Asymmetric dihydroxylations of enynes with a trisubstituted C=C bond. An unprecedented route to γ-lactone building blocks with a quaternary stereocenter

Article abstract of DOI:10.1021/ol103061g

En route to a comprehensive set of hydroxylactone building blocks (4R,5R)-, (4R,5S)-, (4S,5R)-, and (4S,5S)-5a, Sharpless asymmetric dihydroxylations of allylic chlorides (E)-and (Z)-9 were performed. They delivered the four stereoisomers of diol 10 with

Full text of DOI:10.1021/ol103061g

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1016–1019
Asymmetric Dihydroxylations of Enynes
with a Trisubstituted CdC Bond. An
Unprecedented Route to γ-Lactone
Building Blocks with a Quaternary
Stereocenter
†
Heike Burghart-Stoll, Tobias Kapferer, and Reinhard Bruckner*
‡
,†
€
€
Institut fu€r Organische Chemie und Biochemie, Albert-Ludwigs-Universitat,
Albertstr. 21, 79104 Freiburg im Breisgau, Germany, and Bayer CropScience AG,
Alfred-Nobel-Str. 50, 40789 Monheim, Germany
reinhard.brueckner@organik.chemie.uni-freiburg.de
Received October 1, 2010
ABSTRACT
En route to a comprehensive set of hydroxylactone building blocks (4R,5R)-, (4R,5S)-, (4S,5R)-, and (4S,5S)-5a, Sharpless asymmetric
dihydroxylations of allylic chlorides (E)- and (Z)-9 were performed. They delivered the four stereoisomers of diol 10 with up to 92% ee and
absolute configurations, which were proven to be in accordance with the Sharpless mnemonic.
Enantiomerically pure tetronic acids 1,1 butenolides 2,2
and 3-methylidenebutanolides 3,3 all with a quaternary
methyl-bearing stereocenter, form the core not only of a
variety of natural products1-3 but also of analogs of
pharmaceutical interest4 (Figure 1). In continuation of
our interest in this kind of compound, which was aroused
by establishing the configuration of a Plagiomnium lactone
through synthesis,5 we conceived sets of stereochemically
homogeneous metal;CdC-containing hydroxylactones
5 (LnM = Bu3Sn, pinacolB, Cp2ClZr, etc.) and CtC-
containing hydroxylactones 6 as versatile precursors of
such structures. We intended to derive 5 via 6 from func-
tionalized diols 7 and those from the isomeric pentenynols
†
€
Albert-Ludwigs-Universitat.
‡ Bayer CropScience AG.
(1) For example, see: (a) Trifonov, L.; Bieri, J. H.; Prewo, R.;
Dreiding, A. S.; Rast, D. M.; Hoesch, L. Tetrahedron 1982, 38, 397–
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50, 255–257. (c) Shirota, O.; Pathak, V.; Hossain, C. F.; Sekita, S.;
Takatori, K.; Satake, M. J. Chem. Soc., Perkin Trans. 1 1997, 2961–
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1998, 62, 2120–2126. See also: Sperry, S.; Samuels, G. J.; Crews, P. J.
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Y.; Yasunaga, K.; Onose, J.-i.; Yoshikawa, K.; Abe, N. Tetrahedron
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^
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€
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Chem.;Eur. J. 2000, 6, 2564–2571. (b) Tan, L.; Chen, C.-y.; Chen,
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r
10.1021/ol103061g
Published on Web 01/27/2011
2011 American Chemical Society

Scheme 2. Asymmetric Dihydroxylations of Allylic Chloride
(E)-9 in the Presence of Buffer (NaHCO3/K2CO3) and Me-
SO2NH2
Figure 1. Retrosynthetic analysis of tetronic acids 1, butenolides
2, and methylidenebutanolides 3, all with a quaternary methyl-
bearing stereocenter at C-5.
another synthesis of 9 from 8 or of any prior selective
preparation of (E)-9 at all. Only (Z)-9 has been described
but not its isomeric purity; it was prepared from alcohol 4.13
Asymmetric Sharpless dihydroxylations14 of (E)-9 using
AD-mix R or β15 and stoichiometric MeSO2NH2 led to
incomplete conversions (15% after 8 d and 19% after 3 d,
respectively) and less satisfactory ee values (69% and 83%,
respectively). Accordingly we varied the amount of
K2OsO2(OH)4 [between 0.2 mol % (in the AD-mixes)
and 2.0 mol %], the amount of phthalazine ligand
[between 1.0 mol % (in the AD-mixes) and 10 mol %],
and the ratio of these reagents [going from 0.2 (in the AD-
mixes) to 1.0]. Employing 1.0 mol % of K2OsO2(OH)4
and 2.0 mol % of the phthalazine ligand resulted in the
asymmetric dihydroxylation (“AD”) giving better yields
(Scheme 2). With (DHQ)2PHAL as the ligand stereocon-
trol reached 85% ee16 (64% yield), but using (DHQD)2-
PHAL weobtainedup to92% ee16 (69% yield). ADs of the
same chloride (E)-9 in the presence of 1.0 mol % of
K2OsO2(OH)4 and 2.0 mol % of the anthraquinones
(DHQ)2AQN or (DHQD)2AQN17 furnished 73% and
86% yields of the diol, respectively. Enantiocontrol dropped
to 54% ee16 in the former case but matched the (DHQD)2-
PHAL value in the latter (92% ee16).
Scheme 1. Stereoselective Syntheses of Chlorides (E)- and (Z)-9
(Isomeric Purity of All Compounds >99:1)
(E)- and (Z)-8. The latter are [1,3]-rearrangement pro-
ducts6 of alcohol 4, which result from the 1,2-addition of
metal acetylides to methylvinylketone7 or to cyclopenta-
diene-protected methylvinylketone8 (followed by a [2 þ 4]
cycloreversion). The originally obtained 15:85 (E)-8/(Z)-8
mixture9 can be separated by careful distillation.9a,10 The
resulting isomers or the mentioned mixture are established
C6 building blocks for the synthesis of oligoterpenes.11
We began by converting the allyl alcohols (E)- and (Z)-8
into the corresponding chlorides (E)- (70% yield) and (Z)-9
(58% yield), respectively, by the nonoxidizing variant of
the Corey-Kim reaction (Scheme 1).12 We are unaware of
€
€
(5) Kapferer, T.; Bruckner, R.; Herzig, A.; Konig, W. A. Chem.;
Eur. J. 2005, 11, 2154–2162.
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(11) For example, see: (a) Isler, O.; Ronco, A.; Huber, W.; Kofler, M.
The same ligands mediated ADs of allylic chloride (Z)-9
(Scheme 3). Enantiocontrol was ca. 90% ee, but yields
were only 41 and 47% with the PHAL-containing and
22-23% with the AQN-containing ligands. Since the
substrate was completely consumed (as indicated by TLC)
we assume that it suffered some competing hydrolysis.18
This would have led via pentenynol 8 to a triol sufficiently
polar that it could have escaped our monitoring and
workup procedures.
€
Helv. Chim. Acta 1947, 30, 1911–1927. (b) Manchard, P. S.; Ruegg, R.;
Schwieter, U.; Siddons, P. T.; Weedon, B. C. L. J. Chem. Soc. 1965,
2019–2026. (c) Davies, A. J.; Khare, A.; Mallams, A. K.; Massy-
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Trans. 1 1984, 2147–2157. (d) Pattenden, G.; Robson, D. C. Tetrahedron
Lett. 1987, 28, 5751–5754.
The only previous attempt of subjecting an allylic chlo-
ride with a trisubstituted CdC bond to an AD reaction
(12) Method: Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett.
1972, 4339–4342.
(15) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang,
Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768–2771 (in the
presence of MeSO2NH2). (b) Footnote 6 in Jeong, K.-S.; Sjo, P.;
Sharpless, K. B. Tetrahedron Lett. 1992, 33, 3833–3836 (in the absence
of MeSO2NH2).
(16) The enantiopurity of this compound was determined by GLC
after acetonide formation (for details see Supporting Information).
(17) Becker, H.; Sharpless, K. B. Angew. Chem. 1996, 108, 447–449.
Angew. Chem., Int. Ed. Engl. 1996, 35, 448–451.
(13) (a) Surmatis, J. D. U.S. Patent 2760998, 1956; Chem. Abstr. 1956,
50, 8705i. (b) Santelli, M.; Bertrand, M. Bull. Soc. Chim. Fr. 1973, 2331–
2335. (c) Preparation of an (E)-9/(Z)-9 mixture from alcohol 4: ref 9a.
(14) Recent reviews: (a) Kolb, H. C.; Sharpless, K. B. In Transition
Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 2004; pp 275-298; Vol. 2. (b) Noe, M. C.; Letavic, M. A.;
Snow, S. L.; McCombie, S. Org. React. 2005, 66, 109–625. (c) Zaitsev,
A. B.; Adolfsson, H. Synthesis 2006, 1725–1756.
€
Org. Lett., Vol. 13, No. 5, 2011
1017

Scheme 3. Asymmetric Dihydroxylations of Allylic Chloride
(Z)-9 in the Presence of Buffer (NaHCO3/K2CO3) and Me-
SO2NH2
Scheme 5. Elaboration of the ul-Configured Chlorodiols
(2R,3S)- and (2S,3R)-10 into Two Sets of lk-Configured tert-
Lactone Building Blocks 6 and 5a
Scheme 6. Elaboration of the lk-Configured Chlorodiols
(2R,3R)- and (2S,3S)-10 into Two Sets of ul-Configured tert-
Lactone Building Blocks 6 and 5a
Scheme 4. Attempted Asymmetric Dihydroxylation of Prenyl
Chloride in the Presence of Buffer (NaHCO3/K2CO3) and
MeSO2NH2
19
a stereochemically comprehensive set of CtC-containing
hydroxylactones 6. These were hydrostannylated23 furnish-
ing the Bu3Sn;CdC-containing hydroxylactones 5a
trans-selectively. The lk-configured hydroxylactones 5a
resulted with 100:0 regioselectivities (Scheme 5), but their
ul-configured counterparts as 86:14 mixtures (Scheme 6).
Further elaboration of these building blocks is under study.
One enantiomer of each diastereomer of the Bu3Sn;
CdC-containing hydroxylactones 5a was elaborated further
by cross-coupling with trans-1-iodobut-2-ene24 (Scheme 7).
Standard Stille couplings25 suffered from loss of the config-
urational integrity of the ethyl-substituted CdC bond. The
Pd-free alternative26 (“Liebeskind coupling”) in the presence
of 1.5 equiv of Cu(I) thiophene-2-carboxylate accomplished
these transformations selectively (0 °C f room temp, e 30
min). The diene-substituted hydroxylactones (-)-(4R,5R)-
and (-)-(4R,5S)-16 resulted in yields of 68% and 95%,
respectively.
affected prenyl chloride (Scheme 4).19 This rendered none
of the expected chlorodiol 12 yet 50% of the dihydroxyla-
tion product 14 (absolute configuration uncertain) of the
surmised in situ hydrolysates 13 and iso-13. Apart from our
own results ADs of allylic chlorides seem to be limited to the
parent compound (i.e., allyl chloride20) and to derivatives
with a trans-disubstituted CdC bond.21
The isomeric chlorodiols 10 were C1 elongated with
KCN and crown ether22 giving the cyanodiols 15 shown
in Schemes 5 and 6. When the latter compounds were
treated with concentrated hydrochloric acid, they rendered
(18) Product loss through epoxide formation appears to be an
unlikely alternative since we dihydroxylated in the presence of a buffer
(NaHCO3/K2CO3). This is common19,21a,21b,21f-21i,21k yet not compul-
sory (footnote 4 in ref 19; ref 21c-e,j) in such cases.
(19) Vanhessche, K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahe-
dron Lett. 1994, 35, 3469–3472.
(20) Kolb, H. C.; Bennani, Y. L.; Sharpless, K. B. Tetrahedron:
We proved the configurational assignments of Schemes 2,
3, and 5-7 for one AD per allylic chloride. The bis(4-
bromobenzoate) 17 of the AD product (þ)-(2S,3R)-10 of
allylic chloride (E)-9 crystallized so that its stereostructure
could be unraveled by anomalous X-ray diffraction
Asymmetry 1993, 4, 133–141.
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Masamune, S. J. Org. Chem. 1997, 62, 8978–8979. (b) Marshall, J. A.;
Jiang, H. Tetrahedron Lett. 1998, 39, 1493–1496. (c) Kobayashi, Y.;
Nakayama, Y.; Yoshida, S. Tetrahedron Lett. 2000, 41, 1465–1468.
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Goodwin, M. B.; Knox, J. E.; Lipinski, C. A.; Keller, T. H.; Barry, C. E.;
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Prunet, J. J. Org. Chem. 1997, 62, 7768–7780.
(24) trans-1-Iodobut-2-ene was prepared in 50% yield (63%: Alexakis,
A.; Duffault, J. M. Tetrahedron Lett. 1988, 29, 5243–6246) from but-1-yne
by successive treatments with DIBAH and iodine.
(25) Stille, J. K. Angew. Chem. 1986, 98, 504–519. Angew. Chem., Int.
Ed. Engl. 1986, 25, 508–524. Farina, V.; Krishnamurthy, V.; Scott, W. J.
Org. React. 1997, 50, 1–652.
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1018
Org. Lett., Vol. 13, No. 5, 2011

Scheme 7. Liebeskind Couplings of Diastereomeric tert-Lac-
tone Building Blocks (-)-(4R,5R)- and (þ)-(4R,5S)-5aa
Scheme 9. Determination of the Absolute Configuration of One
of the lk-Configured Chlorodiols 10 (Top Row)
a 95% yield was calculated referring to the alkenylstannane precur-
sor, which contains the trans-disubstituted CdC bond. The yield of
(-)-(4R,5S)-16 relative to the total amount of the two alkenylstannane
substrates was 82%.
Scheme 8. Absolute Configuration of One of the ul-Configured
Chlorodiols 10
Figure 2. Facial selectivity of the AD of allylic chlorides. A
common stereochemical control element for substrates with a
trisubstituted CdC bond (left) and a disubstituted CdC bond
(right) is highlighted.
(Scheme 8). The proof of the absolute configuration of
AD-product (þ)-(2S,3S)-10 of allylic chloride (Z)-9focused
on its tertiary stereocenter. It was incorporated in a seven-
step sequence27 in the optically active lactone (-)-(S)-18
with a single stereocenter (Scheme 9). Its 3D structure
became clear when its antipode (þ)-(R)-18 resulted in
seven analogous steps27 from chlorodiol (þ)-(2S,3R)-10,
the configuration of which had been elucidated after the
esterification shown in Scheme 8.
of any one of the two Csp2-H bonds in the latter
substrate determines the facial selectivity of attack by a
Sharpless-type OsO4 complex. Figure 2 underscores this
point. This selectivity conforms with the stereoselectiv-
ity, which the “Sharpless mnemonic” predicts for the
ADs of all kinds of substrates with a trisubstituted or a
trans-disubstituted CdC bond.29
The steric course of the AD reactions of pentenynyl
chlorides (E)- and (Z)-9 concurs with the outcome of
ADs of allylic chlorides where the steric course was
not just postulated (e.g., refs 19 and 21a,c,d,g,j) but
evidenced by X-ray crystallography, identification
with independently synthesized reference compounds,
conversion into natural products of established stereo-
structure, or NMR analysis of diastereomeric deriva-
tives.21b,e,f,h,i,k,28 It should be emphasized that the diag-
nosis of such a stereochemical analogy is only meaningful
if the following presupposition is made: in the transition
state of the AD of an allylic chloride with either a tri- or
disubstituted CdC bond, the orientation of the only
Csp2-H bond in the former substrate or the orientation
Disconcertingly, our stereoselectivities (E)-9 þ AD-mix
R f (2R,3S)-10 and (Z)-9 þ AD-mix R f (2R,3R)-10 were
the exact opposite of what was reported for the ADs of
some ethers, which share a methylated pentenynyl unit with
our substrates.30 These inconsistencies are the subject of the
following paper and resolved therein.
Acknowledgment. The authors thank Dr. Jens Geier
€
(Institut fur Organische Chemie und Biochemie, Albert-
Ludwigs-Universitat Freiburg) for the X-ray analysis and
€
Dr. Thomas Netscher (DSM, Basel) for donations of both
(E)- and (Z)-8.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of gas chromatograms,
and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
€
(27) Burghart-Stoll, H.; Bruckner, R. Manuscript in preparation. It
is unlikely that the transformations of Scheme 9 are the shortest
conceivable stereochemical correlation between the chlorodiols
(þ)-(2S,3S)-10 and (þ)-(2S,3R)-10. However, for reasons beyond the
present context we needed a nonracemic sample of lactone 18. What
mattered was the efficiency of the route and not the configuration of 18.
At some point we had converted (þ)-(2S,3S)-10 into levorotatory 18 and
(þ)-(2S,3R)-10 into dextrorotatory 18. These transformations provided
the latest stereochemical information for completing the configurational
assignments of the present study as a spin-off result.
ꢀ
€
(29) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.;
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Lubben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita, T. J. Org.
Chem. 1991, 56, 4585–4588. (c) Reference 15b. (d)Kolb, H. C.;Andersson,
P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1994, 116, 1278–1291.
€
(28) Richardson, T. I.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,
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