One-pot desymmetrizing hydroformylation/carbonyl ene cyclization process: Straightforward access to highly functionalized cyclohexanols

Article abstract of DOI:10.1021/ol8016148

(Chemical Equation Presented) Rapid access to highly functionalized alkylidene cyclohexanols through a one-pot desymmetrizing hydroformylation/ carbonyl ene cyclization starting from simple bisalkenylcarbinols is reported. Mechanistic insight into the carbonyl ene reaction is given, highlighting the importance of hyperconjugative substituent effects.

Full text of DOI:10.1021/ol8016148

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5321-5324
One-Pot Desymmetrizing
Hydroformylation/Carbonyl Ene
Cyclization Process: Straightforward
Access to Highly Functionalized
Cyclohexanols
Aure´lien Bigot, Daniel Breuninger, and Bernhard Breit*
Institut fu¨r Organische Chemie und Biochemie, Freiburg Institute for AdVanced Studies
(FRIAS), Albert-Ludwigs-UniVersita¨t Freiburg, Albertstrasse 21,
D-79104 Freiburg, Germany
bernhard.breit@chemie-freiburg.de
Received July 21, 2008
ABSTRACT
Rapid access to highly functionalized alkylidene cyclohexanols through a one-pot desymmetrizing hydroformylation/carbonyl ene cyclization
starting from simple bisalkenylcarbinols is reported. Mechanistic insight into the carbonyl ene reaction is given, highlighting the importance
of hyperconjugative substituent effects.
Densely functionalized cyclohexanes are structural elements that
are ubiquitous in natural and synthetic bioactive molecules.1
The variety of functionality and substitution patterns found
continues to drive efforts toward the development of new
synthetic methods. Particularly attractive is the access to this
class of compounds from simple acyclic precursors through
atom economic procedures with control of all levels of
selectivity.2 In this context, recent advances have been made
relying on transition metal catalysis3 or organocatalysis.4 We
recently disclosed the stereoselective synthesis of important
carbahexoses based on a desymmetrizing hydroformylation and
subsequent carbonyl ene cyclization in a one-pot process.5 The
planar-chiral catalyst-directing group, the o-(diphenylphospha-
nyl)ferrocenylcarbonyl (o-DPPF)6moiety (Scheme 1), attached
to the symmetrical bis-2-propenyl-methanol allowed for dias-
tereotopic alkene group and face discrimination in the hydro-
(4) See, for example: (a) Enders, D.; Grondal, C. Angew. Chem., Int.
Ed. 2007, 46, 1570. (b) Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell,
R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 9202. (c) Cabrera,
S.; Alema´n; an, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2007, 47, 121. (d) Tan, B.; Chua, P. J.; Li, Y.; Zhong, G. Org.
Lett. 2008, 10, 2437.
(1) Bayo´n, P.; Marjanet, G.; Toribio, G.; Ramon, A.; de March, P.;
Figueredo, M.; Font, J. J. Org. Chem. 2008, 73, 3486.
(2) (a) Trost, B. M. Science 1991, 254, 1471. Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259.
(3) See, for example: (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan,
R. J. Chem. ReV. 1996, 96, 635. (b) Aubert, O.; Buisine, M.; Malacria, M.
Chem. ReV. 2002, 102, 813. (c) Plumet, J.; Gomez, A. M.; Lopez, J. C.
Mini-ReV. Org. Chem. 2007, 4, 201.
(5) Bigot, A.; Breit, B. Chem. Commun. 2008, DOI: 10.1039/
8817786D.
(6) Breit, B.; Breuninger, D. Synthesis 2005, 16, 2782.
10.1021/ol8016148 CCC: $40.75
Published on Web 11/12/2008
2008 American Chemical Society

Scheme 1
.
One-Pot Desymmetrizing Hydroformylation/Carbonyl
Ene Cyclization Process
Scheme 3
.
Preparation of Dialkenylcarbinol o-DPPF Esters
1a-ia
a See Supporting Information for detailed procedures.
Subsequent esterification with the o-(diphenylphosphanyl-
)ferrocene carboxylic acid (o-DPPFA) under a dual activation
protocol and BOP as coupling reagent7b furnished the desired
esters 1a–i in good yields. Desymmetrizing hydroformylation
conditions applied to 1a-i provided syn-aldehydes 3a-i in high
yields and with good to excellent diastereoselectivities as a
function of the steric demand of the substituent R (Table 1).9
formylation of 1a to furnish selectively the syn-aldehyde
intermediate.7 Subsequent carbonyl ene cyclization and cleavage
of the directing group in the same pot gave gave both optical
antipodes of 2, either starting from (Sp)-o-DPPF ester or its (Rp)
enantiomer. Further selective and protecting group-free trans-
formations provided the carbocyclic analogues of four important
2,6-dideoxysugars in a straightforward manner.
We herein report on the development, limitation, and scope
of this one-pot desymmetrizing hydroformylation/carbonyl ene
cyclization reaction of various dialkenyl-carbinol o-DPPF esters
(1, Scheme 2), which provides a rapid access to a variety of
Table 1. Desymmetrizing Hydroformylation of 1a-i
Scheme 2. Concept of This Study
functionalized alkylidene substituted cyclohexanols, particularly
interesting for further design of carbohydrate mimetics.8 In
particular, the role of the substituent R at the allylic position
was probed in the course of this study and revealed interesting
stereoelectronic effects on the ene cyclization step.
a Ratio was determined by integration of 1H NMR spectrum of the crude.
b Isolated yields of the syn/anti mixture. c Temperature was 50 °C, and the
reaction stopped after 40 h. d 14% of five other aldehydes were detected.
For the synthesis of dialkenylcarbinols of type 7 we adopted
the route formerly developed7b of double addition of alkenyl-
metal species to ethylformate (Scheme 3). Carbinols 7a-i were
obtained in satisfactory to good yields.
(7) (a) Breit, B.; Breuninger, D. J. Am. Chem. Soc. 2004, 126, 10244.
(b) Breit, B.; Breuninger, D. Eur. J. Org. Chem. 2005, 18, 3916.
(8) (a) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300.
(b) Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. ReV. 2007,
107, 1919.
In a first set of experiments, we examined the ene cycliza-
tion10,11 of aldehyde 3a in the presence of various Lewis acid
promoters (Table 2). Interestingly, when employing Sc(OTf)3
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Org. Lett., Vol. 10, No. 23, 2008

Table 2. Cyclization of 3a under Lewis Acidic Activation
Table 3. Cyclization of 3b-i under Lewis Acidic Conditions
entrya Lewis acid equiv (mol %) time (h)b ene/Prins 4a:5ac
1
2
3
4
5
6
Sc(OTf)3
BF3·THF
B(C6F5)3
Me2AlCl
Me2AlCl
SnCl4(THF)2
20
20
20
100
50
20
1
2
2
79:21
85:15
89:11
92:8
94:6
91:9
1
6d
<0.5
a All reactions were performed in THF at 70 °C except for entries 4
and 5, which were run at 25 °C. b At quantitative conversion. c Ratio was
determined by integration of 1H NMR spectrum of the crude mixture.
d Conversion was incomplete (90%).
(entry 1), a mixture of two products was formed composed
of the ene cyclization product 4a and a bridged bicyclic ether
5a (Prins product, vide infra) in a ratio of 79:21. BF3·THF
complex and B(C6F5)3 (entries 2 and 3) gave better selectivi-
ties in favor of the ene product, but the reaction proceeded
slower. A much better result was obtained with Me2AlCl;
however, stoichiometric amounts of Lewis acid were required
(entries 4 and 5). Finally SnCl4(THF)2 (entry 6) was found
to be the best compromise in terms of reactivity and
selectivity since a substoichiometric amount (20 mol %)
promoted the cyclization smoothly in less than 30 min with
high selectivity (91:9 ene/Prins ratio).
Thus, SnCl4(THF)2 also catalyzed the cyclization of syn-
aldehydes 3b-h to furnish ene products 4 with good
chemoselectivity and excellent stereoselectivity (Table 3).
In all cases the exocyclic alkene function possesses the
E-configuration, and the newly formed secondary alcohol
stereocenter had in all cases the axial configuration as proven
by NOESY experiments. Notably, when R was an alkyl
substituent, aldehydes 3b-f underwent a fast ene cyclization
(entries 1-5) with excellent control of E/Z-configuration,
regardless of the size of R. With an oxygen-substituted alkyl
substituent R (entry 6), the reaction proceeded significantly
more slowly and with decreased ene/Prins selectivity. For
the phenyl-substituted derivative (entry 7), the cyclization
a All reactions were performed with 20 mol % SnCl4(THF)2 except for
entry 1, which was run with 5 mol %, and entry 8, which was run with 40
mol %. BF3·THF (20 mol %) was used in entry 7. b Conversion determined
1
by integration of H NMR spectrum of the crude mixture.
was even slower, and the furyl derivative syn-3i did not react
at all (entry 8). These observations indicated that the ene
cyclization is strongly affected by the electronic properties
of the allylic substituent R, the better σ-electron-donating
groups leading to higher reactivity and selectivity, irrespec-
tive of their steric demand.
For synthetic purpose, these optimized conditions of
cyclization could be combined with the hydroformylation
in a one-pot process (Table 4). Simple addition of the Lewis
acid to the crude mixture of the hydroformylation reaction
led directly from 1a-h to ene products 4a-h, respectively,
in fair to good yields and excellent selectivity.
A rational accounting for the formation of the reaction
products and the stereochemical outcome of the cyclization
reaction is depicted in Scheme 4. Thus, assuming a bicyclic
transition state with minimization of syn-pentane interactions
would account for the formation of both the E-configured
alkene function and the axial hydroxy group.
(9) For determination of relative and absolute configuration, see: Breit,
B.; Breuninger, D. Eur. J. Org. Chem. 2005, 18, 3916.
(10) (a) For a review on the ene reaction, see: Mikami, K.; Shimizu,
M. Chem. ReV. 1992, 92, 1021. (b) For recent advances on intramolecular
carbonyl ene reaction, see: Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2008, 47, 1469.
Furthermore, such a bicyclic transition state places the
allylic substituent R in an ideal position to allow hypercon-
jugative stabilization of the positive charge developing at
C2 in the course of the cyclization.12 This would account
for the observed higher reactivity of the alkyl-substituted
derivatives 3b-f (Table 3, entries 1-5) and the lower
(11) For mechanistic aspects of the type II carbonyl ene cyclization,
see: (a) Johnston, M. I.; Kwass, J. A.; Beal, R. B.; Snider, B. B. J. Org.
Chem. 1987, 52, 5419. (b) Braddock, D. C.; Hii, K. K.; Brown, J. M. Angew.
Chem., Int. Ed. 1998, 37, 1720. (c) Mondal, N.; Mandal, C. S.; Das, G. K.
J. Mol. Struct. 2004, 680, 73.
Org. Lett., Vol. 10, No. 23, 2008
5323

Scheme 4. Subsequent 1,2-migration of the o-DPPF ester
through anchimeric assistance and ring closure by alkoxide
nucleophilic displacement yields bicyclic ether 5.13
Table 4. One-Pot Desymmetrizing Hydroformylation/Carbonyl
Ene Cyclization Process
Further support for our mechanistic rationale was provided
by the experiment with the silyl-substituted derivative 1j.14
The C-Si bond is known as one of the best hyperconjugative
donors.15 Thus, cyclization of the corresponding syn-alde-
hyde obtained through directed hydroformylation occurred
without the need for Lewis acid catalysis by simple heating.
The ene cyclization product 4j was obtained in a clean
reaction as a single diastereomer (Scheme 5).
Scheme 5. Silicon Effect: No Need of Lewis Acid
a Combined yields after chromatography. b Ratio was determined by
integration of 1H NMR spectrum of the isolated products. c Hydroformylation
was carried out at 50 °C. d BF3·THF (20 mol %) was used.
In summary, starting from simple acyclic bisalkenyl
carbinols a set of highly functionalized cyclohexanols could
be obtained through a practical two-step, one-pot protocol.
In the course of the hydroformylation excellent control of
diastereoselectivity is provided by our chiral catalyst-
directing o-DPPF group. The subsequent ene-cyclization
occurred also with excellent levels of diastereocontrol. Both
enantiomers are formally accessible starting from the cor-
responding enantiopure o-DPPF esters. Furthermore, our
experiments gave mechanistic insights into the influence of
hyperconjugative interactions of the allylic substituent R on
the rate of the carbonyl ene cyclization.
reactivity for substituents with a reduced σ-donor character
(Table 3, entries 7 and 8).
As a rationale for the formation of the bridged bicyclic
ether 5, we propose a Prins-type attack to the activated
aldehyde furnishing the cationic intermediate depicted in
Scheme 4. Proposed Mechanism
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie, the DFG via the International
Research Training group “Catalysts and Catalytic Reactions
for Organic Synthesis” (GRK 1038). We thank Dr. M. Keller,
M. Lutterbeck and C. Giesin (University of Freiburg) for
analytical support and technical assistance.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL8016148
(12) The hyperconjugative stabilizing effect in the ene cyclization has
been reported for allylsilanes: (a) Monti, H.; Laval, G.; Fe´raud, M. Eur. J.
Org. Chem. 1999, 8, 1825. (b) Barbero, A.; Castreno, P.; Garc´ıa, C.; Pulido,
F. J. J. Org. Chem. 2001, 66, 7723. (c) Barbero, A.; Castreno, P.; Fernandez,
G.; Pulido, F. J. J. Org. Chem. 2005, 70, 10747.
(13) For examples of intramolecular trapping of the intermediate
carbocation in the course of Prins reactions, see: (a) Mullen, C. A.; Gagne,
M. Org. Lett. 2006, 8, 665. (b) Mikami, K.; Shimizu, M. Tetrahedron 1996,
52, 7287.
(14) For preparation of 1j, see ref 7.
(15) Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu,
X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 183.
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