Divergent reactions for racemates: Catalytic, enantioselective, and regiodivergent nitroso diels-alder reactions

Article abstract of DOI:10.1002/anie.200701631

(Chemical Equation Presented) Two products out of eight possible isomers are obtained from the [CuPF₆(MeCN)₄]-catalyzed, highly enantioselective, and regiodivergent nitroso Diels-Alder reactions of 6-substituted 1,3-cyclohexadienes (

Full text of DOI:10.1002/anie.200701631

Communications
DOI: 10.1002/anie.200701631
Asymmetric Catalysis
Divergent Reactions for Racemates: Catalytic, Enantioselective, and
Regiodivergent Nitroso Diels–Alder Reactions**
Chandan Kumar Jana and Armido Studer*
Kinetic resolution of racemates is a widely used strategy for
the synthesis of enantioenriched compounds.[1] In the ideal
case only one enantiomer reacts; hence, only half of the
starting material is converted. However, in a parallel kinetic
resolution both enantiomers are converted into non-enantio-
meric products.[1,2] According to Vedejs and Jure,[1c] parallel
kinetic resolution is a variation of a divergent reaction of a
racemic mixture (divergent RRM) in which two complemen-
tary reagents or catalysts react with racemates leading to two
non-enantiomeric products.[1–3] However, in a divergent RRM
a single catalyst or reagent reacts with racemates to give two
distinct products with high enantioselectivity.[1c] Herein we
report on a divergent RRM in which racemic cyclohexadienes
of type 1 undergo catalytic enantioselective nitroso Diels–
Alder reactions to form the two major compounds ent-anti-2
and anti-3 (Scheme 1). In contrast to the other reported
examples of divergent RRMs[3] in which the catalyst controls
the reaction giving four possible products, the present system
deals with the selective formation of two products out of eight
possible isomers!
To reduce the complexity of the system during catalyst
screening we first studied the nitroso Diels–Alder reaction
with the highly enantioenriched diene 1a (R = (S)-
CHPhOTBDPS (TBDPS = tert-butyldiphenylsilyl), 98% ee)
readily obtained by our recently reported desymmetrization
of 1,4-cyclohexadiene (the ent series in Scheme 1 can be
neglected).[4,5] The reactions were conducted in CH2Cl2 in the
presence of [CuPF6(MeCN)4] (10 mol%), a chiral diphos-
phine (10 mol%) and 2-nitrosopyridine (À788C for 6 h then
À208C for 12 h) to provide 2a and 3a. CuI catalysis has been
shown by Y. and H. Yamamoto to be well suited for
conducting nitroso Diels–Alder reactions.[6] Ligands 4–8
were tested (among others), and the product ratio was
1
determined by H NMR spectroscopy (Table 1).[7]
All the cycloadditions proceeded cleanly, and the prod-
ucts were isolated in quantitative combined yields. The
Scheme 1. All of the possible isomers that can be formed in the
reaction of a racemic diene 1 with an arylnitroso compound.
R=phenyl, alkyl; Ar=2-pyridyl
Table 1: Nitroso Diels–Alder reaction using different ligands and
enantiomerically highly enriched 1a.[a]
[*] C. K. Jana, Prof. Dr. A. Studer
NRW Graduate School of Chemistry
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität
Corrensstrasse 40, 48149 Münster (Germany)
Fax: (+49)281-83-36523
Entry Ligand Ratio
Ratio
anti/syn syn-2a / syn-3a / anti-2a / anti-3a
1
2
3
4
4
5
6
7
8
98:2
83:17
88:12
84:16
>99:1
>99:1
>99:1
2
16
10
16
–
–
1
2
–
–
–
–
78
38
45
7
20
45
43
77
98
5
E-mail: studer@uni-muenster.de
5
2
[**] A.S. thanks Novartis Pharma AG for financial support (Novartis
Young Investigator Award). We thank the NRW Graduate School of
Chemistry for supporting our work (stipend to C.K.J.). Solvias AG is
acknowledged for donation of various chiral ligands.
6
ent-8
8
–
–
95
7[b]
95[c]
5[d]
[a] Structures are given in Scheme 1 and Eq. (1) (R=(S)-CHPhOTBDPS,
Ar=2-pyridyl). [b] Reaction was performed with ent-1 (R=(R)-
CHPhOTBDPS). [c] Yield for ent-anti-2a. [d] Yield for ent-anti-3a.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
6542
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Chemie
reaction with (S)-difluorphos (4)[8a] as a ligand provided the
adducts 2a and 3a with high diastereoselectivity (anti/
syn=98:2; Table 1, entry 1). However, the regiochemistry
for the anti isomers was not well controlled (78:20). Worse
results were obtained with Binap[8b] (Table 1, entry 2): both
the anti/syn ratio and the regioselectivity for the major anti
isomers were low. The reaction with (R)-Solphos (6)[8c]
afforded a similar result (Table 1, entry 3). The “walphos”
ligand 7[8d] yielded the anti isomers 2a and 3a with good
regioselectivity (1:11); however, only a moderate anti/syn
selectivity was obtained (Table 1, entry 4). Pleasingly, excel-
lent diastereo-and regioselectivity were achieved with the
walphos ligand 8[8d] (Table 1, entry 5). Moreover, we found
that with the enantiomeric ligand ent-8 the regioselectivity
could be reversed (Table 1, entry 6). As expected, high
diastereoselectivity was obtained upon using ent-8. Thus it
was not surprising that the enantiomeric diene ent-1a reacted
with excellent selectivity under identical conditions with the
walphos ligand 8 (Table 1, entry 7).
substrates tested, the diastereoselectivity was lower for diene
1c (anti/syn = 7:1). The smaller CH2OTBDPS group does not
effectively shield the syn face of the diene. Similar results
were obtained for the benzyl-substituted diene 1d and diene
1e bearing an acyloxymethyl group showing that the silyloxy
group is not required for high enantioselectivities. The best
result was obtained for with Ph-substituted diene 1 f. For all
dienes investigated, the ent-anti-2 isomers are always formed
in slightly lower yields but higher enantioselectivities than the
anti-3 adducts. Mechanistic studies on this divergent RRM are
currently underway and will be reported in a full paper.
Finally we applied our new method to the synthesis of
peracetylated 2-epi-validamine (11), which belongs to the
class of pseudosugars or carbasugars with interesting biolog-
ical activity.[10] To this end the N O bond in ent-anti-3c
À
(89% ee),[9] which is readily prepared from rac-1c with ligand
ent-8, was cleaved using [Mo(CO)6] and NaBH4.[11] Subse-
quent desilylation (TBAF) and acetylation gave cyclohexene
9 (Scheme 2). Diastereoselective OsO4-catalyzed dihydrox-
ylation and acetylation afforded the corresponding penta-
acetylated carbasugar 10. Cleavage of the 2-pyridyl group was
The stage was set for the study of the divergent nitroso
Diels–Alder reaction of racemic diene 1a [Eq. (1)]. The
products ent-anti-2a and anti-3a were isolated (column
chromatography, SiO2) in excellent combined yields and
high enantiomeric excess.[9] Other possible isomers were not
identified. The nitroso Diels–Alder reaction was also tested
with racemic dienes 1b–f (Table 2). The reaction with 1b
occurred with excellent anti/syn selectivity to give ent-anti-2b
and anti-3b with high enantioselectivities.[9] Hence the addi-
tional chiral center in the substituent R of the test substrate
1a does not influence the stereochemistry. The reaction with
diene 1c provided ent-anti-2c in 42% yield with excellent
enantioselectivity (99% ee).[9] The regioisomer anti-3c was
isolated with 88% ee (45% yield).[9] As compared to the other
Scheme 2. a) [Mo(CO)6], NaBH4, MeOH/H2O; b) TBAF, THF;
c) 1. MeMgCl, THF; 2. AcCl; d) K2OsO2(OH)4, NMO, acetone/H2O;
e) Ac2O, pyridine. TBAF=tetrabutylammonium fluoride, NMO=4-
methylmorpholine N-oxide.
achieved by hydrogenolysis using H2 and Rh/C[12] to give 11
([a]2D5 = + 16.5 degcm3 gÀ1 dmÀ1
,
c = 12.6 mgcmÀ3, CHCl3;
Table 2: Nitroso Diels–Alder reaction using dienes 1b–e.
[a]2D5 = + 18.0 degcm3 gÀ1 dmÀ1, c = 11.0 mgcmÀ3, CHCl3[10b]).
In conclusion, we have developed a [CuPF6(MeCN)4]-
catalyzed highly enantioselective regiodivergent nitroso
Diels–Alder reaction. The starting dienes are readily avail-
able, and the products obtained are valuable compounds for
the synthesis of biologically interesting carbasugars. We
believe that divergent reactions on racemates can be observed
for other Diels–Alder reactions of unsymmetrical dienophiles
with racemic cyclic dienes. This might evolve to a general
concept in the field of stereoselective cycloadditions. Work
along this line is underway.
Diene
R
ent-anti-2
anti-3
Yield [%]
Yield [%]
ee [%]
ee [%]
1b
CMe2OTMS[e]
CH2OTBDPS
CH2Ph
CH2OAc
Ph
48
42
40
39
45
95
99
98
98
98
52
45
43
42
54
89
88
84
82
94
1c[a]
1d[b]
1e[c]
1 f[d]
Received: April 13, 2007
Published online: July 25, 2007
[a] One of the syn isomers, 2c or 3c, was formed in 13% yield. [b] The syn
isomers 2d and 3d were formed in 17% combined yield. [c] The syn
isomers 2e and 3e were formed in 19% combined yield. [d] The syn
isomers were formed in trace amounts (<1%). [e] TMS=trimethylsilyl.
Keywords: asymmetric catalysis · carbasugars · copper ·
.
cycloaddition · natural products
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Communications
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Angew. Chem. Int. Ed. 2007, 46, 6542 –6544