Enantioselective Conversion of Achiral Cyclohexadienones to Chiral Cyclohexenones by Desymmetrization

Article abstract of DOI:10.1021/acs.orglett.6b03186

The enantioselective reduction of prochiral 4,4-disubstituted 2,5-cyclohexadienones to chiral 2-cyclohexenones has been accomplished by the use of a carefully selected chiral bisphosphine-CuI complex and diisobutylaluminum hydride-hexamethylphosphoric triamide complex. This reagent has provided access to a key bicyclic intermediate for the total synthesis of the natural enantiomer of the pentacyclic sesterterpene retigeranic acid that involves spatial discrimination between CH₃ and CH₂CH₂R substituents, an operation that has been elusive previously. In addition, a second method for desymmetrization is described using catalytic enantioselective [4 + 2]-cycloaddition of cyclopentadiene to prochiral 4,4-disubstituted 2,5-cyclohexadienones.

Full text of DOI:10.1021/acs.orglett.6b03186

Letter
pubs.acs.org/OrgLett
Enantioselective Conversion of Achiral Cyclohexadienones to Chiral
Cyclohexenones by Desymmetrization
Yixin Han, Simon Breitler, Shao-Liang Zheng, and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: The enantioselective reduction of prochiral 4,4-disubstituted 2,5-cyclohexadienones to chiral 2-cyclohexenones
has been accomplished by the use of a carefully selected chiral bisphosphine−CuI complex and diisobutylaluminum hydride−
hexamethylphosphoric triamide complex. This reagent has provided access to a key bicyclic intermediate for the total synthesis of
the natural enantiomer of the pentacyclic sesterterpene retigeranic acid that involves spatial discrimination between CH3 and
CH2CH2R substituents, an operation that has been elusive previously. In addition, a second method for desymmetrization is
described using catalytic enantioselective [4 + 2]-cycloaddition of cyclopentadiene to prochiral 4,4-disubstituted 2,5-
cyclohexadienones.
enantiomers of 3 might be made enantioselectively from 2 and
ome years ago, we described an effective, stereocontrolled
Ssynthesis of the Himalayan lichen-derived natural product methyl vinyl ketone using a chiral pyrrolidine derivative, thus to
( )-retigeranic acid (1, Figure 1).1,2
enable an enantioselective synthesis of retigeranic acid.
Unfortunately, despite the use of a variety of chiral pyrrolidines,
only modest enantioselection (ca. 1.5:1) was observed, a result
that clearly was a consequence of the involvement of both E-
and Z-enamines 5 and 6 in the Michael addition to methyl vinyl
ketone (Figure 2).
Figure 1. Retigeranic acid (1).
The synthesis was facilitated by the efficient synthesis3 of the
intermediates ( )-3 and ( )-4 starting with the cheap
commercially available aldehyde 2 (“melon aldehyde”) and
methyl vinyl ketone, as shown in Scheme 1.
Figure 2. E- and Z-Enamines 5 and 6.
The bicyclic intermediate 4 was efficiently elaborated to the
pentacyclic target ( )-1 by the strategic application of two
cycloaddition reactions. It was initially envisaged that the
That lack of control of E/Z-geometry can be ascribed to the
nearly equal steric bulk of a methyl and methylene group and
the very small energetic difference between 5 and 6. The
inability to control the E/Z-geometry in reactive enamine
intermediates remains an unsolved problem.
Scheme 1. Synthesis of Intermediate 4
Recently, we have returned to the quest for an
enantioselective synthetic route to the key chiral enone 3
with the results that are described herein. The approach which
we have taken to the enantioselective synthesis of 4 involves the
Received: October 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03186
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enantioselective reductive desymmetrization of the correspond-
ing cyclohexadienone 7 which was readily prepared from 3, as
shown in Scheme 2.
Scheme 3. Reductive Desymmetrization of 7 Using (A) (S)-
DTBM-SEGPHOS (8) and (B) (R,R)-Ph-BPE (9)
Scheme 2. Oxidation/Reductive Desymmetrization
Sequence for the Enantioselective Preparation of 3
The success of such a desymmetrization4 would again
depend on finding a solution to the heretofore unsolved
problem of differentiation between CH3 and CH2CH2R groups.
Our hope was that such a distinction might be realizable by the
nucleophilic addition of a Cu(I)-hydride reagent in which a
bulky chiral bisphosphine ligand is bound to copper.
Enantioselective Cu(I)-hydride reduction of α,β-unsaturated
enones has recently been studied in detail by the Buchwald5
and Lipshutz6 groups.
Our initial experiments on the enantioselective reduction of
7 to (+)-3 were conducted under the optimum conditions
reported by Lipshutz et al. using the (S)-DTBM-SEGPHOS
ligand and Cu(OAc)2·H2O and phenylsilane in toluene at
temperatures between −78 °C and −20 °C.6
Scheme 4. Upgrade of Enantiomeric Purity from (+)-3 to
These reactions were slow (very slow at −78 °C) and
generally required 3−5 days to achieve maximum conversion,
but unfortunately the ee values of the enone 3 were only in the
range of 35% to 50%. The other chiral bisphosphines studied
gave even lower ee’s of 3.7 In view of these results, we decided
to try the method developed in our laboratory several years ago
involving a chiral bisphosphine, CuI, diisobutylaluminum
hydride (DIBAL), and hexamethylphosphoric triamide
(HMPA).8 It was gratifying that this method afforded good
results with (S)-DTBM-SEGPHOS (8, Scheme 3A) and even
better results with (R,R)-Ph-BPE (9, Scheme 3B) using 10 mol
% ligand and CuI in each case.9
(−)-4
MnO2 in CH2Cl2 gave pure enone (−)-4, [α]2D3 = −145.7 (c
= 0.51, CHCl3) of 99% ee by HPLC analysis on a Chiralcel OD-
H column.
The dextrorotatory enantiomer was obtained using both (S)-
8 and (R,R)-9. The absolute configuration of (+)-3 was
The enantioselective reduction using the Cu(I)-9 hydride
reagent from DIBAL and CuI was also applied to the
cyclohexadienones 11 and 13 with the results indicated in
Scheme 5. The very high enantioselectivity of the desymmet-
rization 11 → 12 is understandable in view of the large
difference in the size of methyl and phenyl substituents.11 More
surpising is the degree of enantioselectivity in the formation of
the γ-methyl-γ-methoxy enone 14.
3
established by cyclization with EtAlCl2 to give the enone
(−)-4.10
The ability of the Cu(I)-9 hydride to reduce 7 to (+)-3 with
9/1 enantioselectivity is impressive, and that encouraged us to
examine a few other γ,γ-disubstituted cyclohexadienones, as
discussed below. It is interesting that three-dimensional
modeling studies of the addition of the Cu(I)-9 hydride
complex to dienone 7 led to the expectation that the
(+)-enantiomer of 3 would be the favored product.
We were able to upgrade the enantiomeric purity of the
chiral product (+)-3 (obtained as described above) from 80% ee
to 99% ee for the cyclization product (−)-4 by the process
outlined in Scheme 4, or simply by chromatography on a chiral
OD-H column.
Scheme 5. Desymmetrization of Dienones 11 and 13
Cyclization of (+)-3 to (−)-4, followed by diastereoselective
reduction (LiAlH4 in ether at −25 °C) and reaction with 4-
bromophenylisocyanate and Et3N in ether, gave the solid 4-
bromophenylcarbamate (+)-10 which could be purified by
recrystallization with ether−hexanes (25:1) to afford product of
99% ee, mp 129−130 °C, [α]2D3 = +34.5 (c = 0.82, CHCl3).
Reductive cleavage (LiAlH4 in THF at reflux) gave the
corresponding 2-cyclohexenol which upon treatment with
B
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We have also studied the selective reduction of the long
known prochiral cyclohexadienone 15 (made from CHCl3, p-
cresol, and aqueous NaOH),12 with surprising results. First, the
reduction of 15 is less enantioselective using DIBAL-HMPA as
a reductant rather than PhSiH3, with Cu(I)-9 as the copper-
hydride source, even though the rate of reduction was
considerably faster than had been observed with the dienone
7 (Scheme 3), 11, or 13 (Scheme 5). Second, the attachment of
the hydride occurred to the opposite β-carbon of 15 relative to
7, 11, or 13, as shown in Scheme 6, and resulted in the
cyclohexanone 16, along with 14% of the saturated ketone 17
(vide infra).
Scheme 8. Enantioselective Desymmetrization of 15 by [4 +
2]-Cycloaddition
Scheme 6. Desymmetrization of Dienone 15
the chiral 2-cyclohexenone 21 by a retro-Diels−Alder reaction.
The optical rotation of 20, and thus the absolute configuration,
was opposite to the product 16 from Cu(I)-9 hydride reduction
of 15, a fact which was further supported by chiral GC analysis
of both products.
Furthermore, the enone in enantioenriched adduct 19 lends
itself to further stereoselective transformations, exemplified by
methyl cuprate addition to afford ketone 22 as a single
diastereomer, which underwent a retro-Diels−Alder reaction to
give functionalized enone 25 (Scheme 9).18
Scheme 9. Conjugate Addition to Enone 19 and Crystal
Structure of Chlorocyclopropane 24
Although chromatographic separation of 16 and 17 was
difficult, pure 16 was readily obtained by the sequence: (1)
bromination to form 18, which could be chromatographically
separated from 17, and (2) debromination. The enantiomeric
excess of 16 obtained by the use of PhSiH3 as the reductant was
77% whereas the use of DIBAL−HMPA reagent afforded
product of 33% ee. The low enantioselectivity of the latter
reaction was intriguing and could not be explained by a racemic
background reaction.13 This prompted us to investigate other
means to obtain this product and also confirm the absolute
configuration of the reduction product 16 by an independent
method.
For this purpose, we devised an entirely different approach to
the enantioselective desymmetrization of prochiral γ,γ-disub-
stituted cyclohexadienones which takes advantage of chiral
oxazaborolidinium cationic catalysis of [4 + 2]-cycloaddition
reactions,14,15 inspired by the transformation shown in Scheme
7.16
The analogous cycloaddition of cyclopentadiene to the
cyclohexadienone 15 proceeded to give the adduct 19 in good
yield and with good stereoselectivity17 using our second-
generation F2/F0·AlBr3 catalyst,14c as shown in Scheme 8.
The chiral adduct 19 could be selectively reduced at the α,β-
double bond by L-Selectride and then thermolyzed to provide
The desired conjugate addition product 22 was accompanied
by two diastereomeric tetracylic monochlorocyclopropanes 23
and 24 which were separable by careful column chromatog-
raphy.19 Unambiguous proof of the absolute configuration of
the tricyclic adduct 19, expected from the established Diels−
Alder pretransition state model,14b was achieved by X-ray
crystallographic analysis of 24.
Scheme 7. Enantioselective [4 + 2]-Cycloaddition
The oxazaborolidinium-catalyzed [4 + 2]-cycloaddition of
cyclopentadiene with cyclohexadienones represents another,
complementary approach for their desymmetrization.
As a result of these studies, the absolute configuration of the
quaternary carbon of enone 16 from the Cu(I)-9 hydride
reduction is thus assigned (S). The low enantioselectivity in this
reaction in combination with the opposite sense of stereo-
C
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2000, 122, 6797−6798. (c) Jurkauskas, V.; Sadighi, J. P.; Buchwald, S.
L. Org. Lett. 2003, 5, 2417−2420.
induction observed in the reductions of 7, 11, and 13 is
intriguing and deserving of further investigation.
(6) (a) Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.;
Lover, A. A. Org. Lett. 2004, 6, 1273−1275. (b) Lipshutz, B. H.;
Tanaka, N.; Taft, B. R.; Lee, C.-T. Org. Lett. 2006, 8, 1963−1966.
(c) Lipshutz, B. H. Synlett 2009, 2009, 509−524.
In summary, we have developed a novel method to
desymmetrize γ,γ-disubstituted cyclohexadienones to chiral
cyclohexenones utilizing the Cu(I)-9 complex and DIBAL−
HMPA as the reductant. The method exerts effective
stereocontrol even in the challenging differentiation between
a methyl (CH3) and methylene (CH2CH2R) group and enables
the asymmetric formal synthesis of the natural enantiomer of
retigeranic acid. Additionally, when faced with an unexpectedly
low ee in the reduction of dichloromethane-substituted
substrate 15, we demonstrated the applicability of oxazaboro-
lidinium-catalyzed [4 + 2]-cycloadditions for the purpose of
desymmetrizing cyclohexadienones. The Diels−Alder adduct
thus obtained could be further exploited to stereoselectively
obtain chiral 3,4,4-trisubstituted cyclohex-2-en-1-ones.
(7) See Supporting Information for details.
(8) (a) Larionov, O. V.; Corey, E. J. Org. Lett. 2010, 12, 300−302.
(b) Corey, E. J.; Huang, A. X. J. Am. Chem. Soc. 1999, 121, 710−714.
(c) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J.
Org. Chem. 1986, 51, 537−540.
(9) Typical experimental procedure: To a flask containing CuI (8.0 mg,
42 μmol) and (R,R)-Ph-BPE (23 mg, 42 μmol) under an atmosphere
of argon was added degassed THF (3.0 mL), and the suspension was
sonicated for 20 min to obtain a clear solution. Then, HMPA (0.44
mL, 2.5 mmol) was added and the solution was cooled to −78 °C
before DIBAL (1 M in DCM, 0.84 mL, 0.84 mmol) was added. After
10 min, dienone 7 (80 mg, 0.42 mmol) was added and the reaction
was warmed to −50 °C. When the substrate was fully converted as
judged by TLC, saturated aqueous NH4Cl (5 mL) and saturated
aqueous Rochelle salt (5 mL) were added. The aqueous phase was
extracted with CH2Cl2 (3 × 10 mL), and the combined organic phases
were washed with brine (5 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by column chromatography (SiO2,
hexanes/ethyl acetate 50:1) afforded the enone (+)-3 (68 mg, 85%
yield, 80% ee) as a colorless oil.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03186.
Crystallographic data for compound 24 (CIF)
Experimental procedures and characterization data for all
reactions and products (PDF)
(10) Paquette, L. A.; Heidelbaugh, T. M. Synthesis 1998, 1998, 495−
508.
(11) Notably, the procedure described herein affords higher
enantioselectivity in the reaction 11→12 compared to a recently
reported rhodium-catalyzed conjugate reduction; see: Naganawa, Y.;
Kawagishi, M.; Ito, J.-I.; Nishiyama, H. Angew. Chem., Int. Ed. 2016, 55,
6873−6876.
(12) (a) Auwers, K.; Winternitz, F.; Jacobson, P. Ber. Dtsch. Chem.
Ges. 1902, 35, 465−471. (b) Auwers, K.; Keil, G. Ber. Dtsch. Chem. Ges.
1902, 35, 4207−4217. (c) Wenkert, A.; Haviv, F.; Zeitlin, A. J. Am.
Chem. Soc. 1969, 91, 2299−2307.
1
Copies of H and 13C NMR spectra, chiral HPLC and
GC traces (PDF)
X-ray crystallographic data for compound 24 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: corey@chemistry.harvard.edu.
ORCID
(13) Treatment of 15 with DIBAL (2 equiv) and HMPA (6 equiv) in
THF at −50 °C afforded unreacted starting material after 14 h.
(14) (a) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100−2117.
(b) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650−1667.
(c) Reddy, K. M.; Bhimireddy, E.; Thirupathi, B.; Breitler, S.; Yu, S.;
Corey, E. J. J. Am. Chem. Soc. 2016, 138, 2443−2453. (d) Thirupathi,
B.; Breitler, S.; Reddy, K. M.; Corey, E. J. J. Am. Chem. Soc. 2016, 138,
10842−10845.
Yixin Han: 0000-0002-4941-092X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Pfizer Inc. for a research grant. Y.H.
acknowledges support from Prof. Zhen Yang and Prof. Jiahua
Chen of Peking University. S.B. acknowledges a postdoctoral
fellowship from the Swiss National Science Foundation.
(15) For a similar, organocatalyzed reaction, see: Takagi, R.; Nishi, T.
Org. Biomol. Chem. 2015, 13, 11039−11045.
(16) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129,
1498−1499.
(17) The product was obtained as a single diastereomer with
1
complete endo-selectivity, as judged by H NMR and NOE studies.
REFERENCES
■
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(19) The relative stereochemistry of these products was independ-
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DOI: 10.1021/acs.orglett.6b03186
Org. Lett. XXXX, XXX, XXX−XXX