Preparation of substituted enol derivatives from terminal alkynes and their synthetic utility

Article abstract of DOI:10.1021/ja803480b

Stereodefined enol derivatives of aldehydes are prepared from terminal alkynes. Specifically, terminal alkynes are known to undergo Cp₂ZrCl₂-catalyzed methylalumination. Here, we show that the resultant vinylalanes can be oxygenated with peroxyzinc species to generate trisubstituted enolates. Electrophilic trapping with carboxylic anydrides or silyl triflates yields trisubstituted enol esters or silanes, respectively. The tandem carbometalation/oxygenation tolerates free and protected alcohols, heterocycles, olefins, and nitriles. Stereodefined enol esters can undergo asymmetric dihydroxylation to yield optically active α-hydroxy aldehydes. Reduction with NaBH₄ provides the diols of 1,1-disubstituted olefins in excellent ee. An application of this methodology to the enantioselective synthesis of the insect pheromone frontalin is presented. Finally, α-hydroxy aldehydes are shown to undergo homologation to a terminal alkyne, reductive amination, oxidation and olefination. Preliminary results indicate that tandem carbometalation/amination can be accomplished with azodicarboxylates. In this way, ene-hydrazines are formed in excellent yield. Copyright

Full text of DOI:10.1021/ja803480b

Published on Web 06/03/2008
Preparation of Substituted Enol Derivatives From Terminal Alkynes and Their
Synthetic Utility
John R. DeBergh, Kathleen M. Spivey, and Joseph M. Ready*
Department of Biochemistry, The UniVersity of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines
BouleVard, Dallas, Texas 75390-9038
Received May 9, 2008; E-mail: joseph.ready@utsouthwestern.edu
Table 1. Preparation of Enol Derivatives from Terminal Alkynesa
Stereodefined enol derivatives of R-branched aldehydes (4) represent
valuable building blocks for organic synthesis, but limited access to
them has compromised their utility. They are most often prepared from
the corresponding aldehyde, although these approaches generally afford
mixtures of olefin stereoisomers.1 Furthermore, current strategies for
obtaining the R-substituted aldehydes themselVes are limited in reaction
scope and require multiple synthetic operations.2 An alternative
synthesis of trisubstituted enol derivatives might involve tandem
carbometalation-oxygenation of terminal alkynes (Scheme 1). In this
regard, we previously documented the carbocupration-oxygenation of
terminal alkynes, in which a vinyl copper intermediate (2, M ) Cu)
t
was oxidized with BuOOLi.3 Electrophilic trapping of the resultant
E-enolate (3) generated E-enol esters and silanes. However, methyl-
substituted products were not accessible by this method because
methyl-cupration of alkynes is not efficient.4 Accordingly, we sought
a general method for obtaining methyl-substituted enol esters and ethers
(4, R′ ) Me). As described below, we have accomplished this objective
and have begun to explore the asymmetric transformations of stereo-
defined enol derivatives.
Scheme 1
Negishi’s catalytic methylalumination reaction provides a comple-
mentary method for carbometalation.5 Methylalumination-oxygenation
of monosubstituted olefins has been reported,6 but analogous chemistry
of alkynes is unknown. Since trialkyl alanes are oxidized cleanly with
molecular oxygen, our initial investigations aimed to oxidize alkenyl
aluminum intermediates (5, Table 1) with O2. These experiments
proved unsuccessful as incomplete conversion and overoxidation
limited yields. Results with the oxenoid tBuOOLi were more promis-
ing.7 With this reagent, we observed 65% conversion of vinylalane
5a (R ) n-C10H21) to the corresponding aldehyde (E+ ) H) with
a Conditions: 1.0 equiv alkyne, 1.2-4 equiv Me3Al, 5-30 mol %
2-methyl-1-dodecene accounting for the remainder of the starting
material. Further evaluation of peroxymetal oxidants revealed that
Cp2ZrCl2, 2.5-30 mol %, H2O or MAO, 0.3 M in CH2Cl2; MeZnOOtBu
(0.3
M
in toluene, 1.3-1.4 equiv to Me3Al). b Isolated yields
peroxyzinc reagents EtZnOOtBu and MeZnOOtBu effected the oxida-
tion of 5a to the corresponding aldehyde with 85% and 98%
conversions, respectively. Thus when 5a was oxidized with freshly
prepared MeZnOOtBu (1.3 equiv to AlMe3) at 0 °C and subsequently
trapped with Bz2O, enol benzoate 4a was obtained in 78% isolated
yield (Table 1, entry 1). Zinc peroxides have been used in epoxidation
reactions,8 but, to the best of our knowledge, they have not been used
previously to oxidize carbanions.
(chromatography not necessary for entries 9-14). c Catalytic nBu3P
added. d BzCl was added after benzoylation of the enolate. See Supporting
Information for complete experimental details.
derivative has been isolated as a single regioisomer with a high
E-isomer content (all E/Z ratios >20/1).10
Trisubstituted, stereodefined enol derivatives of this type were
previously inaccessible, and their ready availability allowed us to
explore new chemistry and evaluate their synthetic utility. In particular,
we envisioned an entry to chiral R-hydroxy aldehydes (7) and 1,2-
diols (8) by employing the enol benzoates in catalytic asymmetric
dihydroxylation (AD) reactions.11,12 As expected, the enol benzoate
substrates afforded dihydroxylated products in high enantiomeric purity
The methylalumination-oxygenation reaction tolerates considerable
functionality including protected and free alcohols, heterocycles, and
olefins.9 Electrophilic trapping is not limited to benzoylation: enol
acetates and TES enol ethers (entries 9-14) were prepared in high
yields as well. Furthermore, in every case studied to date, the enol
9
7828 J. AM. CHEM. SOC. 2008, 130, 7828–7829
10.1021/ja803480b CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Dihydroxylation (AD) of Enol Benzoatesa
Table 3. Synthesis of Stereodefined Ene-hydrazines (16) from
Terminal Alkynesa,b
entry
R1
R2
product
yield (%)b
i
1
2
3
4
5
6
nC10H21
CH2Ph
-(CH2)3OH
-(CH2)3OSi(iPr)3
3-thienyl
CO2 Pr
16a
16b
16c
16d
16e
16f
79
90
86
83
77
84
i
CO2 Pr
i
CO2 Pr
i
CO2 Pr
i
CO2 Pr
t
CH2Ph
CO2 Bu
a Methylalumination as in Table 1; 1.5-3 equiv azodicarboxylate. See
Supporting Information for complete experimental details. b Isolated
yields.
a All AD reactions were performed under standard conditions: AD-mix,
t
0.1 M in BuOH/H2O, 0 °C. b Unless noted otherwise, ee values determined
by HPLC. See Supporting Information for details. c Isolated yields from 4.
Tandem carbometalation-oxidation is not limited to carbon-oxygen
bond formation. Indeed, in preliminary experiments we found that vinyl
alane 5 could be aminated in high yields with azodicarboxylates (Table
3).17 Hydrogenation and deprotection of 16f provided the free amine
in >90% yield.18 With access to stereodefined enol and enamine
derivatives, future studies will seek to engage these materials in a
variety of asymmetric transformations.
d Percent ee from ref 11a. e Reaction run with 1.0 equiv MeSO2NH2 added.
Scheme 2. Total Synthesis of (+)-Frontalina
Acknowledgment. We thank Professor Jef De Brabander (UT
Southwestern) for insightful discussions related to frontalin. Financial
support was provided by the Robert A. Welch Foundation, NIGMS,
and the NSF (CAREER). J.R.D. is supported by a fellowship from
the Frank and Sara McKnight Fund for Biochemical Research.
a Reagents and conditions: (a) PdCl2, CuCl,O2, DMF/H2O (7:1), quant; (b)
t
AD-mix-ꢀ, MeSO2NH2, NaHCO3, BuOH/H2O (1:1), 0 °C, 18 h, 85%; (c)
[Me4N]BH(OAc)3, AcOH, CH3CN, 76%; (d) AD-mix-ꢀ, tBuOH/H2O, 0 °C.
Supporting Information Available: Complete experimental proce-
dures and characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 3. Transformations of R-Hydroxy Aldehydesa
References
(1) (a) Wasserman, H. H.; Keller, L. S. Tetrahedron Lett. 1974, 15, 4355. (b)
Mukaiyama, T.; Murakami, M.; Yamaguchi, M. Chem. Lett. 1980, 9, 529.
(2) (a) Wittig, G.; Frommeld, H. D.; Suchanek, P. Angew. Chem., Int. Ed.
1963, 2, 683. (b) Stork, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85,
2178. (c) Enders, D.; Eichenauer, H. Tetrahedron Lett. 1977, 18, 191. (d)
Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450. (e) Reviews :
Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517. (f) Clarke, M. L.
Current Org. Chem. 2005, 9, 701.
a Reagents and conditions: (a) (MeO)2POCN2COMe, K2CO3, MeOH,
0 °C-room temp; (b) BnNH2, toluene, 4 Å MS, 105 °C; NaBH4, MeOH, 0 °C;
(c) I2, KOH, MeOH, 0 °C; (d) Bu3PCH2CO2EtBr, NaHCO3, toluene, 90 °C.
(3) Zhang, D.; Ready, J. M. Org. Lett. 2005, 7, 5681.
(4) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(5) (a) Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985,
107, 6639. (b) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. 1993, 32, 1068.
(6) (a) Shaughnessy, K. H.; Waymouth, R. M. J. Am. Chem. Soc. 1995, 117,
5873. (b) Kondakov, D. Y.; Negishi, E.-i. J. Am. Chem. Soc. 1995, 117,
10771.
(Table 2, all entries g94% ee from 4). In contrast, many 1,1-
disubstituted olefins (6) are poor substrates for AD; therefore, AD of
the enol benzoates, followed by a reductive workup with NaBH4,
presents a highly enantioselective route to these substances. Of note,
controlling stereochemistry of the olefin is critical: a 9:1 E/Z mixture
of 4a was converted to 8a in 81% ee under the conditions outlined in
Table 2. The utility of the AD reaction was exemplified in the total
synthesis of the insect pheromone (+)-frontalin (10, Scheme 2).13 Enol
(7) Moller, M.; Husemann, M.; Boche, G. J. Organomet. Chem. 2001, 624,
47.
(8) (a) Yamamoto, N. Chem. Lett. 1989, 1149. (b) van der Deen, H.; Kellogg,
R. M.; Feringa, B. L. Org. Lett. 2000, 2, 1593. (c) Lewinski, J.; Ochal, Z.;
Bojarski, E.; Tratkiewicz, E.; Justyniak, I.; Lipkowki, J. Angew. Chem.,
Int. Ed. 2003, 42, 4643. (d) Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am.
Chem. Soc. 2005, 127, 14668.
(9) Free-OH groups are benzoylated in the enol products.
(10) Cp2ZrCl2-catalyzed methylalumination occurs with ca. 95:5 regioselectivity.
However, no products derived from oxidation of the minor regioisomer
were detected in the crude reaction mixtures. See Lipshutz, B. H.; Butler,
T.; Lower, A. J. Am. Chem. Soc. 2006, 128, 15396.
(11) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483. (b) AD of vinyl sulfones: Evans, P.; Leffray, M. Tetrahedron
2003, 59, 7973. (c) AD of enol ethers : Hashiyama, T.; Morikawa, K.;
Sharpless, K. B. J. Org. Chem. 1992, 57, 5067.
benzoate
9 was treated consecutively with AD-mix ꢀ and
[Me4N]BH(OAc)3 to yield (+)-frontalin in 93% ee and in 49% overall
yield from the commercially available alkyne 1i. In comparison, the
1,1-disubstituted olefin 11 was dihydroxylated with poor selectivity
and in low yield with AD-mix ꢀ.
The enantioenriched R-hydroxy aldehydes obtained from the
dihydroxylations are useful materials for further synthetic manipulation
(Scheme 3). For example, following AD, an Ohira-Bestmann ho-
mologation of aldehyde 7b provided propargylic alcohol 12 in 77%
yield. Reductive amination of 7b proceeded smoothly to yield the
corresponding amino alcohol (13, 84% yield).14 Alternatively, the same
starting material (7b) could be oxidized to its methyl ester (14, 92%),15
or undergo olefination to afford an R,ꢀ-unsaturated ester (15, 68%,
E:Z ) 14.3:1).16
(12) Benzoyl substituents are known to interact favorably with AD ligands: (a)
Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117,
10805. (b) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319.
(13) Schuster, C.; Knollmueller, M.; Gaertner, P. Tetrahedron: Asymmetry 2006,
17, 2430, and references therein.
(14) Rieger, D. L. J. Org. Chem. 1997, 62, 8546.
(15) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett. 1992, 33, 4329.
(16) Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591.
(17) Erdik, E.; Ay, M. Chem. ReV. 1989, 89, 1947.
(18) See Supporting Information for complete experimental details.
JA803480B
9
J. AM. CHEM. SOC. VOL. 130, NO. 25, 2008 7829