Chiral synthesis via organoboranes. 43. Selective reductions. 58. Reagent-controlled diastereoselective reduction of (+)- and (-)-α-chiral ketones with (+)- and (-)-B-chlorodiisopinocampheylborane

Article abstract of DOI:10.1021/jo951207r

Asymmetric reduction of (+)- and (-)-α-chiral ketones with (+)- and (-)-B-chlorodiisopinocampheylborane provides the product alcohols in very high diastereomeric excess, with the matched pairs providing > 100:1 selectivity and the mismatched pairs showing 4:1-15:1 selectivity. The high selectivity achieved even in the mismatched pairs reveals the power of the reagent to control the stereochemical outcome. The rates of the reaction of the matched pairs are faster than those of the mismatched pairs. In all the cases studied thus far, the (-)-reagent (^dIpc₂BCl) and (S)-ketone or the (+)-reagent (^lIpc₂BCl) and (R)-ketone constitute matched pairs and the (-)-reagent and (R)-ketone or the (+)-reagent and (S)-ketone constitute mismatched pairs. A possible mechanism for the reductions is discussed.

Full text of DOI:10.1021/jo951207r

J . Org. Chem. 1996, 61, 95-99
95
Ch ir a l Syn th esis via Or ga n obor a n es. 43. Selective Red u ction s.
58. Rea gen t-Con tr olled Dia ster eoselective Red u ction of (+)- a n d
(-)-r-Ch ir a l Keton es w ith (+)- a n d
(-)-B-Ch lor od iisop in oca m p h eylbor a n e
P. Veeraraghavan Ramachandran, Guang-Ming Chen,1 and Herbert C. Brown*
H. C. Brown and R. B. Wetherill Laboratories of Chemistry, Purdue University,
West Lafayette, Indiana 47907
Received J uly 5, 1995X
Asymmetric reduction of (+)- and (-)-R-chiral ketones with (+)- and (-)-B-chlorodiisopinocam-
pheylborane provides the product alcohols in very high diastereomeric excess, with the matched
pairs providing >100:1 selectivity and the mismatched pairs showing 4:1-15:1 selectivity. The
high selectivity achieved even in the mismatched pairs reveals the power of the reagent to control
the stereochemical outcome. The rates of the reaction of the matched pairs are faster than those
of the mismatched pairs. In all the cases studied thus far, the (-)-reagent (dIpc2BCl) and (S)-
ketone or the (+)-reagent (lIpc2BCl) and (R)-ketone constitute matched pairs and the (-)-reagent
and (R)-ketone or the (+)-reagent and (S)-ketone constitute mismatched pairs. A possible
mechanism for the reductions is discussed.
In tr od u ction
of preparing optically pure carbonyl compounds with an
R-quaternary carbon atom.8 The reduction of ethyl
1-methyl-2-oxocyclopentanecarboxylate (2) with 0.50 equiv
of (-)-1 at rt provided the unreacted (R)-keto ester in 75%
enantiomeric excess (ee) (eq 1). The product ethyl 1-meth-
A decade ago, Masamune and co-workers reviewed
double asymmetric synthesis as a strategy for stereo-
chemical control in organic synthesis.2 They proposed a
rule which relates the results of single asymmetric
reactions with the outcome of double asymmetric reac-
tions. Since the introduction of the concept of matched
and mismatched pairs in double asymmetric reactions,2
organic chemists have exploited the matched interactions
of two optically active reactants in multistep synthesis.3
In our program of chiral synthesis via organoboranes,4
we have studied the effectiveness of our R-pinene-based
reagents in double asymmetric synthetic situations and
demonstrated the excellent control of diastereofacial
selectivity in acyclic carbon-carbon bond-forming reac-
tions using pinane-based allyl- and crotylborane re-
agents,5 making possible several valuable applications
for key steps in important syntheses.3 Similar success
was exhibited by pinane-based reagents in enolboration-
aldolizations also.6 Though we had introduced (+)- and
(-)-B-chlorodiisopinocampheylboranes (l- and dIpc2BCl;
Aldrich, (+)- and (-)-DIP-Chloride, (+)- and (-)-1) as
successful reagents for the asymmetric reduction of
several classes of prochiral ketones,7 these reagents have
not been tested for double asymmetric reductions.
Recently, we carried out the kinetic resolution of
several R-tertiary ketones with (+)- and (-)-1, as a means
(1)
yl-2-hydroxycyclopentanecarboxylate (3) obtained was
shown to be 91% [(1S,2S)-trans]-3, 2% [(1R,2R)-trans]-
3, and 7% [(1R,2S )-cis]-3. When the reagent used for
the reduction was increased to 0.60 equiv, the % ee of
the recovered ketone improved to 96%, and with 0.65
equiv of the reagent, essentially optically pure ketone was
recovered. The product alcohol now had a composition
of 80% [(1S,2S)-trans]-3, 5% [(1R,2R)-trans]-3, and 15%
[(1R,2S )-cis]-3. This clearly shows that while the ee of
the ketone improved, the extent of the diastereomeric
excess achieved in the alcohol decreased with increasing
amounts of the reagent. The reduction of the racemic
ketone with 1.1 equiv of (-)-1 provided an isomeric ratio
of 51% [(1S,2S)-trans]-3, 8% [(1R,2R)-trans]-3, and 41%
[(1R,2S )-cis]-3 (eq 1). This ratio reveals that in asym-
metric reductions using (-)- or (+)-1 the opposite isomers
of the ketone provide one of the diastereomers of the
product alcohol, either predominantly or exclusively.
Analysis of the kinetic resolution of racemic 1-meth-
ylnorcamphor (4) reveals the same phenomenon. We
(1) Postdoctoral Research Associate on a Grant from the U.S. Army
Research Office.
(2) Masamune, S.; Choy, W.; Peterson, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(3) For example: Wang, Z.; Deschenes, D. J . Am. Chem. Soc. 1992,
114, 1090.
(4) Brown, H. C.; Ramachandran, P. V. J . Organomet. Chem. 1995,
500, 1.
(5) Brown, H. C.; Bhat, K. S.; Randad, R. S. J . Org. Chem. 1987,
52, 3701.
(6) (a) Paterson, I.; Cumming, J . G.; Smith, J . D.; Ward, R. A.
Tetrahedron Lett. 1994, 35, 441. (b) Paterson, I.; Lister, M. A.
Tetrahedron Lett. 1988, 29, 585.
(7) (a) Brown, H. C.; Chandrasekharan, J .; Ramachandran, P. V. J .
Am. Chem. Soc. 1988, 110, 1539. DIP-Chloride is a trademark of the
Aldrich Chemical Co. (b) The superscripts d and l refer to (+)- and
(-)-R-pinene, respectively, used to prepare the corresponding (-)- and
(+)-DIP-Chloride, respectively.
(8) Ramachandran, P. V.; Chen, G. M.; Brown, H. C. J . Org. Chem.
1996, 61, XXX.
0022-3263/96/1961-0095$12.00/0 © 1996 American Chemical Society

96 J . Org. Chem., Vol. 61, No. 1, 1996
Ramachandran et al.
Ta ble 1. Asym m etr ic Red u ction of r-Ch ir a l Keton es w ith (-)- a n d (+)-1 u n d er Nea t Con d ition s a t Room Tem p er a tu r e
product alcohol,b %
reactn
isol
exo,a
%
endo,a
%
ketone
reagent time, h yield, %
(1S,2S) (1S,2R) (1R,2R) (1R,2S)
(S)-ethyl 1-methyl-2-oxo-cyclopentanecarboxylate
(S)-ethyl 1-methyl-2-oxo-cyclopentanecarboxylate
(R)-ethyl 1-methyl-2-oxo-cyclopentanecarboxylate
(R)-ethyl 1-methyl-2-oxo-cyclopentanecarboxylate
(1S)-1-methylnorcamphor
(1S)-1-methylnorcamphor
(1R)-1-methylnorcamphor
(1R)-1-methylnorcamphor
(1R)-1-methylnorcamphor
(1S)-camphenilone
(1S)-camphenilone
(1R)-camphenilone
(1R)-camphenilone
(1S)-camphor
(1S)-camphor
(1S)-camphor
(1R)-camphor
(1R)-camphor
(-)-1
(+)-1
(-)-1
(+)-1
(-)-1
(+)-1
(-)-1
(-)-1
(+)-1
(-)-1
(+)-1
(-)-1
(+)-1
(-)-1
(+)-1
(+)-1
(-)-1
(+)-1
1
72
72
1
70
69
72
66
91
90
88
98
89
86
91
83
97
95
97
97
95
95
g99 (t)c
19 (t)c
18 (t)c
g99 (t)c
g99
11
12
7
g99
0
94
0 (c)c
81 (c)c
82 (c)c
0 (c)c
0
89
88
93
0
g99
19
0
81
19
g99
81
0
0.5
g99
11
0
89
2
2
12
7
g99
88
93
0
48d
0.5
1
12
12
1
g99
6
g99
0
94
6
93
7
7
g99
93
0
0
g99
e1
68
79
66
0.5
g99e
32
g99
32
21
e1
68
79
10
96d
10
21
34
34
g99
66
1
0.5
g99e
1
a
b
Determined by direct analysis on a SPB-5 capillary column. Determined as a derivative on a capillary column. c (t) )trans and (c)
) cis. At -25 °C. e Crystallization from hexane gave essentially pure exo-9.
d
were initially surprised to observe that the reduction of
(()-4 with 0.50 equiv of (-)-1 provides the contrather-
modynamic9 (1S,2S)-exo-1-methyl-2-norbornanol as the
major product (86%) (eq 2). But a close examination
workup provides the hydroxy ester, analyzed as the
trifluoroacetate with a Chiraldex-GTA capillary column10
to be exclusively ethyl [(1S,2S)-trans]-1-methyl-2-hy-
droxycyclopentanecarboxylate [(1S,2S)-3] (eq 3). On the
(2)
(3)
contrary, the reduction of (R)-2 with (-)-1 is slower,
complete only after 72 h, producing a mixture of hydroxy
esters, 81% [(1R,2S)-cis ]-3 and 19% [(1R,2R)-trans]-3 (eq
4). The difference in the rate of reduction is in accord
with the kinetic resolution experiments described previ-
(4)
revealed that when the (1S)-ketone is preferentially
reduced, with (-)-1, the reagent that produces predomi-
nantly (S)-alcohols,7 we obtain (1S,2S)-1-methyl-2-nor-
bornanol. Reduction of (()-4 with a stoichiometric
amount of (-)-1 produces 52% (1S,2S)-5 (exo), 7%
(1R,2R)-5 (exo), and 41% (1R,2S)-5 (endo), i.e., 41% of the
endo-product and 59% of the exo-alcohol. This predicts
that the reaction of optically pure (1S)-4 with (-)-1
should provide (1S,2S)-5 (exo) exclusively, whereas (1R)-4
with (-)-1 should provide (1R,2S)-5 (endo) predomi-
nantly. As a corollary, the reduction of (1R)-4 and (1S)-4
with (+)-1 should provide (1R,2R)-5 (exo) exclusively and
(1S,2R)-5 (endo) predominantly, respectively. To test the
validity of these predictions, in the hope of better
understanding the capability of DIP-Chloride for double
asymmetric reductions, we undertook an examination of
the reaction of representative optically pure ketones with
optically pure antipodes of the reagent. The results of
this study are presented and discussed here.
ously, when (()-2 was resolved with (-)-1 to provide (R)-2
and with (+)-1 to obtain (S)-2.8 The combination of (S)-2
and (-)-1, the reagent that produces predominantly (S)-
alcohols, appears to constitute a matched pair, whereas
the combination of (R)-2 and (-)-1 constitutes a mis-
matched pair. As can be expected from the foregoing
result, the antipode of the reagent, (+)-1, with (R)-2
provides the trans-hydroxy ester [(1R,2R)-trans]-3 es-
sentially exclusively, whereas the reaction of (+)-1 with
(S)-2 gives 81% of the cis-hydroxy ester [(1S,2R)-cis]-3
predominantly (Table 1).
The double asymmetric reduction of optically pure
1-methyl-2-norbornanones, (1R)- and (1S)-4, with (+)-
and (-)-1 reveals similar control by the reagent. Reduc-
tion of (1S)-1-methyl-2-norbornanone with the matching
reagent, (-)-1, results in a complete reaction in only 0.5
h, and the usual workup provides (1S,2S)-1-methyl-2-
norbornanol ((1S,2S)-5 (exo)) as the exclusive product
(eq 5).
Resu lts a n d Discu ssion
The reduction of (S)-2 with (-)-1 under neat condition
at rt is complete in 1 h, and the usual diethanolamine
(9) Rei, M. H. J . Org. Chem. 1979, 44, 2760.
(10) Chiraldex-GTA is a trademark of Alltech Associates, Inc.

Chiral Synthesis via Organoboranes
J . Org. Chem., Vol. 61, No. 1, 1996 97
(Table 1), thus displaying the control of the reagent over
the stereochemical outcome in the mismatched cases also.
The reduction of camphor (8) using hydride reagents
provides a classic example of the role of steric effects on
the course of the reductions. The extreme steric require-
ments of the camphor structure control the endo-ap-
proach of the hydride, even with the least sterically
demanding reagent, sodium borohydride, providing the
exo-product almost exclusively (98%). Accordingly, the
reduction of camphor provides a major test for 1. As
expected, the reduction of (1S)-8 with (-)-1 provides
99.7% of [(1S)-exo]isoborneol and 0.3% of [(1S)-endo]-
borneol (eq 9). The slower reacting mismatched pair
(5)
The reduction of the mismatched ketone, (1R)-4 with
(-)-1 is slower, requiring 2 h for completion, and provides
88% of (1R,2S)-1-methyl-2-norbornanol ((1R,2S)-5 (endo))
and 12% of (1R,2R)-5 (exo) (eq 6). The endo product
increases to 93% when the reaction is conducted at -25
°C. The fact that there is not a large difference in the
(6)
(9)
(1R)-8 and (-)-1 gave a product ratio of 66% [(1R)-endo]-
borneol and 34% [(1R)-exo]isoborneol (eq 10).
rate of reduction of the matched and mismatched pair of
the reagent and the ketone in this case provides an
explanation for our observation that we are forced to use
1.4 equiv of the reagent at 0 °C for the kinetic resolution
of (()-4.8
(10)
The results are identical for the reduction of (1R)-4 and
(1S)-4 with the antipode of the reagent, (+)-1 (Table 1).
While the (1S,2S)-product is exo for 1-methyl-2-nor-
bornanol, a similar product from the reduction of 3,3-
dimethyl-2-norbornanone (camphenilone, 6), (1S,2S)-3,3-
dimethyl-2-norbornanol (7), is endo. This provides an
excellent opportunity to demonstrate control by the
reagent in this double asymmetric reduction. On the
basis of the reductions of 2 and 4 with (+)- and (-)-1
described above, if the (1S)-ketone and (-)-reagent are
the matched pair, and assuming that the product is
formed depending on the proven capability of the (-)-
reagent to form the (S)-alcohol, it is anticipated that the
reduction would produce the endo-alcohol from this
combination, whereas the exo-alcohol should be obtained
from the mismatched pair. Indeed, treatment of (1S)-6
with (-)-1 results in a relatively rapid reaction at rt (1
h), and the product is exclusively (1S,2S)-7 (endo) (eq 7).
The enantiomers are produced in the reduction of the
antipodes of 8 with (+)-1. The reduction of (1S)-8 with
(+)-1 was also carried out at -25 °C when the reaction
was decelerated (4 d for completion), but improves the
endo:exo ratio to 79:21 (Table 1).
For convenience, all of the results of the double
asymmetric reductions with (+)- and (-)-1 are sum-
marized in Table 1.
Mech a n ism of Red u ction . The tentative model of
the transition state that we proposed earlier to explain
and predict the configuration of products from reductions
using 17 can be utilized to rationalize the differences in
the rate of the reduction and the control of the stereo-
chemistry by the reagent. For example, for the reduction
of (1S)-(+)- and (1R)-(-)-4 with (-)-1 (dIpc2BCl), four
transition state models are possible that will provide each
of the four diastereomers [Scheme 1, parts a-d]. In the
favored transition state for both (1S)- and (1R)-ketones,
the ketone approaches the reagent with its quaternary
carbon atom having the 1-methyl group away from the
methyl group at the 2-position of the apopinane structure
of the reagent [Scheme 1, parts a and c. As can be seen
from the model, under favored situations, (1S)-ketone
produces the exo-alcohol and (1R)-ketone produces the
endo-alcohol. Strong steric interactions between the two
methyl groups allow the reagent to control the stereo
outcome.
(7)
The reaction of the mispatched pair (1R)-6 with (-)-1
requiring 12 h at rt for complete reduction, reveals a
better selectivity than the product from the reduction
of (1R)-4, 93% (1R,2S)-7 (exo) and 7% (1R,2R)-7 (endo)
(eq 8).
Of the two disfavored models, the interactions between
the 2-methyl group of the reagent and the 1-methyl group
of the (1S)-ketone (Scheme 1, part b seems to be very
prominent, making this the least favored transition state.
This leads to the exclusive formation of (1S,2S)-5 (exo).
However, the model in Scheme 1, part d, for (1R)-ketone
is not as hindered as part b and contributes to the partial
formation of (1R,2R)-5 (exo).
(8)
In comparison, the reduction of (1R)-6 with (+)-1 gives
g99% (1R,2R)-7 (endo) and the reaction of (1S)-6 with
(+)-1 gives 94% (1S,2R)-7 (exo) and 6% (1S,2S)-7 (endo)
This model probably can be used to account for the
differences in the rates of the reduction for the two

98 J . Org. Chem., Vol. 61, No. 1, 1996
Ramachandran et al.
Sch em e 1
Red u ction of Keton es w ith 1. Gen er a l P r oced u r e. An
oven-dried 50 mL round bottom flask equipped with a septum-
capped side arm, magnetic stirring bar, and a connecting tube
was cooled to rt in a stream of nitrogen. The ketone (10 mmol)
and DIP-Chloride (12 mmol) were transferred to the flask in
a glovebag. The reaction mixture was stirred at appropriate
temperatures until the reaction was complete as shown by the
11B NMR spectrum of a methanolyzed aliquot (δ 32). EE (25
mL) was added, followed by diethanolamine (24 mmol), and
the mixture was stirred for 2 h when the boron components
precipitated as a complex. This precipitate was filtered and
washed with pentane. The combined filtrates were concen-
trated and chromatographed using vacuum liquid chromatog-
raphy on silica gel. R-Pinene was eluted with pentane,
followed by elution of the alcohol with pentane:EE (1:1). The
cis/ trans or exo/ endo ratio of the alcohols was determined by
comparing them with the product obtained from the reduction
of the ketone with NaBH4. The reactions of individual ketones
are presented below.
isomers of the ketone. A comparison of the favored
transition state models [Scheme 1 parts a and c] shows
that there could be a larger interaction between the
bridge methylene group of the ketone and the 2-methyl
group of the reagent in part c as compared to part a which
causes a slower reaction rate for the (1R)-ketone. Such
an interaction in the disfavored model might also be
contributing to the complete absence of (1S,2R)-5 (endo)
from the (1S)-ketone.
Con clu sion s
In conclusion, we have demonstrated that the predict-
able nature of the reduction of prochiral ketones with
DIP-Chloride can be extended for the reagent-controlled
reduction of chiral ketones where the matched pairs show
g99% diastereoselectivity and the mismatched pairs
show a diastereoselectivity of 68-94%. The rates of the
reactions of the matched pairs are faster than those of
the mismatched pairs. In all the cases studied, the (-)-
reagent and (S)-ketone or the (+)-reagent and (R)-ketone
constitute matched pairs and the (-)-reagent and (R)-
ketone or the (+)-reagent and (S)-ketone constitute
mismatched pairs. We believe that this capability of our
versatile reagent should find further applications in
organic synthesis. We are continuing to study the scope
and limitations of this double asymmetric reduction.
Red u ction of Eth yl (S)-(+)-1-Meth yl-2-oxocyclop en -
ta n eca r boxyla te ((S)-2). (a ) With (-)-1. (S)-(+)-2 (5.2
mmol, 0.89 g) was treated with 2.02 g (6.3 mmol) of (-)-1 at
rt as described in the general procedure. The reaction was
complete in 1 h. Workup and chromatography provided 0.63
g (70%) of the product hydroxy ester 3. Analysis of the TFA
derivative of this product on a Chiraldex-GTA column revealed
a composition of g99% [(1S,2S)-trans]-3. The other diastere-
omer could not be detected by GC. [R]25 ) +24.80 (c 3.2,
D
CHCl3). 1H NMR δ (ppm) (CDCl3): 1.21 (s, 3H), 1.24-1.29 (t,
J ) 7.1 Hz, 3H), 1.53-2.08 (m, 6H), 2.09-2.10 (d, J ) 3.7 Hz,
1H), 4.12-4.19 (q, J ) 7.1 Hz, 2H), 4.31-4.37 (m, 1H). 13C
NMR δ (ppm) (CDCl3): 14.09, 17.16, 19.02, 30.86, 33.79, 52.00,
60.48, 76.79, 177.75. Anal. Calcd for C9H16O3: C, 62.75; H,
9.37. Found: C, 62.42; H, 9.63.
Exp er im en ta l Section
(b) With (+)-1. (S)-(+)-2 (3.1 mmol, 0.52 g) was treated
with 1.18 g (3.7 mmol) of (+)-1 at rt as described in the general
procedure. The reaction was complete in 72 h. Workup and
chromatography provided 0.37 g (69%) of the product hydroxy
ester which showed a composition of 81% [(1S,2R)-cis]-3 and
19% [(1S,2S)-trans]-3.
Red u ction of Eth yl (R)-(-)-1-Meth yl-2-oxocyclop en -
ta n eca r boxyla te ((R)-2). (a ) With (-)-1. (R)-(-)-2 (3.0
mmol, 0.51 g) was treated with 1.18 g (3.7 mmol) of (-)-1 at
rt as described in the general procedure. The reaction was
complete in 72 h. Workup and chromatography provided 0.37
g (72%) of the product hydroxy ester 3 which showed an
isomeric composition of 82% [(1R,2S)-cis]-3 and 18% [(1R,2R)-
trans]-3.
Gen er a l Meth od s. Techniques for handling air-sensitive
compounds have been previously described.11 Analyses of the
menthyl chloroformate (MCF) derivatives12 were performed on
a gas chromatograph (GC) using a SPB-5 capillary column (30
m), at appropriate temperatures. Some of the product alcohols
were converted to the trifluoroacetates and analyzed on a
Chiraldex-GTA capillary column (23 m).
Ma ter ia ls. Ethyl ether (EE) (Mallinckrodt) was used as
such. (+)- and (-)-camphor, trifluoroacetic anhydride, (+)- and
(-)-DIP-Chloride, diethanolamine, and menthyl chloroformate
were all obtained from Aldrich Chemical Co. Enantiomerically
pure isomers of ethyl 1-methylcyclopentanecarboxylate, 1-
methylnorcamphor, and camphenilone were prepared by the
kinetic resolution of their racemates using appropriate enan-
tiomers of DIP-Chloride.8
(b) With (+)-1. (R)-(-)-2 (1.4 mmol, 0.23 g) was treated
with 0.53 g (1.7 mmol) of (+)-1 at rt as described in the general
procedure. The reaction was complete in 1 h. Workup and
chromatography provided 0.16 g (66%) of the product hydroxy
ester which showed a composition of g99% [(1R,2R)-trans]-3.
(11) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Syntheses via Boranes; Wiley-Interscience: New York, 1975;
Chapter 9.
(12) Westley, J . W.; Halpern, B. J . Org. Chem. 1968, 33, 3978.
The other diastereomer could not be detected by GC. [R]25
)
D

Chiral Synthesis via Organoboranes
J . Org. Chem., Vol. 61, No. 1, 1996 99
-24.52 (c 3.1, CHCl3). The 1H and 13C NMR spectra were
identical to those obtained from (1S,2S)-trans]-3. Anal. Calcd
for C9H16O3: C, 62.75; H, 9.37. Found: C, 62.38; H, 9.60.
Red u ction of (1S)-(+)-1-Meth yln or ca m p h or ((1S)-4).
(a ) With (-)-1. (1S)-(+)-4 7.6 mmol, 0.94 g) was treated with
2.93 g (9.1 mmol) of (-)-1 at rt as described in the general
procedure. The reaction was complete in 0.5 h. Workup and
chromatography provided 0.87 g (91%) of the product alcohol,
mp 75-76 °C. Analysis of the MCF derivative of the alcohol
on a SPB-5 capillary column showed an isomeric composition
of g99% (1S,2S)-5. The other diastereomer could not be
Red u ction of (1R)-(-)-Ca m p h en ilon e ((1R)-6). (a ) With
(-)-1. (1R)-(-)-6 (3.6 mmol, 0.50 g) was treated with 1.38 g
(4.3 mmol) of (-)-1 at rt as described in the general procedure.
The reaction was complete in 12 h. Workup and chromatog-
raphy provided 0.42 g (83%) of the product which showed a
composition of 93% (1R,2S)-7 and 7% (1R,2R)-7.
(b) With (+)-1. (1R)-(-)-6 (4.0 mmol, 0.55 g) was treated
with 1.55 g (4.8 mmol) of (+)-1 at rt as described in the general
procedure. The reaction was complete in 1 h. Workup and
chromatography provided 0.54 g (97%) of the product alcohol,
mp 74-75 °C, analyzed to be exclusively (1R,2R)-7. The other
detected by GC. [R]25 ) -0.81 (c 2.95, CHCl3).13 1H NMR δ
diastereomer could not be detected by GC. [R]25 ) -20.9 (c
D
D
3.02, CHCl3). The H and 13C NMR spectra were identical to
1
(ppm) (CDCl3): 1.14 (s, 3H), 1.40-1.41 (d, J ) 4.2 Hz, 1H),
0.95-1.82 (m, 8H), 2.13-2.18 (m, 1H), 3.44-3.50 (m, 1H). 13
C
those obtained from (1S,2S)-7. Anal. Calcd for C9H16O: C,
77.08; H, 11.51. Found: C, 77.27; H, 11.72.
NMR δ (ppm) (CDCl3): 16.05, 30.26, 32.98, 35.89, 40.05, 43.01,
47.39, 77.40. Anal. Calcd for C8H14O: C, 76.13; H, 11.19.
Found: C, 75.88; H, 11.40.
Red u ction of (1S)-(-)-Ca m p h or ((1S)-8). (a ) With (-)-
1. (1S)-(-)-8 (6.2 mmol, 0.94 g) was treated with 2.40 g (7.5
mmol) of (-)-1 at rt as described in the general procedure. The
reaction was complete in 0.5 h. Workup and chromatography
provided 0.91 g (95%) of the product alcohol. Analysis of the
alcohol on a SPB-5 capillary column showed an isomeric
composition of 99.7% (1S,2S)-9 and 0.3% (1S,2R)-9. Crystal-
lization of this material from hexane provided material of
(b) With (+)-1. (1S)-(+)-4 (3.9 mmol, 0.48 g) was treated
with 1.49 g (4.6 mmol) of (+)-1 at rt as described in the general
procedure. The reaction was complete in 2 h. Workup and
chromatography provided 0.44 g (90%) of the product alcohol
which showed an isomeric composition of 89% (1S,2R)-5 and
11% (1S,2S)-5.
Red u ction of (1R)-(-)-1-Meth yln or ca m p h or ((1R)-4).
(a ) With (-)-1. (1R)-(-)-4 (5.8 mmol, 0.72 g) was treated with
2.23 g (7.0 mmol) of (-)-1 at rt as described in the general
procedure. The reaction was complete in 2 h. Workup and
chromatography provided 0.64 g (88%) of the product which
showed a composition of 88% (1R,2S)-5 and 12% (1R,2R)-5.
At -25 °C, the reaction was complete in 48 h and workup
provided 98% of the product alcohol which showed an isomeric
composition of 93% (1R,2S)-5 and 7% (1R,2R)-5.
g99.9% de, mp 212-214 °C. [R]25 ) +34.6 (c 5.35, EtOH)
D
which corresponds to g99% ee on the basis of the maximum
rotation reported in the literature.14
(b) With (+)-1. (1S)-(-)-8 (7.5 mmol, 1.14 g) was treated
with 2.88 g (9.0 mmol) of (+)-1 at rt as described in the general
procedure. The reaction was complete in 10 h. Workup and
chromatography provided 1.12 g (97%) of the product alcohol
which showed an isomeric composition of 68% (1S,2R)-9 and
32% (1S,2S)-9.
(b) With (+)-1. (1R)-(-)-4 (8.3 mmol, 1.03 g) was treated
with 3.2 g (9.9 mmol) of (+)-1 at rt as described in the general
procedure. The reaction was complete in 0.5 h. Workup and
chromatography provided 0.93 g (89%) of the product alcohol,
mp 75-76 °C, which showed an isomeric composition of g99%
(1R,2R)-5. The other diastereomer could not be detected by
At -25 °C, the reaction was complete in 96 h and workup
provided 97% of the product alcohol which showed an isomeric
composition of 79% (1S,2R)-9 and 21% (1S,2S)-9.
Red u ction of (1R)-(+)-Ca m p h or ((1R)-8). (a ) With (-)-
1. (1R)-(+)-8 (10.1 mmol, 1.55 g) was treated with 3.92 g (12.2
mmol) of (-)-1 at rt as described in the general procedure. The
reaction was complete in 10 h. Workup and chromatography
provided 1.48 g (95%) of the product alcohol which when
analyzed on a SPB-5 capillary column showed an isomeric
composition of 66% (1R,2S)-9 and 34% (1R,2R)-9.
GC. [R]25 ) +0.82 (c 4.76, CHCl3).13 The 1H and 13C NMR
D
spectra were identical to those obtained from (1S,2S)-5. Anal.
Calcd for C8H14O: C, 76.13; H, 11.19. Found: C, 75.88; H,
11.56.
Red u ction of (1S)-(+)-Ca m p h en ilon e ((1S-6)). (a ) With
(-)-1. (1S)-(+)-6 (4.9 mmol, 0.67 g) was treated with 1.88 g
(5.9 mmol) of (-)-1 at rt as described in the general procedure.
The reaction was complete in 1 h. Workup and chromatog-
raphy provided 0.59 g (86%) of the product alcohol, mp 74-75
°C. Analysis of the MCF derivative of the alcohol on a SPB-5
capillary column showed it to be exclusively (1S,2S)-7. The
(b) With (+)-1. (1R)-(+)-8 (7.2 mmol, 1.10 g) was treated
with 2.78 g (8.7 mmol) of (+)-1 at rt as described in the general
procedure. The reaction was complete in 0.5 h. Workup and
chromatography provided 1.05 g (95%) of the product alcohol
which showed an isomeric composition of 99% (1R,2R)-9 and
1% (1R,2S)-9. Crystallization of this material from hexane
provided material of g99.9% de. [R]25 ) -34.26 (c 5.64,
D
other diastereomer could not be detected by GC. [R]25
)
D
EtOH) which corresponds to g99% ee on the basis of the
+21.4 (c 3.45, CHCl3). 1H NMR δ (ppm) (CDCl3): 0.86 (s, 3H,
endo-CH3), 0.98 (s, 3H), 1.12-1.70 (m, 6H), 1.37 (s, 1H), 1.75-
1.80 (m, 1H), 2.24-2.30 (m, 1H,), 3.63-3.68 (d, 1H). 13C NMR
δ (ppm) (CDCl3): 18.12, 19.92, 24.54, 30.52, 33.74, 37.90, 43.90,
48.25, 80.36. Anal. Calcd for C9H16O: C, 77.08; H, 11.51.
Found: C, 77.11; H, 11.70.
maximum rotation reported in the literature.14
Ack n ow led gm en t . Financial support from the
United States Army Research Office (DAAH-94-G-0313)
is gratefully acknowledged.
(b) With (+)-1. (1S)-(+)-6 (5.0 mmol, 0.70 g) was treated
with 1.94 g (6.0 mmol) of (+)-1 at rt as described in the general
procedure. The reaction was complete in 12 h. Workup and
chromatography provided 0.64 g (91%) of the product alcohol
which revealed an isomeric composition of 94% (1S,2R)-7 and
6% (1S,2S)-7.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR of
compounds (1S,2S)- and (1R,2R)-3, 5, and 7 (12 pages). This
material is contained in libraries on 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.
(13) Berson reports that a compound of ∼30% optical purity in
chloroform (c 4.6) showed a rotation that was too small to measure.
Berson, J . A.; Walia, J . S.; Remanick, A.; Suzuki, S.; Reynold-Warnhoff,
P.; Willner, D. J . Am. Chem. Soc. 1961, 83, 3986.
J O951207R
(14) Pickard, R. H.; Littlebury, W. O. J . Chem. Soc. 1907, 91, 1973.