Metal-dependent reaction tuning with cyclopentylmetal reagents: Application to the asymmetric synthesis of (+)-α-conhydrine and (S)-2-cyclopentyl-2- phenylgrycolic acid

Article abstract of DOI:10.1002/chem.200801603

The reaction profile of the cyclopentyl organometallic reagents with the aliphatic ketones can be tuned to reduction or addition by changing the metal atom. Cyclopentylmagnesium bromide (CPMB) reduces aromatic and aliphatic aldehydes and ketones to the corresponding alcohols without any C-C bond formation and shows good diastereoselectivity in the reduction of the substituted cyclic and polycyclic ketones as well as chiral α-oxygenated aliphatic ketones. However, in the presence of 10 mol% of ZnClα ₂, the cyclopentylmagnesium halides follow a normal Grignard addition to the ketones to give tertiary alcohols with complete diastereoselectivity. The reductive as well as the addition protocols were used for the asymmetric synthesis of two medicinally important compounds, (+)-α-conhydrine and (S)-2-cyclopentyl-2-phenylglycolic acid.

Full text of DOI:10.1002/chem.200801603

FULL PAPER
DOI: 10.1002/chem.200801603
Metal-Dependent Reaction Tuning with Cyclopentylmetal Reagents:
Application to the Asymmetric Synthesis of (+)-a-Conhydrine and
(S)-2-Cyclopentyl-2-phenylglycolic Acid
Siddharth Roy, Anubha Sharma, Soumyaditya Mula, and Subrata Chattopadhyay*[a]
Abstract: The reaction profile of the
cyclopentyl organometallic reagents
with the aliphatic ketones can be tuned
to reduction or addition by changing
the metal atom. Cyclopentylmagnesium
bromide (CPMB) reduces aromatic
and aliphatic aldehydes and ketones to
the corresponding alcohols without any
the substituted cyclic and polycyclic ke-
tones as well as chiral a-oxygenated
aliphatic ketones. However, in the
presence of 10 mol% of ZnCl2, the cy-
clopentylmagnesium halides follow a
normal Grignard addition to the ke-
tones to give tertiary alcohols with
complete diastereoselectivity. The re-
ductive as well as the addition proto-
cols were used for the asymmetric syn-
thesis of two medicinally important
compounds, (+)-a-conhydrine and (S)-
2-cyclopentyl-2-phenylglycolic acid.
Keywords: aldehydes · asymmetric
synthesis
· Grignard reaction ·
À
C C bond formation and shows good
ketones · reduction
diastereoselectivity in the reduction of
Introduction
of the Grignard reagents for carbon–carbon bond formation
remains a challenging task. Herein, we report that the reac-
tion specificity of the organometallic reagents derived from
halocyclopentanes can be efficiently tuned by using two dif-
ferent metals. The developed protocols were also used for
the syntheses of two biologically active compounds.
While Grignard and organolithium reagents continue to
À
remain the popular choices for C C bond formation in or-
ganic chemistry,[1,2] their reactions with ketones can follow
unusual pathways, such as the reduction of carbonyls to al-
cohols or the enolization of ketones to give aldol products.[3]
The use of alkylmetal reagents with minimum basicity and
maximum nucleophilicity[4,5] can enhance the nucleophilicity
of the alkylating reagent to achieve the desired addition to
the ketones. The reduction of a carbonyl compound by
RMgX proceeds by transfer of its a-hydrogen atom to the
carbonyl group with simultaneous formation of alkenes
from RMgX. With Grignard reagents, prepared especially
from a bulky secondary alkyl halide, and where generation
of the alkene is sterically favoured, the reduction route can
become predominant, and in some cases, overwhelming.
Under these conditions, the RMgX can be profitably used
as a reducing agent, provided RX is easily available and in-
expensive, and the Grignard reagent offers good selectivity
in the reduction. At the same time, the use of the latter type
Results and Discussion
The initial motivation for the present work stems from our
interest in developing efficient asymmetric syntheses of the
esters of tertiary hydroxy acids of compounds such as oxy-
butynin (1a) and 1b, which are potent muscarinic antago-
nists for the treatment of centric and peripheral choline dys-
functions.[6] Tertiary hydroxy acids and their derivatives are
also important intermediates in the asymmetric synthesis of
a variety of medicinal agents[7] and natural products.[8]
Hence, we have recently developed[9a] an efficient method
for the asymmetric construction of the tertiary carbinol skel-
eton 4 by the addition of different Grignard reagents to the
ketones 3, amenable from the glyceraldehyde derivative 2
(Scheme 1). The method was subsequently used[9b] for the
synthesis of the acid segment 5a of oxybutynin. It was envis-
aged that extension of a similar strategy might provide 5b,
which is required for the synthesis of 1b. However, our at-
tempted addition of cyclopentylmagnesium bromide
(CPMB) to aldehyde 2 furnished the reduced alcohol with-
[a] S. Roy,+ A. Sharma,+ S. Mula,+ Prof. S. Chattopadhyay
Bio-Organic Division, Bhabha Atomic Research Centre
Mumbai 400 085 (India)
Fax : (+91)22-5505151
E-mail: schatt@barc.gov.in
[+] These authors contributed equally.
Chem. Eur. J. 2009, 15, 1713 – 1722
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excellent yields (91–96%, Table 1, entries 1–8). However,
ortho-methoxy ketone 6i furnished the reduced product 7i
(66%) along with the Grignard addition product 7i’ (25%)
(Table 1, entry 9). With ortho-bromo ketone 6j, besides the
expected reduced product 7j, a minor amount (4–7%) of
the aldol product 7j’ (Table 1, entry 10) was also obtained.
Presumably, the ortho-methoxy group in 6i assisted the
Grignard addition through chelation. Likewise, the bromo
group in 6j assisted enolization of the COCH3 group leading
to the aldol product. Overall, for the unsubstituted, and m-
and p-substituted aryl carbonyl compounds including the
bulky ketone, such as 6h, CPMB was found to be an excel-
Scheme 1. Asymmetric construction of the tertiary carbinol skeleton 4
for the synthesis of the acid segment 5a of oxybutynin. R1, R2 = alkyl/
aryl.
À
lent reducing agent without leading to any C C bond forma-
tion. The presence of an ortho-substituent with the capacity
to coordinate with CPMB, however, produced some of the
normal Grignard addition/aldol compounds as well. With
the aliphatic substrates 6k–m, the reduced products 7k–m
along with different amounts of the cyclopentyl addition
products 7k’–m’ were formed (Table 1, entries 11–13). Nota-
bly, CPMB did not reduce the olefin group in 6l, thus show-
ing complete chemoselectivity in the reduction or the addi-
tion steps (Table 1, entry 12).
out any trace of the cyclopentyl addition product. This
result prompted us to explore the potential of CPMB as a
reducing agent for a variety of aldehydes and ketones
(Scheme 2).
Next we turned our attention to the reduction of cyclic
substituted ketones by CPMB, as this reaction would pro-
vide important information on its ability to carry out diaste-
reoselective reduction. For this purpose, ketones 8a–g
(Scheme 3) were used as the substrates (Table 2).
Scheme 2. The use of CPMB as a reducing agent for a series of aromatic
and aliphatic aldehydes and ketones.
Reactions with acyclic aldehydes/ketones: The studies were
carried out with a series of aromatic and aliphatic alde-
hydes/ketones 6a–m (Scheme 2) and a 1m solution of
CPMB in THF, and the results are summarized in Table 1.
The reaction proceeded uneventfully with aromatic sub-
strates 6a–h to furnish the corresponding alcohols 7a–h in
Table 1. Reduction of acyclic aldehydes and ketones by CPMB.
Entry Substrate R1
R2
Product(s) Yield
[%][a]
1
2
3
4
6a
6b
6c
6d
C6H5
H
H
H
H
7a
7b
7c
7d
95
91
91
95
4-MeOC6H4
4-BrC6H4
3,4-methylene-
dioxy-C6H3
C6H5
4-MeOC6H4
4-BrC6H4
C6H5
5
6
7
8
6e
6 f
6g
6h
Me
Me
Me
Ph
Me
Me
H
7e
7 f
7g
7h
7i/7i’
7j/7j’
7k/7k’
7l/7l’
93
96
94
95
66/25
78/4–7
41/37
26/44
74/15
9
6i[b]
6j[b]
6k[b]
6l[b]
6m[b]
2-MeOC6H4
2-BrC6H4
PhCH2
Scheme 3. Reduction of cyclic substituted ketones by CPMB.
10
11
12
13
PhCH=CH
H
Reduction of cyclic ketones: The reduction of a carbonyl
function involves the formation of two new bonds: one be-
tween a hydride from the reagent and the carbonyl carbon
atom, and a second between the metal of the reagent and
CH
N
CH3(CH)5 7m/7m’
[a] Yields of isolated products; [b] 6i and 6k–m also gave some Grignard
addition products, and a minor quantity of aldol product was formed
with 6j.
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Metal-Dependent Reaction Tuning
FULL PAPER
Table 2. Reduction of cyclic substituted ketones by CPMB.
and 8d), the respective alkyl groups are placed too remotely
from the carbonyl site to offer any steric restriction, and the
approach of the reducing agent from either side of the car-
bonyl group is equally favourable. Thus, the predominant
product of their reduction with CPMB would produce the
thermodynamically more stable trans alcohols 9c and 9d, re-
spectively, as was observed with CPMB.
Entry Substrate
Product Yield
[%][a]
cis/trans
1
2
3
4
2-methylcyclohexanone (8a)
9a
9b
9c
9d
89
91
91
95
68:32
100:0
0:100
0:100
3-methylcyclohexanone (8b)
4-methylcyclohexanone (8c)
4-tert-butylcyclohexanone
(8d)
The reducing agent can approach the unhindered ketone
group of cholestan-3-one (8e) from either an axial or equa-
torial direction.[11e] In the transition state, however, the
bulky alkoxide group cannot occupy a pseudoaxial position,
since it would be sterically hindered by the axial hydrogen
atoms on C1 and C5. Further, the solvent-induced stabiliza-
tion of the ion is also hindered in such a position.[11f] Thus,
the preferred transition state would be that with the alkox-
ide group in a pseudoequatorial position, producing pre-
dominantly the b-cholestan-3-ol (9e). In consonance with
this idea, CPMB also exclusively produced b-cholestan-3-ol,
as evident from the resonances of the CH(OH) proton at
5
cholestanone (8e)
9e
93
0:100
(b-alco-
hol)
22:78
92:8
6
7
camphor (8 f)
9 f
9g
90
60
flavanone (8g)[b]
[a] Yields of isolated products; [b] the cyclopentyl addition product
(ca. 25%) was also obtained.
the carbonyl oxygen atom. If hydride transfer is more im-
portant in the transition state, then steric approach control
predominates. However, when metal–oxygen bond forma-
tion is more important, product development control is the
major factor. With substituted cyclohexanones, this situation
would lead to axial or the thermodynamically more stable
equatorial alcohols, respectively. However, although appa-
rently an equatorial approach of a bulky reducing agent is
considered sterically more favourable, it would also result in
a transition state containing an alkoxide ion. The difference
between the free energies of the two isomers in such a
series is very small (1–3 kcalmolÀ1), and the product distri-
bution ratio is governed by an even smaller difference (ꢀ
1 kcalmolÀ1) in the activation energies of the transition
states. Further, besides the steric bulk of the reducing
agent,[10a] its ionic character also plays an important role in
controlling the above two processes.[10b] The increased cova-
lent character of the reagent such as CPMB would assist
greater hydrogen bridging,[10c] which would increase the
electrophilic character of the metal, favouring the attack of
its carbonyl oxygen atom in the early transition state. In this
process, the intermediate stages of the reduction are gov-
erned by the steric requirements of the products, and prod-
ucts with an equatorial hydroxy group would result.
In 2-methylcyclohexanone (8a), the methyl group is
placed equatorially to minimize steric congestion. For its re-
duction, CPMB would coordinate with the carbonyl group
preferentially from the equatorial side because of the ab-
sence of steric repulsion between the 2,6-axial hydrogen
atoms of the cyclohexane ring and the cyclopentyl group.[11a]
Consequently, the subsequent hydrogen transfer to the car-
bonyl group would result in the predominant formation of
cis-2-methylcyclohexanol. With CPMB, alcohol 9a was ob-
tained in 68:32 ratio of cis and trans isomers.
1
d)=3.57 ppm in the H NMR spectrum.
Camphor (8 f), however, presents an interesting case, as
one of its bridgehead gem dimethyl groups is placed almost
above the ketone group. Thus, the course of its reduction is
dictated by the 7,7-dimethyl substituents in its rigid bicyclic
system, leading to a predominantly endo attack. However,
the resultant pseudo-exo transition state would also be con-
siderably hindered by the bridgehead methyl group. The net
result would be the production of a mixture of exo (isobor-
neol) and endo (borneol) products. We obtained a mixture
of isoborneol/borneol in 78:22 ratio, as revealed from inte-
gration of the signal for the carbinol CH proton at dꢁ4.0
(borneol) and 3.6 ppm (isoborneol) in the 1H NMR spec-
trum.
4-Flavanone (8g) structurally resembles 8b, although it
exists as a skewed chair conformer, somewhat flattened by
the C5=C6 double bond and the oxygen atom at the 4 posi-
tion. Its phenyl substituent at C3 is in a pseudoequatorial
position, as revealed from the NMR spectrum. The presence
of the fused benzene ring would facilitate an axial approach
of CPMB towards its ketone function because of the lack of
a 1,3-diaxial interaction, resulting in the formation of an
equatorial alcohol. This was also borne out by the fact that
reduction of 8g with CPMB produced the cis product 9g
only.[11g]
We have also carried out the reduction of 8a–g with
NaBH4 to confirm our results by comparison of the physical
and spectral data of the resultant alcohols (data not shown).
CPMB produced better results in most of the cases and pro-
vided the alcohols 9a–g with higher purity, as is evident
1
from their clean H NMR spectra.
With 3-methylcyclohexanone (8b), the thermodynamically
more stable cis (diequatorial) isomer was formed exclusive-
ly, as evident from the CH(OH) resonances at d=3.9–
4.0 ppm in 1H NMR spectrum.[11b] This conformer is far
more stable than the corresponding diaxial conformer by
3.65 kcalmolÀ1 owing to the steric effect of the methyl
group.[11c] With 4-methyl and 4-tert-butylcyclohexanone (8c
These above results prompted us to explore the potential
of CPMB for diastereoselective reduction (Scheme 4) of
chiral ketones 3a–h, which were used by us earlier for the
synthesis of chiral tertiary alcohols.[9a] The reduction strategy
was particularly important since the resultant 3-alkylglycer-
ols have been extensively used by us for the synthesis of var-
ious bioactive compounds.[12a–j]
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1715

S. Chattopadhyay et al.
selectivity in the reduction of the substrates 3a–g.[13] CPMB
showed slightly less diastereoselectivity than K-selectride in
the reduction of 3a–g. However, features such as low cost,
ease of preparation and the nonhazardous nature of CPMB
offer distinct advantages for its use in asymmetric reduction.
Evidently, the formation of cyclopentene during the process
is the driving force for the reducing action of CPMB. Com-
pared with the sp3-hybridized cyclopentyl system, cyclopen-
tene is devoid of sterically unfavourable hydrogen–hydrogen
eclipsing interactions. This is not the case with cyclohexyl-
magnesium bromide, which furnishes the normal Grignard
addition products with ketones such as 3h.[9b]
Scheme 4. Diastereoselective reduction with CPMB. PCC=pyridinium
chlorochromate. i) RMgX/THF or Et2O; ii) PCC/NaOAc/CH2Cl2;
iii) CPMB/THF.
Diastereoselective reduction of a-oxygenated chiral ketones
with CPMB: For this study, ketones 3a–h, prepared by
using reported procedures,[9a,13] were subjected to reaction
with CPMB (Table 3). Irrespective of their alkyl chain
length and presence of unsaturation or an aryl group, all the
substrates were reduced by CPMB to give mixtures of the
anti- and syn-alkylglycerols 10a–h and 11a–h (Table 3, en-
tries 1–8) without the formation of any noticeable Grignard
The high syn selectivity offered by CPMB in the reduction
of 3a–h suggested that the hydride transfer takes place pri-
marily by the Felkin–Anh model.[15a,b] Between the two pos-
sible open-chain Felkin–Anh conformers (Scheme 5), OC1
Table 3. Diastereomeric reduction of the chiral ketones 3a–h.
Entry
Substrate
R
6/7[a]
Yield [%][b]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
Me
Et
0:100
20:80
10:90
17:83
16:84
21:79
21:79
22:78[c]
91
73
80
92
91
90
91
90
allyl
nBu
nHex
nDec
nDodec
Ph
[a] Based on yields of isolated products; [b] total yield of the diastereo-
mers; [c] determined from the H NMR spectrum.
Scheme 5. Felkin–Anh model for the syn selectivity of CPMB in the re-
duction of 3a–h.
1
addition product. In all the cases, the reduction proceeded
with good syn selectivity as revealed from their NMR
data.[13] Amongst the substrates, higher syn selectivity was
obtained with those possessing small chain alkyl groups
(3a–e). It is worth noting that the addition of RMgX to 2
proceeds with predominant anti selectivity.[12] Thus, the pres-
ent reductive protocol is complementary to the direct
Grignard addition route and provides better diastereoselec-
tivity. The diastereomeric products, other than 10h/11h,
were easily separated by conventional column chromatogra-
phy. The relative ratio of the diastereomeric carbinols 10h/
11h could be easily ascertained by integration of the
has the minimum gauche interaction and hence is thermody-
namically more stable than OC2.[16] Consequently, the reduc-
tion takes place through the OC1 conformation leading to
the syn-alcohols preferentially. The possibility of a a-chela-
tion controlled reaction leading to the anti alcohols would
be less probable, considering the bulk of the cyclohexyl and
cyclopentyl groups in the substrates and reagent, respective-
ly. With K-selectride, the chelate-controlled reaction could
be excluded completely in view of the greater bulk of the re-
ducing agent as well as the presence of K+ as the counter-
ion. This explains the exclusive diastereoselectivity observed
with K-selectride.[13] Given that CPMB is a less bulky Mg-
based reducing agent, the reduction might also proceed par-
tially through the chelate-controlled pathway, furnishing the
anti-alcohols as the minor products (see below).
1
PhCH(OH) resonances in the H NMR spectra, which ap-
peared as two doublets at d=4.51 (major, syn) and
4.93 ppm (minor, anti). The result assumes significance given
that reaction of PhMgBr with 2 gave an approximately 1:1
mixture of syn and anti products (data not shown).
Although long known, the reducing action of Grignard re-
agents has been used only sporadically in preparative organ-
ic synthesis.[14a–c] The present results established CPMB as a
promising agent for the reduction of both aromatic and ali-
phatic aldehydes and ketones, as well as diastereoselective
reduction of substituted cyclic and a-oxygenated chiral ke-
tones. Earlier, K-selectride was found to offer exclusive syn
Asymmetric synthesis of (+)-a-conhydrine (20): The 1-hy-
droxyalkyl substituted piperidine alkaloid, conhydrine (20),
was considered a suitable target for a first application of the
above methodology to natural product synthesis. This struc-
tural framework is frequently encountered in natural alka-
loids.[17] Conhydrine is a hemlock alkaloid, which is isolated
from the seeds and leaves of the poisonous plant Conium
maculatum, whose extracts were used in ancient Greece for
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Chem. Eur. J. 2009, 15, 1713 – 1722

Metal-Dependent Reaction Tuning
FULL PAPER
the execution of criminals.[18] A large number of auxiliary-
supported or chiral pool asymmetric syntheses of the un-
natural b-conhydrine[19a–h] and (À)-a-conhydrine[20a–e] have
been documented.
For the synthesis of 20 (Scheme 6), alcohol 11b was ben-
zylated to 12, which on treatment with CuCl2·2H2O in
MeOH gave diol 13. Monotosylation of its primary hydroxy
function followed by treatment with base afforded epoxide
14. Its reaction with the Grignard reagent prepared from
bromide 15 in the presence of CuBr·Me2S proceeded
smoothly to furnish 16. Its invertive azidation with diphenyl-
Scheme 7. Addition of a cyclopentyl group to ketone 3h. i) CPMC or
CPLi or CP3MgLi or CPMC + 10 mol% ZnCl2.
Finally, our attempt with CPMC in the presence of
10 mol% of ZnCl2 gave a satisfactory result, furnishing 21
(80%) and 10h+11h (15%)
(Table 4, entry 4). Presumably,
the reaction proceeded via the
trialkylzinc(II) ate complex,[24]
generated in situ from CPMC
and ZnCl2. It was gratifying to
note that 21 was formed as a
single diastereomer, as re-
vealed from its 1H and
13C NMR spectra. To the best
of our knowledge, this is the
first report of absolute diaster-
ocontrol using this reagent.
In the earlier reports,[23,24]
the organometallic reagents,
prepared from other alkyl/aryl
Scheme 6. Synthesis of 20. THP=tetrahydropyranyl, PPTS=pyridinium p-toluenesulfonate, Ms=methanesul-
fonyl. i) BnBr/NaH/THF/D (86%); ii) CuCl2·2H2O/MeOH/D (92%); iii) pTsCl/py, K2CO3/MeOH (75%);
iv) THPO
ACHTUNGTRENNUNG(CH2)3Br (15)/Mg/THF/CuBr·Me2S (78%); v) DPPA/Ph3P/DEAD/THF (84%); vi) MeOH/PPTS
(92%); vii) H2/10% Pd-C/EtOAc, Boc2O (91%); viii) MsCl/Et3N/À788C, TFA/CH2Cl2 (67%).
Table 4. Reaction courses of different cyclopentylmetal reagents to 3h.
Entry Reagent Yield of 10h/ Yield of
11h[b] 21 [%][c]
phosphoryl azide (DPPA) in the presence of diethyl azodi-
carboxylate (DEAD) and triphenylphosphine afforded 17,
which on depyranylation gave 18. This compound was con-
verted into protected amine 19 by a one-pot catalytic hydro-
genation in the presence of Boc2O (Boc=tert-butyloxycar-
bonyl).[21] Its mesylation, and subsequent acidic removal of
the Boc group by trifluoroacetic acid (TFA) afforded 20.
T
[8C] 10h+11h
[%][a]
1
2
3
CPMC
CPLi
CPMC (1 equiv) +
CPLi (2 equiv)
CPMC + ZnCl2
(10 mol%)
25
90
20:80
44:56 25
45:55 50
0
À40 55
À78 35
4
0
15
44:56 80
Asymmetric synthesis of (S)-2-cyclopentyl-2-phenylglycolic
acid (5b): The designated tertiary hydroxy acid 5b is the
key chiral segment of the muscarinic receptor antagonist
1b,[6a–e] which shows better efficacy than the widely used
drug oxybutynin.[6f] Like oxybutynin, (S)-1b displays a
better therapeutic profile than (Æ)-1b, highlighting the im-
portance of chiral drugs.[22]
The synthesis required the addition of a cyclopentyl group
to ketone 3h, for which CPMB was inadequate. It was envis-
aged that the required task could be accomplished with a cy-
clopentylmetal reagent containing a soft metal atom. The re-
sults of our studies (Scheme 7) in that direction are summar-
ized in Table 4. Although cyclopentylmagnesium chloride
(CPMC) was ineffective, cyclopentyllithium (CPLi) fur-
nished the reduced product 10h+11h (55%) along with the
desired alkyl addition product 21 (25%) (Table 4, entries 1
and 2). In light of this result, we attempted the reaction with
(CP)3MgLi,[23] prepared in situ from a 1:2 mixture of CPMC
and CPLi. (CP)3MgLi furnished 21 (50%) as the major
product along with 10h+11h (35%) (Table 4, entry 3).
[a] Total yield of the diastereomers; [b] determined from the 1H NMR
spectrum; [c] based on yields of isolated products.
halides and softer metals, were shown to carry out alkyl ad-
dition to the ketone function without reducing it. In con-
trast, our results revealed that the reducing action of the cy-
clopentylmetal reagents can at best be controlled by varying
the reaction conditions but not excluded completely. The
unique property of these reagents is also evident from the
fact that by following the reported procedure,[24] when we
attempted the reaction by stirring a mixture of CPMC and
ZnCl2 for 10 min followed by addition of 3h, only the re-
duced product was obtained. This result suggested that
unlike the other RMgX compounds, reaction of CPMC (or
CPMB) with ZnCl2 was very slow, confirming the unique-
ness of the latter reagents. The problem was overcome by
stirring CPMC and ZnCl2 for 2 h before the addition of 3h.
The results of Tables 3 and 4 revealed that, other than
CPMB and CPMC, the cyclopentylmetal reagents did not
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1717

S. Chattopadhyay et al.
show any diastereoselectivity in the reduction of 3h. The
presence of a softer metal (Li or Zn) in the other reagents is
expected to enable some chelation-controlled reduction, fur-
nishing both anti- and syn-alcohols 10h and 11h.
Conclusion
Overall, we have disclosed that by careful choice of metal,
the reaction profile of the organometallic reagents derived
from halocyclopentanes can be tuned. The cyclopentyl
Grignard reagents CPMB or CPMC act exclusively as re-
ducing agents that can be used for the diastereoselective re-
duction of cyclic/polycyclic as well as chiral a-oxygenated
ketones. The reagent can be prepared in any organic
chemistry laboratory by using readily available and inexpen-
sive chemicals. It is nonhazardous, stable at room tempera-
ture, easily disposable and is a promising substitute for more
expensive and exotic reagents such as K-selectride especially
for asymmetric reduction of the ketones such as 3a–h. In
the presence of only 10 mol% ZnCl2, however, CPMC fur-
nishes the corresponding tricyclopentylzincate(II), which
adds to the ketone to furnish the tertiary alcohols. Using
both these protocols, we formulated highly enantiocontrol-
led syntheses of a-conhydrine and the core acid unit (S)-5b
of a medicinally important compound.
On the basis of our previous results[9a] on the addition of
Grignard reagents to chiral ketones, we assigned a 2R,3S
configuration for 21. This assignment was subsequently con-
firmed by converting it into the known compound (S)-5b.
The diastereoselectivity of the addition of the trialkylzinca-
te(II) complex can be explained with the help of the possi-
ble six-membered transition states (I and II; Scheme 8).[24]
Experimental Section
IR spectra were recorded as films with a JASCO model A-202 spectro-
1
photometer. H (200 MHz) and 13C NMR (50 MHz) spectra were record-
ed in CDCl3 with a Bruker AC-200 instrument. Optical rotations were re-
corded on a JASCO DIP-360 digital polarimeter. All organic extracts
were dried over anhydrous Na2SO4. The chiral ketones 3a–g[13] and 3h[9b]
were synthesized by following our own reported procedures.
Scheme 8. Possible six-membered transition states for the addition of tri-
alkylzincate(II) to chiral ketones.
General method for the reaction of CPMB with various carbonyl com-
pounds: To a stirred solution of the aldehyde/ketone (2.0 mmol) in THF
(10 mL) was added CPMB (3.0 mmol, 1m solution in THF) dropwise at
room temperature. After stirring the mixture for around 3 h (monitored
by TLC), the reaction was quenched with aqueous 10% NH4Cl, and the
mixture was filtered and concentrated in vacuo. The residue was dis-
solved in Et2O, and the organic layer was washed with water and brine
and dried. Solvent removal in vacuo and column chromatography of the
residue afforded the respective alcohols.
Between these, I with R3 (cyclohexanedioxy group) in the
equatorial position is more favoured. The other transition
state II suffers from extensive diaxial steric interaction be-
tween the Cl and R3 groups. In view of this situation, the re-
action proceeds via I to furnish (2R,3S)-21.
For the synthesis of 5b (Scheme 9), alcohol 21 was benzy-
lated[25] to give 22, which on treatment 3% methanolic HCl
gave diol 23. Cleavage of its diol function with NaIO4 fur-
nished 24. Its debenzylation with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) to 25, followed by oxidation with
NaClO2 gave the target acid (S)-5b. The physical, spectral
and optical data of our synthetic sample compared very well
with the reported values,[6a–d] confirming its S stereochemis-
try. The enantiomeric excess of (S)-5b was determined by
HPLC (Chiracel OD-H column, mobile phase 95% hexane/
5% isopropyl alcohol).
1-Cyclopentyl-1-(2’-methoxyphenyl)ethan-1-ol (7i’): colourless oil;
1H NMR (200 MHz, CDCl3, TMS): d=1.38–1.68 (m containing a s at d=
1.50, 11H), 2.54–2.61 (m, 1H), 3.86 (s, 3H), 6.87–6.97 (m, 2H), 7.17–
7.33 ppm (m, 2H); 13C NMR (50 MHz, CDCl3, TMS): d=25.4, 25.9, 27.4,
27.5, 31.7, 49.1, 55.4, 76.7, 111.4, 120.7, 127.1, 127.7, 135.7, 156.7 ppm; IR
(film): n˜ =3551, 3060, 1568 cmÀ1
; elemental analysis calcd (%) for
C14H20O2: C 76.33, H 9.15; found: C 76.48, H 9.22.
2,4-Di(2’-bromophenyl)-4-oxobutan-2-ol (7j’): colourless oil; 1H NMR
(200 MHz, CDCl3, TMS): d=1.25 (s, 3H), 1.78 (s, 1H), 3.44 (d, J=
18.0 Hz, 1H), 4.47 (d, J=18.0 Hz, 1H), 6.95–7.18 (m, 2H), 7.25–7.62 (m,
5H), 7.94 ppm (d, J=8.2 Hz, 1H); 13C NMR (50 MHz, CDCl3, TMS): d=
30.8, 49.6, 73.2, 120.7, 126.2, 129.2, 129.5, 131.3, 131.8, 132.0, 135.4, 146.5,
199.9 ppm; IR (film): n˜ =3485, 1675 cmÀ1; elemental analysis calcd (%)
for C16H14Br2O2: C 48.27, H 3.54, Br
40.14; found:
39.95.
C 47.12, H 3.38, Br
1-Cyclopentyl-2-phenylethan-1-ol
(7k’): colourless oil;
1H NMR
(200 MHz, CDCl3, TMS): d=1.26–1.96
(m, 10H), 2.55–2.66 (m, 1H), 2.89–
2.95 (m, 1H), 3.58–3.67 (m, 1H), 7.25–
7.31 ppm (m, 5H); 13C NMR (50 MHz,
CDCl3, TMS): d=25.7, 25.9, 28.6, 29.4,
42.8, 45.6, 76.6, 126.3, 128.5, 129.5,
Scheme 9. Synthesis of 5b. i) NaH/BnBr/Bu4NI/THF/D (96%); ii) 3% HCl/MeOH (87%); iii) NaIO4/
MeCN·H2O (92%); iv) DDQ/CH2Cl2 (80%); v) NaClO2/TEMPO/MeCN (77%).
1718
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1713 – 1722

Metal-Dependent Reaction Tuning
FULL PAPER
139.0 ppm; IR (film): n˜ =3365 cmÀ1; elemental analysis calcd (%) for
C13H18O: C 82.06, H 9.53; found: C 81.93, H 9.68.
3.78 (m, 2H), 3.82–3.95 and 4.16–4.31 (two m, 1H), 4.50 and 4.93 ppm
(2ꢁd, 72:28, J=7.2 and 4.2 Hz, 1H); 13C NMR (50 MHz, CDCl3): d=
23.7, 24.0, 25.1, 34.7, 34.9, 36.1, 36.5, 64.4, 65.5, 72.9, 75.9, 79.1, 79.8,
110.1, 110.6, 126.1, 127.0, 127.6, 128.2, 128.5, 139.8, 140.1 ppm; IR (film):
n˜ =3625, 1589 cmÀ1; elemental analysis calcd (%) for C16H22O2 (246.16):
C 78.01, H 9.00; found: C 77.79, H 8.88.
3-Phenylprop-2E-en-1-ol (7l): colourless oil; 1H NMR (200 MHz, CDCl3,
TMS): d=1.76 (broad, 1H), 4.32 (d, J=5.6 Hz, 1H), 6.23 (dt, J=16.0,
5.6 Hz, 1H), 6.61 (d, J=16.0 Hz, 1H), 7.23–7.40 ppm (m, 5H); 13C NMR
(50 MHz, CDCl3, TMS): d=63.6, 126.5, 127.7, 128.6, 131.0, 136.7 ppm;
IR (film): n˜ =3356, 1603, 971 cmÀ1
.
AHCTUNGTERG(NNUN 2R,3R)-3-Benzyloxy-1,2-cyclohexylidenedioxypentane (12): To a stirred
1-Cyclopentyl-3-phenylprop-2E-en-1-ol (7l’): colourless oil; 1H NMR
(200 MHz, CDCl3, TMS): d=1.25–1.88 (m, 8H), 2.00–2.12 (m, 1H), 4.07
(t, J=6.8 Hz, 1H), 6.23 (dd, J=15.8, 6.8 Hz, 1H), 6.57 (d, J=15.8 Hz,
1H), 7.23–7.40 ppm (m, 5H); 13C NMR (50 MHz, CDCl3, TMS): d=25.6,
26.1, 28.9, 29.8, 43.2, 71.7, 125.6, 126.3, 128.1, 128.4, 129.6, 130.4,
136.8 ppm; IR (film): n˜ =3360, 1598, 967 cmÀ1; elemental analysis calcd
(%) for C14H18O: C 83.12, H 8.97; found: C 83.27, H 8.81.
Octadecan-7-ol (7m): colourless oil; 1H NMR (200 MHz, CDCl3, TMS):
d=0.87 (dist. t, J=7.0 Hz, 6H), 1.25 (s, 26H), 1.41–1.50 (m, 4H), 3.52–
3.59 ppm (m, 1H); 13C NMR (50 MHz, CDCl3, TMS): d=13.9, 22.5, 25.5,
29.3, 29.5, 31.8, 37.3, 71.7 ppm; IR (film): n˜ =3595 cmÀ1; elemental analy-
sis calcd (%) for C18H38O: C 79.92, H 14.16; found: C 80.08, H 14.15.
7-Cyclopentyloctadecan-7-ol (7m’): colourless oil; 1H NMR (200 MHz,
CDCl3, TMS): d=0.85 (dist. t, J=6.8 Hz, 6H), 1.25 (brs, 30H), 1.37–1.55
(m, 9H), 1.88–1.94 ppm (m, 1H); 13C NMR (50 MHz, CDCl3, TMS): d=
14.1, 22.7, 23.7, 25.6, 26.1, 29.3, 29.6, 30.0, 30.4, 31.9, 37.7, 47.5, 75.2 ppm;
IR (film): n˜ =3445 cmÀ1; elemental analysis calcd (%) for C23H46O: C
81.58, H 16.79; found: C 81.42, H 13.89.
suspension of pentane-washed NaH (0.864 g, 18.00 mmol, 50% suspen-
sion in oil) in THF (30 mL) was added 11b (3.0 g, 15.00 mmol) in THF
(20 mL) at room temperature over a period of 30 min. After reflux of the
mixture for 1 h, BnBr (3.70 g, 21.64 mol) in THF (20 mL) was added, and
the mixture was heated at reflux for an additional 1 h, then brought to
room temperature. The mixture was poured into ice-cold water, the or-
ganic layer was separated, and the aqueous portion was extracted with di-
ethyl ether. The combined organic extracts were washed with water and
brine and dried. Solvent removal in vacuo gave a residue, which was puri-
fied by column chromatography (silica gel, 0–10% EtOAc/hexane) to
afford 12 (3.74 g, 86%): colourless oil; [a]2D2 =+29.52 (c=1.03, CHCl3);
1H NMR (200 MHz, CDCl3, TMS): d=0.95 (t, J=6.8 Hz, 3H), 1.26–1.48
(m, 4H), 1.53–1.76 (m, 8H), 3.27–3.40 (m, 1H), 3.56–3.69 (m, 1H), 3.82–
3.98 (m, 1H), 4.15–4.22 (m, 1H), 4.56–4.85 (m, 2H), 7.17–7.40 ppm (m,
5H); 13C NMR (50 MHz, CDCl3): d=9.3, 23.9, 24.0, 25.2, 35.0, 36.3, 66.1,
72.6, 77.7, 80.3, 109.5, 127.6, 127.8, 128.3, 138.7 ppm; IR (film): n˜ =3088,
1102 cmÀ1; elemental analysis calcd (%) for C18H26O3 (290.19): C 74.45,
H 9.02; found: C 74.63, H 8.86.
AHCTUNGRETG(NNUN 2R,3R)-3-Benzyloxypentan-1,2-diol (13): A mixture of 13 (3.70 g,
2-Methylcyclohexanol (9a): colourless oil; 1H NMR (200 MHz, CDCl3,
TMS): d=0.92 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.4 Hz, 3H), 1.19–1.41 (m,
4H), 1.58–1.70 (m, 5H), 1.93 (brs, 1H), 3.06–3.11 and 3.73–3.80 ppm (2ꢁ
m, 1H); 13C NMR (50 MHz, CDCl3, TMS): d=16.8, 18.5, 20.6, 24.4, 25.1,
25.6, 28.7, 32.4, 33.6, 35.4, 35.8, 40.2, 71.1, 76.4 ppm; IR (film): n˜ =
12.76 mmol) and CuCl2·H2O (20 mol%) in MeOH (30 mL) was stirred at
approximately 508C until 12 disappeared (as monitored by TLC, ca. 4 h).
The mixture was concentrated in vacuo, treated with water (25 mL) and
extracted with EtOAc (3ꢁ25 mL). The combined organic extracts were
washed with water (2ꢁ10 mL) and brine (1ꢁ5 mL), dried and concen-
trated in vacuo. The residue was subjected to column chromatography
(silica gel, 0–5% MeOH/CHCl3) to obtain pure 13 (2.46 g, 92%): colour-
less oil; [a]2D2 =+29.12 (c=1.36, CHCl3); 1H NMR (200 MHz, CDCl3,
TMS): d=0.95 (t, J=6.8 Hz, 3H), 1.49–1.68 (m, 2H), 1.71–1.94 (brs,
2H), 3.42–3.52 (m, 1H), 3.67–3.80 (m, 3H), 4.58 (q, J=11.6 Hz, 2H),
7.33 ppm (m, 5H); 13C NMR (50 MHz, CDCl3): d=10.2, 21.6, 65.6, 70.9,
3431 cmÀ1
.
3-Methylcyclohexanol (9b): colourless oil; 1H NMR (200 MHz, CDCl3,
TMS): d=0.88 (d, J=7.2 Hz, 3H), 1.10–1.41 (m, 4H), 1.54–1.71 (m, 3H),
1.89–1.94 (m, 2H), 3.54 ppm (m, 1H); 13C NMR (50 MHz, CDCl3, TMS):
d=22.2, 24.1, 31.3, 33.9, 35.1, 44.4, 70.4 ppm; IR (film): n˜ =3356 cmÀ1
.
4-Methylcyclohexanol (9c): colourless oil; 1H NMR (200 MHz, CDCl3,
TMS): d=0.89 (d, J=6.4 Hz, 3H), 1.13–1.40 (m, 4H), 1.64–1.71 (m, 3H),
1.87–1.93 (m, 2H), 3.51 ppm (m, 1H); 13C NMR (50 MHz, CDCl3, TMS):
75.7, 81.2, 127.6, 128.0, 128.3, 138.9 ppm; IR (film): n˜ =3406, 1067 cmÀ1
;
elemental analysis calcd (%) for C12H18O3 (210.13): C 68.54, H 8.63;
found: C 68.48, H 8.48.
d=21.8, 31.7, 33.3, 35.5, 70.8 ppm; IR (film): n˜ =3349 cmÀ1
.
1
4-tert-Butylcyclohexanol (9d): colourless oil; H NMR (200 MHz, CDCl3,
TMS): d=0.82 (s, 9H), 0.87–1.22 (m, 5H), 1.73–1.78 (m, 2H), 1.95–2.01
(m, 2H), 2.19 (brs, 1H), 3.49 ppm (m, 1H); 13C NMR (50 MHz, CDCl3,
(2R,3R)-3-Benzyloxy1-1,2-epoxypentane (14): To a cooled (À58C) and
stirred solution of 13 (2.4 g, 11.43 mmol) and pyridine (1.1 mL,
13.71 mmol) in CH2Cl2 (20 mL) was added p-toluenesulfonyl chloride
(TsCl, 2.18 g, 11.43 mmol). The mixture was stirred at À58C for 3.5 h and
at 08C overnight, then poured into water and extracted with CHCl3. The
organic extract was washed with water and brine, dried and concentrated
in vacuo. The crude product was purified by column chromatography
(silica gel, 0–10% EtOAc/hexane) to afford the pure monotosylate
(3.72 g, 89%): colourless oil; [a]2D2 =+2.64 (c=1.06, CHCl3); 1H NMR
(200 MHz, CDCl3, TMS): d=0.85 (t, J=6.4 Hz, 3H), 1.47–1.74 (m, 2H),
1.80 (broad, 1H), 2.41 (s, 3H), 3.39–3.51 (m, 1H), 3.72–3.85 (m, 2H),
3.98–4.12 (m, 1H), 4.15–4.22 (m, 1H), 4.36–4.68 (m, 1H), 7.24–7.32 (m,
7H), 7.78 ppm (d, J=8.2 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=9.8,
21.6, 22.6, 69.6, 70.9, 72.3, 79.4, 127.9, 128.4, 129.8, 129.9, 132.6, 138.0,
TMS): d=25.5, 27.5, 32.1, 35.7, 47.0, 70.8 ppm; IR (film): n˜ =3413 cmÀ1
.
5a-Cholestan-3-ol (9e): white solid; m.p. 1408C (lit.[10b] 141–1478C);
1H NMR (200 MHz, CDCl3, TMS): d=0.63 (s, 3H), 0.85 (d, J=6.8 Hz,
3H), 0.93 (d, J=6.8 Hz, 6H), 1.07–1.45 (m containing a s at d 1.42, 24H),
1.50–1.92 (m, 10H), 2.26 (s, 1H), 3.42–3.63 ppm (m, 1H); 13C NMR
(50 MHz, CDCl3, TMS): d=11.8, 12.0, 18.4, 20.9, 22.3, 22.5, 23.6, 23.9,
27.7, 27.9, 28.4, 29.4, 31.1, 31.8, 35.2, 35.5, 35.9, 36.7, 37.8, 39.2, 39.7, 42.3,
44.6, 54.1, 55.9, 56.2, 71.0 ppm; IR (film): n˜ =3607 cmÀ1
.
Isoborneol/borneol (9 f): white solid; m.p. 1958C; 1H NMR (200 MHz,
CDCl3, TMS): d=0.80 and 0.84 (2ꢁs, 3H), 0.88 (s, 3H), 0.92 (s, 3H),
1.28–1.39 (m, 3H), 1.60–1.76 (m, 2H), 1.86 (s, 1H), 2.03–2.08 (m, 1H),
2.27–2.36 (m, 1H), 3.43–3.61 (isoborneol) and 3.95–3.97 ppm (borneol)
(two m, 1H); 13C NMR (50 MHz, CDCl3, TMS): d=11.3, 13.3, 18.6, 20.0,
20.4, 25.8, 27.2, 28.2, 29.6, 33.8, 38.9, 40.3, 45.0, 46.3, 48.9, 49.4, 77.3,
145.0 ppm; IR (film): n˜ =3454, 1599, 1372, 1178 cmÀ1
.
To a stirred suspension of anhydrous K2CO3 (2.11 g, 15.29 mmol) in
MeOH (30 mL) was added the above tosylate (3.72 g, 10.22 mmol). The
mixture was stirred for 2 h and then filtered. The residue was washed
with diethyl ether (2ꢁ10 mL), and the combined filtrates were concen-
trated in vacuo. The residue was taken up in Et2O (40 mL) and washed
with water and brine, dried and concentrated in vacuo to obtain the
crude product, which was purified by column chromatography (silica gel,
0–5% Et2O/hexane) to furnish 14 (1.64 g, 75% from 13): colourless oil;
[a]2D2 =+12.04 (c=1.16, CHCl3); 1H NMR (200 MHz, CDCl3, TMS): d=
0.97 (t, J=7.2 Hz, 3H), 1.54–1.73 (m, 2H), 2.72–2.77 (m, 2H), 2.80–2.94
(m, 1H), 3.15–3.23 (m, 1H), 4.62 (q, J=12.0 Hz, 2H), 7.32 ppm (m, 5H);
13C NMR (50 MHz, CDCl3): d=10.2, 21.8, 41.7, 57.7, 65.4, 80.4, 127.6,
79.8 ppm; IR (film): n˜ =3466 cmÀ1
.
Flavan-4-ol (9g): white solid; m.p. 1028C (lit.[11g] 998C); 1H NMR
(300 MHz, CDCl3, TMS): d=1.67 (s, 1H), 2.15–2.23 (m, 1H), 2.51- 2.62
(m, 1H), 5.08–5.16 (m, 1H), 5.20 (dd, J=11.4, 1.4 Hz, 1H), 6.88–7.03 (m,
2H), 7.18–7.25 (m, 1H), 7.35–7.53 ppm (m, 6H); 13C NMR (50 MHz,
CDCl3, TMS): d=39.9, 65.7, 77.1, 116.7, 121.0, 125.7, 126.1, 127.0, 128.2,
128.7, 129.1, 140.5, 154.5 ppm; IR (film): n˜ =3299 cmÀ1
.
ACHTUNGTRENNUNG(1S/R,2R)-2,3-Cyclohexylidenedioxy-1-phenylpropan-1-ol (10h/11h): col-
1
ourless oil; [a]2D2 =+11.00 (c=0.604, CHCl3); H NMR (200 MHz, CDCl3,
TMS): d=1.22–1.30 (m, 4H), 1.52–1.69 (m, 6H), 2.06 (brs, 1H), 3.67–
Chem. Eur. J. 2009, 15, 1713 – 1722
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1719

S. Chattopadhyay et al.
128.0, 128.3, 138.9 ppm; IR (film): n˜ =3062, 1108 cmÀ1; elemental analysis
calcd (%) for C12H16O2 (192.12): C 74.97, H 8.39; found: C 75.14, H 8.54.
NaHCO3 was added, and the mixture was extracted three times with
CHCl3. The combined organic extracts were washed with brine, dried,
and concentrated in vacuo. The residue was purified by column chroma-
ACHTUNGTRENNUNG(5R,6R)-1-Tetrahydropyranyloxy-6-benzyloxyoctan-5-ol (16): To a cooled
tography (silica gel, 0–10% CH3OH/CHCl3) to give 20 (0.055 g, 67%).
(À108C) and stirred solution of the Grignard reagent prepared from the
bromide 15 (2.23 g, 10.0 mmol) and Mg (0.288 g, 12.0 mmol) in THF
(40 mL) was added CuBr·Me2S (5 mol%) followed by 14 (1.60 g,
8.33 mmol) in THF (15 mL). The mixture was stirred at the same temper-
ature for 6 h and then at 08C for 12 h. The reaction was quenched with
aqueous saturated NH4Cl (ca. 2 mL), and the organic extract was separat-
ed and dried. Solvent removal followed by column chromatography
(silica gel, 0–15% EtOAc/hexane) furnished 16 (2.18 g, 78%): colourless
oil; [a]2D2 =+10.93 (c=1.08, CHCl3); 1H NMR (200 MHz, CDCl3, TMS):
d=0.95 (t, J=6.4 Hz, 3H), 1.26–1.77 (m, 14H), 2.04 (brs, 1H), 3.37–3.48
(m, 3H), 3.54–3.62 (m, 1H), 3.72–3.86 (m, 2H), 4.49–4.71 (m, 3H),
7.34 ppm (m, 5H); 13C NMR (50 MHz, CDCl3): d=9.0, 19.6, 22.4, 25.5,
29.7, 30.7, 31.7, 62.3, 67.6, 71.8, 72.0, 72.3, 72.6, 80.9, 98.8, 127.9, 128.0,
128.4, 138.1 ppm; IR (film): n˜ =3423, 1454, 1031 cmÀ1; elemental analysis
calcd (%) for C20H32O4 (336.23): C 71.39, H 9.59; found: C 71.48, H 9.64.
[18e]
viscous liquid; [a]2D2 =+8.33 (c=0.81, EtOH), (lit.
[a]2D5 =+8.0 (c=
1.7, EtOH)); 1H NMR (200 MHz, CDCl3, TMS): d=0.96 (t, J=7.0 Hz,
3H), 1.36–1.47 (m, 6H), 1.55–1.63 (m, 2H), 2.44 (br s, 2H), 2.86–2.89 (m,
1H), 3.06–3.17 (m, 1H), 3.14–3.19 (m, 1H), 3.44–3.49 (m, 1H), 3.52–
3.64 ppm (m, 1H); 13C NMR (50 MHz, CDCl3): d=13.8, 19.4, 24.8, 25.7,
25.4, 56.3, 67.2, 70.0 ppm; IR (film): n˜ =3507 cmÀ1
.
Procedure for reaction of 3h with CPLi: To a stirred solution of the
CPLi [prepared from chlorocyclopentane (0.658 g, 6.33 mmol) and Li
(0.044 mg, 6.33 mmol)] in THF (20 mL) was added 3h (0.519 g,
2.11 mmol) in THF (10 mL) at À408C. After stirring the mixture for 4 h
at the same temperature, the reaction was quenched with aqueous satu-
rated NH4Cl. The organic layer was separated, the aqueous layer was ex-
tracted with EtOAc, and the combined organic extracts were washed
with brine and dried. Removal of the solvent in vacuo and column chro-
matography (silica gel, 0–15% EtOAc/hexane) of the residue furnished
pure 10h/11h and 21.
ACHTUNGTRENNUNG(5S,6R)-1-Tetrahydropyranyloxy-5-azido-6-benzyloxyoctane (17): To a so-
lution of 16 (2.18 g, 6.49 mmol) and triphenylphosphine (1.88 g,
7.18 mmol) in dry THF (30 mL) at 08C was added DEAD (1.04 g,
7.18 mmol) dropwise followed by DPPA (1.98 g, 7.18 mmol). The mixture
was stirred at 08C for 30 min and at room temperature for 3 h. The reac-
tion mixture was poured into water and extracted with ether. The organic
layer was washed with water and brine and dried. Solvent removal in
vacuo followed by column chromatography (silica gel, 0–10% EtOAc/
hexane) of the residue gave 17 (1.97 g, 84%): colourless oil; [a]2D5 =+6.61
(c=1.00, CHCl3); 1H NMR (200 MHz, CDCl3, TMS): d=0.91 (t, J=
6.8 Hz, 3H), 1.24–1.85 (m, 14H), 3.25–3.74 (m, 4H), 3.80–3.88 (m, 2H),
4.48–4.62 (m, 3H), 7.33 ppm (m, 5H); 13C NMR (50 MHz, CDCl3): d=
9.6, 19.4, 23.5, 25.4, 27.0, 29.6, 30.7, 31.2, 51.2, 62.3, 67.2, 67.5, 72.5, 82.4,
98.8, 127.4, 127.6, 128.0, 128.3, 128.6, 138.3 ppm; IR (film): n˜ =2099, 1454,
1181 cmÀ1; elemental analysis calcd (%) for C20H31N3O3 (361.24): C
66.45, H 8.64, N 11.62; found: C 66.48, H 8.78, N 11.41.
Procedure for reaction of 3h with (CP)3MgLi: To a cooled (À788C) solu-
tion of CPLi (10.0 mmol, 1m in THF) was added CPMC (5.0 mmol, 1m
in THF) under argon. After stirring the solution at the same temperature
for 1 h, 3h (0.684 g, 2.78 mmol) in THF (10 mL) was added. The mixture
was stirred at À788C for 5 h and treated with aqueous saturated NH4Cl.
The organic layer was separated, and the aqueous layer was extracted
with EtOAc. The combined organic extracts were washed with brine,
dried and concentrated in vacuo. The residue was subjected to column
chromatography (silica gel, 0–15% EtOAc/hexane) to furnish the pure
products.
AHCTUNGTREG(NNUN 1S,2R)-1-Cyclopentyl-1-phenyl-2,3-cyclohexylideneglycerol (21): To a
stirred solution of CPMC (1.0m in THF, 11 mL, 11 mmol) was added
ZnCl2 (0.149 g, 10 mol%) at room temperature under argon. After stir-
ring the mixture for 2 h, the solution was cooled to 08C, and 3h (2.03 g,
8.25 mmol) was added. The mixture was stirred for 4 h at 08C, quenched
with aqueous saturated NH4Cl, and extracted with EtOAc. The combined
organic extracts were washed with brine, dried and concentrated in
vacuo. The residue was purified by column chromatography (silica gel, 0–
15% EtOAc/hexane) to give 21 (2.09 g, 80%) along with 10/11h (0.307 g,
15%). 21: colourless oil; [a]2D5 =+5.88 (c=1.99, CHCl3); 1H NMR
(200 MHz, CDCl3, TMS): d=1.15–1.68 (m, 17H), 1.68–1.91 (m, 1H), 2.23
(brs, 1H), 2.27–2.50 (m, 1H), 3.78 (t, J=7.2 Hz, 1H), 4.03 (t, J=7.2 Hz,
1H), 4.51 (t, J=7.2 Hz, 1H), 7.16–7.38 (m, 3H), 7.38–7.55 ppm (m, 2H).
13C NMR (50 MHz, CDCl3): d=23.8, 23.9, 24.8, 25.2, 26.4, 27.0, 35.0,
35.7, 47.1, 65.1, 76.9, 79.6, 109.3, 126.6, 126.7, 127.5, 142.9 ppm; IR (film):
ACHTUNGTRENNUNG(5S,6R)-5-Azido-6-benzyloxyoctan-1-ol (18): A solution of 17 (1.90 g,
5.26 mmol) and pyridinium p-toluenesulfonate (0.1 g) in MeOH (25 mL)
was heated at reflux for 3 h. Most of the solvent was removed in vacuo,
and the residue was diluted with H2O and extracted with EtOAc. The or-
ganic extract was washed with H2O and brine and dried. Solvent removal
in vacuo followed by column chromatography (silica gel, 0–15% EtOAc/
hexane) of the residue gave 18 (1.34 g, 92%): colourless oil; [a]2D5 =+7.17
(c=1.30, CHCl3); 1H NMR (200 MHz, CDCl3, TMS): d=0.96 (t, J=
6.8 Hz, 3H), 1.26–1.32 (m, 4H), 1.67–1.79 (m, 4H), 3.31–3.61 (m, 4H),
4.62 (q, J=12.0 Hz, 2H), 7.40 ppm (m, 5H); 13C NMR (50 MHz, CDCl3):
d=9.6, 23.3, 29.4, 29.7, 51.6, 63.1, 72.5, 80.1, 127.9, 128.5, 137.8 ppm; IR
(film): n˜ =3448, 2102 cmÀ1; elemental analysis calcd (%) for C15H23O2N3
(277.18): C 64.95, H 8.36, N 15.15; found: C 65.14, H 8.40, N 15.06.
n˜ =3408, 3060, 1588, 1480 cmÀ1
C20H28O3 (316.20): C 75.91, H 8.92; found: C 75.82, H 8.78.
AHCTUNGTERG(NNUN 1S,2R)-1-Benzyloxy-1-cyclopentyl-1-phenyl-2,3-cyclohaxanedioxypro-
; elemental analysis calcd (%) for
ACHTUNGTRENNUNG(5S,6R)-5-tert-Butoxycarbonylaminoctan-1,6-diol (19): To a suspension of
10% Pd-C (50 mg) saturated with H2 in EtOAc (20 mL) was added 18
(0.500 g, 1.81 mmol) and Boc2O (0.5 mL, 2.17 mmol), and the mixture
stirred for 24 h. The mixture was passed through a small pad of celite,
and the eluent concentrated in vacuo to obtain a residue, which on
column chromatography (silica gel, 0–30% EtOAc/hexane) gave 19
(0.430 g, 91%): colourless oil; [a]2D5 =+9.12 (c=0.81, CHCl3); 1H NMR
(200 MHz, CDCl3, TMS): d=0.96 (t, J=6.8 Hz, 3H), 1.25–1.37 (m con-
taining a s at d 1.34, 13H), 1.71–1.87 (m, 4H), 3.54–3.72 (m, 3H), 3.81–
3.86 ppm (m, 1H); 13C NMR (50 MHz, CDCl3): d=10.1, 19.4, 23.2, 29.5,
pane (22): To a stirred suspension of pentane-washed NaH (0.091 g,
3.79 mmol) in THF (10 mL) was added 21 (1.0 g, 3.16 mmol) in THF
(30 mL) and the mixture was heated at reflux for 2 h. The mixture was
brought to room temperature, benzyl bromide (0.648 g, 3.79 mmol) and
Bu4NI (0.12 g) were added, and the mixture was heated at reflux further
for 12 h. The reaction was quenched with aqueous saturated NH4Cl, the
organic layer was separated, and the aqueous layer was extracted with
EtOAc. The combined organic extracts were washed with brine, dried
and concentrated to obtain a residue, which on column chromatography
(silica gel, 0–10% EtOAc/hexane) furnished pure 22 (1.23 g, 96%): col-
ourless oil; [a]2D4 =+4.46 (c=0.81, CHCl3); 1H NMR (200 MHz, CDCl3,
TMS): d=1.17–1.75 (m, 17H), 1.75–1.96 (m, 1H), 2.21–2.47 (m, 1H),
3.96–4.24 (m, 1.5H), 4.58 (s, 2H), 4.47–4.93 (m, 1.5H), 7.13–7.57 ppm (m,
10H); 13C NMR (50 MHz, CDCl3): d=23.9, 24.0, 24.8, 25.1, 25.3, 26.8,
27.8, 33.7, 36.0, 49.3, 66.3, 72.1, 78.8, 83.1, 109.1, 126.4, 126.8, 126.9, 127.4,
29.7, 60.2, 63.8, 72.5, 78.1, 155.6 ppm; IR (film): n˜ =3512 cmÀ1
.
(+)-a-Conhydrine (20): To a cooled (À788C) and stirred solution of 19
(0.420 g, 1.60 mmol) in CH2Cl2 (10 mL) was injected methanesulfonyl
chloride (0.15 mL, 1.92 mmol) followed by triethylamine (0.270 mL,
1.92 mmol). The mixture was stirred for 1 h at the same temperature, and
then aqueous ammonium chloride (3 mL) was added. The mixture was
washed with brine, dried and concentrated in vacuo, and the residue
passed through a small pad of silica gel.
127.6, 127.8, 128.3, 139.3, 140.0 ppm; IR (film): n˜ =3087, 1585, 1495 cmÀ1
;
elemental analysis calcd (%) for C27H34O3 (406.25): C 79.76, H 8.43;
found: C 79.61, H 8.45.
To a cooled (08C) and stirred solution of the above product in dry
CH2Cl2 (5 mL) was added TFA (0.3 mL, 0.143 mmol). The reaction mix-
ture was stirred at room temperature for 18 h, aqueous saturated
AHCTUNGTRENNUNG
1720
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Chem. Eur. J. 2009, 15, 1713 – 1722

Metal-Dependent Reaction Tuning
FULL PAPER
stirred at room temperature until completion of the reaction (as moni-
tored by TLC, 5.0 h). After the acid was neutralized with aqueous 10%
NaHCO3, the mixture was concentrated in vacuo, and the residue was
chromatographed (silica gel, 0–5% MeOH/CHCl3) to furnish pure 23
(0.568 g, 87%): colourless oil; [a]2D6 =+5.79 (c=0.69, CHCl3); 1H NMR
(200 MHz, CDCl3, TMS): d=1.28–1.64 (m, 6H), 1.64–2.04 (m, 4H), 2.71–
2.97 (m, 1H), 3.57–3.76 (m, 1H), 3.81–3.96 (m, 1H), 4.05–4.24 (m, 1H),
4.61 (d, J=11.8 Hz, 1H), 4.71 (d, J=11.8 Hz, 1H), 7.27–7.46 ppm (m,
10H); 13C NMR (50 MHz, CDCl3): d=25.2, 25.7, 27.2, 28.1, 44.7, 63.0,
66.2, 75.7, 85.6, 126.6, 127.0, 127.3, 127.4, 128.1, 128.2, 128.5, 128.8, 138.4,
139.3 ppm; IR (film): n˜ =3410, 1581, 1061 cmÀ1; elemental analysis calcd
(%) for C21H26O3 (326.19): C 77.27, H 8.03; found: C 77.42, H 8.24.
Rakita in Handbook of Grignard Reagents, Marcel Dekker, New
York, 1996; c) H. G. Richey, Jr. in Grignard Reagents: New DeVel-
opment, Wiley, New York, 2000.
[2] Reviews: a) Y.-H. Lai, Synthesis 1981, 585–604; b) J. J. Eisch, Orga-
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mermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis, V. A. Vu,
Angew. Chem. 2003, 115, 4438–4456; Angew. Chem. Int. Ed. 2003,
42, 4302–4320; d) A. Inoue, H. Shinokubo, K. Oshima, J. Synth.
Org. Chem. Jpn. 2003, 61, 25–36.
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jima, Y. Kamiya, J. Am. Chem. Soc. 1989, 111, 4392–4398.
(S)-2-Cyclopentyl-2-phenyl-2-benzyloxyacetaldehyde (24): To
a cooled
(08C) and stirred solution of 23 (0.499 g, 1.53 mmol) in CH3CN-H2O
(6:4, 15 mL) was added NaIO4 (0.492 g, 2.3 mmol). The mixture was
stirred for 2.0 h at the same temperature and then filtered. The filtrate
was concentrated in vacuo to obtain a residue, which was taken up in di-
ethyl ether (15 mL). The ether layer was washed successively with water,
aqueous 10% NaHSO3, water, aqueous 10% Na2S2O3, water and brine.
After drying, the extract was concentrated in vacuo, and the residue was
purified by column chromatography (silica gel, 0–10% EtOAc/hexane)
to give 24 (0.414 g, 92%): colourless oil; [a]2D2 =+3.8 (c=0.66, CHCl3);
1H NMR (200 MHz, CDCl3, TMS): d=1.36–1.80 (m, 8H), 2.48–2.74 (m,
1H), 4.47 (d, J=12.0 Hz, 1H), 4.57 (d, J=12.0, 1H), 7.26–7.54 (m, 10H),
9.98 ppm (s, 1H); 13C NMR (50 MHz, CDCl3): d=25.1, 25.2, 26.6, 27.3,
47.2, 67.1, 87.7, 126.9, 127.5, 127.6, 127.8, 128.3, 128.4, 136.8, 138.6.
202.6 ppm; IR (film): n˜ =2854, 1723 cmÀ1; elemental analysis calcd (%)
for C20H22O2 (294.16): C 81.60, H 7.53; found: C 81.41, H 7.32.
[4] a) M. Sassian, D. Panov, A. Tuulmets, Appl. Organomet. Chem.
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3258–3263; b) H. G. Richey, Jr., J. P. DeStephano, J. Org. Chem.
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(S)-2-Cyclopentyl-2-phenyl-2-hydroxyacetaldehyde (25): To a stirred so-
lution of 24 (0.40 g, 1.36 mmol) in CH2Cl2 (10 mL) containing water
(0.5 mL) was added DDQ (0.461 g, 2.04 mmol). The mixture was stirred
for 5 h at 258C, and aqueous saturated NaHCO3 was added to the mix-
ture, which was extracted with CH2Cl2. The organic extract was washed
with water and brine, dried and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, 0–15% EtOAc/hexane)
to afford 25 (0.222 g 80%): colourless oil; [a]2D3 =+4.1 (c=0.83, CHCl3);
1H NMR (200 MHz, CDCl3, TMS): d=1.30–1.75 (m, 8H), 2.40–2.69 (m,
1H), 7.26–7.41 (m, 5H), 9.92 ppm (s, 1H); 13C NMR (50 MHz, CDCl3):
d=25.1, 25.3, 26.5, 27.4, 47.1, 67.0, 126.6, 128.2, 136.1, 138.9, 202.3 ppm;
IR (film): n˜ =3475, 2854, 1723 cmÀ1; elemental analysis calcd (%) for
C13H16O2 (204.12): C 76.44, H 7.90; found: C 76.21, H 8.01.
(S)-2-Cyclopentyl-2-phenylglycolic acid (5b): To a solution of 25 (0.09 g,
0.44 mmol) in CH3CN (5 mL) and sodium phosphate (pH 6.5) buffer
(2 mL) were added 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO)
(0.018 g, 0.12 mmol) and NaClO2 (0.56 g, 0.62 mmol), and the mixture
was stirred at 558C for 2 days. The mixture was brought to room temper-
ature, diluted with H2O (10 mL) and extracted with EtOAc. The organic
extract was washed with water and brine, dried and concentrated in
vacuo. The residue was subjected to preparative TLC (silica gel, 15%
EtOAc/hexane) to furnish pure (S)-5b (0.075 g, 77%): colourless solid;
m.p. 1148C, (lit.[6d] 115–1168C); [a]D22 =+2.2 (c=0.27, MeOH), [lit.[6d]
+2.0 (MeOH)]; 1H NMR (200 MHz, CDCl3, TMS): d=1.36–1.83 (m,
8H), 1.83–2.01 (m, 2H), 7.31–7.67 ppm (m, 5H); 13C NMR (50 MHz,
CDCl3): d=25.4, 25.7, 26.9, 27.3, 46.4, 66.8, 126.9, 128.2, 136.1, 138.9,
180.4 ppm; IR (film): n˜ =3546, 1708 cmÀ1
.
Acknowledgements
We acknowledge the contribution of one of the reviewers who, on succes-
sive occasions, requested amplification and extension of the discussion
and arguments, thereby making possible this unusually detailed treatment
of the factors influencing the behaviour of the cyclic ketones.
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Received: August 4, 2008
Published online: January 7, 2009
1722
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1713 – 1722