Anthracene cycloadducts as highly selective chiral auxiliaries

Article abstract of DOI:10.1021/jo702724t

(Chemical Equation Presented) A new chiral auxiliary was designed and easily prepared from a Diels-Alder cycloadduct of an enantiomerically pure anthracene with maleimide. Excellent diastereoselectivities in Diels-Alder reactions, conjugate additions, and aldol reactions employing these auxiliaries are now reported.

Full text of DOI:10.1021/jo702724t

SCHEME 1. Nucleophilic Cleavage of the Oxazolidinones
Anthracene Cycloadducts as Highly Selective
Chiral Auxiliaries
Xiang Liu and John K. Snyder*
Boston UniVersity, Department of Chemistry, Boston,
Massachusetts 02215
jsnyder@bu.edu
SCHEME 2. Synthesis of Auxiliary 4
ReceiVed December 21, 2007
A new chiral auxiliary was designed and easily prepared from
a Diels-Alder cycloadduct of an enantiomerically pure
anthracene with maleimide. Excellent diastereoselectivities
in Diels-Alder reactions, conjugate additions, and aldol
reactions employing these auxiliaries are now reported.
stereogenic substituent of the anthracene can be selectively
manipulated by simple procedures, such as reductions and
Grignard additions. The simple preparation of the crystalline
lactam 4 from readily obtainable chiral anthracene 26 makes it
a candidate as a facially restrictive chiral auxiliary. The recent
work of Sua´rez7 on the use of a levoglucosenone-anthracene
cycloadduct, which also produces a facially restrictive chiral
auxiliary for Diels-Alder chemistry, has led us to report our
work on 4.
Acylation of 4 produces a Lewis acid chelation site to lock
an R,â-unsaturated carbonyl moiety (acrylate, crotonate etc)
above a rigidly positioned aryl ring, providing the desired facial
selectivity. Initial studies focused on cycloadditions of croto-
nylated auxiliary 5, readily prepared following Evans’ acylation
procedure (88%),8 with cyclopentadiene (Table 1).
Extensive screening of Lewis acids demonstrated that the
reaction could be promoted by several catalysts with high endo/
exo selectivities (Table 1). The rates and selectivities were
dependent upon the Lewis acid; SnCl4 (entries 1 and 2), TiCl4
(entry 3), Et2AlCl (entry 4), Me2AlCl (entry 5), and BF3‚OEt2
all gave very high catalytic activities (100% conversion in 3 h
or less at -100 °C), but SnCl4 showed much better diastereo-
selectivity favoring endo-I cycloadduct 6a (entries 1 and 2).
The best selectivity was achieved with ZrCl4, though the reaction
was sluggish at -78 °C. With ZrCl4 (10 mol %) at -50 °C, an
endo/exo diastereoselectivity of >200:1 with an endo-I/endo-
II diastereoselectivity of 75:1 was obtained in 6 h. The selectivity
was slightly lower when Me2AlCl or Et2AlCl were used. Other
Chiral auxiliaries have found wide applications in a variety
of chirality transfer reactions with some of the best known
auxiliaries belonging to the Evans class of oxazolidinones.1 In
the past two decades, these auxiliaries (1) have proven to be
among the best for controlling stereoselectivity in Diels-Alder,
aldol, and many other reactions. Subsequent to Evans’ initial
reports, many related auxiliaries have been synthesized and
investigated,2 and the search for universally applicable chiral
auxiliaries has continued, as exemplified by the nice contribution
from the Boeckman group with their camphor-derived auxiliary.3
“Cleavability” of the auxiliaries can be an issue in chiral
auxiliary methodology (Scheme 1). While LiOOH is frequently
applied to remove Evans’ type auxiliaries, greatly favoring
regioselective cleavage of the exocyclic carbonyl group, un-
wanted endo cleavage has been observed with some sterically
congested acyl imides.4
Previously, we reported highly diastereoselective cycloaddi-
tions between enantiomerically pure anthracenes bearing C9
stereogenic groups with maleimides (Scheme 2).5 We also
demonstrated that the imide carbonyl remote to the original
(1) Reviews: (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta
1997, 30, 3. (b) Evans, D. A.; Shaw, J. T. Actual. Chim. 2003, 35.
(2) Recent reviews: (a) Gnas, Y.; Glorius, F. Synthesis 2006, 1899. (b)
Evans, D. A.; Helmchen, G.; Ruping, M.; Wolfgang, J. In Asymmetric
Synthesis: The Essentials, Christmann, M., Bra¨se, S., Eds.; Wiley-VCH:
Weinheim, Germany, 2007; p 3.
(3) Boeckman, R. K., Jr.; Shao, P.; Wrobleski, S. T.; Boehmler, D. J.;
Heintzelman, G. R.; Barbosa, A. J. J. Am. Chem. Soc. 2006, 128, 10572
and references therein.
(4) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141.
(5) (a) Burgess, K. L.; Corbett, M. S.; Eugenio, P.; Lajkiewicz; N. J.;
Liu, X.; Sanyal, A.; Yan, W.; Yuan, Q.; Snyder, J. K. Bioorg. Med. Chem.
2005, 13, 5299. For related work, see: (b) Bawa, R. A.; Jones, S.
Tetrahedron 2004, 60, 2765 and references therein.
(6) (a) Reiners, I.; Martens, J. Tetrahedron: Asymmetry 1997, 8, 27.
(b) Sanyal, A.; Snyder, J. K. Org. Lett. 2000, 2, 2527.
(7) Sarotti, A. M.; Spanevello, R. A.; Sua´rez, A. G. Org. Lett. 2006, 8,
1487.
(8) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238.
10.1021/jo702724t CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/06/2008
J. Org. Chem. 2008, 73, 2935-2938
2935

TABLE 1. Lewis Acid-Catalyzed Cycloadditions of Crotonate 5
with Cyclopentadiene
SCHEME 3. Synthesis of Auxiliary 8
Lewis acid
(equiv)
T
time
(h)
entrya
(oC)
endo/exob endo-I/endo-IIb
1
2
3
4
5
6
7
8
9
SnCl4 (1.1)
SnCl4 (0.2)
TiCl4 (1.1)
Et2AlCl (1.4)
Me2AlCl (1.4) -100
BF3·OEt2 (1.4) -100
ZrCl4 (1.4)
ZrCl4 (0.1)
ZrCl4 (0.1)
AlCl3 (1.4)
-100
-100
-100
-100
0.25
7
0.25
0.25
0.25
3
0.5
2
6
97/1
82/1
125/1
83/1
90/1
50/1
66/1
101/1
>200/1
32/1
32/1
28/1
2.4/1
13.2/1
12/1
17/1
52/1
40/1
75/1
31/1
-32
-32
-50
As hoped, significantly higher selectivity was achieved with
8 employing aluminum catalysts, though with cycloadducts still
arising from the s-trans conformation (Table 2). With Me2AlCl,
only one endo diastereomer, endo-I, was detected. Surprisingly,
BF3‚OEt2 also provided very high selectivity, giving the same
stereoisomer as the chelating Lewis acids. Interestingly, ZrCl4
proved to be less selective than in the previous case with
auxiliary 4. One possible reason for this reduced selectivity with
ZrCl4 might be that the allyl group in 9 renders formation of
the bipyramidal complexation of Zr (IV) too hindered, leading
to increased population of the s-cis enamide conformation and,
hence, producing slightly greater amounts of the endo-II
adduct.
10
-32 12
a All reactions were run in CH2Cl2, 0.1 M 5, 5 equiv of cyclopentadiene;
all gave 100% conversion by H NMR. b Endo/exo and endo-I/endo-II ratios
from HPLC ((R,R)-Whelk-O, 1% IPA/hexanes). Authentic exo adducts were
prepared by separate means for structure confirmation.9
catalysts such as Cu(OTf)2, Mg(OTf)2, Zn(OTf)2, TMSI, and
Ti(OiPr)4 gave lower reactivity and/or lower selectivity.
The stereochemical assignment of 6a was established by
cleaving the auxiliary exclusively at the exocyclic imide
carbonyl with LiOH and comparison of the optical rotation of
the resultant carboxylic acid with the literature value.10 Supris-
ingly, this assignment indicated that the crotonyl bond was
aligned in the s-trans orientation during the cycloaddition,11
assuming dicarbonyl chelation of the Lewis acid, which is
strongly supported by the requirement of 1.4 equiv of the
aluminum catalysts to maximally accelerate the reaction and to
achieve the optimal diastereoselectivity.8 Given the variation
of the endo-I/endo-II ratios with the catalyst, introduction of a
group “R” on the γ-position of the lactam was considered with
the hope of enforcing the chelation pathway, particularly with
aluminum catalysts (Figure 1).
TABLE 2. Lewis Acid Catalyzed Cycloadditions of Crotonate 9
Lewis acid
(equiv)
T
time yieldb
endo-I/
entrya
(oC)
(h)
(%)
endo/exoc endo-IIc
1
2
3
4
5
SnCl4 (0.2)
Et2AlCl (1.4)
Me2AlCl (1.4) -100 0.25
BF3·OEt2 (1.4) -100 5.5
ZrCl4 (0.1)
-100
7
99
96
98
97
98
no exo
107/1
160/1
73/1
70/1
-100 0.25
210/1
>300/1
100/1
25/1
-32
2
66/1
a All reactions were run in CH2Cl2, 0.1 M with 5 equiv of cyclopenta-
diene. b Isolated yields. c Endo/exo and endo-I/endo-II ratios from HPLC
((R,R)-Whelk-O, 1% IPA/hexanes).
FIGURE 1. Proposed transition state to improve diastereofacial
selectivity with aluminum catalysts.
Reduction of cycloadduct 3 to the hemiaminal followed by
allylation5a,12 gave γ-allyl lactam 8, also crystalline, as a single
diastereomer (94%, two steps). Crotylation as before gave 9,
ready for the Diels-Alder chemistry (Scheme 3).
The application of these auxiliaries to other dienes and
dienophiles also succeeded with excellent yields and diastereo-
selectivities (Table 3). Structure assignments followed basic
hydrolyses8 to remove the auxiliary, affording known com-
pounds.9 With less reactive dienophiles such as 2,3-dimethyl-
1,3-butadiene and isoprene, auxiliary 4 was applied since the
allyl group in 8 dramatically slowed the reaction. The more
reactive catalyst TiCl4 was needed to propel these reactions to
completion. All cycloadducts could be rationalized as resulting
from top-face approach to the dienophile in the s-trans confor-
mation as depicted in Figure 1.
(9) See the Supporting Information.
(10) (a) Kouklovsky, C.; Pouilhes, A.; Langlois, Y. J. Am. Chem. Soc.
1990, 112, 6672. (b) Berson, J. A.; Hammons, J. H.; McRowe, A. W.;
Bergman, R. G.; Remanick, A.; Houston, P. J. J. Am. Chem. Soc. 1967,
89, 2590.
(11) (a) Oelichmann, H.-J.; Bougeard, D.; Schrader, B. Angew. Chem.
1982, 648. (b) Chamberlin, A. R.; Reich, S. H. J. Am. Chem. Soc. 1985,
107, 1440.
(12) Burgess, K. L.; Lajkiewicz, N. J.; Sanyal, A.; Yan, W.; Snyder, J.
K. Org. Lett. 2005, 7, 31.
2936 J. Org. Chem., Vol. 73, No. 7, 2008

TABLE 3. Lewis Acid Catalyzed Cycloadditons
TABLE 5. TiCl4-Promoted Aldol Reactions Using Auxiliary 8
entry conditionsa
R1
R2
yieldb (%) product, dec (%)
yieldb product
(%)
1
2
3
4
A
A
B
B
H
H
Ph
isopropyl
90
88
91
93
24, >96
25, >96
26, >96
27, >96
entry/Xc R1
dienophile
conditionsa
dec (%)
Me Ph
Me isopropyl
1/4
2/8
3/8
4/4
5/4
H
H
Ph
cyclopentadiene
cyclopentadiene
cyclopentadiene
A, 0.25 h
A, 0.25 h
A, 2 h
95
96
12, 93
13, >96
14, >96
15, >96
16, >96
94
a Conditions A: 0.1 M in CH2Cl2, 2 equiv of TiCl4, -40 °C, 5 min,
then 2 equiv of DIPEA, -40 °C, 2 h; 1.5 equiv of RCHO, -100 °C, 5 h.
Conditions B: 0.1 M in CH2Cl2, 2 equiv of TiCl4 -40 °C, 5 min, then 4
equiv of TMEDA, -40 °C, 1 h; 1.5 equiv of RCHO, -100 °C to rt.
b Isolated yields. c de determined by H NMR.
Me 1,3-cyclohexadiene B, 10 h
Me 2,3-dimethyl-
1,3-butadiene
87d
90
B, 12 h
6/4
Me isoprene
B, 8 h
85
17, >96
a Conditions A: 0.1 M in CH2Cl2, 1.4 equiv Me2AlCl, -100 °C.
Conditions B: 0.1 M in CH2Cl2, 1 equiv of TiCl4, entries 5 and 6 at
-32 °C, 4 at -5 °C. b Isolated yield. c de determined by NMR. d 10% exo
product isolated.
SCHEME 4. Examples of Auxiliary Cleavage
TABLE 4. 1,4-Additions Employing Auxiliaries 4 and 8
entry/Xc
R
conditionsa
yieldb (%)
product, dec (%)
1/4
2/8
3/4
4/8
Bu
Bu
Ph
Ph
A
B
A
B
85
80
81
80
18, >96%
19, 15:1
20, >96%
21, 8:1
when TiCl4 (2 equiv) and DIPEA (4 equiv) were applied. The
configurations of 24-27 were confirmed by reductive cleavage
of the auxiliary (LiAlH4) and comparison with authentic diols.9
The auxiliary can also be easily cleaved and recovered under
different conditions (Scheme 4). Quantitative basic hydrolysis
of 6a using Evans’ conditions,8 for example, gave 28 with 100%
recovered auxiliary, while Weinreb-type amidation yielded 29,
also with completely recovered auxiliary, a procedure that should
be applicable to adduct diversification.
a Conditions A: 2.0 equiv of CuI‚0.75Me2S in THF, 1.8 equiv of RLi,
-32 °C, 30 min; 1.5 equiv of TMSI, -100 °C; substrate added in THF,
-100 °C. Conditions B: 2.0 equiv of CuI‚0.75Me2S in Et2O, 1.8 equiv of
RLi, -32 °C, 30 min; substrate added in Et2O, -78 °C. b Isolated yields.
c de determined by H NMR.
Other applications of these auxiliaries were also examined,
beginning with 1,4-additions.13 Excellent yields and good to
excellent diastereoselectivities were observed (Table 4).
In conclusion, new, facially restrictive chiral auxiliaries 4 and
8 were designed and synthesized in good yields, and on
multigram scales. The rigid diastereofacial structures exert
excellent stereocontrol in Diels-Alder reactions, and have also
proven successful in the limited number of conjugate additions
and aldol reactions examined to date. Further applications of
these auxiliaries to other reactions are under investigation.
Either R- and S-adducts could be generated selectively
depending upon conditions. Under chelation conditions, Li+
chelates with the two carbonyl groups of 9, and the cuprate
reagent adds from the top face of the crotonate, aligned in the
s-cis orientation. Under the nonchelation conditions, TMSI was
applied as a catalyst with 4, which provided the opposite
diastereomer. The absolute configurations were established by
cleavage of the auxiliary and comparison of optical rotation of
the resultant carboxylic acids with literature values.9
Experimental Section
Auxiliary 8 was also useful in Evans’ syn-aldol reaction
(Table 5).14 Excellent yields and selectivities were achieved for
the reactions of propionate 23 when TiCl4 (4 equiv) and
TMEDA (4 equiv) were applied at -40 °C, followed by
aldehyde addition at -78 °C. Even for the problematic acetate
aldol reaction,15 only a single isomer was observed by NMR
General Procedure A: Acylation of Auxiliaries 4 and 8. To
a solution of 4 or 8 in anhydrous THF (0.25 M) at -78 °C was
added n-BuLi (1.1 equiv, 2.5 M in hexanes) with stirring. After 1
h, freshly distilled acid chloride (1.3 equiv) was added, and the
reaction mixture was allowed to warm to rt with stirring for 4 h,
and then the reaction was quenched with saturated aqueous
ammonium chloride. The mixture was extracted with EtOAc, and
then the combined organic layers were washed with brine, dried
(13) For a recent report of similar 1,4-additions with Evans’ auxiliary,
see: Dambacher, J.; Anness, R.; Pollock, P.; Bergdahl, M. Tetrahedron
2004, 60, 2097.
(14) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894.
(15) (a) Crimmins, M. T.; Shamszad, M. Org. Lett. 2007, 9, 149. For a
recent review: (b) Kimball, D. B.; Silks, L. A., III. Curr. Org. Chem. 2006,
10, 1975.
J. Org. Chem, Vol. 73, No. 7, 2008 2937

over sodium sulfate, and filtered. The solvent was removed in vacuo
and the residue was purified by flash chromatography on silica gel.
General Procedure B: Lewis Acid Promoted Diels-Alder
Reactions Using Auxiliaries 4 and 8. To a solution of dienophile
5 or 11 in anhydrous CH2Cl2 (0.1 M) at the desired temperature
was added the appropriate amount of Lewis acid (see Tables 1-3).
After the mixture was stirred for 5 min, freshly distilled diene (5
equiv) was added, and the reaction mixture was stirred at the same
temperature until TLC showed no starting material remained. The
reaction was quenched with 1 N HCl and then extracted with
CH2Cl2. The combined organic layers were washed with brine, dried
over Na2SO4, and filtered, and then the solvent was removed in
vacuo. The residue was loaded onto a short silica plug (∼2 cm) in
a disposable pipet and then eluted first with hexanes to remove
excess diene and then with EtOAc to recover the cycloadduct
mixture. The diastereoselectivities were determined by 400 MHz
1H NMR on this mixture. Diastereomeric excesses of cycloadducts
6 and 10 were also determined by HPLC analysis (Tables 1 and
2). Further purification by flash chromatography gave the main
cycloadduct, if necessary (see the Supporting Information).
General Procedure C: Conjugate Addition to 5. To a slurry
of CuI‚0.75 Me2S (2.0 equiv) in THF was added the organolithium
reagent (1.8 equiv) at -32 °C. After being stirred for 30 min, the
mixture was cooled to -100 °C, followed by the dropwise addition
of TMSI (1.5 equiv) via syringe with stirring. After 10 min, the
crotonate solution (5, 0.1 M in THF) was added dropwise via
syringe, and the reaction mixture was stirred at the same temperature
for 6 h. The reaction was quenched with saturated aqueous
ammonium chloride, and then the solution was extracted with
EtOAc. The combined organic layers were washed with brine, dried
over Na2SO4, and filtered, and the solvent was removed in vacuo.
to rt. The mixture was extracted with CH2Cl2, the combined organic
layers were washed with brine, dried over Na2SO4, and filtered,
and the solvent was removed in vacuo. The residue was loaded
onto a short Celite plug (∼2 cm) in a disposable pipet and then
eluted with CH2Cl2 to afford the aldol adduct mixture. The
diastereoselectivities were determined by 400 MHz H NMR on
this mixture. Further purification by flash chromatography gave
the main adduct (24, 25, see the Supporting Information).
1
General Procedure F: Aldol Reactions of 23. To a solution of
propionate 23 in anhydrous CH2Cl2 (0.1 M) at -40 °C was added
TiCl4 (1 M in CH2Cl2, 2.0 equiv). After the mixture was stirred
for 5 min, freshly distilled TMEDA (4 equiv) was added. After
the mixture was stirred at the same temperature for 1 h, the reaction
was cooled to -100 °C, followed by the dropwise addition of
freshly distilled RCHO (1.5 equiv) via syringe. After being stirred
for 2 h, the reaction mixture was allowed to slowly warm to rt
over 4 h and then quenched with saturated aqueous ammonium
chloride. The mixture was extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over Na2SO4, and
filtered, and the solvent was removed in vacuo. The residue was
loaded onto a short Celite plug (∼2 cm) in a disposable pipet and
then eluted with CH2Cl2 to afford the aldol adduct mixture. The
1
diastereoselectivities were determined by 400 MHz H NMR on
this mixture. Further purification by flash chromatography gave
the main adduct (26, 27, see the Supporting Information).
Auxiliary Cleavage via Weinreb-Type Amidation. To a stirred
solution of cycloadduct 6a (129 mg, 0.284 mmol, 1.0 equiv) in
THF (2.8 mL) was added Me2AlCl (0.68 mL, 1 M in hexanes, 2.4
equiv) at -78 °C. After 30 min, morpholine (68 µL, 0.68 mmol,
2.4 equiv) was added, and the reaction mixture was allowed to
slowly warm to rt and stirred for 3 h. The reaction was quenched
with saturated aqueous ammonium chloride (2 mL), and the
resultant slurry was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried over Na2SO4 and filtered, and
solvent was removed in vacuo to afford crude 29 and 4. Purification
by flash chromatography gave pure 29 (hexanes/EtOAc, 1:1, Rf
1
The diastereoselectivities were determined by 400 MHz H NMR
on this crude mixture. Further purification by flash chromatography
gave the main adduct (18, 20, see the Supporting Information).
General Procedure D: Conjugate Addition to 9. To a slurry
of CuI‚0.75 Me2S (2.0 equiv) in Et2O was added the organolithium
reagent (1.8 equiv) at -32 °C. After being stirred for 30 min, the
mixture was cooled to -78 °C followed by the dropwise addition
of the crotonate solution (9, 0.1 M in Et2O) via syringe, and the
reaction mixture was allowed to stir at the same temperature for
6 h. The reaction was quenched with saturated aqueous ammonium
chloride, and then the solution was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4, and filtered, and the solvent was removed in vacuo. The
0.31, 59 mg, 94% yield) as a colorless oil: [R]25 -101.7 (c 0.6,
D
CHCl3); IR (NaCl) 1639 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.06
(d, J ) 7.2 Hz, 3H), 1.38 (ddd, J ) 8.4, 2.0, 1.4 Hz, 1H), 1.54 (br
d, J ) 8.4 Hz, 1H), 2.11 (qdd, J ) 7.2, 4.6, 1.6 Hz, 1H), 2.40 (dd,
J ) 4.6, 3.6 Hz, 1H), 2.44 (br s, 1H), 2.88 (br s, 1H), 3.40-3.70
(overlap, 8H), 5.79 (dd, J ) 5.6, 2.8 Hz, 1H), 6.29 (dd, J ) 5.6,
3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 47.4, 57.0, 60.4, 62.7,
63.05, 63.08, 64.6, 64.8, 75.2 (2C), 113.6, 118.4, 138.4; HRMS
(ESI) m/z 222.1487 ([M + 1]+, 19%), calcd for C13H20NO2
222.1494. Auxiliary 4 was also recovered (94 mg, 0.284 mmol,
100%).
1
diastereoselectivities were determined by 400 MHz H NMR on
this crude mixture. Further purification by flash chromatography
gave the main adduct (19, 21, see the Supporting Information).
General Procedure E: Aldol Reactions of 22. To a solution
of acetate 22 in anhydrous CH2Cl2 (0.1 M) at -40 °C was added
TiCl4 (1 M in CH2Cl2, 2.0 equiv). After being stirred for 5 min,
freshly distilled DIPEA (2 equiv) was added. The reaction mixture
was stirred at the same temperature for 2 h and then cooled to
-100 °C, followed by the addition of freshly distilled RCHO (1.5
equiv) dropwise via syringe. After being stirred for 5 h, the reaction
was quenched with 1 N HCl at -100 °C and then allowed to warm
Supporting Information Available: General information,
1
experimental procedures, characterization data, and copies of H
and 13C NMR spectra of all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO702724T
2938 J. Org. Chem., Vol. 73, No. 7, 2008