Catalytic diastereoselective reduction of α,β-epoxy and α,β-aziridinyl ynones

Article abstract of DOI:10.1021/ol203114a

The Noyori transfer hydrogenation of α,β-epoxy and α,β-aziridinyl ynones leads to the corresponding α,β-epoxy or α,β-aziridinyl propargylic alcohols with high reagent-controlled diastereoselectivity.

Full text of DOI:10.1021/ol203114a

ORGANIC
LETTERS
2012
Vol. 14, No. 2
516–519
Catalytic Diastereoselective Reduction
of r,β-Epoxy and r,β-Aziridinyl Ynones
ꢀ
Valerie Druais, Christophe Meyer,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received November 21, 2011
ABSTRACT
The Noyori transfer hydrogenation of R,β-epoxy and R,β-aziridinyl ynones leads to the corresponding R,β-epoxy or R,β-aziridinyl propargylic
alcohols with high reagent-controlled diastereoselectivity.
The catalytic asymmetric synthesis of chiral secondary
propargylic alcohols is an important research area due to
the highly versatile utility of these building blocks and their
extensive use as key intermediates in numerous total
syntheses of bioactive natural products.1 To achieve this
goal, catalytic asymmetric alkynylation of aldehydes2 and
reduction of ynones3,4 can be employed as complementary
methods. Among the latter class of transformations, the
Noyori transfer hydrogenation of ynones, catalyzed by
(η6-arene)ruthenium(II) complexes comprising a mono-
N-tosylated diamine as a chiral ligand, constitutes a powerful
method to synthesize propargylic alcohols with high en-
antiomeric purity.4 It is also worth noting that a high level
of reagent-controlled diastereoselectivity has been ob-
served in the reduction of ynones possessing a stereocenter
at the R or β position of the carbonylgroup, including cases
where the latter is substituted by a heteroatom.5
Herein, we report that the Noyori transfer hydrogena-
tion of ynones bearing stereocenters substituted by an
oxygen atom at both the R and β positions can be problem-
atic and induce a strong substrate/reagent mismatch pairing.
By contrast, high levels of reagent-controlled diastereo-
selectivities can be observed in the case of R,β-epoxy or
R,β-aziridinyl acetylenic ketones.
(1) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 1995.
(2) For a recent review, see: Trost, B. M.; Weiss, A. H. Adv. Synth.
Catal. 2009, 351, 963–983.
(3) (a) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc.
1996, 118, 10938–10939. (b) Parker, K. A.; Ledeboer, M. W. J. Org.
Chem. 1996, 61, 3214–3217.
(4) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738–8739.
(5) For examples with ynones bearing a stereocenter at the β position,
see: (a) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40,
3667–3670. (b) Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett.
At the outset of our studies was the assumption that
optically active 1,2,3-triols of type A, possessing one
€
2003, 5, 733–736. (c) Shin, Y.; Fournier, J.-H.; Fukui, Y.; Bruckner,
A. M.; Curran, D. P. Angew. Chem., Int. Ed. 2004, 43, 4634–4637. (d)
Maki, K.; Motoki, R.; Fujii, K.; Kanai, M.; Kobayashi, T.; Tamura, S.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 17111–17117. (e) Trost,
B. M.; Frederiksen, M. U.; Papillon, J. P. N; Harrington, P. E.; Shin, S.;
Shireman, B. T. J. Am. Chem. Soc. 2005, 127, 3666–3667. (f) Fukui, Y.;
Bruckner, A. M.; Shin, Y.; Balachandran, R.; Day, B. W.; Curran, D. P.
Org. Lett. 2006, 8, 301–304. (g) Ferrie, L.; Reymond, S.; Capdevielle, P.;
Cossy, J. Org. Lett. 2007, 9, 2461–2464. (h) Mandel, A. L.; Bellosta, V.;
Curran, D. P.; Cossy, J. Org. Lett. 2009, 11, 3282–3285. For ynones
bearing a stereocenter at the R position, see ref 4 and (i) Marshall, J. A.;
Bourbeau, M. P. Org. Lett. 2003, 5, 3197–3199. (j) Marshall, J. A.; Ellis,
K. Tetrahedron Lett. 2004, 45, 1351–1353. (k) Cantagrel, G.; Meyer, C.;
Cossy, J. Synlett 2007, 2983–2986. (l) Barbazanges, M.; Meyer, C.;
Cossy, J. Org. Lett. 2008, 10, 4489–4492. (m) Handa, M.; Scheidt,
K. A.; Bossart, M.; Zheng, N.; Roush, W. R. J. Org. Chem. 2008, 73,
1031–1035.
(6) Representative examples include aspicilin; see: (a) Hesse, O.
J. Prakt. Chem. 1900, 62, 430–480. (b) Huneck, S.; Schreiber, K.; Steglich,
W. Tetrahedron 1973, 29, 3687–3693. For erythromycin A, see: (c) Pal, S.
Tetrahedron 2006, 62, 3171–3200. For triyne carbonate L-660,631, see:
(d) Lewis, M. D.; Menes, R. Tetrahedron Lett. 1987, 28, 5129–5132. (e)
Wright, J. J.; Puar, M. S.; Pramanik, B.; Fishman, A. J. Chem. Soc.,
Chem. Commun. 1988, 413–414. (f) Lewis, M. D.; Duffy, J. P.; Heck, J. V.;
Menes, R. Tetrahedron Lett. 1988, 29, 2279–2282. (g) Yadav, J. S.;
Rajagopal, D. Tetrahedron Lett. 1990, 31, 5077–5080. For penarolide
sulfate A1, see: (h) Nakao, Y.; Maki, T.; Matsunaga, S.; van Soest,
R. W. M.; Fusetani, N. Tetrahedron 2000, 56, 8977–8987. (i) Mohapatra,
D. K.; Bhattasali, D.; Gurjar, M. K.; Khan, M. I.;Shashidhara, K. S. Eur.
J. Org. Chem. 2008, 6213–6224.
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10.1021/ol203114a
Published on Web 01/04/2012
2012 American Chemical Society

propargylic alcohol, should be valuable building blocks
for the synthesis of trihydroxylated arrays (or their
derivatives) which are encountered in many natural
products.6 With the aim of developing an efficient catalytic
asymmetric route toward 1,2,3-triols A, it was envisaged to
achieve the Noyori transfer hydrogenation of R,β-dihy-
droxy ynones B (or protected derivatives) which would be
obtained by an enantioselective Sharpless dihydroxylation
applied to enynones C. Alternatively, 1,2,3-triols A could
be synthesized by ring opening with an oxygen nucleophile
of R,β-epoxy propargylic alcohols D7,8 which would arise
from the Noyori transfer hydrogenation of R,β-epoxy
ynones E. The latter compounds would be readily acces-
sible from R,β-epoxy alcohols F. To our knowledge,
ynones B or E had never been involved as substrates in
Noyori transfer hydrogenation (Scheme 1).
reduction of ynone 3 catalyzed by the enantiomeric com-
plex (S,S)-[Ru]-I (10 mol %) [i-PrOH/CH2Cl2 (10:1)] was
slightly slower (2 h, rt) and led to a 52:48 mixture of
propargylic alcohols 4a and 4b which points out a strong
substrate/reagent mismatch pairing.12 For comparison,
reduction of ynone 3 was carried out with BH3 SMe2
3
in the presence of the oxazaborolidine (R)-Me-CBS
(THF, À30 °C) and a diastereomeric mixture of propargylic
alcohols 4a and 4b was obtained with high diastereoselec-
tivity (4a/4b = 95:5; 84%).3b In the presence of oxazabor-
olidine (S)-Me-CBS, the diastereoselectivity was much
lower (4a/4b = 33:67; 86%) and controlled by the reagent
only to a moderate extent.13 Reduction of ynone 3 under
Luche’s conditions14 led to a 73:27 mixture of the epimeric
alcohols 4a and 4b (88%) as a result of a rather modest
FelkinÀAnh control15 exerted by the stereocenter at the
R position of the carbonyl group (Scheme 2).12
Scheme 1. Catalytic Asymmetric Route toward 1,2,3-Triols A
Scheme 2. Reduction of Ynone 3
Enynone 1 was selected as the test substrate9 and sub-
jected to a Sharpless enantioselective dihydroxylation
using AD-mix β to afford the corresponding enantio-
enriched R,β-dihydroxy ketone 2 (62%, ee = 95%).10
Attempts to achieve the Noyori reduction of the non-
protected R,β-dihydroxy ynone 2, catalyzed by either
(R,R)- or (S,S)-[Ru]-I (5À10 mol %) (i-PrOH, rt), did
not provide the expected diastereomeric 1,2,3-triols. In-
stead, 5-endo-dig cyclization of the R hydroxyl group to the
alkyne took place as the major competing pathway.11
Unfortunately, neither the bis-TBS ether nor the bis-
acetate derived from 1,2-diol 2 could be reduced under
the same conditions even by using a high catalyst loading
(up to 15 mol %). However ynone 3, synthesized by
protection of the 1,2-diol 2 as an acetonide (cat. TsOH,
Me2C(OMe)2, rt, 86%), underwent successful Noyori
transfer hydrogenation in the presence of (R,R)-[Ru]-I
(10 mol %) [i-PrOH/CH2Cl2 (10:1), 0.5 h, rt] and afforded
a 92:8 diastereomeric mixture of propargylic alcohols
4a and 4b which was isolated in 73% yield. By contrast,
The Noyori transfer hydrogenation of ketones is known
to occur by a metalÀligand bifunctional catalysis from an
18-electron ruthenium hydride complex intermediate. A
simultaneous transfer of the hydride and the protic NÀH
(axial) occurs to the carbonyl group, and a stabilizing
arene CÀH/π interaction with the alkyne is responsible
for the high face selectivity observed in the reduction of
ynones.16 In the case of catalyst (R,R)-[Ru]-I, a match
pairing is observed with ynone 3 since reduction can
proceed through a FelkinÀAnh transition state TSa.
(7) For a review on the ring opening of R,β-epoxy alcohols, see:
Behrens, C. H.; Sharpless, K. B. Aldrichimica Acta 1983, 16, 65–79.
(8) For the synthesis of 1,2,3-triols from R,β-epoxy alcohols, see: (a)
Roush, W. R.; Brown, R. J.; DiMare, M. J. Org. Chem. 1983, 48, 5083–
5093. (b) Roush, W. R.; Straub, J. A.; VanNieuwenhze, M. S. J. Org.
Chem. 1991, 56, 1636–1648. (c) For a recent contribution, see: Mukerjee,
P.; Abid, M.; Schroeder, F. C. Org. Lett. 2010, 12, 3986–3989.
(9) For the preparation of the substrates, see Suppporting
Information.
(12) Diastereomeric ratios were determined in all cases by analysis of
the crude product by 1H NMR spectroscopy.
(13) Strong match/mismatch pairing has been previously noted dur-
ing the CBS reduction of an ynone possessing an adjacent acetonide
derived from an anti-1,2-diol; see: RajanBabu, T. V.; Nugent, W. A.;
Taber, D. F.; Fagan, P. J. J. Am. Chem. Soc. 1988, 110, 7128–7135.
(14) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(15) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1224.
(16) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed.
2001, 40, 2818–2821.
(10) Marson, C. M.; Edaan, E.; Morrell, J. M.; Coles, S. J.; Hursthouse,
M. B.; Davies, D. T. Chem. Commun. 2007, 2494–2496.
(11) This transformation has been previously reported in the pre-
sence of mercuric salts; see ref 10.
Org. Lett., Vol. 14, No. 2, 2012
517

Conversely, the normal face selectivity of the catalyst
generated from (S,S)-[Ru]-I would impose hydride deliv-
ery through a disfavored anti-FelkinÀAnh transition state
TSb (Scheme 3).
investigated.9 The latter ynones were thus subjected to
transfer hydrogenation catalyzed by either (S,S)- or
(R,R)-[Ru]-I (5 mol %) in i-PrOH or i-PrOH/CH2Cl2
(10:1) (Table 1).18
Table 1. Noyori Transfer Hydrogenation of
(Triisopropylsilylethynyl) R,β-Epoxy Ketones (R = TIPS)
Scheme 3. Transition States for Reagent-Controlled Transfer
Hydrogenation of Ynone 3
Since protection of the 1,2-diol as an isopropylidene
acetal in ynone 3 may be responsible for the difficulty in
achieving high reagent-controlled diastereoselective Noyori
reduction in the mismatched manifold, we investigated the
reactivity of the less sterically demanding R,β-epoxy acety-
lenic ketones E. The readily available R,β-epoxy ynone 5
(ee = 94%)9 was subjected to transfer hydrogenation using
catalysts (S,S)- and (R,R)-[Ru]-I (i-PrOH, rt). Under these
conditions, a diastereomeric mixture of propargylic alcohols
6a and 6b was obtained in each case with rather moderate
but reagent-controlled diastereoselectivity (6a/6b = 75:25
and 6a/6b = 13:87, respectively). It is well-known that
R,β-epoxy ketones can be reduced to anti-R,β-epoxy alcohols
under conditions that favor Cram-chelate control but access
to syn-R,β-epoxy alcohols is more difficult.17 Reduction of
ynone 5 by NaBH4 in the presence of CaCl2 (MeOH, 0 °C)
was found to proceed with a modest level of diastereocontrol
(6a/6b = 30:70; 86%) presumably due to the low steric
hindrance of the acetylenic chain (Scheme 4). Thus, the
development of highly diastereoselective reagent-controlled
reduction of R,β-epoxy ynones would be particulaly
interesting.
a Catalyst (5 mol %), i-PrOH, rt, 1.5 h. b Catalyst (5 mol %), i-PrOH/
CH2Cl2 (10:1), rt, 1.5 h. c Et2O, 0 °C. d MeOH, 0 °C.
Reactions occurred smoothly (rt, 1.5 h), and the corre-
sponding syn- or anti-R,β-epoxy propargylic alcohols
12aÀ16a or 12bÀ16b, respectively, were obtained with
uniformely high reagent-controlled diastereoselectivities
(dr g88:12) whether the oxirane is trans-R,β-disubstituted
(substrates 7 and 8) or cis-R,β-disubstituted (substrates
9 and 10), irrespective of the nature of the substituent (linear
or branched) at the β carbon, or R,R,β-trisubstituted
(ynone 11) (Table 1).12,19 The high reagent-controlled
Scheme 4. Reduction of R,β-Epoxy Ynone 5
(17) (a) Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K. Tetra-
hedron 1995, 51, 679–686. (b) Li, K.; Hamann, L. G.; Koreeda, M.
Tetrahedron Lett. 1992, 33, 6569–6570. (c) Fujii, H.; Oshima, K.;
Utimoto, K. Chem. Lett. 1992, 967–970. (d) Nakata, T.; Tanaka, T.;
Oishi, T. Tetrahedron Lett. 1981, 22, 4723–4726. (e) For a review on
R,β-epoxy ketones, see: Lauret, C. Tetrahedron: Asymmetry 2001, 12,
2359–2383.
(18) The catalyst can be added as a solid or as a solution in CH2Cl2.
(19) To confirm the stereochemical outcome, reduction of represen-
tative ynones 7, 10, and 11 was also achieved with achiral reagents such
as Zn(BH4)2 or NaBH4/CaCl2 to afford the anti-R,β-epoxy alco-
hols (12b, 15b, and 16b) as the major diastereomers.
As silylated acetylenic ketones are excellent substrates in
Noyori enantioselective reductions,4 the reactivity of sev-
eral (triisopropylsilylethynyl) R,β-epoxy ketones 7À11 was
17c
17a
518
Org. Lett., Vol. 14, No. 2, 2012

diastereoselectivity observed in the Noyori transfer hydro-
genation of R,β-epoxy acetylenic ketones is noteworthy
Table 2. Noyori Transfer Hydrogenation of R,β-Aziridinyl
Ynones
since reduction of such substrates using BH3 SMe2 in the
presence of (R)- or (S)-Me-CBS reagent can lead to a
strong substrate/reagent mismatch pairing.20
3
Due tothe high levelsof diastereoselectivity observedfor
the Noyori transfer hydrogenation of R,β-epoxy ynones, it
was envisaged to examine the reactivity of several structu-
rally related N-tosyl-R,β-aziridinyl ynones 17À19 and 20,
readily prepared from L-serine or L-threonine, respectively
(Table 2).9
For ynones 17À19 possessing a monosubstituted azir-
idine, diastereoselective reagent-controlled Noyori reduc-
tion could be achieved whatever the substituent on the
alkyne (R = n-Pr, CH2OTr, or TIPS); however the use
of catalyst (S,S)-[Ru]-I generally led to slower reactions
requiring a higher catalyst loading to reach completion.
Ynone 20 possessing a cis-R,β-disubstituted aziridine also
underwent reagent-controlled transfer hydrogenation, and
itisworth noting thatthe diastereoselectivity washigh only
in the presence of catalyst (S,S)-[Ru]-I (Table 2).21
In conclusion, we have reported that the Noyori trans-
fer hydrogenation of R,β-epoxy ynones, contrary to other
R,β-dialkoxy ynones, as well as R,β-aziridinyl ynones can
proceed with a high level of reagent-controlled diastereos-
electivitytodeliver R,β-epoxy orR,β-aziridinylpropargylic
alcohols that constitute highly functionalized useful build-
ing blocks for the synthesis of natural products.
a Isolated yield of the major pure diastereomer.
Acknowledgment. V.D. thanks the MRES for a grant.
(20) Li, J.; Park, S.; Miller, R. L.; Lee, D. Org. Lett. 2009, 11, 571–574.
(21) Reduction of 1-(1-phenylethyl)aziridines-2-acylaziridines can
proceed with a high level of Felkin-Anh (L-selectride) or Cram-chelate
(NaBH4/ZnCl2) diastereocontrol; see: (a) Yun, J. M.; Sim, H. S.; Lee,
W. K.; Ha, H.-J. J. Org. Chem. 2003, 68, 7675–7680. (b) Singh, A.; Kim,
B.; Lee, W. K.; Ha, H.-J. Org. Biomol. Chem. 2011, 9, 1372–1380.
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 2, 2012
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