Desymmetrizations of meso-tert-norbornenols by rhodium(i)-catalyzed enantioselective retro-allylations

Article abstract of DOI:10.1039/c0cc01950j

Rhodium-catalyzed desymmetrizations of meso-tert-norbornenols by retro-allylations generate allyl-rhodium species that allow for a rich and diverse downstream reactivity.

Full text of DOI:10.1039/c0cc01950j

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Desymmetrizations of meso-tert-norbornenols by rhodium(I)-catalyzed
enantioselective retro-allylationswz
Michael Waibel and Nicolai Cramer*
Received 18th June 2010, Accepted 4th August 2010
DOI: 10.1039/c0cc01950j
Rhodium-catalyzed desymmetrizations of meso-tert-norborne-
nols by retro-allylations generate allyl-rhodium species that
allow for a rich and diverse downstream reactivity.
The allylation of carbonyl groups is a reaction of fundamental
importance to organic chemistry.1 On the other hand, the
reverse reaction pathway—retro-allylation from tertiary
homoallylic alcohols—is a process observed with a range of
main group and transition-metals.2 Yorimitsu and Oshima
disclosed in seminal contributions that the released late transi-
tion-metal allyl species can be used in coupled allylation
processes.3 Contrasting carbonyl allylation reactions,4 cata-
lytic enantioselective variants of retro-allylations are limited to
two examples. Hayashi and co-workers demonstrated kinetic
resolutions of racemic tertiary alcohols with a chiral rhodium
catalyst.5 We have recently reported one example of an
enantioselective palladium(0)-catalyzed arylative retro-
allylation allowing the preparation of a highly substituted
cyclohexene using a taddol-based phosphoramidite ligand.6
Herein, we report the complementary reaction profile of
allyl rhodium species 3s/3p generated by desymmetrization of
bicyclic meso-tert-norbornenols 1 and illustrate their synthetic
potential and variable reactivity (Scheme 1).
Scheme 2 Proposed pathway for the formation of enone 8.
reversibility and the small differences in activation barriers
of such additions/eliminations of rhodium hydrides to 6, we
sought to explore conditions to address the selective formation
of specific product branches.
Refluxing a solution of 4a in the presence of 2.5 mol%
[Rh(cod)(OH)]2, 6 mol% (R)-Binap and caesium carbonate11
in toluene gave ring opened enone 8a in 79% yield, albeit in a
moderate enantiomeric ratio of 75 : 25 (Table 1, entry 1).
Screening of a range of chiral diphosphines (Scheme 3) led
to the identification of Josiphos L6 as a promising ligand
giving 8a with an er of 91 : 9 (entry 9). Performing the reaction
at 115 1C and replacing toluene with chlorobenzene increased
the yield from initially 36% to 74% (entry 10).
A simultaneous coordination of the alkoxide and the olefin
moiety7 of 4 to a chiral Rh(I)-complex induces an enantio-
selective retro-allylative C–C bond cleavage leading to allyl
rhodium species either as their s- (5s) or a p-bound (5p)
complex (Scheme 2).8 b-Hydride elimination forms regioiso-
meric dienes 69 and a rhodium hydride species, which in turn,
is prone to re-addition to the formed diene.10 Re-additions in a
1,2- or 1,4-fashion could lead to enolate 7 and subsequent
metal or base promoted isomerization yields more stable
enone 8 as the terminal product. In view of the facile
Table 1 Optimization of the desymmetrizationa
Entry
Ligand L*
% Yieldb
erc
1
2
(R)-Binap
79
83
89
37
83
83
36
74
62
71
65
75 : 25 (ꢀ)
78 : 22 (ꢀ)
76 : 24 (ꢀ)
93 : 7 (ꢀ)
82 : 18 (ꢀ)
79 : 21 (ꢀ)
91 : 9 (+)
91 : 9 (+)
61 : 39 (ꢀ)
90 : 10 (ꢀ)
74 : 26 (ꢀ)
(R)-H8-Binap (L1)
(R)-Segphos (L2)
(R)-DTBM-Segphos (L3)
(R)-DM-Segphos (L4)
(R)-Difluorphos (L5)
L6
L6
ent-L7
ent-L8
ent-L9
3
Scheme 1 Desymmetrization of meso-tert-norbornenols 1 by metal
6d
promoted retro-allylation.
7
8
9
Laboratory of Organic Chemistry, ETH Zurich, HCI H 304,
Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
E-mail: nicolai.cramer@org.chem.ethz.ch; Fax: +41 44 632 1328;
Tel: +41 44 632 6412
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. CCDC 779921. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc01950j
10e,f
11e,f
12e,f
13e,f
a
Conditions: 0.05 mmol 4a, 2.5 mol% [Rh(OH)(cod)]2, 6.0 mol% L*,
b
1.0 equiv. Cs2CO3, toluene (0.15 M), 110 1C, 12 h. Isolated product
8a. By HPLC with a CSP (sign of the optical rotation). At
c
d
e
f
120 1C. PhCl instead of toluene. At 115 1C.
c
346 Chem. Commun., 2011, 47, 346–348
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Scheme 3 Utilized ligands L* (DTBM = 3,5-tBu-4-MeO-C6H2).
With the optimized conditions, we then explored the
influence of substituent R on the tertiary alcohol (Table 2).
Aromatic groups with different steric and electronic properties
are well tolerated and have little impact on the reactivity and
selectivity of the process (entries 1–5). Although substituent R
is oriented away from the reaction site, small alkyl groups
cause diminished enantioselectivities (entries 6 and 7).
Scheme 4 Proposed reaction pathways for the formation of diene 11.
Noteworthy, when the base was omitted in the retro-allylation
reaction of 4a, regio-isomeric b-hydride elimination of 5
became the dominant pathway and led to presumed diene 9
(Scheme 4). Subsequent 1,4-addition might form allyl-
rhodium species 10, which again undergoes H elimination
accounting for the observed diene 11, formed in 77% yield
and an er of 78 : 22. On the other hand, when vinyl substituted
tert-alcohol 4h was submitted to the reaction conditions,
formation of diene 13 as well as aromatic product 14 was
observed (Scheme 5). This suggests a preferential re-addition
of the rhodium hydride species to the terminal, activated olefin
instead of the cyclohexadiene moiety of 6h.12 Enolate 12 might
subsequently isomerize to the more stable enone 13 or
aromatize to arene 14. Fine-tuning of the reaction condition
by the addition of ten equivalents of cyclohexene mitigated the
undesired oxidation to arene 14.
Scheme 5 Pathways for the formation of diene 13.
For example, performing the retro-allylation of 15 with
[Rh(OH)(cod)]2, L6 and caesium carbonate (conditions A),
presumably forms regio-isomeric diene 17. The concomitantly
formed rhodium hydride species then selectively reduces
the carbonyl group of 17 yielding 18 over the previously
dominant 1,4-reduction of the diene moiety. In contrast,
[Rh(OAc)(C2H4)2]2, L6 and 4 A molecular sieves instead of
caesium carbonate (conditions B) selectively provide diene 20
with an exo-methylene group by the following mechanistic
scenario: a 1,4-hydrorhodation of 17 leads to alkyl rhodium
species 19, which in turn undergoes b-alkoxide elimination to
Modifications of the bicyclic framework 1, for example 15
lacking the tetrahydrofuran reveal that subtle differences of
the substrate have a significant impact on the reactivity profile
of the allyl rhodium species (Scheme 6). In addition, slight
modifications of the reaction conditions impact the fate of the
putative organometallic species 16 as well.
Table 2 Formation of enones 8a
Entry
4
R
8
% Yieldb
erc
1
4a
4b
4c
4d
4e
4f
Ph
8a
74
65
84
80
88
85
86
91 : 9 (+)
91 : 9 (ꢀ)
2d
3
4-MeO–Ph
4-F–Ph
2-Me–Ph
1-Naphthyl
Me
ent-8b
8c
8d
8e
8f
8g
91 : 9 (+)
88 : 12 (+)
90 : 10 (+)
80 : 20 (+)
85 : 15 (+)
4
5
6
7
4g
Bu
a
Conditions: 0.05 mmol 4, 2.5 mol% [Rh(OH)(cod)]2, 6.0 mol% L6,
b
1.0 equiv. Cs2CO3, PhCl (0.15 M), 115 1C, 12 h. Isolated
product 8. By HPLC with a CSP (sign of the optical rotation).
c
d
ent-L6 was used.
Scheme 6 Proposed reaction pathways for the formation of 18 or 20.
Chem. Commun., 2011, 47, 346–348 347
c
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Table 3 Formation of alcohols 18 and dienes 20a
N. C. thanks the Fonds der Chemischen Industrie for a
Liebig-Fellowship. M. W. thanks the Roche Research
Foundation and the Alexander von Humboldt Foundation
for fellowships. We are grateful to Solvias for MeOBiphep,
Takasago for Segphos and H8-Binap and Umicore for
rhodium salts.
Notes and references
Entry 15 Condition R
18/20 % Yieldb erc
y Crystallographic data for 21: C25H27N3O5, M = 449.51, triclinic,
space group P1, a = 7.9939 (5) A, b = 11.9064 (9) A, c = 13.8485 (12)
A, a = 68.816 (3)1, b = 77.480 (4)1, g = 72.174 (3)1, V = 1161.6 (2)
A3, Z = 2, Dcalc = 1.285 Mg mꢀ3, T = 100 K, reflections collected:
6601, independent reflections: 4009 (Rint = 0.062), R(all) = 0.0818,
wR(gt) = 0.1508. CCDC 779921.
1
15a A
15a B
15b A
15b B
15c A
15c B
15d A
15d B
Ph
Ph
18a
20a
76
68
78 : 22 (+)
95 : 5 (ꢀ)
88 : 12 (ꢀ)
98 : 2 (ꢀ)
89 : 11 (+)
99 : 1 (ꢀ)
88 : 12 (ꢀ)
98 : 2 (ꢀ)
ꢀ
2
3d
4
4-MeO–C6H4 ent-18b 75
4-MeO–C6H4 20b
4-Cl–Ph
4-Cl–Ph
3,5-Me–C6H3 ent-18d 75
3,5-Me–C6H3 20d 81
82
72
71
5
18c
20c
6
7d
8
1 S. C. Denmark and N. G. Almstead, in Modern
Carbonyl Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000,
ch. 10, pp. 299–401.
a
Conditions A: 0.05 mmol 15, 5 mol% [Rh(OH)(cod)]2, 12.0 mol%
ent-L6, 1.0 equiv. Cs2CO3, PhCl (0.15 M), 120 1C, 12 h; Conditions B:
0.05 mmol 15, 5 mol% [Rh(OAc)(C2H4)2]2, 12.0 mol% ent-L6,
2 For an overview see: (a) H. Yorimitsu and K. Oshima, Bull. Chem.
Soc. Jpn., 2009, 82, 778–792; Recent examples with zinc:
(b) P. Jones, N. Millot and P. Knochel, Chem. Commun., 1998,
2405; (c) P. Jones and P. Knochel, Chem. Commun., 1998, 2407;
(d) P. Jones and P. Knochel, J. Org. Chem., 1999, 64, 186; with tin:
(e) A. Yanagisawa, T. Aoki and T. Arai, Synlett, 2006, 2071; with
gallium: (f) S. Hayashi, K. Hirano, H. Yorimitsu and K. Oshima,
Org. Lett., 2005, 7, 3577; with ruthenium: (g) T. Kondo, K. Kodoi,
E. Nishinaga, T. Okada, Y. Morisaki, Y. Watanabe and
T. Mitsudo, J. Am. Chem. Soc., 1998, 120, 5587; with nickel:
(h) D. Necas, M. Tursky and M. Kotora, J. Am. Chem. Soc., 2004,
126, 10222; (i) Y. Sumida, S. Hayashi, K. Hirano, H. Yorimitsu
and K. Oshima, Org. Lett., 2008, 10, 1629.
3 (a) S. Hayashi, K. Hirano, H. Yorimitsu and K. Oshima, J. Am.
Chem. Soc., 2006, 128, 2210; (b) Y. Takada, S. Hayashi,
K. Hirano, H. Yorimitsu and K. Oshima, Org. Lett., 2006, 8,
2515; (c) S. Hayashi, K. Hirano, H. Yorimitsu and K. Oshima,
J. Am. Chem. Soc., 2007, 129, 12650; (d) M. Iwasaki, S. Hayashi,
K. Hirano, H. Yorimitsu and K. Oshima, J. Am. Chem. Soc., 2007,
129, 4463; (e) M. Iwasaki, S. Hayashi, K. Hirano, H. Yorimitsu
and K. Oshima, Tetrahedron, 2007, 63, 5200; (f) M. Iwasaki,
H. Yorimitsu and K. Oshima, Bull. Chem. Soc. Jpn., 2009, 82,
249; (g) M. Iwasaki, H. Yorimitsu and K. Oshima, Synlett, 2009,
2177.
4 For reviews on enantioselective carbonyl allylation see:
(a) J. W. J. Kennedy and D. G. Hall, Angew. Chem., Int. Ed.,
2003, 42, 4732; (b) S. E. Denmark and J. Fu, Chem. Rev., 2003,
103, 2763; (c) I. Marek and G. Sklute, Chem. Commun., 2007, 1683;
(d) D. G. Hall, Synlett, 2007, 1644.
5 R. Shintani, K. Takatsu and T. Hayashi, Org. Lett., 2008, 10, 1191.
6 M. Waibel and N. Cramer, Angew. Chem., Int. Ed., 2010, 49, 4455.
7 L. Xue, K. C. Ng and Z. Lin, Dalton Trans., 2009, 5841.
8 Ring-opening reactions of oxa- and aza-bicyclic compounds follow
a distinctively different mechanism. For leading references see:
(a) M. Lautens, K. Fagnou and S. Hiebert, Acc. Chem. Res., 2003,
36, 48; (b) M. Lautens and S. Hiebert, J. Am. Chem. Soc., 2004,
126, 1437.
b
20 mg 4 A MS, PhCl (0.15 M), 120 1C, 12 h. Isolated product
18 or 20. Determined by HPLC with a CSP (sign of the optical
d
rotation). With L6.
c
yield 20.13 A range of secondary alcohols 18 and methylene
cyclohexenes 20 can be accessed from norbornenols 15 using
these complementary conditions (Table 3). The observed
enantioselectivities for the formation of 20 (entries 2, 4, 6, 8)
are excellent and generally significantly higher than those for
the formation of 18 (entries 1, 3, 5, 7), demonstrating a
pronounced effect of the added base on the selectivity.11 The
relative configuration of the secondary alcohol function of 18
was assigned by X-ray crystal structure analysis of the
Diels–Alder adduct 21 obtained from 18a and 4-phenyl-3H-
1,2,4-triazoline-3,5-dione (PTAD) (Scheme 7).y 14 This selectivity
suggests a facial reduction of the carbonyl group as depicted
for 17 (Scheme 5).
In summary we showed that bicyclic meso-tert-norbornenols
can be desymmetrized by retro-allylation mechanisms with
chiral rhodium(I) catalysts. Subtle differences of the substrate
structure and more importantly of the reaction conditions lead
to diverging reaction pathways and hold the promise of a
further rich downstream chemistry. Ongoing research is
directed towards a deeper understanding and control of the
individual steps as well as the development of synthetic
applications.
9 At least two regioisomeric dienes 6 were observed as transients, but
they mostly convert to 8 duringthe course of the reaction.
10 (a) F. Shibahara, J. F. Bower and M. J. Krische, J. Am. Chem.
Soc., 2008, 130, 6338; (b) F. Shibahara, J. F. Bower and
M. J. Krische, J. Am. Chem. Soc., 2008, 130, 14120;
(c) J. F. Bower, R. L. Patman and M. J. Krische, Org. Lett.,
2008, 10, 1033.
11 The inorganic base is required to ensure a high reactivity and clean
reaction, however at the expense of some enantioselectivity.
12 Small, but detectable amounts of 12 are formed during the
reaction.
13 (a) M. Lautens, C. Dockendorff, K. Fagnou and A. Malicki, Org.
Lett., 2002, 4, 1311; (b) L. Navarre, S. Darses and J.-P. Genet, Chem.
Commun., 2004, 1108; (c) T. Miura, T. Sasaki, T. Harumashi and
M. Murakami, J. Am. Chem. Soc., 2006, 128, 2516.
14 For determination of the absolute configuration of ent-18d see
ESI.z Retro-allylations with L6 proceed Re with the norbornenol
scaffold.
Scheme 7 Determination of the relative configuration of 18 as its
Diels–Alder adduct 21.
c
348 Chem. Commun., 2011, 47, 346–348
This journal is The Royal Society of Chemistry 2011