Highly enantioenriched propargylic alcohols by oxazaborolidine-mediated reduction of acetylenic ketones

Full text of DOI:10.1021/jo9612943

J . Org. Chem. 1996, 61, 9021-9025
9021
High ly En a n tioen r ich ed P r op a r gylic
Sch em e 1
Alcoh ols by Oxa za bor olid in e-Med ia ted
Red u ction of Acetylen ic Keton es
J ordi Bach, Ramon Berenguer, J ordi Garcia,*
Teresa Loscertales, and J aume Vilarrasa
Departament de Qu ı´ mica Org a` nica, Div. III,
Universitat de Barcelona, C/ Mart ı´ i Franqu e` s 1-11,
0
8028 Barcelona, Catalonia, Spain
Received J uly 9, 1996
Development of new or improved methods for the
asymmetric reduction of ketones has gained considerable
1
significance during the past years, not only because the
optically active secondary alcohols are often present in
natural products but also due to the fact that such
compounds are valuable intermediates in organic syn-
thesis. In this connection, R,â-alkynyl ketones such as
During the past recent years, oxazaborolidines have
emerged as an important advance in the enantioselective
reduction of ketones. Several research groups have
developed chiral 1,3,2-oxazaborolidines (e.g., compounds
6-9) which can act as efficient catalysts in the borane
reduction of a wide range of structurally different ke-
tones.8 However, reports on reduction of R,â-acetylenic
1
have achieved much importance since the acetylenic
moiety of propargylic alcohols 2 can be transformed into
many other functional groups (Scheme 1).2
Midland’s B-isopinocampheyl-9-borabicyclo[3.3.1]nonane
3
a-c
(
Alpine-Borane, 3),
Brown’s B-chlorodiisopinocam-
9
3
d
ketones are very scarce and it is generally accepted that
pheylborane (DIP-Chloride, 4), and Noyori’s Binal-H
5) are excellent reagents for the conversion of 1 to 2.
4
“the reduction of R,â-acetylenic ketones in the oxazaboro-
lidine systems proceeds with only mediocre enantio-
selectivity”.2
(
Successful enantioselective reductions of a number of
alkynyl ketones have also been reported by using other
reagents.5
c
,6
Nevertheless, none of these reagents are of general
application and none afford alcohols with high optical
purity (g90% ee) from both unhindered and hindered
alkynyl ketones. Thus, a reagent which provides a
general access to highly enantiomerically enriched pro-
pargylic alcohols would be desirable.
In this connection, we have described (R)- and (S)-B-
methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, (R)- and
(S)-7, two catalysts derived from phenyglycine, which we
7
have utilized in the borane-mediated reduction of aro-
10
matic, saturated, and R,â-alkenyl ketones. Herein, we
(
5) Enzymatic reductions: (a) Bradshaw, C. W.; Hummel, W.; Wong,
(
1) For leading reviews on enantioselective reduction of ketones,
C.-H. J . Org. Chem. 1992, 57, 1532. (b) Ansari, M. H.; Kusumoto, T.;
Hiyama, T. Tetrahedron Lett. 1993, 34, 8271. Chiral aluminum or
boron hydrides: (c) Cohen, N.; Lopresti, R. J .; Neukom, C.; Saucy, G.
J . Org. Chem. 1980, 45, 582. (d) Vigneron, J . P.; Bloy, V. Tetrahedron
Lett. 1980, 21, 1735. (e) Corey, E. J .; Boaz, N. W. Tetrahedron Lett.
1984, 25, 3055. (f) Wender, P. A.; Ihle, N. C.; Correia, C. R. D. J . Am.
Chem. Soc. 1988, 110, 5904.
see: (a) Brown, H. C.; Cho, B. T.; Park, W. S.; Ramachandran, P. V.
J . Org. Chem. 1987, 52, 5406. (b) Singh, V. K. Synthesis 1992, 605. (c)
Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16. (d)
Midland, M. M.; Morrell, L. A. In Houben-Weyl Methods of Organic
Chemistry; Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann,
E., Eds.; Thieme Verlag: Stuttgart, 1995; Vol. E21d, p 4049.
(
2) (a) Mukai, C.; Kataoka, O; Hanaoka, M. J . Org. Chem. 1993,
8, 2946. (b) Midland, M. M.; Lee, P. E. J . Org. Chem. 1981, 46, 3933.
c) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1995, 36, 9153. (d)
Ohmori, K.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1995, 36,
519. Enantiomerically enriched propargylic alcohols have been used
(6) For optically active propargylic alcohols prepared by other routes,
see: (a) Mukaiyama, T.; Susuki, K. Chem. Lett. 1980, 255. (b) Mori,
A.; Ishihara, K.; Arai, I.; Yamamoto, H. A. Tetrahedron 1987, 43, 755.
(c) Burgess, K.; J ennings, L. D. J . Am. Chem. Soc. 1991, 113, 6129.
(d) Corey, E. J .; Cimprich, K. A. J . Am. Chem. Soc. 1994, 116, 3151.
(e) Oguni, N.; Satoh, N.; Fujii, H. Synlett 1995, 1043. (f) L u¨ tjens, H.;
Nowotny, S.; Knochel, P. Tetrahedron: Asymmetry 1995, 6, 2675. See
also ref 2b.
(7) For instance, 3 cannot be applied to the reduction of tert-butyl
alkynyl ketones whereas 4 reduces efficiently this type of hindered
ketones but fails for other ketones with lower steric requeriments (see
ref 2e).
(8) For recent reviews, see: Wallbaum, S.; Martens, J . Tetrahe-
dron: Asymmetry 1992, 3, 1475. Deloux, L.; Srebnik, M. Chem. Rev.
1993, 93, 763. Also see: Franot, C.; Stone, G. B.; Engeli, P.; Sp o¨ ndlin,
C.; Waldvogel, E. Tetrahedron: Asymmetry 1995, 6, 2755 and refer-
ences therein. Hong, Y.; Gao, Y.; Nie, X.; Zepp, C. M. Tetrahedron Lett.
1994, 35, 6631. Gajda, T. Tetrahedron: Asymmetry 1994, 5, 1965.
Willems, J . G. H.; Dommerholt, F. J .; Hammink, J . B.; Vaarhorst, A.
M.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1995, 36, 603. Dubois,
L.; Fiaud, J .-C.; Kagan, H. B. Tetrahedron: Asymmetry 1995, 6, 1097.
Meier, C.; Laux, W. H. G. Tetrahedron 1996, 52, 589. Schwink, L.;
Knochel, P. Tetrahedron Lett. 1996, 37, 25.
5
(
6
as intermediates in many synthesis of natural and/or biologically active
products: (e) Ramachandran, P. V.; Teodorovic, A. V.; Rangaishenvi,
M. V.; Brown, H. C. J . Org. Chem. 1992, 57, 2379 and ref 6 therein. (f)
Michelet, V.; Besnier, I.; Tanier, S.; Touzin, A. M.; Genet, J . P.;
Demoute, J . P. Synthesis 1995, 165 and refs 3-9 therein. (g) Roush,
W. R.; Sciotti, R. J . J . Am. Chem. Soc. 1994, 116, 6457. (h) Zhu, G.;
Lu, X. J . Org. Chem. 1995, 60, 1087. (i) Marshall, J . A.; Xie, S. J . Org.
Chem. 1995, 60, 7230. (j) Borzilleri, R. M.; Weinreb, S. M.; Parvez, M.
J . Am. Chem. Soc. 1995, 117, 10905. (k) Mukai, C.; Hanaoka, M.
Synlett 1996, 11.
(3) (a) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano,
A. J . Am. Chem. Soc. 1980, 102, 867. (b) Brown, H. C.; Pai, G. G. J .
Org. Chem. 1985, 50, 1384. (c) Midland, M. M.; McLoughlin, J . I.;
Gabriel, J . J . Org. Chem. 1989, 54, 159. (d) Dhar, R. K. Aldrichimica
Acta 1994, 27, 43. Also see ref 2e.
(4) (a) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J . Am.
Chem. Soc. 1984, 106, 6717. (b) Bringmann, G.; Gassen, M.; Lardy, R.
Tetrahedron 1994, 50, 10245.
S0022-3263(96)01294-7 CCC: $12.00 © 1996 American Chemical Society

9
022 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
Ta ble 1. Red u ction of Acetylen ic Keton es 10 a n d 11
Sch em e 2
a
w ith BH3‚SMe2 in th e P r esen ce of (R)-7, in THF a t 0 °C
entry
ketone
alcohol
yield (%)b
ee (%)b
c
1
2
3
4
5
10a
11a
10b
11b
10c
(R)-12a
(R)-13a
(R)-12b
(R)-13b
(R)-12c
92 (80)
73 (65)
65 (70)
60 (65)
80 (71)
70 (75)
90 (84)
d
90 (80)
d
93 (85)
d
90 (88)
d
95 (95)
d
6
11c
(R)-13c
97 (95)
a
Reactions, monitored by TLC (silica gel, CH2Cl2), finished in
<
5 min. b Isolated yields, with 1.2 equiv of BH3‚SMe2 and 1.0 equiv
report that oxazaborolidines 7 also efficiently catalyze the
borane reduction of several R,â-acetylenic ketones. The
relative performance of oxazaborolidines 6-9 with regard
to the asymmetric reduction of sterically crowded carbo-
nyl groups of R,â-acetylenic ketones and their dicobalt-
hexacarbonyl complexes has also been investigated.
of (R)-7. Within parentheses, yields and ee values using 0.2 equiv
of (R)-7. c Determined by HPLC analysis of the benzoate deriva-
d
tives with a Chiralcel OD-H chiral column. Determined by HPLC
(Tracer Spherisorb column) and/or F NMR analysis of the
corresponding Mosher esters.
1
9
Sch em e3a
Resu lts a n d Discu ssion
P r ep a r a tion of r,â-Acetylen ic Keton es. A repre-
sentative set of trimethylsilyl acetylenic ketones (RC-
3
(O)CtCSiMe , ketones 10a -c) with different bulky alkyl
groups (R) were prepared in good yields by reaction of
bis(trimethylsilyl)acetylene with the corresponding acyl
chloride under Friedel-Crafts conditions (Scheme 2).11
We envisaged that the presence of the easily removable
trimethylsilyl group in the acetylenic moiety could be
beneficial to prevention of undesirable additions to the
triple bond. However, for the sake of comparison, the
desilylated ketones 11a -c (obtained from 10a -c) were
also included in the present reduction study.
a
(
2
i) K2CO3, MeOH/H2O; (ii) H2, Lindlar cat., MeOH; (iii) O3,
CH Cl -MeOH (1:1); (iv) NaBH .
2
4
known chiral 1,2-diols 14 (Scheme 3),16 except for the
configuration of 13c (and also 12c after desilylation),
which was determined by comparison of the sign of
1
2
1
7
specific rotation with that given in the literature.
As shown in Table 1, reduction of R,â-acetylenic
ketones with very different steric requirements proceeds
with consistency and predictable stereochemistry to give
propargylic alcohols of high optical purity (90-97% ee
when 1 equiv of (R)-7 is used). Apparently, the presence
Oxa za bor olid in e-Med ia ted Red u ction s of Yn on es
1
0 a n d 11. Treatment of ketones 10a -c and 11a -c with
BH ‚SMe in the presence of (R)-7, in THF at 0 °C, gave
a clean conversion into propargylic alcohols 12a -c and
3a -c, respectively, within a few minutes.13 The results
3
2
of Me Si does not change significantly the selectivities
(compare entries 1, 3, and 5 to entries 2, 4, and 6,
3
1
are summarized in Table 1. It is worth noting that even
a very hindered ketone like 10c is reduced quite fast
under these conditions.1
The absolute configurations of propargylic alcohols 12
and 13 were determined by chemical correlation with the
respectively). An increase of the steric requirements
around the carbonyl group (from ketone 10a to ketone
10c) causes a rise in the enantioselectivity. This and the
fact that alcohols of the R configuration are mainly
obtained may be explainedsaccording to the mechanism
proposed by Corey et al.18 for analogous oxazaborolidine-
mediated reactionssby a transition state in which the
acetylenic moiety acts as the smaller group (see Scheme
4).
4,15
(9) Morita et al. have recently reported the reduction of an acetylenic
ketone catalyzed by proline-derived oxazaborolidine [(S)-6, R ) Me and
Bu] in low yields and enantioselectivity: Morita, S.; Otsubo, K.;
Matsubara, J .; Ohtani, T.; Uchida, M. Tetrahedron: Asymmetry 1995,
6
, 245. See also ref 2c. During the preparation of this manuscript a
Red u ction of Ma sk ed Acetylen ic Keton es. Despite
the good performance of (R)-7 in the reduction of acetyl-
enic ketones, we have also explored the possibility of
improving these results (which was specially desirable
for unbranched or R-monobranched ketones 10a ,b and
11a ,b) by temporary transformation of the acetylenic
moiety in a bulkier group that could enhance (or reverse)
the selectivity. In this regard, the hexacarbonyldicobalt
Note has appeared reporting the efficient reduction of a few acetylenic
ketones with an excess of (S)-6 (R ) Me) at -30 °C: Parker, K. A.;
Ledeboer, M. W. J . Org. Chem. 1996, 61, 3214.
(
10) (a) Berenguer, R.; Garcia, J .; Gonz a` lez, M.; Vilarrasa, J .
Tetrahedron: Asymmetry 1993, 4, 13. (b) Berenguer, R.; Garcia, J .;
Vilarrasa, J . Tetrahedron: Asymmetry 1994, 5, 165. (c) Bach, J .;
Berenguer, R.; Garcia, J .; Vilarrasa, J . Tetrahedron Lett. 1995, 36,
3
425. (d) Bach, J .; Berenguer, R.; Farr a` s, J .; Garcia, J .; Meseguer, J .;
Vilarrasa, J . Tetrahedron: Asymmetry 1995, 6, 2683.
11) (a) Birkofer, L.; Ritter, A.; Uhlenbrauck, H. Chem. Ber. 1963,
(
1
9
9
8
6, 3280. (b) Karpf, M.; Dreiding, A. S. Helv. Chim. Acta 1979, 62,
52.
complexes of the ynones seemed a very attractive choice
since these compounds are easy to obtain and, after the
carbonyl reduction step, the triple bond can be regener-
(12) (a) Wender, P. A.; McKinney, J . A.; Mukai, C. J . Am. Chem.
Soc. 1990, 112, 5369. (b) Schmidt, H.; Arens, J . F. Recl. Trav. Chim.
Pays-Bas 1967, 86, 1138.
ated with the aid of a mild oxidant as Ce(IV) (see Scheme
(13) Reactions were monitored by TLC. Triple-bond hydroboration
2c
5
). Very recently, Corey et al. reported the reduction of
byproducts were not detected. Temperature appeared to be crucial: an
attempt to reduce 10a at rt lead to a complex mixture of products,
whereas reduction at -40 °C was much slower and gave alcohol 12a
in lower yield and stereoselectivity (64%, 39% ee.).
(16) (a) Compound 14a : J eong K.-S.; Sj o¨ , P.; Sharpless, K. B.
Tetrahedron Lett. 1992, 33, 3833. (b) Compound 14b: Naemura, K.;
Mizo-oku, T.; Kamada, K.; Hirose, K.; Tobe, Y.; Sawada, M.; Takai, Y.
Tetrahedron: Asymmetry 1994, 5, 1549. (c) Compound 14c: Huszthy,
P.; Bradshaw, J . S.; Zhu, C. Y.; Izatt, R. M. J . Org. Chem. 1991, 56,
3330.
(17) Kluge, A. F.; Kertesz, D. J .; O-Yang, C.; Wu, H. Y. J . Org. Chem.
1987, 52, 2860.
(18) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V.
K. J . Am. Chem. Soc. 1987, 109, 7925.
(19) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
(14) In this connection it is timely to point out that, in our hands,
reduction of 10c with neat (-)-DIP-Chloride at rt yielded a 70% of
alcohol (-)-12c (97% ee.) after 2 days. The R configuration was
assumed for the resulting alcohol in agreement with the mechanism
accepted for such reductions.
(
15) A similarly crowded ketone, 4,4-dimethyl-1-(trimethylsilyl)-1-
t
pentyn-3-one (10d , R ) Bu ) was subjected to identical reduction
conditions, with parallel results: 97% ee and 93% ee (using 1 equiv
and 0.2 equiv of (R)-7, respectively).

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9023
Sch em e 4
Sch em e 6
We carried out the reduction of 15a using oxazaboro-
lidines 8a , derived from (-)-ephedrine, and 8b, derived
from (-)-norephedrine,1 in which the lack of a phenyl
group at the R-face (in comparison to 6 and 7) makes that
R-face more available for complexation. Reductions were
almost complete in both experiments in <10 min at 0 °C
but with moderate stereoselectivities (entries 4 and 5).
In light of these results, it seemed reasonable to inves-
tigate an oxazaborolidine such as 8c in which not only
the nitrogen but also the boron atom was unsubstituted.
Unfortunately, in this case the reduction did not work
well. It should be borne in mind that, unlike 8a and 8b,
oxazaborolidine 8c must be prepared at rt (the reaction
cannot be carried to completion by heating since trim-
erization to borazine predominates) and the probable
presence of several boron species can cut down yield and
selectivity. Finally, looking for a catalyst in which the
â-face was more blocked, we studied the oxazaborolidine
(4R,5S)-9, derived from commercially available (1S,2R)-
2-amino-1,2-diphenylethanol.20 A fast reduction of both
linear ketone 15a and R-monobranched ketone 15b, with
a gratifying 97% ee, was observed (entries 6 and 7). With
nonsilylated ketones 16a and 16b the results, although
Sch em e 5
0a
Ta ble 2. Red u ction of Hexa ca r bon yld icoba lt Com p lexes
1
5 a n d 16 w ith BH3‚SMe2 in th e P r esen ce of
Oxa za bor olid in es, in THF a t 0 °Ca
alcohol
(overall confign,
yield, %)
reactn
time
% eeb
entry ketone oxazaborolidine
1
2
3
4
5
6
7
8
9
15a
15a
15a
15a
15a
15a
15b
16a
16b
(R)-7
(R)-7
(R)-6
3 h
1 h
48 h
12a (34)
12a (65)
12a (35)
12a (90)
12a (77)
S, 89
S, 92
S, 10
R, 85
R, 81
S, 97
S, 97
S, 85
S, 82
c
d
(4S,5R)-8a
(4S,5R)-8b
(4R,5S)-9
20 min
25 min
30 min
12a (88)
12b (85)
(4R,5S)-9
(4R,5S)-9
(4R,5S)-9
1 h
21
not so good, were satisfactory (entries 8 and 9). With
45 min 13a (86)
1 h 13b (93)
regard to ketones 15c and 16c, oxazaborolidines 7 and 9
did not show any catalytic effect (no reaction occurred),
probably due to the fact that the steric hindrance around
the carbonyl groups of these substrates was too great.
The origin of the enantioselectivity observed in the
cases shown in Table 2 can be explained by an exo
complex like 17 in which the huge cobalt complex moiety
is located far from the Me group on the boron atom
a
1
.1 equiv of oxazaborolidine and 1.2 equiv of BH3‚SMe2, in
THF, unless otherwise indicated; deprotection with CAN/MeOH
b
(
see Experimental Section). Determined as indicated in Table 1.
c
d
2
.2 equiv of BH3‚SMe2 was used in this case. Catecholborane
as the reducing agent, in toluene at -57 °C.
the Co
pentyl in Scheme 1) to the corresponding alcohol with
7% ee using a modified proline-derived oxazaborolidine
(R)-6, R ) Me SiCH ].
Ketones 10 and 11 were easily and quantitatively
transformed into their hexacarbonyldicobalt complexes
15 and 16, respectively) with octacarbonyldicobalt in
2 6
(CO) adduct of non-3-yn-2-one (1, R ) Me, R′ )
(Scheme 6). On the other hand, the fact that at least 1
9
[
equiv of oxazaborolidine is needed to complete the
reduction suggests that, in contrast with reduction of
ynones, the first expected product is a complex (18) which
does not liberate easily the oxazaborolidine (7 or 9) in
the reaction mixture, so that a true catalytic cycle is
3
2
(
pentane. The R-unbranched ketone 15a was chosen as
a representative model to optimize the oxazaborolidine-
mediated reduction step. As shown in Table 2, an
experiment of reduction of 15a with BH
presence of 1.2 equiv of (R)-7 gave a low yield of alcohol
entry 1). Some improvement was observed when 2.2
22
lacking.
In summary, we have achieved an efficient and general
approach to highly enantiomerically enriched propargylic
alcohols by borane-mediated, oxazaborolidine-catalyzed
reduction of ketones. A judicious choice of the catalyst
3
‚SMe
2
in the
(
equiv of borane was used (entry 2). Moreover, reduction
with a proline-derived oxazaborolidine [(R)-6, R ) Me]
was also unsuccessful under the conditions reported for
R,â-enones (entry 3).8 Apparently, steric requirements
of ketone 15a prevented an efficient complexation with
oxazaborolidines 6 and 7. We supposed that a less
congested catalyst could be more appropiate.
(
20) Quallich, G. J .; Woodall, T. M. Tetrahedron Lett. 1993, 34, 4145.
Its enantiomer, (1R,2S)-2-amino-1,2-diphenylethanol, is also com-
mercially available.
(21) By contrast, oxazaborolidine 9 showed
performance in the reduction of noncomplexed acetylenic ketones (74%
yield, 69% ee, for ketone 10a ). In the same way, reduction of 10a with
catecholborane in the presence of (R)-6 at -57 °C showed an acceptable
yield but a moderate selectivity (82% yield, 81% ee).
a less satisfactory

9
024 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
(
7 or 9) and ketone (either in its acetylenic or hexacar-
min, t
R
(S) ) 22.0 min); R
32.1 °C; [R]20
+248.0 (c 1, CHCl ); H NMR δ 1.64 (br s, 3 H),
3
13
f
0.52 (CH
2
Cl
2
/MeOH, 95:5); mp 131.1-
1
1
4
6
1
D
bonyldicobalt complex form) allows one to obtain diverse
homochiral propargylic alcohols. Thus, while ynones 10
and 11 give propargylic alcohols of the R configuration
.99 (s, 1 H), 6.95-7.45 (m, 13 H), 7.76 (m, 2 H); C NMR δ
1.7, 79.5, 126.0, 126.2, 126.5, 127.0, 127.2, 127.3, 127.4, 128.5,
28.6, 140.0, 143.8, 146.4.
(
>90% ee) with (R)-7, their cobalt complexes afford
(
R)-B-Meth yl-4,5,5-tr ip h en yl-1,3,2-oxa za bor olid in e [(R)-
propargylic alcohols of the S configuration with (R)-7
(
(
26
7
].
Trimethylboroxine (0.87 g, 7.0 mmol) was added to a
moderate yields, excellent ee) as well as with (4R,5S)-9
excellent yields and ee for 15a and 15b).
solution of (R)-(+)-2-amino-1,1,2-triphenylethanol (3.00 g, 10.4
mmol) in 20 mL of dry toluene, and the mixture was stirred
under Ar at rt for 1 h. The solution was concentrated (1 atm)
to ca. 5 mL. Toluene (20 mL) was added, and the solution was
concentrated again at 1 atm. The process was repeated once
more. This last solution was diluted with toluene up to 25 mL
Exp er im en ta l Section
All the solvents were distilled from an appropiate drying agent
1
and stored under Ar: H NMR δ 0.48 (s, 3 H), 3.65 (br s, 1 H),
and stored under a nitrogen atmosphere. The crude products
were purified by column chromatography on silica gel of 230-
4
5
1
1
.38 (s, 1 H), 6.8-7.4 (m, 15 H); 13C NMR δ 69.0, 91.3, 126.0,
26.2, 126.8, 126.9, 127.1, 127.3, 127.5, 127.9, 128.0, 142.1, 142.7,
47.6; 11B NMR δ 39.
00 mesh (flash chromatography). Thin-layer chromatograms
were performed on HF 254 silica gel plates (using CH
Cl /MeOH, or CH Cl /hexane as the eluent, as indicated after
the R values). Melting points are uncorrected. H, C, and
F NMR spectra were obtained in CDCl at 200, 50.3, and 282.2
MHz, respectively; chemical shifts are given in ppm with respect
2 2 2
Cl , CH -
Gen er a l P r oced u r e for Red u ction of Acetylen ic Keton es
2
2
2
1
13
w ith Bor a n e Ca ta lyzed by (R)-7: Red u ction of Keton e 10a .
A solution of 10a (115 mg, 0.50 mmol) in THF (0.5 mL) was
slowly (ca. 1 mmol/h) added to a solution of (R)-7 (0.5 mmol)
f
1
9
3
1
1
and BH
3
2
‚SMe (60 µL, 0.60 mmol) in THF (1 mL) at 0 °C under
to internal TMS, and J values are quoted in hertz. B NMR
spectra were recorded in THF at 96.2 MHz, with respect to an
external standard of BF
measured on a Perkin-Elmer 681 on NaCl plates (film) or in KBr;
only the most significant absortions, in cm , are indicated.
Microanalyses were performed by the Serveis Cient ´ı fico-T e` cnics
Ar. Upon completion of the addition, TLC revealed the disap-
pearance of the starting ketone. Reaction was cautiously
quenched by addition of MeOH (1 mL) at 0 °C. The solution
was stirred for 15 min at rt and then concentrated under
vacuum. The residue was purified by flash chromatography
3
‚Et
2 6 6
O in C D . Infrared spectra were
-
1
(
SiO
methylsilyl)-1-pentyn-3-ol, (R)-12a : oil; R
NMR δ 0.22 (s, 9H), 1.62 (bs, 1H), 2.02 (m, 2 H), 2.81 (m, 2H),
.40 (t, J ) 7.2 Hz, 1 H), 7.20-7.40 (m, 5H); 13C NMR δ 0.0,
31.5, 39.2, 62.3, 90.0, 106.5, 126.1, 128.5, 128.6, 141.4; IR (neat)
2 2 2
, CH Cl ) to yield 107 mg (92%) of (R)-5-phenyl-1-(tri-
(Universitat de Barcelona). Chemical ionization mass spectra
2
7
1
1
1b
11b
f 2 2
0.40 (CH Cl ); H
(
NH
3
) are given in m/ z. Acetylenic ketones 10b
and 10d ,
as well as oxazaborolidines 6 (R ) Me), 8a , 8b,25 and 9,
2
3
24
20
4
were prepared according to published procedures.
R)-1,1,2-Tr ip h en yl-2-a m in oeth a n ol.2
6
(
Methyl (R)-phe-
2
0
8
45, 1245, 1610, 2120, 3590-3100; [R]
D
-20.2 (c 3, CHCl
]). Anal. Calcd for C14
OSi: C, 72.36; H, 8.67. Found: C, 72.24; H, 8.52.
An analytical sample of 12a was benzoylated (PhCOCl, Et
DMAP cat., CH Cl ). The analysis of this derivative by HPLC
Chiralcel OD-H, hexane/isopropyl alcohol, 99.8:0.2, t (S) ) 9.3
3
);
nylglycinate hydrochloride (10.0 g, 0.050 mol) was added por-
tionwise to phenylmagnesium bromide (150 mL, 3 M in Et O)
at 0 °C under Ar over 2 h. The cooling bath was removed, and
the reaction mixture was stirred at room temperature for 7 h.
The solution was poured into crushed ice (300 g) and concd HCl
+
MS (NH
3
/CI) 250 (100) ([M + NH
4
20
H -
2
3
N,
2
2
(
R
(50 mL) with mechanical stirring. The mixture was stirred
min, t (R) ) 13.7 min) revealed 90% ee.
R
vigorously for 1 h, and the precipitate, amino alcohol hydrochlo-
ride, was collected by filtration and washed with water and then
diethyl ether. The filtrate was stirred in 1.5 M NaOH (150 mL)
for 1 h. Afterward, 200 mL of diethyl ether was added and the
resulting mixture was stirred for 3 h. The organic layer was
decanted, washed with small portions of water until pH ∼7, and
dried. The solvent was removed, and the solid was recrystallized
from ethanol to afford the product as a white solid (10.5 g, 73%).
Enantiomeric purity (>99.8:0.2) was determined by HPLC
(R)-1-Cycloh exyl-3-(t r im et h ylsilyl)-2-p r op yn -1-ol ((R)-
1
f 2 2
12b): 65% yield; oil; R 0.48 (CH Cl ); H NMR δ 0.22 (s, 9H),
1.05-1.40 (m, 5 H), 1.45-2.10 (m, 7 H), 4.18 (d, J ) 7.3 Hz, 1
H); 13C NMR δ 0.0, 26.0, 28.2, 28.6, 44.1, 67.7, 90.2, 105.9; IR
2
0
(neat) 820, 1200, 1420, 2120, 3500-3010; [R]
D
-3.5 (c 3,
]). Anal. Calcd for C12
OSi: C, 68.51; H, 10.54. Found: C, 68.33; H, 10.60.
+
CHCl
3
); CIMS 228 (100) ([M + NH
4
22
H -
An analytical sample was converted into the corresponding
Mosher ester derived from (R)-Mosher acid. HPLC analysis of
the sample (Tracer Spherisorb column, hexane/THF, 99.9:0.1,
(
Chiralcel OD-H, hexane/isopropyl alcohol, 95:5, t
R
(R) ) 18.4
22) A 11B NMR experiment (BF
3 2
‚Et O as the external reference)
t
R
(R,R) ) 9.3 min, t
(R)-1-(Tr icyclo[3.3.1.13 ]d ec-1-yl)-3-(t r im et h ylsilyl)-2-
R
(R,S) ) 11.4 min) revealed 93% ee.
(
,7
was carried out by mixing a sample of ketone 15a with 1.1 equiv of
oxazaborolidine 9 and 1.2 equiv of BH ‚SMe in THF. We observed
that the sharp signal corresponding to BH ‚SMe (ca. δ -20) and that
3
2
p r op yn -1-ol ((R)-12c): 80% yield; mp 60.1-61.0 °C; R
0.44
f
3
2
1
(CH
2
Cl
2
); H NMR δ 0.22 (s, 9 H), 2.05 (m, 3 H), 1.59-1.80 (m,
one corresponding to 9 (δ 35.1) were gradually replaced by two new
peaks at δ 32.3 and -19.5, which may be attributed to structure 18.
1
3
1
7
3 H), 3.88 (s, 1H); C NMR δ 0.1, 28.2, 37.0, 37.9, 37.6, 52.8,
1.9, 90.7, 104.8; IR (KBr) 835, 1240, 2110, 3510-3090; [R]
2
0
3 2
Addition of an excess of BH ‚SMe to the sample did not modify the
D
observed 11B NMR shifts. However, in a parallel experiment, when an
excess of Et N was added, besides a fast formation of the BH
-2.47 (c 1, CHCl
for C16 26OSi: C, 73.22; H, 9.98. Found: C, 73.22; H, 10.02.
F NMR analysis of the corresponding Mosher ester revealed
5% ee.
R)-4,4-Dim et h yl-1-(t r im et h ylsilyl)-1-p en t yn -3-ol ((R)-
); CIMS 280 (100) ([M + NH
+
4
]). Anal. Calcd
3
3
3
‚NEt
3
H
complex (ca. δ -15) with the remaining borane, a slower transforma-
tion of the peak at δ 32.3 to the former at δ 35.1 (corresponding to 9)
and the disappearance of the peak at δ -19.5 was observed. In
summary, oxazaborolidine 9 is regenerated by Et
but not by the excess of borane present in the reaction mixture.
19
9
(
3
N (a good Lewis base)
1
12d ): 60% yield; mp 45.1-46.0 °C; R
.27 (s, 9 H), 1.09 (s, 9 H), 1.95 (bs, 1H), 4.02 (s, 1H); C NMR
δ 0.0, 25.3, 35.8, 71.8, 90.3, 105.7; IR (KBr) 825, 1235, 2120,
590-3080; [R]20
+3.9 (c 1, CHCl ). Anal. Calcd for C10
OSi: C, 65.15; H, 10.93. Found: C, 64.85; H, 10.83.
f 2 2
0.45 (CH Cl ); H NMR δ
13
0
3
D
3
20
H -
An analytical sample was transformed into the corresponding
Mosher ester derived from (R)-Mosher acid. HPLC analysis of
the sample (Tracer Spherisorb column, hexane/THF, 99.9:0.1,
t
R
(R,R) ) 8.9 min, t
R
(R,S) ) 11.3 min) revealed 97% ee.
(
23) Mathre, J .; J ones, T. K.; Xavier, L. C.; Blacklock, T. J .; Reamer,
27
(
R)-5-P h en yl-1-p en tyn -3-ol ((R)-13a ): 73% yield; oil; R
f
R. A.; Mohan, J . J .; J ones, E. T.; Hoogsteen, K.; Baum, M. W.;
Grabowski, E. J . J . J . Org. Chem. 1991, 56, 751.
1
0
2
(
2 2
.26 (CH Cl ); H NMR δ 1.80 (bs, 1H), 2.00-2.13 (m, 2 H), 2.70-
.85 (m, 2H), 2.52 (d, J ) 2.2 Hz, 1H) 4.32 (m, 1 H), 7.10-7.35
(24) J oshi, N. N.; Srebnik, M.; Brown, H. C. Tetrahedron Lett. 1989,
m, 5H); 13C NMR δ 31.8, 39.6, 62.0, 73.8, 85.2, 126.6, 129.0,
20
3
1
1
0, 5551.
(
994, 116, 8516.
(
25) Quallich, G. J .; Blake, J . F.; Woodall, T. M. J . Am. Chem. Soc.
141.6; IR (neat) 1010, 1420, 2100, 3400-3010; [R]
D
+4.0 (c 0.7,
26) A less detailed procedure (not optimized) can be found in ref
0b.
(27) Pirrung, M. C. J . Org. Chem. 1987, 52, 1635.

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9025
CHCl
3
); CIMS 178 (100) ([M + NH
4
+]). 19F NMR analysis of
Ca ta lyzed by Oxa za bor olid in es 7, 8a , 8b, a n d 9. Red u ction
of Keton e 15a Ca ta lyzed by (4R,5S)-9. A solution of 215 mg
(0.42 mmol) of ketone 15a in 1 mL of THF was added dropwise
the corresponding Mosher ester revealed 90% ee.
1
7
(
R)-1-Cycloh exyl-2-p r op yn -1-ol ((R)-13b). Compound
(
0
R)-13b was prepared as above for (R)-12a : 60% yield; oil; R
f
over ∼30 min to a solution of 50 µL (0.5 mmol) of BH
3
‚SMe
2
1
.31 (CH
2
Cl
2
); H NMR δ 1.10-1.38 (m, 5 H), 1.55-1.95 (m, 6
and 0.46 mmol of (4R,5S)-9 (from a toluene solution after
removing the solvent under vacuum) in 1 mL of THF, at 0 °C
under Ar. After 30 min, the reaction was cautiously quenched
(TLC monitoring) by adding 0.5 mL of MeOH, and then the
mixture was stirred for additional 30 min. The mixture was
carried to dryness, and the residue was filtered through a pad
of silica gel (hexane/CH Cl , 1:1) to afford, after removing the
H), 2.21 (bs, 1 H), 2.46 (d, J ) 2.2 Hz, 1 H), 4.18 (dd, J ) 2.2,
6
1
3
.3 Hz, 1 H); C NMR δ 25.7, 25.8, 26.3, 27.9, 28.4, 43.8, 66.9,
20
7
+
3.6, 83.9; IR (neat) 1015, 1430, 2105, 3280, 3400-3000; [R]
D
1
7
25
9.9 (c 1, diethyl ether) [lit. [R]
D
2
-11.2 (c 1, Et O) for S
+
]), 173 (100) ([M + N H ]).
2 7
+
isomer]; CIMS 156 (25) ([M + NH
4
1
9
F NMR analysis of the corresponding Mosher ester revealed
0% ee.
2
2
9
solvent under vacuum, a crude containing the hexacarbonyldi-
cobalt complex of the propargylic alcohol derived from 15a . The
residue was dissolved in 5 mL of MeOH, and an excess (∼5
(
R)-1-(Tr icyclo[3.3.1.13,7]d ec-1-yl)-2-p r op yn -1-ol ((R)-13c):
1
7
1
0% yield; mp 79.0-80.0 °C; R
f
0.44 (CH
2
Cl
2
); H NMR δ 1.45-
.90 (m, 13 H), 2.03 (s, 3 H), 2.47 (d, J ) 1.0 Hz, 1H), 3.88 (s, 1
2
equiv) of CAN was added at rt. After 30 min, 3 mL of H O was
1
3
H); C NMR δ 28.1, 36.9, 37.0, 37.5, 53.4, 71.4, 74.2, 82.8; IR
added and the aqueous layer was extracted with diethyl ether
3 × 8 mL). The organic phase was washed with brine and then
dried over Na SO . Evaporation of solvent yielded 86 mg (0.36
2
0
(
KBr) 1330, 1440, 2330, 3000-3400; [R]
D
+14.3 (c 0.2, EtOH);
(
+
+
CIMS 208 (84) ([M + NH
4
]), 225 (100) ([M + N H ]). Anal.
2 7
2
4
Calcd for C13H18O: C, 82.06; H, 9.53. Found: C, 81.88; H, 9.65.
mmol, 88%) of 12a . An analytical sample of the alcohol was
transformed into its benzoyl derivative and then analyzed by
HPLC (97% ee).
1
9
F NMR analysis of the corresponding Mosher ester revealed
7% ee.
9
Gen er a l P r oced u r e for Con ver sion of P r op a r gylic Al-
R ed u ct ion of Ket on e 15a w it h Bor a n e Ca t a lyzed b y
coh ols in to 1,2-Diols: (R)-4-P h en yl-1,2-bu ta n ed iol1 ((R)-
6a
(
4S,5R)-8c. To a solution of (-)-norephedrine (47 mg, 0.31
1
4a ). A mixture of 86 mg (0.53 mmol) of (R)-13a , 5 mg of Pd/
CaCO , and 5 µL of quinoline in 2 mL of benzene was shaken at
rt under a hydrogen atmosphere for 40 min. Within this time,
2.1 mL (∼0.5 mmol) of hydrogen had been consumed. The
mixture was filtered through a pad of Celite, and the filtrate
was diluted with 120 mL of CH Cl . After being washed with
.1 M aqueous HCl (5 mL) and brine (20 mL), the solution was
dried over Na SO and the solvent removed in vacuo. The
residue, containing almost pure allylic alcohol, was dissolved in
mL of CH Cl /MeOH 1:1, and the solution was then treated
mmol) of in THF (2 mL) was added BH ‚SMe (68 µL, 0.68 mmol)
3
2
3
under Ar at rt, and the mixture was stirred overnight. The
solution was then cooled at 0 °C, and a solution of 161 mg (0.31
mmol) of ketone 15a in 1 mL of THF was added dropwise over
1
∼
30 min. After an additional 45 min stirring at this tempera-
2
2
ture, reaction was cautiously quenched with 0.5 mL of MeOH.
Workup as above afforded 15 mg (22%) of alcohol 12a . An
analytical sample of the alcohol was transformed into its benzoyl
derivative and then analyzed by HPLC (20% ee.).
0
2
4
3
2
2
with a stream of ozone at -78 °C. The progress of the reaction
Red u ction of Keton e 15a Ca ta lyzed by (R)-6. To a stirred
solution of 0.06 mmol of (R)-6 and 159 mg (0.30 mmol) of ketone
15a in 3 mL of toluene was added dropwise 68 µL (0.6 mmol) of
catecholborane in 0.5 mL of toluene at -78 °C under Ar. The
solution was allowed to warm to -57 °C and stirred for 48 h.
The reaction was then quenched by addition of 0.5 mL of MeOH,
and the solvent was removed under vacuo. Flash chromatog-
raphy of the crude afforded 57 mg (35%) of the desired alcohol,
recovering 95 mg (60%) of the starting ketone 15a . Oxidative
treatment of alcohol (CAN, MeOH) as described above yielded
24 mg (35%) of alcohol 12a . An analytical sample of the alcohol
was transformed into its benzoyl derivative and then analyzed
by HPLC (ca. 10% ee.).
was monitored by TLC. When the reaction was complete, the
excess of ozone was removed by a stream of N
2
and 76 mg (2
was added at -78 °C. After 15 min at this
mmol) of NaBH
4
temperature, the reaction mixture was allowed to warm to rt
over 1 h. The suspension was recooled in an ice-water bath,
1
% AcOH (2 mL) was added, and the solution then was stirred
for 15 min. The mixture was extracted with CH Cl
(3 × 5 mL),
and the organic layer was washed with saturated NaHCO (5
mL). The organic extracts were dried (Na SO ) and evaporated
in vacuo. The residue was chromatographed on silica gel (CH
Cl /MeOH, 95:5) to afford 43 mg (0.26 mmol, 50% overall yield)
of (R)-14a as a colorless oil: R
2
2
3
2
4
2
-
2
1
f
2 2
0.11 (CH Cl /MeOH, 95:5); H
NMR δ 1.60-1.75 (m, 2 H), 2.55-2.80 (m, 2 H), 3.40-3.75 (m,
1
3
5
1
3
H), 7.15-7.30 (m, 5 H); C NMR δ 31.7, 34.5, 66.6, 71.5, 125.9,
Ack n ow led gm en t. This work was supported by the
Comisi o´ n Interministerial de Ciencia y Tecnolog ´ı a
(CICYT) in connection with the Project SAF93-0201. A
doctorate studenship to J .B. from the CIRIT (Generali-
tat de Catalunya) is gratefully acknowledged. We also
thank L. Beumer from J . T. Baker (Deventer, NL) for
kindly supplying HPLC Chiralcel chiral columns and
for technical assistance.
28.3, 128.4, 141.6; IR (neat) 1020, 1050, 1080, 1440, 1590,
2
0
15a
20
010-3700; [R]
D
+27.1 (c 1, EtOH) (lit.
[R]
D
-34.1 (c 1,
EtOH) for isomer S).
(
R)-1-(Tr icyclo[3.3.1.13,7]d ec-1-yl)-1,2-eth a n ed iol16b ((R)-
1
4c): overall yield 32%; mp 108.0-109.2 °C; R 0.36 (CH Cl
f
2
2
/
1
MeOH, 9:1); H NMR δ 1.57-1.85 (m, 12 H), 1.97 (m, 3 H), 3.22
(
1
dd, J ) 9.0, 3.3 Hz, 1 H), 3.43-3.60 (m, 1 H), 3.70 (dd, J )
0.8, 3.3 Hz, 1 H); 13C NMR δ 28.2, 37.2, 38.2, 53.4, 62.3, 80.1;
20
IR (neat) 1090, 1340, 1450, 3010-3550; [R]
D
-9.2 (c 0.5, EtOH)
1
5b
22
(lit. [R]
D
+19.2 (c 1, EtOH) for isomer S).
16c
(
R)-3,3-Dim eth yl-1,2-bu ta n ed iol ((R)-14d ): overall yield
2%; mp 40-42 °C (lit. 41-42 °C); R 0.25 (CH Cl /MeOH 9:1);
f 2 2
Su p p or tin g In for m a tion Ava ila ble: Preparation and
physical and spectroscopical data of acetylenic ketones 10a -d
11a -c and of hexacarbonyldicobalt complexes 11a -c and
1
5c
2
1
H NMR δ 0.90 (s, 9 H), 2.80 (bs, 2 H), 3.44 (dd, J ) 2.7, 9.6 Hz,
1
H), 3.55 (t, J ) 9.6 Hz, 1 H), 3.79 (dd, J ) 2.7, 9.6 Hz, 1 H);
C NMR δ 25.8, 29.7, 63.2, 77.2; IR (neat) 1090, 1653, 2840,
1
6a -c (2 pages). This material is contained in libraries on
1
3
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
2
0
15c
20
2
918, 3080-3490; [R]
c 0.77, CHCl )).
Gen er a l P r oced u r e for Red u ction of Hexa ca r bon yld i-
coba lt Com p lexes of Acetylen ic Keton es w ith BH ‚SMe
D
-16.2 (c 0.2, CHCl
3
) (lit. [R]
D
-25.88
(
3
3
2
J O9612943