Asymmetric dihydroxylation of disubstituted allenes

Article abstract of DOI:10.1016/j.tetlet.2005.09.138

Asymmetric dihydroxylation of 1,1-disubstituted and 1,3-disubstituted allenes can be used to synthesize chiral α-hydroxy ketones. We have also obtained α,α′-dihydroxy ketones with high enantioselectivity from 1,3-disubstituted allenes. Low conversion of the dihydroxylation of chiral allenes can be used as a kinetic resolution of sterically hindered allenes.

Full text of DOI:10.1016/j.tetlet.2005.09.138

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8095–8098
Asymmetric dihydroxylation of disubstituted allenes
Steven A. Fleming,* Renmao Liu and J. Ty Redd
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA
Department of Chemistry and Biochemistry, Southern Utah University, Cedar City, UT 84720, USA
Received 10 September 2005; revised 20 September 2005; accepted 21 September 2005
Available online 10 October 2005
Abstract—Asymmetric dihydroxylation of 1,1-disubstituted and 1,3-disubstituted allenes can be used to synthesize chiral a-hydroxy
ketones. We have also obtained a,a0-dihydroxy ketones with high enantioselectivity from 1,3-disubstituted allenes. Low conversion
of the dihydroxylation of chiral allenes can be used as a kinetic resolution of sterically hindered allenes.
Ó 2005 Elsevier Ltd. All rights reserved.
We recently reported the asymmetric dihydroxylation
(AD) of arylallenes as a synthetic methodology for the
formation of a-hydroxy ketones.1 We were impressed
by the complete regioselectivity and the high degree of
stereoselectivity in the synthesis of chiral a-hydroxy
ketones using this methodology (see Scheme 1). This
procedure can be considered along with the other meth-
ods for asymmetric synthesis of a-hydroxy ketones.2
Other metal-catalyzed oxidation reactions of allenes
have been reported, which lead to racemic a-hydroxy
ketones.3
The synthesis of the 1,1-disubstituted allenes (1, 2, and 3)
shown in Scheme 2 was performed using the same proce-
dure as the mono-substituted allenes reported in our pre-
vious paper. That is, ethynyl Grignard was added to the
corresponding ketone and the resulting propargyl alco-
hol was reduced with LAH in an SN20 fashion.5
We found that the SN20 reaction was successful for for-
mation of allenes 4 and 5 from their corresponding alky-
nols, which were formed by addition of the anion of
1-octyne to the corresponding aldehydes.6 The alkyne
needed for the synthesis of the tert-butyl substituted
allene 6 was not readily available, so the procedure of
Jiang and Si7 was used and it gave the necessary propar-
gyl alcohol in good yield. Use of the LAH reaction on
the alkynol for the formation of 6 was not successful.
Fortunately, reaction with tin hydride under radical
conditions as described by McGrath and co-workers
gave allene 6.8 Synthesis of 1,3-diphenylallene (7) using
this tin hydride procedure was complicated by undesired
by-products. Its synthesis was performed as described by
Bergman and co-workers.9 This method involves an
SN20 addition of a phenyl anion onto the mesylated
propargyl alcohol. Although this gives a good yield of
In order to determine the utility of this reaction we have
explored the AD reaction with disubstituted allenes. We
expected that the 1,1-disubstituted allene would be as
regioselective as the mono-substituted examples. The
fact that the resulting tertiary alcohol would be stereo-
genic and non-epimerizable was an attractive feature.
We also were drawn to the 1,3-disubstituted case be-
cause that class of allenes is chiral and there was poten-
tial for kinetic resolution using the AD reaction at low
conversion. This was intriguing for mechanistic pur-
poses, but it also has significant potential as a method
for obtaining optically active allenes.4
O
OH
OH
BrMg
LAH
AD mix
R
R
R
R
AlCl3
O
Scheme 1. Dihydroxylation of arylallenes.
*
Corresponding author. Tel.: +1 801 422 4054; fax: +1 801 422 0153; e-mail: steve_fleming@byu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.138

8096
S. A. Fleming et al. / Tetrahedron Letters 46 (2005) 8095–8098
1
2
3
4
5
6
7
Scheme 2. Allenes 1–7.
the allene, we have found that this particular allene (7) is
not very stable.
of over-oxidation, which gave a 1,3-dihydroxy ketone.
There was no over oxidation product noted in the AD
reaction of allene 3.
Our results for the asymmetric dihydroxylation are
shown in Table 1. The major product for the dihydroxyl-
ation of allenes 1, 2, and 3 was the corresponding hydr-
oxy methyl ketone of each. That is, the oxidation occurs
regioselectively across the more substituted alkene as ex-
pected. The enantioselectivity, however, was not very
impressive. We have found that the best % ee for these
non-aryl substituted allenes was on the order of 20%,
but typically it was much less. The AD was more well
behaved in the reaction with 3-phenyl-1,2-butadiene
(3). In this case the Sharpless b-AD mix gave the tertiary
a-hydroxy ketone (8) in good yield and excellent enantio-
selectivity (see Scheme 3). The identity of the resulting
hydroxy ketone was verified by spectroscopic data.10
The enantiomeric excess for the chiral R hydroxy
ketones obtained from the allenes were determined by
chiral column chromatography. The a-AD mix is less
selective1 but does form the enantiomeric a-hydroxy
ketone in each case. Both AD mixes are reported to be
>95% optically pure.11 The only undesired product
(<5%) for the dihydroxylation of 1 or 2 was the result
Dihydroxylation of the 1,3-disubstituted allenes pre-
sented an interesting challenge. Our previous experience
with aryl substituted allenes led us to believe that we
would be able to control the regioselectivity of the oxi-
dation. We expected that the more nucleophilic double
bond of the allene would react first. Although our re-
sults were consistent with this prediction, we also found
numerous over-oxidation products in these examples.
Allene 4 gave a good yield of 1-hydroxy-1-phenyl-2-
nonanone (9).13 Unless considerable care was taken,
the over-oxidized 1-phenyl-1,2-nonadione (10) was also
obtained. We were familiar with the diketone because
it is a minor product in the asymmetric dihydroxylation
of the mono-substituted allenes. In addition to com-
pound 10, however, we also obtained the dihydroxy-
ketone 11 (see Scheme 4). The stereochemical
relationship between the hydroxyl groups in diol 11 is
not known at this time. The two over-oxidized products
are not formed in high yield and several attempts to
selectively form the diol in preference to dione 10 have
failed. We are continuing to explore the possibility of
controlling the formation of two stereocenters with the
single step oxidation by intentionally over-oxidizing
1,3-disubstituted allenes with the Sharpless b-mix.
Table 1. Asymmetric dihydroxylation of allenes
Allene % Recovered % Hydroxy % eea
allene (% ee) ketone
Over-oxidized
(config) products
The naphthyl substituted allene (5) behaved similarly to
the phenyl compound. The major product was the de-
sired a-hydroxy ketone and the over-oxidized products
were also observed. Presumably the yields of a-hydroxy
ketone formation for the naphthyl compound are better
because of the increased p-stacking that exists in the chi-
ral ligand.
1
2
3
4
5
6
7
20
19
<10
29
28
72
29
40
40
not obsd
50 (R)
<5
<5
<5
—
25
20
48
60
86 (R)
79 (R)
89 (R)
64 (R)
—
25 (37)
24 (15)
18 (99)
29 (98)
a % ee from b-mix reaction based on Chiracel OD (for alcohols) or
We synthesized allene 6 in order to maximize the steric
preference for one enantiomer of the allene over the
other. It follows that this would allow for kinetic resolu-
tion of the allene. Indeed we found that the bulkiness of
the tert-butyl group was sufficient to stop the oxidation
of one of the enantiomers. Even with prolonged reac-
tion times the less reactive enantiomer was only slightly
consumed. Instead the additional oxidant reacted to
give the further oxidized product of the reactive enan-
tiomer (see Table 2). The major oxidized product
chiral shift reagent12 (for allenes).
OH
AD
O
72% yield
86% ee
3
8
was
1-hydroxy-4,4-dimethyl-1-phenyl-2-pentanone.14
Scheme 3. Asymmetric dihydroxylation of allene 3.

S. A. Fleming et al. / Tetrahedron Letters 46 (2005) 8095–8098
8097
C6H13
AD
OH
OH
OH
O
C6H13
C6H13
C6H13
+
+
O
O
O
4
9
10
11
Scheme 4. Asymmetric dihydroxylation of 1-phenyl-1,2-nonadiene.
Table 2. Asymmetric dihydroxylation of 4,4-dimethyl-1-phenyl-1,2-pentadiene (6)
Amount of oxidant
AD mix
% Allene
(% ee)
% a-Hydroxy
ketone (% ee)
% a,a0-Dihydroxy
ketone (% de)
3-Hydroxy
pentanedione (% ee)
0.004 equiv Os
0.008 equiv Os
0.008 equiv Os
b
b
a
29 (59)
18 (>99)
11 (>94)
15 (<5)
40 (64)
20 (45)
12 (34)
28 (53)
10 (21)
6 (54)
20 (34)
9 (10)
OH
OH
OH
O
OH
O
t-Bu
AD
t-Bu
t-Bu
O
t-Bu
t-Bu
Ph
Ph
Ph
Ph
+
+
+
Ph
O
O
O
6
Scheme 5. Asymmetric dihydroxylation of 1-phenyl-4,4-dimethyl-1,2-pentadiene.
This a-hydroxy ketone was isolated at best in yields
around 40%, consistent with the selective reaction with
only one enantiomer of the allene (see Scheme 5). The
electron rich aryl-substituted alkene was the more reac-
tive site. We also obtained trace amounts of the 1,2-pen-
tanedione and the 1,3-dihydroxy-2-pentanone as in the
AD reaction of allenes 4 and 5. A fourth product iso-
lated in this reaction was 3-hydroxy-4,4-dimethyl-1-phen-
yl-1,2-pentanedione.
In light of the poor reactivity of the alkyl substituted
allenes 1 and 2 with the AD mixes, we chose to extend
the survey of mono-substituted allenes. We examined
the reactivity of 1,2-octadiene and 4-phenyl-1,2-butadi-
ene.16 The results of the octadiene were consistent with
the other alkyl substituted allenes. Very poor enantio-
selectivity was observed in the formation of 3-hydroxy-
2-octanone (28% yield, 58% ee). But much to our
surprise, the benzyl substituted allene gave very good
enantioselectivity of 3-hydroxy-4-phenyl-2-butanone
(see Scheme 6).17 This single result does more to clarify
the selectivity of the Sharpless reagent than any of the 14
other allenes we have studied. It is apparent that there is
a p-stacking component to the phthalizine and/or quin-
oline substrates of the AD mix that facilitates the oxida-
tion process. Although we previously argued this fact,
we also felt that the styryl nature of the phenyl substi-
tuted allenes was a major factor. But this result indicates
that although a stabilized carbocation helps in the yield
of dihydroxylation, it is not essential for an enantiose-
lective reaction.
We were pleased to find that the Sharpless AD mixes
were able to resolve the sterically hindered allene 6.
When the reaction was performed with a limiting
amount of oxidant, the recovered allene was found to
be nearly pure enantiomer (see Table 2). Using the
AD b-mix results in recovery of the R enantiomer of 6
and the a-mix allows isolation of the S enantiomer.8b
The kinetic resolution of allenes has been reported pre-
viously.15 Few examples exist that compare to the proce-
dure we report here. Although utility is limited since we
were unable to perform complete kinetic resolution on
allenes 4 or 5 using this methodology. The enantiomeric
enrichment of unreacted allene, when the oxidant was
the limiting reagent, was typically <40% for these
allenes.
In summary, we have established that the asymmetric
dihydroxylation of allenes is a suitable method for enan-
tioselective formation of a-hydroxy ketones. We have
explored the scope of this methodology with respect to
1,1-disubstituted and 1,3-disubstituted allenes. We also
have found that AD can be used for kinetic resolution
of sterically hindered allenes.
We were intrigued by the possibility of resolving 1,3-di-
phenyl-1,2-propadiene (7), we expected that the chiral
environment would be very selective for this compound.
The limited solubility and the inherent instability of this
compound made it more challenging to find the best
conditions for asymmetric dihydroxylation, but we were
finally successful in obtaining an excellent kinetic resolu-
tion of the chiral diphenyl allene. The best results were
obtained when the reaction was run at 0 °C and to
70% conversion. The recovered allene was obtained in
98% ee as shown by HPLC analysis.
O
AD
Ph
Ph
30% yield
77% ee
OH
Scheme 6. Asymmetric dihydroxylation of 4-phenyl-1,2-butadiene.

8098
S. A. Fleming et al. / Tetrahedron Letters 46 (2005) 8095–8098
ee (Chiracel ODH; 10% ethanol in hexane; 1 ml/min),
Supplementary data
retention time: t(R) = 4.87 min, t(S) = 5.81 min; [a]D ꢀ9.1
(CHCl3, c 2.2 g/l). For reference to 3-ethyl-3-hydroxy-2-
heptanone see: (b) Hamri, A.; Pera, M.-H. J. Heterocyclic
Chem. 1987, 24, 1629–1633. No optical rotation observed.
Literature reference for 3-hydroxy-3-phenyl-2-butanone
(8) see: (c) Harder, T.; Loehl, T.; Bohe, M.; Wagner, K.;
Hoppe, D. Tetrahedron Lett. 1994, 35, 7365–7368. HPLC
86% ee (Chiracel OD; 5% isopropyl alcohol in hexane;
0.8 ml/min), retention time: t(R) = 9.04 min, t(S) =
9.68 min; [a]D ꢀ229 (CHCl3, c 8.56 g/l).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.09.138.
References and notes
1. Carroll, S.; Fleming, S. A.; Hirschi, J.; Liu, R.; Pace, J. L.;
Redd, J. T. Tetrahedron Lett. 2004, 45, 3341–3343.
11. The AD mixes were obtained from Aldrich Chemical and
used without further purification.
2. (a) Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55,
3715–3717; (b) Schwarz, J. B.; Meyers, A. I. J. Org. Chem.
1998, 63, 1619–1629; (c) Bradshaw, C. W.; Fu, H.; Shen,
G.-J.; Wong, C.-H. J. Org. Chem. 1992, 57, 1526–1532; (d)
Lefker, B. A.; Hada, W. A.; McGarry, P. J. Tetrahedron
Lett. 1994, 35, 5205–5208; (e) Masui, M.; Ando, A.;
Shioiri, T. Tetrahedron Lett. 1988, 29, 2835–2838; (f)
Hashiyama, T.; Morikawa, K.; Sharpless, B. K. J. Org.
Chem. 1992, 57, 5067–5068; (g) Lopp, M.; Paju, A.;
Kanger, T.; Pehk, T. Tetrahedron Lett. 1997, 38, 5051–
12. Mannschreck, A.; Munninger, W.; Burgemeister, T.;
Gore, J.; Cazes, B. Tetrahedron 1986, 42, 399–408.
13. Literature reference for 1-hydroxy-1-phenyl-2-nonanone
(9): (a) Machrohi, F.; Namy, J.-L.; Kagan, H. B.
Tetrahedron Lett. 1997, 38, 7183–7186. HPLC 79% ee
(Chiracel OD; 10% isopropyl alcohol in hexane; 1 ml/
min), retention time: t(R) = 6.98 min, t(S) = 6.08 min; [a]D
ꢀ213 (CHCl3, c 4.85 g/l). Literature reference for 1-
phenyl-1,2-nonadione (10): (b) Chang, C. L.; Kumar, M.
P.; Liu, R. S. J. Org. Chem. 2004, 69, 2793–2796. See
Supplementary data section for spectral data of 1,3-
dihydroxy-1-phenyl-2-nonanone (11).
´
5054; (h) Solladie-Cavallo, A.; Lupattelli, P.; Jierry, L.;
Bovicelli, P.; Angeli, F.; Antonioletti, R.; Klein, A.
Tetrahedron Lett. 2003, 44, 6523–6526.
14. Spectral data for 1-hydroxy-4,4-dimethyl-1-phenyl-2-pen-
tanone are: 1H NMR (CDCl3, 500 MHz) d 0.95 (9H, s,
3CH3), 2.24 (2H, ABq, J = 15.5 Hz, CH2), 4.43 (1H, d,
J = 4 Hz, OH), 5.02 (1H, d, J = 4 Hz, CH), 7.26–7.38 (5H,
m, Ar); 13C NMR (CDCl3, 125 MHz) d 209.03, 131.64,
130.41 (2C), 129.28 (2C), 128.83, 80.85, 50.19, 31.48, 29.82
(3C); HRMS calcd for C13H18O2 206.1307, found 206.1310;
HPLC 64% ee (Chiracel OD; 10% isopropyl alcohol in
hexane; 1 ml/min) t(R) = 6.06 min t(S) = 7.25 min.
15. (a) Waters, W. L.; Linn, W. S.; Caserio, M. C. J. Am.
Chem. Soc. 1968, 90, 6741–6749; (b) Moore, W. R.;
Anderson, H. W.; Clark, S. D. J. Am. Chem. Soc 1973, 95,
835; (c) See Ref. 9.
16. Literature reference for 1,2-octadiene: (a) Crandall, J. K.;
Sujka, S. A. J. Am. Chem. Soc. 1972, 94, 5084–5086.
Literature reference for 4-phenyl-1,2-butadiene: (b) Hirao,
T.; Misu, D.; Yao, K.; Agawa, T. Tetrahedron Lett. 1986,
27, 929–932.
17. 3-Hydroxy-4-phenyl-2-butanone is a known compound,
see: Ley, S. V.; Mitchell, C.; Pears, D.; Ramarao, C.; Yu,
J.-Q.; Zhou, W. Org. Lett. 2003, 5, 4665–4668. HPLC 77%
ee (Chiracel OD; 10% isopropyl alcohol in hexane; 1 ml/
min) t(R) = 8.35 min t(S) = 10.23 min [a]D ꢀ40 (CHCl3, c
7.2 g/l).
3. (a) Laux, M.; Krause, N. Synlett 1997, 765–766; (b)
Sakaguchi, S.; Watase, S.; Sakata, Y.; Nishiyama, Y.;
Ishii, Y. J. Org. Chem. 1994, 59, 5681–5686.
4. (a) Hoffmann-Ro¨der, A.; Krause, N. Angew. Chem., Int.
Ed. 2002, 41, 2933–2935; (b) McGrath, M. J.; Fletcher, M.
T.; Konig, W. A.; Moore, C. J.; Cribb, B. W.; Allsopp, P.
G.; Kitching, W. J. Org. Chem. 2003, 68, 3739–3748.
5. (a) Claesson, A.; Olsson, L.-I. J. Am. Chem. Soc. 1979,
101, 7302–7311. Literature for 1 see Ref. 3b. Literature for
2: (b) Wotiz, J. H.; Mancuso, D. E. J. Org. Chem. 1957,
22, 207–210. Literature for 3: (c) Dieter, R. K.; Yu, H.
Org. Lett. 2001, 3, 3855–3858.
6. For spectral data of 4 see: Tius, M. A.; Pal, S. K.
Tetrahedron Lett. 2001, 42, 2605–2608. See supplemental
section for spectral data of allene 5.
7. Jiang, B.; Si, Y. G. Tetrahedron Lett. 2002, 43, 8323–
8325.
8. (a) See Ref. 4b. For spectral data of 6 see: (b) Elsevier, C.
J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726–3730.
9. Michael, F. E.; Duncan, A. P.; Sweeney, Z. K.; Bergman,
R. G. J. Am. Chem. Soc. 2003, 125, 7184–7185.
10. For synthesis of racemic 3-hydroxy-3-methyl-2-nonanone
see: (a) Stacy, G. W.; Mikulec, R. A.; Razniak, S. L.; Starr,
L. D. J. Am. Chem. Soc. 1957, 79, 3587–3591. HPLC 50%