and
acylation, we went on to investigate the more challenging
second alkylation to afford quaternary carbon centers.
Our initial attempts to effect introduction of the second
alkyl group employed the lithium enolate generated by
treatment of 12 with LDA as before. The resulting lithium
enolate afforded products 16 and 17 in low chemical yield
with poor diastereoselectivity. We first ascertained whether
the problem lay in inefficient or nonselective enolate
formation. The enolate generated with LDA was readily
trapped with TBS chloride in quantitative yield. Analysis of
the resulting N,O-keteneacetal by NOE showed that enolate
formation was highly Z-selective.7 Thus problems with
enolate formation are not the origin of the low reactivity
and selectivity.
To rule out unusually stable enolate aggregates, we utilized
lithium salts and HMPA to disrupt aggregation. However,
little improvement in the diastereoselectivity was observed.
The major product was determined to be (S)-17, which
supports the model invoking chelation coupled with steric
factors to control the diastereoselectivity.
Despite some prior successes,4 recent literature reports
document continuing difficulties in achieving high diastereo-
selectivities and yields in the creation of quaternary carbon
centers.10 Since imides derived from 2 have been shown to
Use of more ionic sodium enolates was expected to
enhance reactivity.1f,11 Generation of the enolate 12 and 15
(6) (a) Boeckman, R. K., Jr.; Liu, Y. J. Org. Chem. 1996, 61, 7984-
7985. (b) Boeckman, R. K., Jr.; Wrobleski, S. T. J. Org. Chem. 1996, 61,
7238-7239. (c) Boeckman, R. K., Jr.; Connell, B. T. J. Am. Chem. Soc.
1995, 117, 12368-12369. (d) Boeckman, R. K., Jr.; Johnson, A. T.;
Musselman, R. A. Tetrahedron Lett. 1994, 35, 8521-8524. (e) Boeckman,
R. K., Jr.; Nelson, S. G.; Gaul, M. D. J. Am. Chem. Soc. 1992, 114, 2258-
2260.
(7) A 12-20% NOE enhancement of the cis methyl, methylene, or
methine protons was observed (difference 1D NOE) upon irradiation of
the methyl groups of the TBS group of the O,N-silylketeneacetal.
(8) (a) Lardicci, L.; Menicagli, R.; Caporusso, A. M.; Giacomelli, G.
Chem. Ind. (London) 1973, 184-185. (b) Evans, D. A.; Takacs, J. M.
Tetrahedron Lett. 1980, 21, 4233-4236.
(9) Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem.
Soc. 1990, 112, 2767-2772.
(10) (a) Hanamoto, T.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett.
1986, 27, 2463-2464. (b) Roth, G. P.; Leonard, S. F.; Tong, L. J. Org.
Chem. 1996, 61, 5710-5711. (c) Schwarz, J. B.; Meyers, A. I. J. Org.
Chem. 1998, 63, 1619-1629. (d) Dalko, P. I.; Brun, V.; Langlois, Y.
Tetrahedron Lett. 1998, 39, 8979-8982. (e) Van der Werf, M. J.; De Bont,
J. A. M.; Swarts, H. J. Tetrahedron: Asymmetry 1999, 10, 4225-4230. (f)
Hosokawa, S.; Sekiguchi, K.; Enemoto, M.; Kobayashi, S. Tetrahedron Lett.
2000, 41, 6429-6433.
3778
Org. Lett., Vol. 3, No. 23, 2001

using sodium diisopropylamide (NDA),12 shown to be >49:1
Z by NOE as above,7 led to high diastereomeric ratios and
modest to excellent yields and conversions upon reaction
with allyl iodide (Table 2). Reaction temperatures of -30
Scheme 1. Stereochemistry of Alkylation of 12
Table 2. Alkylations Creating a Quaternary Center
case of nitrogen.11,16 Compounding the difficulties is the
increased tendency of electron-rich enolates to decompose
to ketene and auxiliary.
To determine if 1 and 2 offered any advantage, 1 was
acylated with benzyloxyacetyl chloride to afford 19. Depro-
tonation of 19 using both sodium and lithium hexamethyl-
disilazane as bases and then treatment with allyl or methyl
iodide afforded the expected monoalkylation products in
good yields (Table 3).17 Unfortunately, only modest diaste-
tempa
yield (conv)
18
R1
(°C)
16 + 17 (%)
16a ,b:17a ,bb,c
(%)
i
12 Pr
12 Pr
15 C(O)Et
0
-30
-40
36 (65)
60 (76)
67 (100)
13.7:1
20.5:1
99:1
0
10
0
i
a General reaction conditions: a solution of 12 in dry THF was added to
2 equiv of NDA in THF at -45 °C, followed by addition of neat allyl
iodide (10 equiv) after 40 min, warming to -30 or 0 °C, and stirring for 4
h. b The diastereomeric ratio was quantified by GLC. c Derivatization was
employed to determine the absolute configuration as detailed in the
Supporting Information.
Table 3. Alkylation of Glycolate 19
to -40 °C were optimal for enhancing reactivity and
inhibiting enolate decomposition. Less polar mixtures of THF
and toluene gave improved diastereoselectivity (as high as
49:1) but did not afford yields or conversions as high as THF
alone.
The major products 16 were determined to have the R
configuration, established by chemical correlation or X-ray
analysis, opposite to that obtained with the lithium enolate.
The stereochemical outcome is best rationalized by assuming
that the sodium enolate orients itself perpendicular to the
endocyclic lactam π system to avoid unfavorable electronic
interactions as do amide and N-acylsultam enolates.13 The
enolate conformation where the C-O bond bisects the C4-
C7 lactam bond is much preferred on the basis of molecular
mechanics calculations (MacroModel, ver. 6, 1998).14 The
electrophile then approaches the least hindered enolate face.
Alkylation of chiral enolates bearing an R-heteroatom have
been extensively studied.1f,15 Chiral imide enolates experience
problems possibly arising from competitive chelation of the
counterion by the heteroatom rather than the imide carbonyl.
Loss of control about the enolate Naux-C bond occurs, which
is required for high levels of diastereoselectivity. Indirect
methods have been used to introduce the heteroatom in the
basea
R2X
yield (%)
drb
1c (%)
LiHMDS
LiHMDS
NaHMDS
NaHMDS
CH2dCHCH2I
CH3I
CH2dCHCH2I
CH3I
74
66
67
62
2.2:1
2.5:1
3.6:1
1.4:1
21
20
32
10
a General reaction conditions: a solution of 19 in dry THF was added to
a 0.5 M solution of base (1.5 equiv) at -78 °C, followed by immediate
addition of neat R2X, warming to -40 °C, and stirring for 24 h. b The
absolute configuration was determined by cleaving the auxiliary to the
Weinreb amide, reducing with DIBAl-H and, comparing the optical rotation
to the known aldehydes.18 c The remainder of the mass is recovered starting
material.
reoselectivites (1.4-3.6:1) were observed favoring the R
isomers 20/22 at the optimal temperature (-40 °C).
(15) (a) Frater, G.; Mueller, U.; Guenther, W. Tetrahedron Lett. 1981,
22, 4221-4224. (b) Kelly, T. R.; Arvanitis, A. Tetrahedron Lett. 1984, 25,
39-42. (c) Helmchen, G.; Wierzchowski, R. Angew. Chem. 1984, 96, 59-
60. (d) Enomoto, M.; Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1985, 26, 1343-1344. (e) Pearson, W. H.; Cheng, M. C. J. Org. Chem.
1986, 51, 3746-3748. (f) Ludwig, J. W.; Newcomb, M.; Bergbreiter, D.
E. Tetrahedron Lett. 1986, 27, 2731-2734. (g) Cardillo, G.; Orena, M.;
Romero, M.; Sandri, S. Tetrahedron 1989, 45, 1501-1508. (h) Burke, S.
D.; Quinn, K. J.; Chen, V. J. J. Org. Chem. 1998, 63, 8626-8627. (i)
Chappell, M. D.; Stachel, S. J.; Lee, C. B.; Danishefsky, S. J. Org. Lett.
2000, 2, 1633-1636. (j) Jung, J. E.; Ho, H.; Kim, H.-D. Tetrahedron Lett.
2000, 41, 1793-1796.
(11) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D.
H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64, 6411-6417.
(12) Lochmann, L.; Trekoval, J. J. Organomet. Chem. 1979, 179, 123-
132.
(13) (a) Pugh, J. K.; Streitwieser, A. J. Org. Chem. 2001, 66, 1334-
1338. (b) Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G.
Tetrahedron Lett. 1988, 29, 3559-3562.
(14) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440-467.
(16) (a) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am.
Chem. Soc. 1990, 112, 4011-30. (b) Evans, D. A.; Britton, T. C.; Dellaria,
J. F., Jr. Tetrahedron 1988, 44, 5525-40.
Org. Lett., Vol. 3, No. 23, 2001
3779

To our surprise, the R diastereomer was major independent
of both base and electrophile, consistent with reaction via a
conformer comparable to that shown in Scheme 2. No
Table 4. Alkylation of Glycolate 24
Scheme 2. Stereochemistry of Alkylation of 19 and 24
basea
R2X
yield (%)
drb
2c (%)
LiHMDS
LiHMDS
NaHMDS
NaHMDS
C6H5CH2Br
CH3I
C6H5CH2Br
CH3I
95
74
99
86
3.5:1
3.8:1
4.4:1
6.4:1
0
11
0
7
a General reaction conditions: a solution of 24 in dry THF was added to
an 0.5 M solution of of the base (1.5 equiv) at -78 °C, followed by
immediate addition of neat R2X, warming to -40 °C, and stirring for 24 h.
b The diastereomeric ratio was determined by 1H NMR. c The remainder
of the mass is recovered starting material.
since varying amounts of 1 and 2 (and occasionally N-
alkylated analogues) were obtained during alkylations of 19
and 24 (Tables 3 and 4). Treatment of 24 with NaHMDS
and CH3I, followed by quenching and aliquot analysis at 1
min intervals, revealed that almost all of 24 was consumed
within 5 min, affording 75% of 27 and 28 (4.7:1) and 25%
lactam 2. Over 24 h, the amount of lactam decreased to 7%
and the diastereomeric ratio steadily increased (see Table
4). When the enolate from 19 was examined, consumption
of 19 was slower. Initially, the S diastereomer predominated
(after 5 min conversion to 20% of 22 and 23 (2.3:1) and
32% of 1), but after 24 h, the diastereomeric ratio 22/23 had
degraded to 0.95-1.4:1. Thus, reversible conversion of the
enolates from both 19 and 24 to the corresponding ketenes
and the lactam anions from 1 and 2 appears to be dramati-
cally impacting stereochemical outcome.19
dependence on counterion supports the idea that the lower
diastereoselectivity results from loss of control over the
C-Naux bond in the enolate.
Further studies of the role of ketene formation in deter-
mining diastereoselectivity are ongoing to enhance stereo-
control in alkylation of R-heteroatom enolates.
To determine whether the bridgehead methyl is critical to
the observed stereochemistry, we examined enolates derived
from 24. As shown in Table 4, alkylation of Li and Na
enolates derived from 24,17 itself obtained by acylation of
2, provided alkylation products 25-27 in excellent yield.
The diastereoselectivity was improved (4.4-6.4:1) some-
what. During our studies Crimmins reported even higher
selectivity for cases limited to allylic iodides.1f
Surprisingly, the major diasteromers (R)-25/(R)-27 ob-
tained using 24 were not only independent of counterion but
were identical to the major products obtained from 19,
inconsistent with our stereochemical model and unprec-
edented for imides derived from 1 and 2 (Scheme 2).
Other factors were thus influencing the stereochemical
outcome. The role of ketene formation was investigated,
Acknowledgment. We are grateful to NIGMS of the
National Institutes of Health for the award of a research grant
(GM-30345) in support of these studies.
Supporting Information Available: Characterization
data for 4b-d, 7-16, 19-20, 22, 24-28 and experimental
procedures for correlation of 16. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL016738I
(18) (a) Fuganti, C.; Grasselli, P.; Servi, S.; Spreafico, F.; Zirotti, C.;
Casati, P. J. Chem. Res., Synop. 1984, 112-113. (b) Solladie, G.; Arce,
E.; Bauder, C.; Carreno, M. C. J. Org. Chem. 1998, 63, 2332-2337.
(19) Control experiments using the lactam anion of 1 and a mixture of
22/23 (9:1) showed no formation of crossover products or change in the
diastereomeric ratio of 22/23.
(17) >98% Z selectivity in enolate formation was verified by NOE.7
3780
Org. Lett., Vol. 3, No. 23, 2001