Enantioselective, organocatalytic oxy-Michael addition to γ/δ-hydroxy-α,β-enones: Boronate-amine complexes as chiral hydroxide synthons

Article abstract of DOI:10.1021/ja076802c

An organocatalytic, enantioselective oxy-Michael addition to achiral γ- and δ-hydroxy-α,β-enones was developed. The key transformation is an unprecedented, asymmetric conjugate addition triggered by complexation between an in situ generated boronic acid hemiester and a chiral amine catalyst. Functionally, the intermediate amine-boronate complex acts as a chiral hydroxide surrogate or synthon. The resultant chiral β-hydroxy-ketones are obtained in good to excellent yields and high ee following mild oxidative removal of the cyclic boronate. Natural products (R,12Z,15Z)-2-hydroxy-4-oxohenicosa-12,15-dienyl acetate and (+)-(S)-streptenol A were synthesized to demonstrate the utility of this reaction. Copyright

Full text of DOI:10.1021/ja076802c

Published on Web 12/13/2007
Enantioselective, Organocatalytic Oxy-Michael Addition to γ/
δ-Hydroxy-r,â-enones: Boronate-Amine Complexes as Chiral Hydroxide
Synthons
De Run Li, Andiappan Murugan, and J. R. Falck*
Departments of Biochemistry and Pharmacology, UniVersity of Texas Southwestern Medical Center,
Dallas, Texas 75390
Received September 8, 2007; E-mail: j.falck@utsouthwestern.edu
Table 1. Base-Catalyzed Oxy-Michael of 4a
Structural motif 1 is present in a wide range of natural products
and synthetic intermediates.1 While Michael additions of hydroxide
or synthetic equivalents to R,â-unsaturated carbonyls represent an
attractive approach to this moiety,2 the strong basicity of the former
and generally poor nucleophilicity or lability of the latter often
entry
base
solvent
time (h)
yieldb (%)
render this option problematic. In its place, the intramolecular oxy-
Michael addition of hemiacetal/hemiketal-derived alkoxides has
emerged as a popular alternative strategy,3 although the resultant
cyclic acetals/ketals can be difficult to remove. In some instances,
satisfactory diastereoselectivity has been attained via exploitation
of adjacent secondary hydroxy or amino stereocenters.4,5 In 2001,
Watanabe et al.6 introduced an asymmetric version of the oxy-
Michael addition utilizing chiral hemiketals derived from D-glucose
and D-fructose in the more challenging case of achiral γ/δ-hydroxy-
R,â-enones. Herein, we reported an unprecedented organocatalytic,
enantioselective oxy-Michael addition to achiral γ/δ-hydroxy-R,â-
enones and its use in the preparation of 1 (eq 1).7 The key
1
2
3
4
5
6
7
8
9
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
DME
48
48
48
48
48
48
16
8
0
0
0
NaHCO3
Na2CO3
pyridine
Et3N
0
42
70
86
87
70
30
82
DABCO
iPr2NH
iPr2NH
iPr2NH
DBU
48
48
80
10
11
CH2Cl2
PhCH3
PMPc
a Reaction conditions: (i) PhB(OH)2 (1.2 equiv), base (20 mol %), 4 Å
MS, room temp; (ii) H2O2, Na2CO3, room temp, 15 min. b Overall for two
steps from enone 4 to diol 6. c PMP ) 1,2,2,6,6-pentamethylpiperidine.
transformation is the asymmetric conjugate addition triggered by
complexation between boronic acid hemiester 3, generated in situ
from γ/δ-hydroxy-R,â-enones, and a chiral amine catalyst. Func-
tionally, the intermediate amine-boronate complex acts as a chiral
hydroxide surrogate or synthon. Mild, oxidative removal of the
boronate moiety from the dioxaborolane (n ) 0) or dioxaborinane
(n ) 1) adduct 2 furnishes 1 in good to excellent overall yield and
% ee.
Figure 1. Proposed asymmetric catalysis.
16 h. The reaction rate for the latter was enhanced even further in
toluene (entry 8), but not in 1,2-dimethoxyethane (DME) (entry
9); the yield showed only a modest solvent dependency. 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) (entry 10) and the highly
hindered 1,2,2,6,6-pentamethylpiperidine (entry 11) offered no
advantage.
Inspired by the pronounced success of push/pull-type bifunctional
organocatalysts,12 we pursued an asymmetric version of this
intramolecular oxy-Michael addition (Figure 1). Coordination of
the carbonyl by the thiourea (the pull) and complexation of the
tertiary nitrogen to boron (the push) were expected to simulta-
neously enhance the nucleophilicity of the boronate oxygen as well
as envelope the enone in a chiral environment.13 Indeed, Michael
addition to 4 in CH2Cl2 mediated by catalyst 712b was complete in
16 h (Table 2, entry 1), > 3 times faster than a similar Et3N
catalyzed addition. More significantly, 12 was obtained in 91% yield
and 91% ee after basic H2O2 workup.14,15 A comparable reaction
in toluene proceeded still faster (8 h), but with significantly reduced
enantioselectivity (65% ee), whereas in DME the rate was slower
(24 h) and the % ee improved modestly to 94%. The less expensive
Recently, this8 and other laboratories9 have highlighted the
nucleophilic properties of organoboronic acids and the unique
stereospecific reactions of their borate complexes. Despite expecta-
tions, when model compound (E)-4-hydroxy-1-phenyl-2-buten-1-
one (4) was mixed with equimolar phenylboronic acid and activated
4 Å molecular sieves in CH2Cl2 (Table 1, entry 1), no intramolecular
Michael addition was observed, even though the hemiester (3: R)
1
Ph, n ) 0) could be detected by H and 13C NMR. Inclusion of
some common bases, namely, bicarbonate (entry 2), carbonate
(entry 3), and pyridine (entry 4), likewise disappointed. However,
a catalytic amount of Et3N (20 mol %, entry 5) gave rise to the
desired dioxaborolane 5 from which diol 6 was secured in 42%
overall yield (50% recovered 4 after 48 h) following workup with
basic H2O2. We attribute this dramatic difference to the in situ
formation of a nucleophilic, pyramidized quaternary boronate
complex.10,11 1,4-Diazabicyclo[2.2.2]octane (DABCO), under oth-
erwise identical conditions, significantly improved the overall
conversion (entry 6), whereas diisopropylamine (20 mol %, entry
7) worked even better and delivered 6 in 86% overall yield in just
9
46
J. AM. CHEM. SOC. 2008, 130, 46-48
10.1021/ja076802c CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Oxy-Michael of γ-Hydroxy-R,â-enones
Scheme 1. Biomimetic Synthesis of Antifungal/Hepatic Protective
Agent from Avocadoa
a Reagents and conditions: (a) H3CP(O)(OMe)2, LDA, THF, -78 °C, 2
h, 90%; (b) [HC(O)CH2OH]2, LiCl, DIPEA, room temp, CH3CN, 2 h, 51%;
(c) (i) PhB(OH)2 (1.2 equiv), 8 (10 mol %), 4 Å MS, CH2Cl2, room temp,
56 h; (ii) H2O2, Na2CO3, room temp, 15 min; (d) AcCl (1.2 equiv), collidine,
CH2Cl2, -78 °C, 10 h.
The scope of the oxy-Michael was further explored using catalyst
8 and a representative sampling of γ-hydroxy-R,â-enones (Table
2). Predictably, arylketones bearing strong electron withdrawing
substituents (entry 3) reacted faster than electron-rich systems
(entries 4 and 5), although the enantioselectivities of the latter were
better.
Aliphatic ketones (entries 6 and 7), regardless of steric congestion
adjacent to the carbonyl (20 vs 22), had retarded reaction rates,
yet still afforded excellent overall yields. The conversion of 24 into
25 (entry 8) thus appears anomalous for its comparatively rapid
rate and may reflect an unanticipated coordination by the terminal
oxygen substituent. The survival of the labile silyl (TES) ether also
testifies to the mildness of the reaction conditions. Importantly,
additional substitution at the olefin (entry 9) or carbinol (entry 10)
was well tolerated and adds to the level of structural complexity
that can be achieved.
To validate the applicability of the foregoing methodology in
natural products total synthesis, acetate 33,16 an extraordinarily
potent antifungal/hepatic protective agent isolated from avocado,
was prepared by a biomimetic route (Scheme 1). Addition of lithium
dimethyl methylphosphonate to methyl linoleate (30) and condensa-
tion of the adduct with glycoaldehyde furnished enone 31 which
was subjected to oxy-Michael addition catalyzed by 8. The product
(R)-diol 32 (90% yield, 91% ee14) was selectively acetylated to
give 33.17
With δ-hydroxy-R,â-enones, oxy-Michael addition proceeded
quite slowly in all solvents, although toluene was generally the best.
Increasing the catalyst loading to 20 mol % and the temperature to
50 °C, however, allowed the reaction to proceed at an acceptable
rate and enantioselectivity for aromatic enones (Table 3: entries
1-3). For the more recalcitrant aliphatic enones (entries 4-6), these
conditions were not sufficient. We, thus, screened a panel of
commercial arylboronic acids to identify 3,4,5-trimethoxyphenyl-
boronic acid as a more efficacious nucleophilic partner, which
furnished aliphatic diols in good to excellent enantioselectivities
at suitable rates. Diol 44 was identical in all respects with (+)-
(S)-streptenol A, one of four known streptenols produced by
Streptomyces luteogriseus that has attracted attention as an immu-
nostimulant as well as an inhibitor of cholesterol biosynthesis and
tumor cells.19
a Isolated yield. b Determined by chiral HPLC; absolute configuration
assigned in analogy with 12 and 33. c Reaction conditions: (i) PhB(OH)2
(1.2 equiv), 7 (10 mol %), 4 Å MS, room temp; (ii) H2O2, Na2CO3, room
temp, 15 min. d Catalyst 8 (10 mol %) was used. e Catalyst 9 (10 mol %)
was used. f Catalyst 10 (10 mol %) was used.
quinine-based catalyst 812b was virtually equivalent to 7 in all
respects (24 h, 95% ee). Notably, catalysts 912b and 1012a in DME
(entry 2) provided access to the opposite enantiomeric diol, 13, in
synthetically useful yields and enantioselectivities (40 h/89% ee
and 48 h/91% ee, respectively). In sharp contrast to the accelerated
rate seen with iPr2NH, catalyst 11, which also contains a secondary
amine, proved surprisingly sluggish and was not pursued further.
In contrast to carboxylic acids, boronic acids and their chiral
complexes have not been well explored as nucleophilic reagents
in organic synthesis. Furthermore, the often idiosyncratic reactivity
9
J. AM. CHEM. SOC. VOL. 130, NO. 1, 2008 47

C O M M U N I C A T I O N S
Table 3. Oxy-Michael of δ-Hydroxy-R,â-enones
(2) For examples of asymmetric Michael additions of oxygen-centered
nucleophiles, see, (a) alcohols: Kano, T.; Tanaka, Y.; Maruoka, K.
Tetrahedron 2007, 63, 8658-8664. (b) Oximes: Bertelsen, S.; Diner, P.;
Johansen, R. L.; Jorgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536-
1537. Vanderwal, C. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
14724-14725. (c) Phenols: Govender, T.; Hojabri, L.; Moghaddam, F.
M.; Arvidsson, P. I. Tetrahedron: Asymmetry 2006, 17, 1763-1767.
(3) Chandrasekhar, S.; Rambabu, C.; Shyamsunder, T. Tetrahedron Lett. 2007,
48, 4683-4685.
(4) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446-2453.
(5) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
128, 9328-9329.
(6) Watanabe, H.; Machida, K.; Itoh, D.; Nagatsuka, H.; Kitahara, T. Chirality
2001, 13, 379-385.
(7) For a review of asymmetric organocatalytic oxy-Michael additions, see:
Berkessel, A.; Groerger, H. Asymmetric Organocatalysis; Wiley-VCH:
Weinheim, Germany, 2005; Chapter 4.
(8) Falck, J. R.; Bondlela, M.; Venkataraman, S. K.; Srinivas, D. J. Org.
Chem. 2001, 66, 7148-7150.
(9) (a) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007,
129, 6686-6687. (b) Oshima, K.; Aoyama, Y. J. Am. Chem. Soc. 1999,
121, 2315-2316. (c) Matteson, D. S. Pure Appl. Chem. 2003, 75, 1249-
1253.
(10) Amine-borate complexes are well-known: Gillis, E. P.; Burke, M. D. J.
Am. Chem. Soc. 2007, 129, 6716-6717.
(11) Rehybridization of the boron center from sp2 to sp3 via coordination with
trivalent nitrogen was unambiguously supported by the upfield chemical
shift in the 11B NMR as described in Supporting Information section and
ref 9b.
(12) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672-12673. (b) Vakulya, B.; Varga, S.; Csa´mpai, A.; Soos, T. Org.
Lett. 2005, 7, 1967-1969.
(13) The critical role played by thiourea hydrogen bonding in the activation
of the enone is evident from a control experiment in which the thiourea
catalyst 8 was replaced with 20 mol% O-benzoylquinine (Shi, M.; Lei,
Z.-Y.; Zhao, M.-X.; Shi, J.-W. Tetrahedron Lett. 2007, 48, 5743-5746).
Diol 12 was obtained in <5% yield and the majority of starting 4 was
recovered unchanged.
a Isolated yield. b Determined by chiral HPLC; absolute configuration
assigned in analogy with natural 44 and chemical correlation of 40 with a
known intermediate (see ref 18). c Reaction conditions: (i) ArB(OH)2 (1.2
equiv), 8 (20 mol %), 4 Å MS, toluene, 50 °C; (ii) H2O2, Na2CO3, room
temp, 15 min. d Catalyst 9 (20 mol %) was used. e Catalyst 10 (20 mol %)
was used.
(14) Enantiomeric ratio measured by chiral HPLC.
(15) Absolute configuration assigned by comparison with literature optical
rotation data: Ticozzi, C.; Zanarotti, A. Tetrahedron Lett. 1994, 35, 7421-
7424.
of boronates offers unique opportunities for stereoselective ma-
nipulations. As an illustration, the oxy-Michael adduct formed in
situ from 4 and phenylboronic acid under catalysis by 8 acted as a
template for the stereoselective addition of allenylboronic acid to
the carbonyl, possibly via intermediate 45 (eq 2). Diol 46 was
generated, without isolation of intermediates, in good overall yield
and diastereoselectivity.20,21 Further developments including dias-
tereoselective and intermolecular oxy-Michael additions are under
investigation.
(16) Synthesis: MacLeod, J. K.; Scha¨ffeler, L. J. Nat. Prod. 1995, 58, 1270-
1273. Interestingly, the (S)-enantiomer is inactive.
(17) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1993, 58, 3791-
3793.
(18) Selective primary silylation of 40 (TBDPSCl, DCM, DMAP, room temp,
10 h) followed by p-methoxybenzylation (PMB-O(NH)CCl3) gave com-
pound (i): [R]20 ) +5.9 (c 0.85, CHCl3); lit. [R]20 ) +4.8 (c 1.49,
D
CHCl3). See, Li,DD. R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang,
L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem. Eur. J. 2006,
12, 1185-1204.
Acknowledgment. 11B NMR was measured by Dr. RenSheng
Luo (UMSL), X-ray analysis was performed by Radha Akella
(UTSW), and financial support was provide by the Robert A. Welch
Foundation and NIH (Grant GM31278, DK38226).
(19) Dollt, H.; Hammann, P.; Blechert, S. HelV. Chim. Acta 1999, 82, 1111-
Supporting Information Available: Synthetic procedures, analyti-
cal data, X-ray, and NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1122 and references cited therein.
(20) A similar diastereoselective addition of allenylboronic acid to â-hydoxy
ketones has been reported: Ikeda, N.; Omori, K.; Yamamoto, H.
Tetrahedron Lett. 1986, 27, 1175-1178.
(21) The absolute configuration of 46 was confirmed by X-ray analysis (see
References
Supporting Information).
(1) Recent review: Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006,
45, 7506-7525.
JA076802C
9
48 J. AM. CHEM. SOC. VOL. 130, NO. 1, 2008