Progressive studies on the novel samarium-catalyzed diastereoselective tandem semipinacol rearrangement/Tishchenko reduction of secondary α-hydroxy epoxides

Article abstract of DOI:10.1002/chem.200304782

A novel and highly diastereoselective samarium-catalyzed tandem rearrangement/reduction of secondary a-hydroxy epoxides, which involves a C1 to C3 carbon migration rearrangement and a very interesting hetero-Tishchenko reduction of the intermediate aldehy

Full text of DOI:10.1002/chem.200304782

FULL PAPER
Progressive Studies on the Novel Samarium-Catalyzed Diastereoselective
Tandem Semipinacol Rearrangement/Tishchenko Reduction of Secondary a-
Hydroxy Epoxides
Chun-An Fan, Xiang-Dong Hu, Yong-Qiang Tu,* Bao-Min Wang, and Zhen-Lei Song[a]
Abstract: A novel and highly diaster-
eoselective samarium-catalyzed tandem
rearrangement/reduction of secondary
a-hydroxy epoxides, which involves a C1
to C3 carbon migration rearrangement
and a very interesting hetero-Tishchen-
ko reduction of the intermediate alde-
hyde and the reductant aldehyde, has
been reported. This reaction could be
developed to provide a facile and ster-
eoselective construction of 2-quarterna-
ry 1,3-diol units with an hydroxymethyl
moiety attached to the diastereogenic
quaternary carbon center. Detailed in-
vestigations have been carried out con-
cerning the screening of the aldehydes as
a reductant, the optimization of reaction
conditions, and the substrate scope of
this tandem reaction. A catalytic cycle
for this reaction, the electronic and
steric effects of the reductant aldehydes,
and the mechanism for the acyl migra-
tion of 1,3-diol monoesters are pro-
posed.
Keywords: alcohols
selectivity rearrangement
samarium ¥ Tishchenko reaction
¥
diastereo-
¥
¥
Introduction
The tandem semipinacol rearrangement/reduction of a-hy-
droxy epoxides is of considerable synthetic importance, as in
one step and with high diastereoselectivity it efficiently
generates 2-quarternary 1,3-diol units,[1] which are used
extensively as key building blocks in organic synthesis[2] or
as important chiral ligands for asymmetric reactions.[3] As part
of our efforts to design and develop this kind of tandem
reaction, we described a samarium-catalyzed tandem reaction
of tertiary a-hydroxy epoxides,[1b] which involves the rear-
rangement of the migrating group R2 from C1 to C2 (rate-
controlling step), as shown in structure I of Figure 1, and
subsequently an immediate Tishchenko reduction of the
potential b-hydroxy ketone with perfect diastereocontrol.
Recently our investigation has resulted in another novel
samarium-catalyzed diastereoselective tandem rearrange-
ment/reduction of secondary a-hydroxy epoxides 1. To the
best of our knowledge, this new kind of catalytic tandem
reaction has not been reported. It involves another semi
Figure 1. Comparison of two types of semipinacol rearrangement of a-
hydroxy epoxides.
pinacol-type rearrangement with C1 to C3 carbon migration
and concomitant formation of an intermediate aldehyde at
the original C2 position, as seen in structure II of Figure 1, and
a subsequent slower hetero-Tishchenko reduction of the
intermediate aldehyde and the reductant aldehyde (rate-
determining step) to afford another kind of 2-quarternary 1,3-
diol unit. The synthetic value of this sequence lies in the
stereoselective derivation of two adjacent stereocenters, one
being a quaternary center bearing a hydroxymethyl moiety,
e,g,i]
which are widely present in many chiral reagents[3a
and
biologically active molecules.[2, 4] Additionally, of particular
importance is the stereoselective construction of the quater-
nary carbon, which has long been an important class of
structural unit.[5]
[a] Prof. Y.-Q. Tu, Dr. C.-A. Fan, X.-D. Hu, B.-M. Wang, Z.-L. Song
Department of Chemistry and
The one-step rearrangement in our samarium-mediated
Lewis acid catalyzed tandem reaction of a-hydroxy-unpro-
tected substrates was not readily accessible for some cases
using the conventional Lewis acid, even though it is equiv-
alent to that reported by Yamamoto et al.[6] However, their
reported one-step transformation required up to two equiv-
alents of the highly sterically hindered, aluminum-based
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (China)
Fax : (‡86)931-8912582
E-mail: tuyq@lzu.edu.cn
Supporting information for this article is available on the WWW under
http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2003, 9, 4301 4310
DOI: 10.1002/chem.200304782
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Y.-Q. Tu et al.
FULL PAPER
Lewis acid MABR [methylaluminum bis(4-bromo-2,6-tert-
butylphenoxide)] and was only applicable to hydroxy-pro-
tected substrates. Consequently, it is of significant interest that
substoichiometric amounts of the easily accessible SmI2
promoted the semipinacol rearrangement/Tishchenko reac-
tion of a-hydroxy-unprotected substrates.
monoesters 2 and/or the corresponding acyl migration prod-
uct 2'.[1b, 9l, 16b,d,f,k,p] Products 2 and 2' were identified to have the
same 2-quaternary 1,3-diol core structure by NMR spectro-
scopy analysis of the products of their methanolysis with
NaOH/MeOH.[14a] To further investigate the relative stereo-
chemistry at C1 and C3 of the products 2 and 2', we prepared
the acetonide[14b] of the 2-quaternary 1,3-diol obtained by
methanolysis of 2 and/or 2'. The two-dimensional NOESY
spectrum revealed an obvious spatial correlation between the
group R1 and H, as shown in cis-A in Figure 2. If the group
CH2OR3 were trans to OR2 in 2 and/or 2', no spatial
correlation would occur in the acetonide trans-B (Figure 2);
therefore, the group CH2OR3 is cis to OR2 on the five-
membered ring in 2 and/or 2'.
Since the introduction of the first useful method for the
generation of samarium(ii) diiodide (SmI2) by Kagan and co-
workers in 1980,[7] SmI2 has received considerable attention
and has been widely used in modern organic synthesis,
especially as a single-electron reducing reagent in stoichio-
metric amounts or in excess.[7, 8] However, only a few reactions
with substoichiometric amounts of SmI2 have been investiga-
ted.[1b, 9] Moreover, to the best of our knowledge, very few
were effective in employing SmI2 to react with epoxides,
whether in a stoichiometric or catalytic fashion. For example,
SmI2 has been applied to promote the deoxygenation,[7, 10] ring
opening,[11] and the reductive coupling of epoxides,[8x] and to
catalyze the rearrangement[9b] and the rearrangement/reduc-
tion of epoxides.[1b] Additionally, SmI2 has also been used in
Tishchenko reactions,[1b, 9c,e,k o] generally in which the hydride
is smoothly transferred from the aldehyde to the inter- or
intramolecular ketone group. But, to the best of our knowl-
edge, there were few examples of homo- or hetero-Tishchen-
ko reactions of two aldehydes catalyzed by SmI2,[9l, 12] in which
the hydride is transferred from one aldehyde to the other. As
a result, it is particularly important that we present our studies
towards the tandem rearrangement/Tishchenko reaction of a-
hydroxy epoxides promoted by substoichiometric amounts of
SmI2, in which the interesting hetero-Tishchenko reaction of
the reductant aldehyde and the intermediate aldehyde
derived from the semipinacol rearrangement takes place.
Herein, we disclose our detailed research results on this
novel samarium-catalyzed tandem reaction.
Figure 2. The determination of C1 and C3 relative stereochemistry in the
product 2 and/or 2'.
In connection with our previous work,[1b] we first screened
the active aldehydes as an effective reductant for this catalytic
tandem reaction. Initially, we selected the secondary a-
hydroxy epoxide 1a (R1 ˆ Ph) as a model substrate, and
benzaldehyde (R ˆ Ph) as a reductive agent. Following the
above-mentioned general procedure, the 2-quaternary 1,3-
diol monoesters 2aa/2'aa were obtained, but only in a
moderate yield of 47%. It occurred to us that this fact could
be caused by the weakhydride-transfer ability of the
reductant PhCHO in this reaction.[1b, 16g] Based on this
consideration, a series of aldehydes with different electronic
and/or steric effects were employed to investigate the tandem
reaction of 1a under parallel experimental conditions, and the
results are tabulated in Table 1.
Results and Discussion
From Table 1 we can see that the yields were dependent, to
some extent, upon the electronic and/or steric effects of the
reductant aldehydes. For example, among the substituted
benzaldehydes used, the aldehydes bearing the meta- or para-
electron-withdrawing groups (entries 3, 4, 6, and 7) gave
better results; the pCl-C6H4CHO was the best. In contrast,
unfavorable electronic effects of the electron-donating groups
in the meta- or para-substituted benzaldehydes (entries 9, 10,
and 12) led to much lower yields than PhCHO. These facts
indicated that reductants based on electron-rich substituted
benzaldehydes could severely retard this reaction. Use of
ortho-substituted benzaldehydes, no matter whether it has an
electron-withdrawing group (entry 2) or electron-donating
group (entry 8), resulted in much lower yields. This fact may
be ascribed to the steric effect of the ortho substituents. To
support this assertion, oF-C6H4CHO, which contains the less
bulky ortho-fluoro substituent,[15] was subjected to this model
reaction and indeed produce the 1,3-diol monoesters 2ad/2'ad
in higher yield (40%) compared with entries 2 and 8.
Accordingly, the steric effect of bulky ortho substituents on
substituted benzaldehydes may be the principal factor that
The secondary a-hydroxy epoxides 1 examined were prepared
in racemic form from the corresponding allylic alcohols
through epoxidation with m-chloroperbenzoic acid
(mCPBA).[13] As described in Scheme 1, a solution of 1
Scheme 1. Samarium-catalyzed tandem reaction of secondary a-hydroxy
epoxides.
(1.0 equiv), SmI2 (0.3 equiv), and the reductant aldehyde
RCHO (6.0 equiv) in Cl(CH2)2Cl was stirred at between room
temperature and approximately 708C (as applicable) under
an argon atmosphere, and a tandem semipinacol rearrange-
ment/Tishchenko reduction proceeded smoothly with high
diastereoselectivity to generate the 2-quaternary 1,3-diol
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Diastereoselective Tandem Reactions
4301 4310
Table 1. Samarium-catalyzed rearrangement/reduction of the secondary a-hydroxy epoxide 1a with various
reductant aldehydes RCHO.[a]
ductant aldehyde, which has
seldom been mentioned in the
previously reported Tishchenko
reaction promoted by SmI2,[1b, 9-
is a rate-determining step
in this tandem sequence.
Entry
R
T [8C]
t [h]
Product
2:2'[b]
Yield[%][c]
1
2
3
4
5
6
7
8
Ph
65
65
65
65
60
60
60
60
60
60
60
60
60
60
60
60
3
4
2
1.5
7
1.5
0.25
2[d]
4
5[e]
3.5
2[d]
4.5
3
2aa/2'aa
2ab/2'ab
2ac/2'ac
2a/2'a
2ad/2'ad
2ae/2'ae
2af/2'af
2ag/2'ag
2ah/2'ah
2ai/2'ai
2aj/2'aj
72:28
80:20
60:40
90:10
63:27
> 98:2
82:18
> 99: < 1
> 99: < 1
> 99: < 1
80:20
47
11
60
63
40
62
55
2
c,e,k o]
o-C6H4Cl
m-C6H4Cl
p-C6H4Cl
o-C6H4F
p-C6H4CF3
p-C6H4NO2
o-C6H4Me
m-C6H4Me
p-C6H4Me
m-C6H4OMe
p-C6H4OMe
2-Furyl
Our further investigations
were aimed at the optimization
of other reaction conditions, the
scope of the substrates, and the
ratios of the two monoester
products 2 and 2'; the corre-
sponding experimental results
are listed in Table 2.
Generally we employed
0.3 equivalents of SmI2 in the
typical procedure, as using less
SmI2 (e.g., 0.2 equiv; Table 2,
entry 5) prolonged the reaction
time and lowered the reaction
yield. Of all the solvents exam-
ined, toluene and 1,2-dichloro-
ethane (Cl(CH2)2Cl) proved to
be compatible with this reac-
9
17
7
52
10
11
12
13
14
15
16
trace
[f]
Cyclohexyl
iPr
nPr
2ak/2'ak
2al/2'al
2am/2'am
85:15
> 98:2
24:76
50
41
56
3.5
3.5
[a] All reactions proceeded with SmI2 (0.3 equiv), the substrate 1a (R1 ˆ Ph, 1.0 equiv) and the reductant
aldehyde RCHO (6.0 equiv) in Cl(CH2)2Cl following the general procedure (see Experimental Section). [b] The
ratios were determined by 1H NMR spectroscopy. [c] Total yields of isolated product 2 and/or 2'. [d] Prolongation
of the reaction time led to more unidentified by-products, as monitored by TLC. [e] After continuing to run for
19 h at 608C, the result obtained was similar to that for 5 h. [f] No desired product 2 and/or 2' was observed; the
semipinacol rearrangement product (b-hydroxy aldehyde) was obtained in 43% yield.
gives rise to the lower yield for this tandem reaction. To our
surprise, mMeO-C6H4CHO (entry 11) gave a good yield of
52% for reasons that remain unclear. In addition, another
type of aromatic aldehyde, 2-furaldehyde, was found to be
ineffective in this reaction. Furthermore, three aliphatic
aldehydes (entries 14 16) gave results approximately equal
to those obtained using PhCHO; the less bulky nPrCHO even
provided a slightly higher yield. To the best of our knowledge,
these facts mentioned above
tion (e.g., entries 4 and 6), but use of coordinative media, such
as THF (entry 7) and CH3CN (entry 8), had a significant
influence on the reaction and gave lower yields and longer
reaction times. This may arise from weakening the samarium-
mediated Lewis acidic property by coordination with the lone
pair of electrons of the solvents. Moreover, temperatures of
approximately 708C were generally necessary for this tandem
reaction to proceed readily. As compared with the Evans
have not been reported in de-
tail in the previous Tishchenko
Table 2. Samarium-catalyzed tandem reaction of secondary a-hydroxy epoxides with pCl-C6H4CHO.
o, 16]
reactions.[1b, 9c,e,k
Entry Substrate[a]
SmI2 [equiv] Solvent
T [8C] t [h] Product[b]
2:2'[c]
Yield [%][d]
On the basis of the above
evaluation, the cheap pCl-
C6H4CHO was finally chosen
as the reductant for this cata-
lytic tandem reaction. Addi-
tionally, for this model experi-
ment, we found that further
decreasing the amounts of al-
dehydes employed made this
reaction slow, and so we gen-
erally used six equivalents of
aldehyde as a reductant for this
reaction.
Notably, the intermediate al-
dehyde, which arose from the
semipinacol rearrangement of
1a during the above reactions,
was observed on TLC, and was
further characterized by NMR
spectroscopy. Importantly, this
fact shows that the hetero-Tish-
chenko reaction of the inter-
mediate aldehyde and the re-
1
2
3
4
5
6
7
8
9
1a (R1 ˆ Ph)
0.3
0.3
0.3
0.3
0.2
0.3
0.3
0.3
0.3
Cl(CH2)2Cl 65
Cl(CH2)2Cl 65
Cl(CH2)2Cl 85
1.5
3
1
2a/2'a
2a/2'a
2a/2'a
2b/2'b
2b/2'b
2b/2'b
2b/2'b
2b/2'b
2c/2'c
2d/2'd
2e/2'e
90:10
45:55
72:28
80:20
67:33
> 99: < 1
19:81
50:50
60:40
> 98:2
63
63
62
75
55
73
58
65
82
76
1a
1a
1b (R1 ˆ Et)
PhCH3
PhCH3
80
80
1
1b
1b
1b
1b
2.5
1.5
8
4
2.5
2
Cl(CH2)2Cl 70
THF
CH3CN
reflux
70
1c (R1 ˆ Bn)
Cl(CH2)2Cl 70
Cl(CH2)2Cl 70
Cl(CH2)2Cl 70
10
11
1d (R1 ˆ nBu) 0.3
1e (R1 ˆ allyl) 0.3
1
< 1: > 99 82
12
1 f[e]
0.3
Cl(CH2)2Cl RT
2
2 f/2'f[f]
< 1: > 99 89
[a] All substrates were racemic. [b] 1,3-Diol monoesters 2: R2 ˆ pCl-C6H4CO, R3 ˆ H; 2': R2 ˆ H, R3 ˆ pCl-
C6H4CO. [c] The ratios were determined by 1H NMR spectroscopy. [d] Total yields of isolated product 2 and/or 2'.
[e] After purification by column chromatography, one single diastereoisomer (threo:erythro 100:0) was obtained
as identified by H NMR spectroscopy; also see ref. [13a]. [f] R ˆ pCl-C6H4.
1
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Y.-Q. Tu et al.
FULL PAPER
ꢀ À
ꢀ À
condition for the Tishchenko reactions of b-hydroxy keton-
es,[9e] the relatively higher temperatures may be responsible
for the semipinacol rearrangement of a-hydroxy epoxides and
the hetero-Tishchenko reduction of the intermediate a-
quaternary b-hydroxy aldehydes.
(CH3(CH2)4C C ) or 1-phenylacetylenyl (C6H5C C ), com-
plex unidentified products formed. Additionally, for the
substrate 1 (R1 ˆ Ph) with a C2 substituent (such as methyl,
other than the hydrogen), only uncharacterized mixtures were
observed in our experiments, possibly as a result of competi-
À
À
As can be seen in Table 2, this catalytic tandem reaction was
effective for six-membered cyclic substrates 1a 1e, and the
substituent R1 could be Et, nBu, allyl, Bn, or Ph. The
comparison of these substituents showed that an sp3-hybri-
dized alkyl group gave a higher yield than an sp2-hybridized
aryl one. This may be due to the fact that the sp2-hybridized
substituent R1 could stabilize the transition state generated
tion between C2 O bond cleavage and the expected C3 O
bond cleavage. Moreover, the substrate 1 (R1 ˆ Me) with two
sterically hindered C5-methyl groups, which was prepared
from isophorol, was also examined, but the desired 1,3-diol
monoesters 2/2' were afforded in a much lower yield of 17%.
With the seven-membered cyclic substrate cis-2,3-epoxy-3-n-
butyl-cycloheptanol, we only obtained the expected product
2/2' in 21% yield.
À
from C3 O bond cleavage of the type shown in structure II of
Figure 1 (also, see below and 3 in Scheme 2), and the resultant
In addition, the ratios of the
2-quaternary 1,3-diol monoest-
ers 2 and 2' relied primarily on
the temperature, the reaction
time, and the structure of prod-
uct 2. Usually, increasing the
temperature (entry 3 of Ta-
ble 2) and prolonging the reac-
tion time (entry 2) should favor
the formation of the product 2'
through acyl migration. More-
over, the structure of 2 could
also affect the ratios of 2 and 2'.
For example (entry 12), at
room temperature for 2 h, the
product 2 f was nearly com-
pletely converted into the more
stable 2'f. These facts imply
that 2' could be a thermo-
dynamic product and that 2
could be
a
kinetic pro-
duct.[1b, 9l, 16b,d,f,k,p]
Scheme 2. Proposed catalytic cycle for rearrangement/reduction of secondary a-hydroxy epoxides.
In the general proce-
dure, when substoichiometric
delocalization, to some extent, may inhibit the C1 to C3
concerted migration catalyzed by the samarium-mediated
Lewis acid.
amounts of SmI2 in THF were added to the solution of the
secondary a-hydroxy epoxide 1 and the reductant RCHO in
aprotic solvent (PhCH3, Cl(CH2)2Cl, THF, or CH3CN), the
deep blue color of freshly prepared SmI2 in THF disappeared
immediately. This observation suggests that SmI2 is not the
actual catalyst, but only a catalyst precursor.[1b, 9e,g,j] Based on
previous reports,[7, 8d] we know that in the presence of the a-
hydroxy epoxide 1 containing a secondary hydroxy group
(R4R5COH), a direct reduction of the reductant RCHO by
SmI2 could also take place in the first stage of our reported
tandem reaction and produce SmIII-mediated alkoxides
To extend the substrate scope, one tandem reaction of the
acyclic substrate 1 f was conducted. Surprisingly, at room
temperature, a new tandem semipinacol rearrangement/
Tishchenko reaction involving an additional aldol-transfer
process[17] tookplace to furnish the unusual product 2'f in
good yield; this product is in fact a very useful chiral resolving
agent intermediate.[3a,g,h] To the best of our knowledge, this is
the first report of such a tandem transformation in the
presence of substoichiometric amounts of SmI2.[9l, 16k,p, 17] In
comparison with the tandem reaction of cyclic substrates 1a
1e, this acyclic case shows that once the enolate precursor
(i.e., the intermediate b-hydroxy aldehyde) was formed
through semipinacol rearrangement, in the presence of the
reductant pCl-C6H4CHO, a stepwise retro-aldol aldolisation
process tookplace faster than the direct Tishchenko reduc-
tion.
4
5
À
À
(I2Sm OCH2R and I2Sm OCR R ) as the catalytically active
species. In fact, both aromatic and aliphatic aldehydes are
effective in the present reaction (see Table 1). Thus, when
aromatic aldehydes were used as reductants in the reaction,
we could not exclude the possibility that the SmIII-mediated
À À
À
À À
pinacol adduct (I2Sm O CHR CHR O SmI2), which was
generated from the pinacol coupling of the aromatic aldehy-
de,[9e,i, 18] serves as an active catalyst. According to these
considerations, whether the SmIII-mediated alkoxide, the
SmIII-mediated pinacol adduct, or a combination of the two
are the catalytically active species remains to be determined.
Furthermore, the success of the tandem reaction was
dependent on substrate structure. For example, when R1 was
an sp-hybridized substituent, such as 1-heptynyl
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Diastereoselective Tandem Reactions
4301 4310
At present, we thinkthe active samarium catalyst may well be
some samarium(iii) entity (a SmIII-mediated Lewis acid,
represented by [Sm] in Scheme 2).
Scheme 3, were unfavorable because of steric hindrance
À À
between X and [Sm] O C in 6a or the cyclopentane moiety
in 6'a. Thus, entries 2 (X ˆ Cl, electron-withdrawing group
(EWG)) and 8 (X ˆ Me, electron-donating group (EDG)) in
Table 1 afforded much lower yields. This fact also indicates
that the electronic effects of the ortho substituents have minor
influence on this reaction. As expected, when the group X was
a less bulky ortho substituent, such as fluorine (entry 5 of
Table 1),[15] a higher yield of 40% was obtained compared
with 11% for entry 2 and 2% for entry 8. In contrast, as
shown in Scheme 4, it is reasonable that no steric effect was
observed in this tandem reaction with the meta- or para-
substituted benzaldehydes. For the meta- or para-substituted
benzaldehydes bearing an electron-withdrawing group X
(X ˆ mCl, pCl, pCF3, pNO2; see 5b in Scheme 4), the
electrophilic reactivity of the carbonyl group of the reductant
aldehydes, to some extent, can be increased by the electron-
deficient substituted phenyls, which is favorable for the
formation of the hemiacetal 6b (corresponding to 6 of
Scheme 2), and then the expected higher yields (55 63%)
were achieved (entries 3, 4, 6, and 7 in Table 1). However, if
the meta or para substituent X is mMe, pMe, or pOMe (see
5'b of Scheme 4), the opposite electronic effect can be found
in the present reaction, and a decrease of the electrophilic
reactivity of the carbonyl group of the reductant aldehydes
results in lower yields (entry 9, 10, and 12 in Table 1).
On the basis of the experimental results above and the
l,o, 7, 8d, 16, 18]
literature reports,[1b, 9c,e,g,j
a possible catalytic cycle
for this tandem reaction is proposed as depicted in Scheme 2.
The catalyst [Sm] is firstly formed in situ from SmI2 and the
reductant RCHO, and then coordinates with the epoxy
oxygen atom and the hydroxy oxygen atom in 1 to afford
À
the complex 3. Subsequently, cleavage of the activated C3 O
bond of the epoxide occurs concomitantly with a C1 to C3
concerted migration with inversion of the configuration at C3
position, and then the complex 4 is formed. Because the
intermediate aldehyde 4' was observed during the reaction, it
shows that the irreversible semipinacol rearrangement (3 ! 4)
is faster than the subsequent Tishchenko reduction (7 ! 8) in
this tandem reaction. Consequently, the catalyst [Sm] can be
rapidly released from 4, and again it coordinates with two
oxygen atoms of 1 to continuously transform 1 into 4 as
described above. Simultaneously, the catalyst [Sm] in the
complex 4 further coordinates with the reductant RCHO to
readily afford the complex 5, and subsequently a [Sm]-
catalyzed nucleophilic attackof the secondary hydroxy to the
carbonyl of RCHO furnishes the hemiacetal 6, then a fast
proton transfer results in the formation of 7. So, an irreversible
intramolecular 1,5-hydride transfer (rate-controlling step)
occurs in the transition state 7, and gives the [Sm]-coordinated
1,3-diol monoesters 8, which further generates the final 1,3-
diol monoesters 2 by releasing the catalyst [Sm] for the next
cycle. As shown in 7, the hemiacetal hydride transfer may be
promoted by not only the transfer of the negative charge from
the catalyst [Sm] to the hemiacetal carbon, but also the
effective overlap of the antibonding orbital of the hemiacetal
In addition, the formation of the thermodynamic product 2'
through acyl migration[1b, 9l, 16b,d,f,k,p] of the kinetic product 2 can
be understood from Scheme 5. Here the driving force for
converting 2 into 2' may result from the fact that the acyl
group (RCO) tends to attach to the primary hydroxyl group
rather than the crowded secondary hydroxyl group.
[19]
À
C H bond with one lone pair on the hemiacetal oxygen.
From the above-proposed mechanism, we could know that
the formation of the samarium-bound hemiacetal 6 is the
premise for the hydride transfer in transition state 7. As a
consequence, any factor influencing the formation of 6 in the
reversible 5 ! 6 equilibrium could affect the rate-controlling
irreversible transformation of 7 into 8. Accordingly, some
characteristic properties of this catalytic tandem reaction can
be explained. For example, when
Conclusion
In conclusion, we have discovered a novel, highly stereo-
selective, samarium-catalyzed tandem semipinacol rearrange-
ment/Tishchenko reduction of secondary a-hydroxy epoxides.
The two different processes in this tandem reaction, namely, a
semipinacol rearrangement of the secondary a-hydroxy
the substituted benzaldehydes
with a bulky ortho-substituent
group X (X ˆ Me, Cl) as a re-
ductant were subjected to this
reaction, the formations of the
hemiacetal intermediates 6a and
6'a (corresponding to
6 in
Scheme 2), as indicated in
Scheme 3. Steric effect of ortho substituents on substituted benzaldehydes in the tandem reaction.
Scheme 4. Electronic effect of meta and para substituents on substituted benzaldehydes in the tandem reaction.
Chem. Eur. J. 2003, 9, 4301 4310
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4305

Y.-Q. Tu et al.
FULL PAPER
on silica gel eluting with a mixture solvent of light petroleum and ethyl
acetate to yield the secondary a-hydroxy epoxide 1.
cis-2,3-Epoxy-3-phenylcyclohexanol (1a): 1H NMR (200 MHz, (CD3)2CO):
d ˆ 7.40 7.25 (m, 5H), 4.12 4.00 (m, 1H), 3.10 (d, J ˆ 2.2 Hz, 1H), 3.05
(brs, 1H; OH), 2.35 2.21 (m, 1H), 1.96 1.82 (m, 1H), 1.73 1.61 (m, 2H),
1.57 1.40 ppm (m, 2H); 13C NMR (50 MHz, (CD3)2CO): d ˆ 142.2, 128.2,
128.2, 127.1, 125.2, 125.2, 66.5, 65.0, 62.6, 28.0, 27.8, 19.4 ppm.
1
cis-2,3-Epoxy-3-ethylcyclohexanol (1b): H NMR (200 MHz, CDCl3): d ˆ
4.05 3.90 (m, 1H), 3.16 (d, J ˆ 3.0 Hz, 1H), 2.51 (d, J ˆ 9.2 Hz, 1H; OH),
1.81 1.15 (m, 8H), 0.95 ppm (t, J ˆ 7.6 Hz, 3H); 13C NMR (50 MHz,
CDCl3): d ˆ 67.2, 64.9, 61.2, 30.1, 28.5, 26.1, 18.7, 8.6 ppm.
cis-2,3-Epoxy-3-benzylcyclohexanol (1c): 1H NMR (200 MHz, CDCl3):
d ˆ 7.34 7.19 (m, 5H), 4.07 3.95 (m, 1H), 3.20 (d, J ˆ 3.0 Hz, 1H), 2.90,
2.84 (ABq, J ˆ 14.4 Hz, 2H), 2.39 (d, J ˆ 8.4 Hz, 1H; OH), 1.74 1.10 ppm
(m, 6H); 13C NMR (50 MHz, CDCl3): d ˆ 136.5, 129.4, 129.4, 128.3, 128.3,
126.6, 66.6, 64.1, 60.8, 43.5, 29.1, 26.6, 17.8 ppm.
Scheme 5. Proposed mechanism for the formation of regioisomeric
product 2'.
cis-2,3-Epoxy-3-n-butylcyclohexanol (1d): 1H NMR (200 MHz, CDCl3):
d ˆ 4.06 3.89 (m, 1H), 3.14 (d, J ˆ 2.8 Hz, 1H), 2.75 (d, J ˆ 9.0 Hz, 1H;
OH), 1.80 1.19 (m, 12H), 0.90 ppm (t, J ˆ 7.0 Hz, 3H); 13C NMR (50 MHz,
CDCl3): d ˆ 67.0, 64.3, 61.5, 37.1, 28.7, 26.8, 26.5, 22.6, 18.5, 13.9 ppm.
epoxides and a hetero-Tishchenko reduction of the inter-
mediate b-hydroxy aldehydes, could be realized by substoi-
chiometric amounts of the easily accessible SmI2 as a catalyst
precursor. Moreover, the latter process could be significantly
affected by the reductant aldehydes with different steric and
electronic effects. We found pCl-C6H4CHO was the most
effective reductant in this reaction, and by further optimizing
the reaction conditions this sequence has been applied to the
one-step construction of another class of 2-quaternary 1,3-diol
unit comprising an hydroxymethyl moiety bearing the dia-
stereogenic quaternary carbon center. On the basis of our
detailed studies, a mechanism for this catalytic tandem
reaction was proposed. According to the catalytic cycle, we
explained the steric effect of ortho substituents and the
electronic effect of meta or para substituents on the substi-
tuted benzaldehydes, and additionally a rationalization was
also proposed for the formation of the thermodynamic acyl
migration product 2'.
cis-2,3-Epoxy-3-allylcyclohexanol (1e): 1H NMR (200 MHz, CDCl3): d ˆ
5.89 5.68 (m, 1H), 5.18 5.15 (m, 1H), 5.10 5.08 (m, 1H), 4.08 3.93 (m,
1H), 3.20 (d, J ˆ 2.8 Hz, 1H), 2.82 (brs, 1H; OH), 2.38 2.32 (m, 2H),
1.80 1.20 ppm (m, 6H); 13C NMR (50 MHz, CDCl3): d ˆ 132.7, 118.1, 67.0,
63.4, 60.9, 41.7, 28.5, 26.4, 18.5 ppm.
threo-1-Phenyl-2,3-epoxy-3-methylbutanol (1 f): 1H NMR (400 MHz,
CDCl3): d ˆ 7.42 7.33 (m, 5H), 4.59 (d, J ˆ 8.2 Hz, 1H), 3.06 (brs, 1H;
OH), 3.01 (d, J ˆ 8.2 Hz, 1H), 1.46 (s, 3H), 1.32 ppm (s, 3H).
General procedure for SmIII-catalyzed tandem semipinacol rearrangement/
Tishchenko reduction of the secondary a-hydroxy epoxides: Unless
otherwise noted, a solution of SmI2 (0.1m in THF, 1.2 mL, 0.3 equiv) was
added dropwise to a stirred solution of the substrate 1 (0.4 mmol, 1.0 equiv)
and the reductant aldehyde (2.4 mmol, 6.0 equiv) in dried Cl(CH2)2Cl
(4.0 mL) at room temperature under an argon atmosphere. The resulting
reaction mixture was stirred at between room temperature and approx-
imately 808C (as necessary). When TLC analysis indicated that the
substrate 1 had disappeared completely, the reaction mixture was treated
with a saturated aqueous NaHCO3 solution (3 mL) followed by CH2Cl2
(10 mL). The organic layer was separated, and the aqueous phase was
carefully extracted with CH2Cl2 (3 Â 10 mL), and the combined extracts
were dried over MgSO4. After removal of the solvent in vacuo, the residue
was purified by column chromatography on silica gel (eluting with 5 !
10% EtOAc in light petroleum) to afford 2 and/or 2'.
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 4'-chlorobenzoate (2a) and
cis-(1-phenyl-2-hydroxycyclopent-1-yl)methyl 4'-chlorobenzoate (2'a): By
following the typical procedure described above for entry 1 in Table 2 and
entry 4 in Table 1, a solution of the substrate 1a (76.0 mg, 0.4 mmol,
1.0 equiv) and pCl-C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL)
was treated with SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 1.5 h at 658C to give the
products 2a/2'a (90:10, 83.3 mg) in a total yield of 63%. For entries 2 and 3
in Table 2, the experimental operation was analogous to that described
above, and the reactions were stirred for 3 h at 658C and for 1 h at 858C,
respectively, to afford the products 2a/2'a in 63% and 62% yield and with
Experimental Section
General: All anhydrous solvents (Cl(CH2)2Cl, PhCH3, CH3CN, and THF)
were dried by standard techniques and freshly distilled before use. All
aldehyde reductants were purchased from Fluka, and also freshly distilled,
except for the pNO2-C6H4CHO, under an argon atmosphere under
ordinary or reduced pressure prior to use. Samarium(ii) diiodide (SmI2)
was prepared from samarium (Fluka) and iodine in dried THF under Ar as
described in the literature.[20] All reactions were monitored by thin-layer
chromatography (TLC) on gel F254 plates. The silica gel (200 300 mesh) for
column chromatography was from the Qingdao Marine Chemical Factory
in China, and the distillation range of light petroleum is 60 908C. 1H NMR
and 13C NMR spectra were recorded in CDCl3 solution (unless otherwise
noted) on an Avance DRX-200 or Bruker AM-400 MHz instrument.
Spectral data are reported in ppm relative to tetramethylsilane (TMS) as
internal standard. The GC-MS and MS data were obtained with EI (70 eV),
and the relative intensity (%) is given in brackets. High-resolution mass
spectral analysis (HRMS) data were measured on the Bruker ApexII by
means of the ESI technique.
1
the ratios of 45:55 and 72:28. 2a: H NMR (400 MHz, CDCl3): d ˆ 8.04
8.01, 7.47 7.45 (AA'BB', 4H), 7.46 7.27 (m, 5H), 5.78 (dd, J ˆ 3.7, 6.4 Hz,
1H), 3.97, 3.80 (ABq, J ˆ 11.3 Hz, 2H), 2.32 2.10 (m, 3H), 2.02 1.90 (m,
1H), 1.90 1.80 (m, 1H), 1.80 1.65 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d ˆ 165.4, 142.6, 139.6, 130.9, 130.9, 128.8, 128.8, 128.8, 128.6, 128.6,
126.9, 126.9, 126.9, 82.2, 67.4, 56.1, 32.0, 31.1, 20.6 ppm; MS (70 eV): m/z
‡
‡
(%): 191 (0.4) [M À ClC6H4CO] , 174 (9) [M À ClC6H4CO2H] , 144 (68),
141 (33) [37ClC6H4CO] , 139 (100) [35ClC6H4CO] , 131 (16), 118 (51), 113
(8) [37ClC6H4] , 111 (25) [35ClC6H4] , 91 (18), 77 (10); HRMS (ESI): m/z
‡
‡
‡
‡
‡
calcd for C19H19O3ClNa: 353.0915; found: 353.0911 [M‡Na] .
1
General procedure for the synthesis of the secondary a-hydroxy epoxides
(1): mCPBA (1.1 equiv) was added to a stirred solution of the allylic alcohol
(1.0 equiv) in CH2Cl2 at 08C.[13] After complete consumption of the
substrate (as monitored by TLC), the reaction mixture was diluted with
CH2Cl2, washed with 10% aqueous K2CO3 solution, and brine, and dried
(MgSO4) overnight. Evaporation of the solvent under reduced pressure
gave the crude product 1, which was purified by column chromatography
2'a: H NMR (400 MHz, CDCl3): d ˆ 7.83 7.81, 7.48 7.46 (AA'BB', 4H),
7.40 7.25 (m, 5H), 4.79, 4.47 (ABq, J ˆ 11.4 Hz, 2H), 4.55 (dd, J ˆ 5.1,
6.3 Hz, 1H), 2.21 2.17 (m, 2H), 2.07 1.95 (m, 1H), 1.95 1.85 (m, 1H),
1.84 1.74 (m, 1H), 1.71 1.60 ppm (m, 1H); 13C NMR (100 MHz, CDCl3):
d ˆ 166.2, 143.6, 139.5, 130.9, 130.9, 128.7, 128.7, 128.5, 128.3, 128.3, 126.8,
126.8, 126.6, 78.5, 69.0, 54.3, 32.9, 32.0, 19.6 ppm; MS (70 eV): m/z (%): 191
‡
‡
(0.08) [M À ClC6H4CO] , 174 (21) [M À ClC6H4CO2H] , 144 (6), 141 (12)
4306
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org Chem. Eur. J. 2003, 9, 4301 4310

Diastereoselective Tandem Reactions
4301 4310
‡
‡
[37ClC6H4CO] , 139 (33) [35ClC6H4CO] , 131 (28), 118 (100), 113 (6)
2H), 2.25 2.15 (m, 1H), 1.94 1.78 (m, 2H), 1.78 1.68 (m, 1H), 1.68 1.48
(m, 3H), 1.45 1.19 (m, 5H), 0.92 ppm (t, J ˆ 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d ˆ 166.0, 139.6, 130.9, 130.9, 128.8, 128.8, 128.6, 82.9,
63.9, 50.9, 33.6, 31.5, 30.9, 26.0, 23.5, 21.0, 14.1 ppm; MS (70 eV): m/z (%):
[37ClC6H4] , 111 (20) [35ClC6H4] , 91 (20), 77 (13); HRMS (ESI): m/z calcd
for C19H20O3Cl: 331.1095; found: 331.1095 [M‡H] .
‡
‡
‡
cis-1-Ethyl-1-hydroxymethylcyclopent-2-yl 4'-chlorobenzoate (2b) and cis-
(1-ethyl-2-hydroxycyclopent-1-yl)methyl 4-chlorobenzoate (2'b): By fol-
lowing the typical procedure described above for entry 4 of Table 2, a
solution of the epoxide 1b (56.8 mg, 0.4 mmol, 1.0 equiv) and pCl-
C6H4CHO (2.4 mmol, 6.0 equiv) in PhCH3 (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 1 h at 808C to give the 2-quaternary 1,3-
diol monoesters products 2b/2'b (80:20, 84.7 mg) in a total yield of 75%.
For entry 5 of Table 2, 0.2 equiv SmI2 was used in the catalytic tandem
reaction; the mixture was stirred for 2.5 h at 808C, and the products 2b/2'b
‡
‡
171 (0.5) [M À ClC6H4CO] , 154 (4) [M À ClC6H4CO2H] , 141 (30)
‡
‡
‡
[37ClC6H4CO] , 139 (100) [35ClC6H4CO] , 113 (10) [37ClC6H4] , 111 (34)
[35ClC6H4] , 98 (47), 67 (25), 55 (21), 41 (30); HRMS (ESI): m/z calcd for
C17H24O3Cl: 311.1408; found: 311.1414 [M‡H] .
‡
‡
cis-(1-Allyl-2-hydroxycyclopent-1-yl)methyl 4'-chlorobenzoate (2'e): By
following the typical procedure described above for entry 11 in Table 2, a
solution of the substrate 1e (61.6 mg, 0.4 mmol, 1.0 equiv) and pCl-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv), and stirred for 1 h at 708C to give the
products 2e/2'e (<1: > 99, 96.6 mg, 82%). 1H NMR (200 MHz, CDCl3):
d ˆ 8.00 7.95, 7.45 7.40 (AA'BB', 4H), 6.00 5.79 (m, 1H), 5.12 (d, J ˆ
10.8 Hz, 1H), 5.11 (d, J ˆ 16.4 Hz, 1H), 4.56, 4.22 (ABq, J ˆ 11.6 Hz, 2H),
3.90 (dd, J ˆ 2.4, 5.6 Hz, 1H), 2.71 (brs, 1H; OH), 2.25 1.95 (m, 3H),
1.95 1.50 ppm (m, 5H); 13C NMR (50 MHz, CDCl3): d ˆ 166.2, 139.6,
134.0, 131.0, 131.0, 128.8, 128.8, 128.5, 118.3, 78.0, 66.4, 50.2, 38.7, 33.0, 30.3,
(67:33, 62.1 mg, 55%) were obtained. For entries 6
8 in Table 2,
Cl(CH2)2Cl, THF, and CH3CN were used as solvents in this reaction,
respectively, and the experimental process was analogous to the typical
procedure; for detailed data see entries 6 8 in Table 2. 2b: 1H NMR
(400 MHz, CDCl3): d ˆ 7.95 7.92, 7.42 7.39 (AA'BB', 4H), 5.14 (dd, J ˆ
3.2, 5.9 Hz, 1H), 3.57, 3.53 (ABq, J ˆ 11.6 Hz, 2H), 2.25 2.15 (m, 2H),
1.92 1.76 (m, 2H), 1.76 1.60 (m, 2H), 1.60 1.50 (m, 1H), 1.35 1.25 (m,
1H), 0.92 ppm (t, J ˆ 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 165.9,
139.6, 130.9, 130.9, 128.8, 128.8, 128.8, 82.6, 63.4, 51.0, 31.5, 30.5, 26.1, 21.0,
‡
20.2 ppm; MS (70 eV): m/z (%): 276 (0.04) [M À H2O] , 253 (0.04) [M À
‡
37
‡
35
‡
ˆ
CH2CH CH2] , 141 (23) [ ClC6H4CO] , 139 (75) [ ClC6H4CO] , 138 (2)
‡
‡
‡
‡
8.2 ppm; GC-MS (70 eV): m/z (%): 143 (1) [M À ClC6H4CO] , 141 (35)
[M À ClC6H4CO2H] , 113 (12) [37ClC6H4] , 111 (36) [35ClC6H4] , 94 (48),
‡
‡
‡
[37ClC6H4CO] , 139 (100) [35ClC6H4CO] , 126 (5) [M À ClC6H4CO2H] ,
79 (100), 55 (27), 41 (47); HRMS (ESI): m/z calcd for C16H20O3Cl:
113 (8) [37ClC6H4] , 111 (26) [35ClC6H4] , 98 (19), 82 (36), 67 (26), 55 (14),
295.1095; found: 295.1094 [M‡H] .
‡
‡
‡
41 (14); HRMS (ESI): m/z calcd for C15H20O3Cl: 283.1095; found: 283.1096
1-(4'-Chlorophenyl)-1-hydroxy-2,2-dimethylprop-3-yl 4'-chlorobenzoate
(2'f): By following the typical procedure described above for entry 12 of
Table 2, a solution of the substrate 1 f (71.2 mg, 0.4 mmol, 1.0 equiv) and
pCl-C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated
with SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 2 h at room temperature to give the
products 2 f/2'f (<1: > 99, 113.3 mg, 89%). 1H NMR (400 MHz, CDCl3):
d ˆ 7.95 7.92, 7.45 7.42 (AA'BB', 4H), 7.33 7.25 (AA'BB', 4H), 4.62 (d,
J ˆ 2.2 Hz, 1H), 4.43, 4.01 (ABq, J ˆ 10.9 Hz, 2H), 2.56 (d, J ˆ 2.2 Hz, 1H;
OH), 1.00 (s, 3H), 0.95 ppm (s, 3H); 13C NMR (50 MHz, CDCl3): d ˆ 165.8,
139.6, 139.4, 133.3, 130.9, 130.9, 128.9, 128.9, 128.8, 128.8, 128.4, 127.9, 127.9,
77.2, 71.0, 39.5, 21.5, 19.4 ppm; GC-MS (70 eV): m/z (%): 213 (0.2)
‡
[M‡H] .
2'b: 1H NMR (400 MHz, CDCl3): d ˆ 7.98 7.95, 7.42 7.39 (AA'BB', 4H),
4.58, 4.23 (ABq, J ˆ 11.6 Hz, 2H), 3.85 3.82 (m, 1H), 2.69 (d, J ˆ 3.8 Hz,
1H; OH), 2.21 1.26 (m, 8H), 0.95 ppm (t, J ˆ 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d ˆ 166.3, 139.6, 130.9, 130.9, 128.6, 128.6, 128.5, 78.4,
65.9, 50.3, 33.2, 30.0, 26.5, 20.4, 8.4 ppm; GC-MS (70 eV): m/z (%): 143 (0.5)
[M À ClC6H4CO] , 141 (25) [37ClC6H4CO] , 139 (79) [35ClC6H4CO] , 126
‡
‡
‡
(3) [M À ClC6H4CO2H] , 113 (14) [37ClC6H4] , 111 (41) [35ClC6H4] , 108
‡
‡
‡
(62), 98 (49), 82 (100), 67 (60), 55 (40), 41 (40); HRMS (ESI): m/z calcd for
‡
C15H20O3Cl: 283.1095; found: 283.1096 [M‡H] .
‡
‡
[M(37Cl) À ClC6H4CHOH] , 211 (0.6) [M(35Cl) À ClC6H4CHOH] , 198
cis-1-Benzyl-1-hydroxymethylcyclopent-2-yl 4'-chlorobenzoate (2c) and
cis-(1-benzyl-2-hydroxycyclopent-1-yl)methyl 4'-chlorobenzoate (2'c): By
following the typical procedure described above for entry 9 in Table 2, a
solution of the substrate 1c (81.6 mg, 0.4 mmol, 1.0 equiv) and pCl-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 2.5 h at 708C to give 2c/2'c (113.0 mg,
82%) in the ratio of 60:40. 2c: 1H NMR (400 MHz, CDCl3): d ˆ 7.94 7.90,
7.44 7.40 (AA'BB', 4H), 7.34 7.20 (m, 5H), 5.27 (dd, J ˆ 2.6, 6.1 Hz, 1H),
3.50, 3.45 (ABq, J ˆ 11.8 Hz, 2H), 3.05, 2.53 (ABq, J ˆ 13.2 Hz, 2H), 2.42
2.30 (m, 1H), 1.97 1.80 (m, 3H), 1.60 1.53 (m, 1H), 1.47 1.39 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d ˆ 166.0, 139.7, 137.6, 131.0, 131.0,
130.6, 130.6, 128.8, 128.8, 128.6, 128.1, 128.1, 126.3, 82.3, 63.0, 52.4, 38.6,
(0.3) [M(37Cl) À ClC6H4CO2H] , 196 (0.9) [M(35Cl) À ClC6H4CO2H] ,
‡
‡
‡
157
(32),
143
(26)
[37ClC6H4CHOH] ,
141
(100)
[35ClC6H4CHOH‡37ClC6H4CO] , 139 (50) [35ClC6H4CO] , 113 (12)
‡
‡
37
‡
35
‡
ˆ
[ ClC6H4] , 111 (19) [ ClC6H4] , 77 (36), 56 (68) [CH2 C(CH3)2]; HRMS
‡
(ESI): m/z calcd for C18H22Cl2O3N: 370.0971; found: 370.0977 [M‡NH4] .
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl benzoate (2aa) and cis-(1-
phenyl-2-hydroxycyclopent-1-yl)methyl benzoate (2'aa): By following the
typical procedure described above for entry 1 in Table 1, a solution of the
substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and PhCHO (2.4 mmol,
6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with SmI2 (0.1m, 1.2 mL,
0.3 equiv) for 3 h at 658C to give the products 2aa/2'aa (72:28, 55.6 mg,
47%). 2aa: 1H NMR (200 MHz, CDCl3): d ˆ 8.03 8.00, (m, 2H), 7.57 7.17
(m, 8H), 5.72 (dd, J ˆ 3.6, 6.4 Hz, 1H), 3.91, 3.76 (ABq, J ˆ 11.2 Hz, 2H),
2.70 (brs, 1H; OH), 2.21 1.60 ppm (m, 6H); 13C NMR (50 MHz, CDCl3):
d ˆ 166.2, 142.8, 133.1, 130.3, 129.6, 129.6, 128.6, 128.6, 128.5, 128.5, 126.9,
126.9, 126.8, 82.0, 67.5, 56.1, 32.0, 31.1, 20.6 ppm; GC-MS (70 eV): m/z (%):
‡
31.1, 29.9, 20.6 ppm; MS (70 eV): m/z (%): 326 (0.01) [M À H2O] , 253 (0.1)
‡
‡
‡
[M À Bn] , 205 (0.1) [M À ClC6H4CO] , 188 (18) [M À ClC6H4CO2H] , 157
(60), 141 (37) [37ClC6H4CO] , 139 (100) [35ClC6H4CO] , 113 (12)
‡
‡
[37ClC6H4] , 111 (35) [35ClC6H4] , 91 (72), 57 (20), 41 (19); HRMS (ESI):
‡
‡
‡
m/z calcd for C20H22O3Cl: 345.1252; found: 345.1261 [M‡H] .
‡
‡
191 (0.6) [M À PhCO] , 174 (27) [M À PhCO2H] , 144 (12), 131 (31), 118
2'c: 1H NMR (400 MHz, CDCl3): d ˆ 8.03 8.00, 7.48 7.46 (AA'BB', 4H),
7.34 7.22 (m, 5H), 4.53, 4.12 (ABq, J ˆ 11.6 Hz, 2H), 4.01 (dd, J ˆ 3.4,
6.1 Hz, 1H), 2.78, 2.60 (ABq, J ˆ 13.5 Hz, 2H), 2.25 2.15 (m, 1H), 1.97
1.85 (m, 1H), 1.85 1.71 (m, 2H), 1.62 1.50 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d ˆ 166.3, 139.7, 137.7, 131.0, 131.0, 130.2, 130.2, 128.9,
128.9, 128.5, 128.4, 128.4, 126.5, 78.0, 65.8, 51.3, 39.5, 32.6, 29.9, 20.1 ppm;
‡
(100), 105 (88) [PhCO] , 91 (21), 77 (50), 51 (12); HRMS (ESI): m/z calcd
‡
for C19H20O3Na: 319.1305; found: 319.1296 [M‡Na] .
2'aa: 1H NMR (200 MHz, CDCl3): d ˆ 7.85 7.81 (m, 2H), 7.57 7.17 (m,
8H), 4.69, 4.39 (ABq, J ˆ 11.4 Hz, 2H), 4.46 (t, J ˆ 6.0 Hz, 1H), 2.70 (brs,
1H; OH), 2.21 1.60 ppm (m, 6H); 13C NMR (50 MHz, CDCl3): d ˆ 167.0,
143.7, 133.0, 130.0, 129.6, 129.6, 128.3, 128.3, 128.2, 128.2, 126.9, 126.9, 126.5,
78.5, 68.8, 54.2, 32.8, 32.0, 19.8 ppm; GC-MS (70 eV): m/z (%): 174 (16)
‡
‡
MS (70 eV): m/z (%): 326 (0.1) [M À H2O] , 253 (0.06) [M À Bn] , 188 (10)
[M À ClC6H4CO2H] , 170 (23), 141 (22) [37ClC6H4CO] , 139 (65)
‡
‡
‡
‡
‡
‡
‡
[35ClC6H4CO] , 113 (12) [37ClC6H4] , 111 (33) [35ClC6H4] , 91 (100), 57
[M À PhCO2H] , 144 (23), 131 (22), 118 (71), 105 (100) [PhCO] , 91 (17),
(16), 41 (26); HRMS (ESI): m/z calcd for C20H22O3Cl: 345.1252; found:
345.1256 [M‡H] .
77 (53), 51 (15); HRMS (ESI): m/z calcd for C19H20O3Na: 319.1305; found:
319.1296 [M‡Na] .
‡
‡
cis-1-n-Butyl-1-hydroxymethylcyclopent-2-yl 4'-chlorobenzoate (2d): By
following the typical procedure described above for entry 10 of Table 2, a
solution of the substrate 1d (68.0 mg, 0.4 mmol, 1.0 equiv) and pCl-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 2 h at 708C to give 2d/2'd (94.4 mg, 76%)
in >98:2 ratio. 1H NMR (400 MHz, CDCl3): d ˆ 7.96 7.93, 7.44 7.41
(AA'BB', 4H), 5.14 (dd, J ˆ 3.1, 5.9 Hz, 1H), 3.56, 3.53 (ABq, J ˆ 12.0 Hz,
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 2'-chlorobenzoate (2ab) and
cis-(1-phenyl-2-hydroxycyclopent-1-yl)methyl 2'-chlorobenzoate (2'ab):
By following the typical procedure described above for entry 2 of Table 1,
a solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and oCl-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 4 h at 658C to give the products 2ab/2'ab
(80:20, 14.5 mg, 11%). 2ab: 1H NMR (200 MHz, CDCl3): d ˆ 7.92 7.89 (m,
Chem. Eur. J. 2003, 9, 4301 4310
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4307

Y.-Q. Tu et al.
FULL PAPER
1H), 7.53 7.29 (m, 8H), 5.85 (dd, J ˆ 3.2, 6.2 Hz, 1H), 4.00, 3.84 (ABq, J ˆ
(21), 77 (8); HRMS (ESI): m/z calcd for C20H19O3F3Na: 387.1179; found:
387.1182 [M‡Na] .
‡
11.2 Hz, 2H), 2.30 1.60 ppm (m, 6H).
2'ab: 1H NMR (200 MHz, CDCl3): d ˆ 7.60 7.28 (m, 9H), 4.80, 4.56 (ABq,
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 4'-nitrobenzoate (2af) and
cis-(1-phenyl-2-hydroxycyclopent-1-yl)methyl 4'-nitrobenzoate (2'af): By
following the typical procedure described above for entry 7 of Table 1, a
solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and pNO2-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 0.25 h at 608C to give the products 2af/
2'af (82:18, 75.0 mg, 55%). 2af: 1H NMR (400 MHz, CDCl3): d ˆ 8.34
8.32, 8.27 8.25 (AA'BB', 4H), 7.49 7.45 (m, 2H), 7.41 7.39 (m, 2H),
7.31 7.27 (m, 1H), 5.85 (dd, J ˆ 3.4, 6.2 Hz, 1H), 3.99, 3.81 (ABq, J ˆ
11.2 Hz, 2H), 2.31 2.15 (m, 3H), 2.05 1.85 (m, 2H), 1.83 1.65 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d ˆ 164.4, 150.6, 142.3, 135.7, 130.7,
130.7, 128.8, 128.8, 127.1, 126.8, 126.8, 123.7, 123.7, 82.9, 67.5, 56.3, 32.2, 31.1,
J ˆ 11.2 Hz, 2H), 4.58 (t, J ˆ 6.2 Hz, 1H), 2.40 1.60 ppm (m, 6H).
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 3'-chlorobenzoate (2ac) and
cis-(1-phenyl-2-hydroxycyclopent-1-yl)methyl 3'-chlorobenzoate (2'ac):
By following the typical procedure described above for entry 3 in Table 1,
a solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and mCl-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 2 h at 658C to give the products 2ac/2'ac
(60:40, 79.3 mg, 60%). 2ac: 1H NMR (200 MHz, CDCl3): d ˆ 8.03 7.93 (m,
2H), 7.57 7.15 (m, 7H), 5.78 (dd, J ˆ 3.2, 6.2 Hz, 1H), 3.95, 3.80 (ABq, J ˆ
11.2 Hz, 2H), 2.65 (brs, 1H; OH), 2.31 1.50 ppm (m, 6H); 13C NMR
(50 MHz, CDCl3): d ˆ 165.0, 142.6, 134.6, 133.1, 132.0, 129.8, 129.6, 129.6,
128.7, 128.7, 127.7, 126.9, 126.9, 82.4, 67.4, 56.2, 32.0, 31.1, 20.6 ppm; GC-MS
‡
20.6 ppm; GC-MS (70 eV): m/z (%): 191 (1.4) [M À NO2C6H4CO] , 174
‡
‡
(10) [M À NO2C6H4CO2H] , 150 (72) [NO2C6H4CO] , 144 (100), 131 (23),
‡
(70 eV): m/z (%): 191 (0.4) [M À ClC6H4CO] , 174 (17) [M À
118 (57), 104 (42), 91 (39), 77 (14); HRMS (ESI): m/z calcd for
‡
‡
ClC6H4CO2H] , 144 (84), 141 (35) [37ClC6H4CO] , 139 (100)
‡
C19H19NO5Na: 364.1155; found: 364.1151 [M‡Na] .
‡
‡
[35ClC6H4CO] , 131 (28), 118 (78), 113 (12) [37ClC6H4] , 111 (35)
2'af: 1H NMR (400 MHz, CDCl3): d ˆ 8.25 8.23, 8.04 8.02 (AA'BB',
4H), 7.49 7.25 (m, 5H), 4.83, 4.54 (ABq, J ˆ 11.2 Hz, 2H), 4.56 (t, J ˆ
5.8 Hz, 1H), 2.31 1.65 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d ˆ
165.0, 150.5, 143.4, 140.4, 130.6, 130.6, 128.4, 128.4, 126.9, 126.7, 126.7, 123.5,
123.5, 78.7, 69.6, 57.1, 33.1, 32.0, 19.8 ppm; GC-MS (70 eV): m/z (%): 174
[35ClC6H4] , 91 (30), 77 (10); HRMS (ESI): m/z calcd for C19H19O3ClNa:
‡
‡
353.0915; found: 353.0911 [M‡Na] .
2'ac: 1H NMR (200 MHz, CDCl3): d ˆ 7.83 7.72 (m, 2H), 7.57 7.15 (m,
7H), 4.74, 4.46 (ABq, J ˆ 11.2 Hz, 2H), 4.52 (t, J ˆ 6.8 Hz, 1H), 2.65 (brs,
1H; OH), 2.31 1.50 ppm (m, 6H); 13C NMR (50 MHz, CDCl3): d ˆ 165.7,
143.5, 134.4, 133.0, 131.8, 129.6, 128.3, 128.3, 127.6, 126.9, 126.8, 126.8, 126.6,
78.6, 69.2, 54.1, 32.9, 31.9, 19.8 ppm; GC-MS (70 eV): m/z (%): 174 (26)
‡
‡
(16) [M À NO2C6H4CO2H] , 150 (14) [NO2C6H4CO] , 144 (5), 131 (31),
118 (100), 104 (20), 91 (21), 77 (8); HRMS (ESI): m/z calcd for
‡
C19H19NO5Na: 364.1155; found: 364.1151 [M‡Na] .
[M À ClC6H4CO2H] , 144 (7), 141 (11) [37ClC6H4CO] , 139 (30)
‡
‡
‡
‡
[35ClC6H4CO] , 131 (32), 118 (100), 113 (6) [37ClC6H4] , 111 (20)
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 2'-methylbenzoate (2ag): By
following the typical procedure described above for entry 8 in Table 1, a
solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and oMe-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 2 h at 608C to give the products 2ag/2'ag
(>99: < 1, 2.5 mg, 2%). 1H NMR (200 MHz, CDCl3): d ˆ 7.96 7.93 (m,
1H), 7.53 7.26 (m, 8H), 5.81 (dd, J ˆ 3.2, 6.2 Hz, 1H), 3.96, 3.79 (ABq, J ˆ
11.0 Hz, 2H), 2.66 (s, 3H), 2.30 1.50 ppm (m, 6H).
[35ClC6H4] , 91 (20), 77 (8); HRMS (ESI): m/z calcd for C19H19O3ClNa:
‡
‡
353.0915; found: 353.0911 [M‡Na] .
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 2'-fluorobenzoate (2ad) and
cis-(1-phenyl-2-hydroxycyclopent-1-yl)methyl 2'-fluorobenzoate (2'ad):
By following the typical procedure described above for entry 5 of Table 1,
a solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and oF-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 7 h at 608C to give the products 2ad/2'ad
(63:37, 50.2 mg, 40%). 2ad: 1H NMR (400 MHz, CDCl3): d ˆ 8.05 8.01
(m, 1H), 7.59 7.51 (m, 1H), 7.50 7.10(m, 7H), 5.81 (dd, J ˆ 4.3, 6.6 Hz,
1H), 3.99, 3.85 (ABq, J ˆ 11.4 Hz, 2H), 2.28 2.12 (m, 2H), 2.08 1.80 (m,
2H), 1.80 1.60 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 164.3,
161.9 (d, 1J(C,F) ˆ 256.4 Hz), 143.2, 134.7 (d, 3J(C,F) ˆ 8.7 Hz), 132.4,
128.6, 128.6, 126.9, 126.9, 126.9, 124.2 (d, 3J(C,F) ˆ 3.6 Hz), 118.6 (d,
2J(C,F) ˆ 10.2 Hz), 117.1 (d, 2J(C,F) ˆ 22.8 Hz), 82.9, 67.8, 55.6, 32.3, 31.4,
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 3'-methylbenzoate (2ah): By
following the typical procedure described above for entry 9 of Table 1, a
solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and mMe-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 4 h at 608C to give the products 2ah/2'ah
(>99: < 1, 21.1 mg, 17%). 1H NMR (200 MHz, CDCl3): d ˆ 7.89 (brs, 2H),
7.49 7.22 (m, 7H), 5.79 (dd, J ˆ 3.4, 6.2 Hz, 1H), 3.98, 3.83 (ABq, J ˆ
11.4 Hz, 2H), 2.44 (s, 3H), 2.36 1.69 ppm (m, 6H); HRMS (ESI): m/z
‡
‡
calcd for C20H22O3Na: 333.1461; found: 333.1456 [M‡Na] .
20.7 ppm; GC-MS (70 eV): m/z (%): 191 (0.1) [M À FC6H4CO] , 174 (10)
‡
‡
[M À FC6H4CO2H] , 144 (54), 131 (13), 123 (100) [FC6H4CO] , 118 (41), 95
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 4'-methylbenzoate (2ai): By
following the typical procedure described above for entry 10 in Table 1, a
solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and pMe-
C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with
SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 5 h at 608C to give the products 2ai/2'ai
(>99: < 1, 8.6 mg, 7%). 1H NMR (200 MHz, CDCl3): d ˆ 7.99 7.95 (m,
2H), 7.49 7.27 (m, 7H), 5.78 (dd, J ˆ 3.4, 6.2 Hz, 1H), 3.97, 3.82 (ABq, J ˆ
11.4 Hz, 2H), 2.44 (s, 3H), 2.36 1.60 ppm (m, 6H).
(17), 91 (13), 77 (5); HRMS (ESI): m/z calcd for C19H19FO3Na: 337.1210;
‡
found: 337.1205 [M‡Na] .
2'ad: 1H NMR (400 MHz, CDCl3): d ˆ 7.83 7.78 (m, 1H), 7.50 7.10 (m,
8H), 4.73, 4.54 (ABq, J ˆ 11.4 Hz, 2H), 4.60 (t, J ˆ 5.9 Hz, 1H), 2.28 2.12
(m, 2H), 2.08 1.80 (m, 2H), 1.80 1.60 ppm (m, 2H); 13C NMR (100 MHz,
1
3
CDCl3): d ˆ 164.5, 161.9 (d, J(C,F) ˆ 256.4 Hz), 143.8, 134.5 (d, J(C,F) ˆ
3
8.9 Hz), 132.2, 128.3, 128.3, 126.9, 126.9, 126.5, 124.0 (d, J(C,F) ˆ 3.6 Hz),
118.5 (d, 2J(C,F) ˆ 10.2 Hz), 117.0 (d, 2J(C,F) ˆ 22.6 Hz), 79.1, 69.6, 53.7,
33.2, 32.4, 20.0 ppm; GC-MS (70 eV): m/z (%): 174 (22) [M À
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 3'-methoxylbenzoate (2aj)
and cis-(1-phenyl-2-hydroxycyclopent-1-yl)methyl 3'-methoxylbenzoate
(2'aj): By following the typical procedure described above for entry 11 of
Table 1, a solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and
mMeO-C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was
treated with SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 3.5 h at 608C to give the
products 2aj/2'aj (80:20, 67.8 mg, 52%). 2aj: 1H NMR (200 MHz, CDCl3):
d ˆ 7.69 7.10 (m, 9H), 5.78 (dd, J ˆ 3.4, 6.2 Hz, 1H), 3.98, 3.89 (ABq, J ˆ
11.4 Hz, 2H), 3.88 (s, 3H), 2.28 1.68 ppm (m, 6H); 13C NMR (50 MHz,
CDCl3): d ˆ 166.1, 159.6, 142.8, 131.6, 129.5, 128.6, 128.6, 126.9, 126.9, 126.9,
121.9, 119.4, 114.3, 82.1, 67.5, 56.1, 55.4, 32.0, 31.1, 20.6 ppm; GC-MS
‡
‡
FC6H4CO2H] , 144 (11), 131 (29), 123 (67) [FC6H4CO] , 118 (100), 95
‡
(21) [FC6H4] , 91 (21), 77 (9); HRMS (ESI): m/z calcd for C19H19FO3Na:
337.1210; found: 337.1205 [M‡Na] .
‡
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl 4'-trifluoromethylbenzoate
(2ae): By following the typical procedure described above for entry 6 in
Table 1, a solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and
pCF3-C6H4CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated
with SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 1.5 h at 608C to give the products
2ae/2'ae (>98:2, 90.2 mg, 62%). 1H NMR (400 MHz, CDCl3): d ˆ 8.22
8.20, 7.77 7.75 (AA'BB', 4H), 7.48 7.27 (m, 5H), 5.83 (dd, J ˆ 3.4, 6.3 Hz,
1H), 4.00, 3.83 (ABq, J ˆ 11.4 Hz, 2H), 2.35 2.15 (m, 3H), 2.05 1.95 (m,
1H), 1.95 1.83 (m, 1H), 1.83 1.70 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d ˆ 165.1, 142.5, 134.7 (q, 2J(C,F) ˆ 32.2 Hz), 133.6, 130.0, 130.0,
‡
(70 eV): m/z (%): 191 (0.6) [M À MeOC6H4CO] , 174 (33) [M À
‡
‡
MeOC6H4CO2H] , 152 (45) [MeOC6H4CO2H] , 144 (27), 135 (100)
‡
‡
[MeOC6H4CO] , 118 (88), 107 (28) [MeOC6H4] , 91 (20), 77 (30); HRMS
‡
(ESI): m/z calcd for C20H22O4Na: 349.1410; found: 349.1417 [M‡Na] .
1
128.8, 128.8, 127.1, 126.9, 126.9, 125.6, 125.6, 123.6 (q, J(C,F) ˆ 271.4 Hz),
2'aj: 1H NMR (200 MHz, CDCl3): d ˆ 7.69 7.10 (m, 9H), 4.77, 4.45 (ABq,
J ˆ 11.2 Hz, 2H), 4.54 (t, J ˆ 6.8 Hz, 1H), 3.80 (s, 3H), 2.28 1.68 ppm (m,
6H); 13C NMR (50 MHz, CDCl3): d ˆ 166.1, 159.5, 142.8, 132.0 126.0
(3C), 129.3, 128.2, 128.2, 126.5, 121.9, 119.7, 113.8, 78.4, 68.8, 55.4, 54.2, 32.8,
82.6, 67.5, 56.2, 32.2, 31.2, 20.6 ppm; GC-MS (70 eV): m/z (%): 191 (0.1)
‡
‡
[M À CF3C6H4CO] , 174 (24) [M À CF3C6H4CO2H] , 173 (40)
‡
‡
[CF3C6H4CO] , 145 (36) [CF3C6H4] , 144 (15), 131 (30), 118 (100), 91
4308
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4301 4310

Diastereoselective Tandem Reactions
4301 4310
32.0, 19.8 ppm; GC-MS (70 eV): m/z (%): 174 (48) [M À
[1] a) Y. Q. Tu, L. D. Sun, P. Z. Wang, J. Org. Chem. 1999, 64, 629; b) C. A.
Fan, B. M. Wang, Y. Q. Tu, Z. L. Song, Angew. Chem. 2001, 113, 3995;
Angew. Chem. Int. Ed. 2001, 40, 3877.
‡
‡
MeOC6H4CO2H] , 152 (56) [MeOC6H4CO2H] , 144 (26), 135 (100)
‡
‡
[MeOC6H4CO] , 118 (92), 107 (26) [MeOC6H4] , 91 (19), 77 (24); HRMS
‡
(ESI): m/z calcd for C20H22O4Na: 349.1410; found: 349.1417 [M‡Na] .
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl
[2] T. Saito, T. Suzuki, M. Morimoto, C. Akiyama, T. Ochiai, K. Takeuchi,
T. Matsumoto, K. Suzuki, J. Am. Chem. Soc. 1998, 120, 11633.
[3] a) W. ten Hoeve, H. Wynberg, J. Org. Chem. 1985, 50, 4508; b) R.
Sjouken, R. Ebens, R. M. Kellogg, Recl. Trav. Chim. 1992, 111, 57;
c) X. Hu, R. M. Kellogg, Synthesis 1995, 533; d) X. Hu, R. M. Kellogg,
Recl. Trav. Chim. 1996, 115, 410; e) X. Hu, R. M. Kellogg, Recl. Trav.
Chim. 1996, 115, 407; f) A. S. C. Chan, W. Hu, C. C. Pai, C. P. Lau, Y.
Jiang, A. Mi, J. Sun, R. Lou, J. Deng, J. Am. Chem. Soc. 1997, 119,
9570; g) T. Vries, H. Wynberg, E. van Echten, J. Koek, W. ten Hoeve,
R. M. Kellogg, Q. B. Broxterman, A. Minnaard, B. Kaptein, S.
van der Sluis, L. Hulshof, J. Kooistra, Angew. Chem. 1998, 110, 2491;
Angew. Chem. Int. Ed. 1998, 37, 2349; h) J. W. Nieuwenhuijzen, R. F. P.
Grimbergen, C. Koopman, R. M. Kellogg, T. R. Vries, K. Pouwer, E.
van Echten, B. Kaptein, L. A. Hulshof, Q. B. Broxterman, Angew.
Chem. 2002, 114, 4457; Angew. Chem. Int. Ed. 2002, 41, 4281; i) H. C.
Aspinall, Chem. Rev. 2002, 102, 1807.
cyclohexanecarboxylate
(2ak) and cis-(1-phenyl-2-hydroxycyclopent-1-yl)methyl cyclohexanecar-
boxylate (2'ak): By following the typical procedure described above for
entry 14 in Table 1, a solution of the substrate 1a (76.0 mg, 0.4 mmol,
1.0 equiv) and C6H11CHO (2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL)
was treated with SmI2 (0.1m, 1.2 mL, 0.3 equiv) for 3 h at 608C to give the
products 2ak/2'ak (85:15, 60.4 mg, 50%). 2ak: 1H NMR (200 MHz,
CDCl3): d ˆ 7.44 7.20 (m, 5H), 5.55 (dd, J ˆ 3.4, 6.0 Hz, 1H), 3.84, 3.70
(ABq, J ˆ 11.2 Hz, 2H), 2.45 1.20 ppm (m, 17H); 13C NMR (50 MHz,
CDCl3): d ˆ 175.7, 142.8, 128.5, 128.5, 126.8, 126.8, 126.7, 81.0, 67.6, 55.7,
43.4, 32.0, 31.0, 29.1, 28.9, 25.7, 25.4, 25.3, 20.5 ppm; GC-MS (70 eV): m/z
‡
‡
(%): 191 (0.4) [M À C6H11CO] , 174 (26) [M À C6H11CO2H] , 144 (36), 131
‡
‡
(36), 118 (100), 111 (9) [C6H11CO] , 91 (25), 83 (89) [C6H11] , 77 (7), 55
(36), 41 (14); HRMS (ESI): m/z calcd for C19H26O3Na: 325.1774; found:
‡
325.1774 [M‡Na] .
[4] The structural units with a quaternary carbon bearing an hydrox-
ymethyl moiety could be applied to the synthesis of some biologically
active molecules. For example, a) J. D. Connolly, R. A. Hill in
Dictionary of Terpenoids, Vol. 1, 1st ed., Chapman and Hall, London,
1991, pp. 299 300; b) G. Bringmann, T. Pabst, P. Henschel, M. Michel,
Tetrahedron 2001, 57, 1269; unpublished results: the total synthesis of
(Æ)-madindoline A and B is ongoing in our group using the core
structure of products from this sequence; for the current synthesis of
Madindoline A and B, see: T. Sunazuka, T. Hirose, T. Shirahata, Y.
2'ak: 1H NMR (200 MHz, CDCl3): d ˆ 7.44 7.24 (m, 5H), 4.52, 4.22 (ABq,
J ˆ 11.2 Hz, 2H), 4.47 (dd, J ˆ 5.2, 6.0 Hz, 1H), 2.45 1.20 ppm (m, 17H);
13C NMR (50 MHz, CDCl3): d ˆ 176.5, 143.6, 128.1, 128.1, 126.4, 126.4,
126.8, 78.4, 68.0, 54.0, 43.1, 32.8, 32.2, 29.5, 28.8, 25.8, 25.7 25.3 (2C),
‡
19.8 ppm; GC-MS (70 eV): m/z (%): 174 (19) [M À C6H11CO2H] , 144 (12),
‡
‡
131 (34), 118 (100), 111 (4) [C6H11CO] , 91 (21), 83 (40) [C6H11] , 77 (7), 55
(27), 41 (12); HRMS (ESI): m/z calcd for C19H26O3Na: 325.1774; found:
‡
325.1774 [M‡Na] .
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl isobutanoate (2al): By fol-
lowing the typical procedure described above for entry 15 of Table 1, a
solution of the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and iPrCHO
(2.4 mmol, 6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with SmI2 (0.1m,
1.2 mL, 0.3 equiv) for 3.5 h at 608C to give the products 2al/2'al (>98:2,
√
Harigaya, M. Hayashi, K. Komiyama, S. Omura, J. Am. Chem. Soc.
2000, 122, 2122; T. Hirose, T. Sunazuka, T. Shirahata, D. Yamamoto, Y.
≈
Harigaya, I. Kuwajima, S. Omura, Org. Lett. 2002, 4, 501.
[5] For recent reviews on stereoselective construction of a quaternary
carbon center, see: a) K. Fuji, Chem. Rev. 1993, 93, 2037; b) D.
Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. 1996, 108, 2880;
Angew. Chem. Int. Engl. Ed. 1996, 35, 2708; c) E. J. Corey, A.
Guzman-Perez, Angew. Chem. 1998, 110, 402; Angew. Chem. Int. Ed.
1998, 37, 388; d) J. Christoffers, A. Mann, Angew. Chem. 2001, 113,
4725; Angew. Chem. Int. Ed. 2001, 40, 4591.
[6] a) K. Maruoka, T. Ooi, H. Yamamoto, J. Am. Chem. Soc. 1989, 111,
6431; b) K. Maruoka, T. Ooi, S. Nagahara, H. Yamamoto, Tetrahedron
1991, 6983;
1
42.9 mg, 41%). H NMR (200 MHz, CDCl3): d ˆ 7.42 7.21 (m, 5H), 5.53
(dd, J ˆ 3.4, 6.2 Hz, 1H), 3.84, 3.70 (ABq, J ˆ 11.4 Hz, 2H), 2.62 (m, 1H),
2.21 1.50 (m, 6H), 1.23 (d, J ˆ 7.0 Hz, 3H), 1.21 ppm (d, J ˆ 7.0 Hz, 3H);
13C NMR (50 MHz, CDCl3): d ˆ 176.7, 142.8, 128.5, 128.5, 126.8, 126.8,
126.7, 81.2, 67.5, 55.8, 34.3, 31.9, 31.0, 20.5, 19.0, 18.9 ppm; GC-MS (70 eV):
‡
‡
m/z (%): 191 (0.4) [M À iPrCO] , 174 (16) [M À iPrCO2H] , 144 (28), 131
‡
(31), 118 (100), 91 (29), 77 (10), 71 (25) [iPrCO] , 43 (68) [iPr]; HRMS
(ESI): m/z calcd for C16H22O3Na: 285.1461; found: 285.1467 [M‡Na] .
‡
cis-1-Hydroxymethyl-1-phenylcyclopent-2-yl butanoate (2am) and cis-(1-
phenyl-2-hydroxycyclopent-1-yl)methyl butanoate (2'am): By following
the typical procedure described above for entry 16 in Table 1, a solution of
the substrate 1a (76.0 mg, 0.4 mmol, 1.0 equiv) and nPrCHO (2.4 mmol,
6.0 equiv) in Cl(CH2)2Cl (4.0 mL) was treated with SmI2 (0.1m, 1.2 mL,
0.3 equiv) for 3.5 h at 608C to give the products 2am/2'am (24:76, 58.6 mg,
56%). 2am: 1H NMR (200 MHz, CDCl3): d ˆ 7.43 7.20 (m, 5H), 5.57 (dd,
J ˆ 3.6, 6.0 Hz, 1H), 3.86, 3.72 (ABq, J ˆ 11.4 Hz, 2H), 3.30 (brs, 1H; OH),
2.38 (t, J ˆ 7.6 Hz, 2H), 2.25 1.49 (m, 8H), 0.99 ppm (t, J ˆ 7.4 Hz, 3H);
13C NMR (50 MHz, CDCl3): d ˆ 173.4, 142.8, 128.5, 128.5, 126.7, 126.7,
126.7, 81.2, 67.6, 55.6, 36.5, 32.0, 31.0, 20.5, 18.5, 13.6 ppm; GC-MS (70 eV):
[7] P. Girard, J. L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980, 102, 2693.
[8] For example: a) H. B. Kagan, M. Sasaki, J. Collin, Pure Appl. Chem.
1988, 60, 1725; b) H. B. Kagan, New J. Chem. 1990, 14, 453; c) G. A.
Molander, Chem. Rev. 1992, 92, 29; d) G. A. Molander in Organic
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e) G. A. Molander, C. R. Harris, Chem. Rev. 1996, 96, 307; f) M.
Kawatsura, E. Kishi, M. Kito, T. Sakai, H. Shirahama, F. Matsuda,
Synlett 1997, 497; g) G. A. Molander, Acc. Chem. Res. 1998, 31, 603;
h) T. Kikukawa, T. Hanamoto, J. Inanaga, Tetrahedron Lett. 1999, 40,
¬
7497; i) J. M. Aurrecoechea, R. Fanƒanas, M. Arrate, J. M. Gorgojo, N.
Aurrekoetxea, J. Org. Chem. 1999, 64, 1893; j) G. E. Keck, C. A.
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A. -M. Laval, Chem. Rev. 1999, 99, 745; l) C. U. Dinesh, H.-U. Reissig,
Angew. Chem. 1999, 111, 874; Angew. Chem. Int. Ed. 1999, 38, 789;
m) K. Ohmori, M. Kitamura, K. Suzuki, Angew. Chem. 1999, 111,
1304; Angew. Chem. Int. Ed. 1999, 38, 1226; n) N. Taniguchi, T. Hata,
M. Uemura, Angew. Chem. 1999, 111, 1311; Angew. Chem. Int. Ed.
‡
‡
m/z (%): 191 (0.3) [M À nPrCO] , 174 (14) [M À nPrCO2H] , 144 (24), 131
‡
‡
(30), 118 (100), 91 (26), 77 (10), 71 (30) [nPrCO] , 43 (29) [nPr] ; HRMS
‡
(ESI): m/z calcd for C16H22O3Na: 285.1461; found: 285.1469 [M‡Na] .
2'am: 1H NMR (200 MHz, CDCl3): d ˆ 7.43 7.20 (m, 5H), 4.53, 4.24 (ABq,
J ˆ 11.2 Hz, 2H), 4.49 (t, J ˆ 5.8 Hz, 1H), 3.30 (brs, 1H; OH), 2.21 (t, J ˆ
7.4 Hz, 2H), 2.14 1.49 (m, 8H), 0.85 ppm (t, J ˆ 7.4 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d ˆ 174.1, 143.6, 128.2, 128.2, 126.8, 126.8, 126.4, 78.5,
68.1, 53.9, 36.2, 32.8, 32.1, 19.8, 18.3, 13.5 ppm; GC-MS (70 eV): m/z (%):
¬
¬
¬
1999, 38, 1232; o) J. M. Concellon, P. L. Bernad, J. A. Perez-Andres,
Angew. Chem. 1999, 111, 2528; Angew. Chem. Int. Ed. 1999, 38, 2384;
p) X. Jiang, C. Wang, Y. Hu, H. Hu, J. Org. Chem. 2000, 65, 3555; q) A.
Caracoti, R. A. Flowers II, Tetrahedron Lett. 2000, 41, 3039; r) L. Yet,
Chem. Rev. 2000, 100, 2963; s) M. Ricci, L. Madariage, T. Skrydstrup,
Angew. Chem. 2000, 112, 248; Angew. Chem. Int. Ed. 2000, 39, 242;
t) T. Kan, S. Nara, T. Ozawa, H. Shirahama, F. Matsuda, Angew.
Chem. 2000, 112, 363; Angew. Chem. Int. Ed. 2000, 39, 355; u) S. M.
Kim, I. S. Byun, Y. H. Kim, Angew. Chem. 2000, 112, 744; Angew.
Chem. Int. Ed. 2000, 39, 728; v) J. M. Concellon, P. L. Bernad, H.
Rodriguez-Solla, Angew. Chem. 2001, 113, 4015; Angew. Chem. Int.
‡
174 (15) [M À nPrCO2H] , 144 (10), 131 (30), 118 (100), 91 (22), 77 (8), 71
‡
‡
(17) [nPrCO] , 43 (19) [nPr] ; HRMS (ESI): m/z calcd for C16H22O3Na:
‡
285.1461; found: 285.1469 [M‡Na] .
Acknowledgement
This workwas financially supported by NSFC (No.29925205, 30271488,
and QT program), FUKTME of China, the Young Teachers× Fund of the
Ministry of Education and the Fund of the Ministry of Education
(No.99209).
¬
Ed. 2001, 40, 3897; w) J. M. Concellon, H. RodrÌguez-Solla, Chem.
Eur. J. 2002, 8, 4493; x) J. L. Chiara, E. Sesmilo, Angew. Chem. 2002,
114, 3376; Angew. Chem. Int. Ed. 2002, 41, 3242; y) G. Masson, S. Py,
Chem. Eur. J. 2003, 9, 4301 4310
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4309

Y.-Q. Tu et al.
FULL PAPER
¬
Y. Vallee, Angew. Chem. 2002, 114, 1850; Angew. Chem. Int. Ed. 2002,
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37.1 pm.
41, 1772.
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Organometallics 1990, 9, 30; e) S.-Y. Onozawa, T. Sakakura, M.
Tanaka, M. Shiro, Tetrahedren 1996, 52, 4291; f) R. Mahrwald, B.
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Miura, K. Takaya, K. Maruoka, Tetrahedron Lett. 1999, 40, 7695;
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[17] For examples of references concerning the aldol-transfer Tishchenko
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[12] In the homo-Tishchenko reaction of aldehydes, some studies indicate
that no reaction could happen using SmI2 as a catalyst, for example:
a) H. Berberich, P. W. Roesky, Angew. Chem. 1998, 110, 1618; Angew.
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Wiley, 1999, pp. 201 245.
Received: January 28, 2003 [F4782]
4310
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4301 4310