An efficient 1,2-chelation-controlled reduction of protected hydroxy ketones via Red-Al

Article abstract of DOI:10.1021/jo800150x

(Chemical Equation Presented) In this paper, we have demonstrated that Red-Al is an efficient chelation-controlled reducing reagent for acyclic acetal (i.e., MOM, MEM, SEM, and BOM) protected α-hydroxy ketones. Typically, diastereomeric ratios (dr) ranged from 5 to 20:1 for the 1,2-anti-diols in good to excellent yields.

Full text of DOI:10.1021/jo800150x

TABLE 1. Reduction of 1a with Red-Ala, b
An Efficient 1,2-Chelation-Controlled Reduction
of Protected Hydroxy Ketones via Red-Al
Naval Bajwa and Michael P. Jennings*
Department of Chemistry, 250 Hackberry Lane, The
UniVersity of Alabama, Tuscaloosa, Alabama 35487-0336
no.
solvent
T, °C
anti
syn
yield (%)
1
2
3
4
5
6
7
8
9
10
toluene
toluene
toluene
toluene
Et2O
THF
DME
MTBE
CH2Cl2
hexane
0
-25
-50
-78
0
>20
>20
>20
>20
>20
17
1
1
1
1
1
1
1
1
1
1
96
96
96
91
94
82
37
92
95
91
jenningm@bama.ua.edu
ReceiVed January 21, 2008
0
0
0
0
8
>20
>20
18
0
a Anti/syn ratios were determined on the crude product via a 360 or
500 MHz H NMR. b Yields are of the isolated and purified compound.
1
mixed results. Both LiBH4 and LiAlH4 have shown limited
success as chelation-controlled reduction reagents.6,7 In order
to be a viable replacement to Zn(BH4)2, the reagent must be
stable, commercially accessible, available in a variety of
solvents, and provide yields and diastereoselectivities that are
analogous (or greater) to that of Zn(BH4)2 or any other hydride
reagent.
In this paper, we have demonstrated that Red-Al is an
efficient chelation-controlled reducing reagent for acyclic
acetal (i.e., MOM, MEM, SEM, and BOM) protected
R-hydroxy ketones. Typically, diastereomeric ratios (dr)
ranged from 5 to 20:1 for the 1,2-anti-diols in good to
excellent yields.
It has been well-established that ethereal moieties can serve
a dual purpose as both a hydroxyl protecting and directing
group.8 During our synthetic studies into the total synthesis of
aigialomycin D, we required quick and chemoselective access
to an anti-1,2-diol motif.9 We envisaged that a 1,2-chelation-
controlled reduction of a protected R-hydroxy ketone would
furnish the desired anti-diol. Upon scanning through a variety
of reducing reagents, we were surprised by the high level of
anti diastereoselectivity (6 f 9:1 dr) that Red-Al (Vitride)
provided when the directing group was a MOM ether. Based
on this observation, we decided to further examine Red-Al as
a chelation-controlled reducing reagent, and our results are
presented herein.
We initially investigated the effect of both solvent and
temperature on the chelation-controlled reduction of MOM-
protected benzoin (1a) with Red-Al, and the results are presented
in Table 1. As shown in entries 1–4, reduction of 1a in toluene
provided high levels of dr (>20:1) for the anti-diol 1b in
exceptional yields and exhibited little to no dependence on the
reaction temperature. Based on this observation, we decided to
investigate other solvents while maintaining the reaction tem-
perature at 0 °C. Unfortunately, reduction of 1a in ethereal
solvents furnished mixed results. When either Et2O or MTBE
The stereoselective reduction of the carbonyl moiety plays a
pivotal role during the multistep synthesis of natural products.
Typically, there are two characteristic approaches which utilize
either a reagent- or substrate-controlled reaction process. The
most efficient tactic is to exploit inherent chiralty to direct
subsequent reactions via the substrate-controlled procedure.
Numerous stereochemical induction models have been put forth
helping to explain and further offer guidance for planning
synthetic routes to targeted compounds via 1,2-asymmetric
induction.1–3 Generally, chelation-controlled reductions of pro-
tected hydroxyl carbonyls provide modest to very high diaster-
eomeric ratios due to the rigid five-membered-ring formation
prior to nucleophilic addition.4 Along this line, there have been
a variety of reagents that have been investigated for such a
substrate-controlled hydride reduction protocol. For example,
the most utilized hydride reagent for 1,2-chelation-controlled
reduction is Zn(BH4)2 and frequently provides high levels of
diastereoselective control.5 However, Zn(BH4)2 has a couple of
major drawbacks as a widespread reducing reagent such as
lengthy preparation time, limited availability (i.e., not com-
mercial), and lack of stability in ethereal solvents. An alternative
reducing reagent to Zn(BH4)2 would be highly desirable. Other
commercial reagents have been investigated and have revealed
(6) Burke, S. D.; Deaton, D. N.; Olsen, R. J.; Armistead, D. M.; Blough,
B. E. Tetrahedron Lett. 1987, 28, 3905.
(1) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828.
(2) (a) Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9, 2199.
(b) Chérest, M.; Felkin, H. Tetrahedron Lett. 1968, 9, 2205. (c) Anh, N. T.;
Eisenstein, O. Tetrahedron Lett. 1976, 17, 155.
(7) (a) Katzenellenbogen, J. A.; Bowlus, S. B. J. Org. Chem. 1973, 38, 627.
(b) Bowlus, S. B.; Katzenellenbogen, J. A. J. Org. Chem. 1974, 39, 3309. (c)
Tokuyama, T.; Shimada, K.; Uemura, M. Tetrahedron Lett. 1982, 23, 2121. (d)
Overman, L. E.; McCready, R. J. Tetrahedron Lett. 1982, 23, 2355. (e) Stork,
G.; Paterson, I.; Lee, F. K. C. J. Am. Chem. Soc. 1982, 104, 4686.
(8) Still, W. C.; McDonald, J. H. Tetrahedron Lett. 1980, 21, 1031.
(9) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
(3) Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367.
(4) (a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748. (b)
Reetz, M. T. Acc. Chem. Res. 1993, 26, 462. and references therein.
(5) Nakata, T.; Tanaka, T. Oishi, T. Tetrahedron Lett. 1983, 24, 2653.
3638 J. Org. Chem. 2008, 73, 3638–3641
10.1021/jo800150x CCC: $40.75 2008 American Chemical Society
Published on Web 03/22/2008

c
TABLE 2. Reduction of 2a–7a with Red-Ala
TABLE 3. Reduction of 8a–11a with Red-Ala, b
-
no.
protecting group
anti
syn
yield (%)
1
2
3
4
5
6
7
MOM (1a)
BOM (2a)
THP (3a)
MEM (4a)
SEM (5a)
Me (6a)
>20 (1b)
>20 (2b)
7 (3b)
>20 (4b)
>20 (5b)
>20 (6b)
2 (7b)
1
1
1
1
1
1
1
96
93
91
89
94
89
TBS (7a)
92d
a Anti/syn ratios were determined on the crude product via a 360 or
500 MHz 1H NMR. b Yields are of the isolated and purified compound.
c All reductions ran at 0 °C in toluene. d Desilylation was observed
under reaction conditions.
were utilized as the solvent, high levels of dr for 1b (>20:1)
were observed with yields comparable to that of toluene.
However, more Lewis basic ethers such as THF and DME led
to inferior yields (82 and 37%, respectively) and lower levels
of dr (8f17:1) for 1b. These two results are not surprising as
one can envision that the more Lewis basic ethers would
compete with the MOM group of 1a for chelation of the Na
cation and lower the probability of the five-membered ring
chelate prior to reduction.
Similar to that of toluene, reduction of 1a with Red-Al in
CH2Cl2 and hexane led to high levels of dr (20:1 and 18:1 anti/
syn, respectively) with excellent isolated yields as shown in
entries 9 and 10 in Table 1.
a Anti/syn ratios were determined on the crude product via a 360 or
500 MHz H NMR. b Yields are of the isolated and purified compound.
1
With the observation that either toluene or CH2Cl2 as solvents
provide the highest levels of dr and isolated yields for the anti-
diol 1b via Red-Al reduction of 1a, the next phase of the
investigation focused on the role of the directing group in
providing high levels of dr. As delineated in Table 2, we chose
to examine the Red-Al reduction of a variety of protected
benzoins (2a–7a) under the optimized reaction conditions of 0
°C and toluene as the solvent from Table 1. Similar to that of
1a, the linear acetal protected ketones 2a (BOM), 4a (MEM),
and 5a (SEM) provided the corresponding anti-diols (2b, 4b,
and 5b) in excellent yields with high levels of dr (>20:1).
Similar to the acetal-protected benzoins 2a, 4a, and 5a, the
reduction of the simple R-methyl ether ketone 6a under the
standardized conditions furnished a virtually identical yield and
dr for the anti-diol 6b. However, the cyclic acetal THP-protected
ketone 3a provided a lower dr for the anti-diol (7:1) with yields
comparable to that of its acyclic acetal counterparts 2b, 4b, and
5b. These results were not unexpected due to the literature
precedence that acyclic acetals (i.e., MOM, MEM, BOM, etc.)
generally undergo efficient 1,2-chelation-controlled reactions,
while the THP acetal typically affords inferior levels of dr.8
Likewise, the TBS-protected benzoin (7a) furnished low levels
of dr (2:1) for the anti-diol in excellent yield, and concomitant
desilylation was observed under the reaction conditions. Based
on the results of Tables 1 and 2, it appeared that a combination
of an acyclic acetal protecting group R to the ketone carbonyl,
Red-Al, and toluene or CH2Cl2 as the solvent afforded excellent
yields and high levels of dr for the resultant anti-diol products
derived from benzoin.
in exploring the scope and limitations of this reaction protocol.
As shown in Table 3, we chose to investigate MOM-protected
R-hydroxy ketones which were diversified by carbon hybridiza-
tion. Thus, reduction of the acetylenic ketone 8a at 0 °C in
toluene furnished the anti-diol 8b in good yield, but with limited
dr (∼2:1). Further lowering the reaction temperature to -78
°C and exchanging the solvent from toluene to CH2Cl2 led to
higher levels of dr (5:1) for 8b in 88% yield. Based on these
new reaction conditions, we investigated the Red-Al reduction
of both E- and Z-R,ꢀ-unsaturated ketones 9a and 10a. Much to
our delight, both 9a and 10a provided excellent yields of 88
and 84% coupled with high levels of dr for the anti-diols 9b
and 10b (12:1 and 9:1, respectively). Lastly, the fully saturated
MOM-protected R-hydroxy ketone 11a readily underwent
reduction with Red-Al at -78 °C and afforded the anti-diol
11b in a 93% yield and a dr of 9:1.
It should be noted that all of the diastereomeric ratios were
of the crude, unpurified products. The relative stereochemical
relationships of 8b–11b (anti versus syn) were determined by
MOM group removal followed by acetonide formation of the
1
subsequent diol. Final H NMR experiments (1D NOE) were
performed and in all cases enhancements were observed for the
cis-hydroxyl methine protons.
With the promising results of Table 3, the next phase of our
investigation into defining the scope and limitations of Red-Al
as a chelating reducing reagent led us to diversifying the carbon
hybridization adjacent to the directing MOM group. As delin-
eated in Table 4, the four investigated structures were similar
to those as shown above, and identical reaction conditions were
also employed (-78 °C and CH2Cl2 as the solvent). Thus, the
While the chelation-controlled Red-Al reduction of protected
benzoins led us to standardized conditions for high levels of dr
and isolated yields for the anti-diols, we were more interested
J. Org. Chem. Vol. 73, No. 9, 2008 3639

TABLE 4. Reduction of 12a–15a with Red-Ala, b
TABLE 5. Reduction of 16a–20a with Red-Ala, b
a Anti/syn ratios were determined on the crude product via a 360 or
a Anti/syn ratios were determined on the crude product via a 360 or
500 MHz H NMR. b Yields are of the isolated and purified compound.
1
500 MHz H NMR. b Yields are of the isolated and purified compound.
1
Red-Al reduction of the acetylenic ketone 12a provided a modest
dr of 8:1 for the anti-diol 12b in a 71% yield. The diastereomeric
ratio for the Red-Al reduction of 12a was higher than that of
8a (8:1 versus 5:1) for the anti-diols 12b and 8b, but one
limitation of Red-Al as a chelation-controlled reducing reagent
that emerged was the proximity of sp-hybridized carbons.10
Much to our delight, reduction of the E- and Z-MOM protected-
R-hydroxy ketones 13a and 14a afforded very high levels of dr
of 19:1 for the E-anti-diol (13b) and 11:1 for the Z counterpart
(14b), both in very high yields of 85 and 88%, respectively.
Similar to that of 11a in Table 3, reduction of the saturated
ketone 15a with Red-Al furnished a yield of 80% with a dr for
the resulting protected anti-diol 15b of 12:1. Based on the results
from Tables 3 and 4, Red-Al has emerged as a very efficient
1,2-chelation controlled reducing agent for benzoin related
structural analogues by providing high levels of dr for the
corresponding anti-diols. The resultant monoprotected homoal-
lylic alcohols derived from these reductions are extremely useful
synthons in contemporary synthetic organic chemistry.
Initially, treatment of 16a with Red-Al in toluene at 0 °C readily
afforded alcohol 16b with a satisfactory level of dr (6:1 by 1H
NMR of the crude product) in a very acceptable 84% yield.
Based on the reaction conditions of Tables 3 and 4, we
reinvestigated the reduction of ketone 16a at -78 °C with
CH2Cl2 as the solvent and observed an increase in dr from 6:1
to 10:1 in a virtually identical yield for the anti-diol 16b. We
were very pleased from this outcome as it greatly expanded
the scope of this reaction beyond that of aromatic ketones.
Keeping with the theme of nonaromatic substrates, we also
examined the Red-Al reduction of three very simple acetal
protected R-hydroxy ketones. Much to our delight, reduction
of the MOM-, SEM-, and BOM-protected ketones 17a–19a with
Red-Al provided the three corresponding anti-diol products
17b–19b with high levels of dr (11 f 12:1) in good to excellent
yields of 84–91%. As mentioned before, the relative stereo-
chemical relationship of 16b (anti versus syn) was determined
by protecting group removal followed by acetonide formation
1
of the subsequent diol. Final H NMR experiments (1D NOE)
The final aspect of our investigation was to examine Red-Al
as a chelation-controlled reducing reagent of nonaromatic MOM
protected R-hydroxy ketones as described in Table 5. During
our synthetic studies into the total synthesis of aigialomycin D,
we required the anti-diol 16b with high levels of dr as the
aliphatic coupling portion en route to the natural product.11
were performed, and enhancements were observed for the cis-
hydroxyl methine protons. For diols 17b–19b, the protecting
groups were removed and NMR experiments (both 1H and 13C)
confirmed that the products were indeed symmetric, as predicted.
While Red-Al has proven to be very successful at chelation
controlled reduction for the synthesis of 1,2-anti-diols, we were
interested in examining the reduction of a MOM-protected
ꢀ-hydroxy ketone. Along this line, stereoselective synthesis of
the resultant anti- or syn-1,3-diol motif is very significant due
to its ubiquitous nature in many bioactive natural products.12
Unfortunately, Red-Al reduction of the known ketone 20a under
(10) In the paper by Takahashi and Tsuji, they report ∼5:1 anti/syn selectivity
for the reduction of a single benzyl-protected R-hydroxy acetylenic ketone with
Red-Al. For more details, see: Takahashi, T.; Miyazawa, Tsuji, J. Tetrahedron
Lett. 1985, 26, 5139.
(11) Bajwa, N.; Jennings, M. P. Tetrahedron Lett. 2008, 49, 390.
3640 J. Org. Chem. Vol. 73, No. 9, 2008

salt) was added. The clear organic layer was washed with saturated
Rochelle’s salt, and the combined aqueous layers were extracted
with ether. The ether layers were dried over anhydrous MgSO4 and
concentrated in vacuo. Purification by flash column chromatography
afforded 1,2-anti-diol product 1b as the major product.
the standard reaction conditions (-78 °C in CH2Cl2) furnished
a 2:1 ratio of syn/anti-diol 20b in 89% yield.13 Thus, one major
limitation of Red-Al was that it provided low levels of dr for
the chelation-controlled reduction of a ꢀ-hydroxy ketone leading
to the 1,3-diol motif.
Reduction of 1a–7a in Toluene. General Procedure for
Table 2. To a stirred solution of 1a–7a in toluene at 0 °C was
added Red-Al in toluene (1 equiv). The resulting solution was
maintained at 0 °C for 2 h, and then 50 mL of saturated sodium
potassium tartrate (Rochelle’s salt) was added followed by extrac-
tion with Et2O. The clear organic layer was washed three times
with brine, dried over MgSO4, and concentrated in vacuo. Purifica-
tion by flash column chromatography afforded the reduced 1,2-
anti-diol products 1b–7b as the major product in good yields
ranging from 89 to 96%.
General Procedure for Tables 3-5. To a stirred solution of
8a–20a in CH2Cl2 at -78 °C was added Red-Al in toluene (1
equiv). The resulting solution was maintained at -78 °C for 2 h,
and then saturated sodium potassium tartrate (Rochelle’s salt) was
added followed by extraction with Et2O. The clear organic layer
was washed three times with brine, dried over MgSO4, and
concentrated under reduced pressure. Purification by flash column
chromatography afforded the 1,2-anti-diol products 8b–19b.
In conclusion, we have shown that Red-Al is an efficient
chelation controlled reducing reagent for acyclic acetal (i.e.,
MOM, MEM, SEM, and BOM) protected R-hydroxy ketones.
Typically, diastereomeric ratios ranged from 5 to 20:1 for the
1,2-anti-diols in good to excellent yields. Unfortunately, the high
levels of dr could not be extended to 1,3-diols via the reduction
of ꢀ-hydroxy ketones. Based on the various ketones investigated,
the described reduction protocol should be quite useful in the
stereoselective synthesis of natural product subunits and/or the
production of valuable organic synthons.
Experimental Section
Reduction of 1a in Various Solvents. General Procedure
for Table 1. To a stirred solution of MOM-protected benzoin (1a)
(0.790 g, 3.1 mmol) dissolved in various solvents such as toluene,
Et2O, THF, DME, MTBE, CH2Cl2, or hexane at temperatures
ranging from 0 to -78 °C as listed in Table 1 was added Red-Al
in toluene (65 wt % in toluene, 0.96 mL, 3.1 mmol, 1 equiv). The
resulting solution was stirred at the respective temperature for 2 h,
and then 50 mL of saturated sodium potassium tartrate (Rochelle’s
Acknowledgment. Support was provided by the University
of Alabama and the NSF (CHE-0115760) for the departmental
NMR facility.
Supporting Information Available: General experimental
procedures for all of the reduction protocols, synthesis of starting
materials, and full characterization data for all new compounds
is provided. In addition, 1H NMR spectral data for the previously
reported compounds are also available. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) (a) Amphotericin B: Vandeputte, J.; Watchtel, J. L.; Stiller, E. T. Antibiot.
Annu. 1956, 587. (b) Cytovaricin: Kihara, T.; Kusakabe, H.; Nakamura, G.;
Sakurai, T.; Isono, K. J. Antibiot. 1981, 34, 1073. (c) Swinholide A: Kobayashi,
M.; Tanaka, J.; Katori, T.; Matsura, M.; Kitagawa, I. Tetrahedron Lett. 1989,
30, 2963. (d) Clavosolide: Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65,
386. (e) Neopeltolide: Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.;
Linley, P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat.
Prod. 2007, 70, 412.
(13) Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.
JO800150X
J. Org. Chem. Vol. 73, No. 9, 2008 3641