[1,3]-Transfer of chirality during the nicholas reaction in γ-benzyloxy propargylic alcohols

Article abstract of DOI:10.1002/chem.200501127

A highly regio- and stereoselective intramolecular [1.5]-hydrogentransfer process is described. Treatment of γ-benzyl-protccted Co ₂(CO)₆-α,γ-acetylenic diols with BF ₃·OEt₂ provides bis-homopropargylic alcohols. The reaction occurs within seconds, tolerates a wide range of functionalities, and provides good yields. When the ether group is located at a stereochemically defined carbon atom, the rearrangement occurs with high stereoselectivity, transferring the chirality of the carbinol center to the newly created stereocenter. The cleavage of the benzyloxy group is totally regioselective when additional benzyl ethers are present. The scope and limitations of this novel process in densely substituted substrates are evaluated, and possible competitive reactions and/or stereochemical influences are also described. A mechanism based on a highly ordered chair-like transition state substantiated by a theoretical study is also included.

Full text of DOI:10.1002/chem.200501127

FULL PAPER
DOI: 10.1002/chem.200501127
[1,3]-Transfer of Chiralityduring the Nicholas Reaction in g-Benzyloxy
Propargylic Alcohols
David D. Díaz, Miguel A. Ramírez, and Víctor S. Martín*[a]
Abstract: A highly regio- and stereose-
lective intramolecular [1,5]-hydrogen-
transfer process is described. Treatment
of g-benzyl-protected Co2(CO)6-a,g-
acetylenic diols with BF3·OEt2 provides
bis-homopropargylic alcohols. The re-
action occurs within seconds, tolerates
a wide range of functionalities, and
provides good yields. When the ether
group is located at a stereochemically
defined carbon atom, the rearrange-
ment occurs with high stereoselectivity,
transferring the chirality of the carbinol
center to the newly created stereocen-
ter. The cleavage of the benzyloxy
group is totally regioselective when ad-
ditional benzyl ethers are present. The
scope and limitations of this novel pro-
cess in densely substituted substrates
are evaluated, and possible competitive
reactions and/or stereochemical influ-
ences are also described. A mechanism
based on a highly ordered chair-like
transition state substantiated by a theo-
retical study is also included.
Keywords: asymmetric synthesis ·
cobalt · natural products · Nicholas
reaction · propargylic alcohols
Introduction
[2,3]-Wittig rearrangement of ethers has also come under
close scrutiny as a carbon–carbon bond-forming reaction of
potential application to the stereodirected synthesis of acy-
clic alcohols.[5] Chirality transfer during [2,3]-sila-Wittig rear-
The synthesis of complex molecules requires powerful meth-
odologies to solve specific structural problems.[1] Key steps
capable of generating defined molecular constitutions and
stereochemistries are critical to accomplish these usually for-
midable tasks.[2] Stereocontrol originating from remote
chiral centers during the construction of polysubstituted acy-
clic systems remains a central theme in the total synthesis of
complex natural products.[1] One possible approach to this
problem is based on chirality transfer[3] mediated by highly
stereocontrolled rearrangement reactions, which requires a
highly ordered transition state. In this context, special atten-
tion has been directed towards [3,3]-sigmatropic rearrange-
ments (Claisen and Cope reactions), which have become
some of the most commonly used and powerful methods for
stereoselective carbon–carbon bond formation, and are sup-
ported by numerous reports concerning intramolecular chir-
ality transfer using chiral substrates.[4] In this regard, the
À
rangements allows the stereoselective formation of Si C
bonds.[6] In the literature, very efficient chirality transfers in
acyclic systems have also been achieved from chiral hetero-
atoms to carbon derivatives,[7] and in chiral metal com-
plexes,[8] palladium(0)-promoted intra- and intermolecular
allylation reactions,[9] and [3,3]-sigmatropic rearrangements
of allylic acetates catalyzed by palladium(ii).[10] In addition,
intramolecular hydrogen transfer is the key step in stereose-
lective processes such as the reduction of b-hydroxy ke-
tones,[11] the aldol-Tishchenko reaction,[12] and some intra-
molecular ionic hydrogenations.[13]
In the present work, we disclose full details of our results
concerning complete chirality transfer in stereoselective in-
tramolecular propargylic reduction in g-benzyl-protected
Co2(CO)6-a,g-acetylenic diols, in which the chirality was in-
troduced by way of an enantioselective Katsuki–Sharpless
epoxidation.[14] The present study also demonstrates that the
chiral integrity of the starting asymmetric center is pre-
served during the hydrogen transfer from the benzylic posi-
tion. In particular, the methodology offers a mild, general
solution to the problem of controlling the stereochemistry in
an alkyl group introduced in a hydrocarbon chain. Beyond
our efforts to delineate the scope and limitations of this pro-
cess, we also report herein on the results of a theoretical
study that provides substantiation of a proposed mechanism.
[a] Dr. D. D. Díaz, Prof. M. A. Ramírez, Prof. V. S. Martín
Instituto Universitario de Bio-Orgµnica “Antonio Gonzµlez”
Universidad de La Laguna
C/Astrofísico Francisco Sµnchez, 2, 38206 La Laguna, Tenerife
(Spain)
Fax : (+34)922-318-571
E-mail: vmartin@ull.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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Results and Discussion
Antecedents: We have previously reported on novel stereo-
selective procedures for obtaining enantiomerically enriched
products based on the Nicholas reaction that involve trap-
ping of the carbocation generated by acid treatment of a
chiral Co2(CO)6-complexed secondary propargylic alcohol
with nucleophiles (Scheme 1). In both the intra- and inter-
molecular methodologies, the stereochemistry at the newly
created stereocenter can be controlled by the existing sub-
stituents on the linear precursors.[15]
Scheme 3. Propargylic reduction in g-benzyloxy propargylic alcohols.
This new process may be formally considered as an alter-
native to standard acetylene coupling, avoiding elimination
reactions and taking advantage of the high reactivity of ace-
tylide anions towards carbonyl compounds.
Synthesis of simple g-benzyloxy propargylic alcohols and
preliminaryresults : To study the generality of this new pro-
cess, we decided to synthesize a series of g-benzyloxy prop-
argylic alcohols, having characterized the stereochemistry at
the ether position. A general methodology starting from
enantiomerically enriched 2,3-epoxy alcohols 3 obtained by
Katsuki–Sharpless epoxidation was developed (Scheme 4).
À
Scheme 1. Influence of existing stereocenters in the formation of C O
bonds using the Nicholas reaction. TBDPS=tert-butyldiphenylsilyl,
CAN=cerium ammonium nitrate.
To study the behavior of this reaction in the presence of
additional functional groups, we turned our attention to the
influence of additional protected hydroxy groups at the
linear propargylic alcohol. However, these studies yielded
some unexpected results. For instance, a,b-acetylenic diol
derivatives afforded the very unstable homopropargylic ke-
tones under the Nicholas reaction conditions (Scheme 2).[16]
Scheme 4. General preparation of simple g-benzyloxy propargylic alco-
hols. CSA=10-camphorsulfonic acid, DIBALH=diisobutylaluminum hy-
dride, PCC=pyridinium chlorochromate.
Scheme 2. Synthesis of homopropargylic ketones from b-benzyloxy prop-
argylic alcohols.
Regioselective opening of 3[19] using Red-Al provided the
corresponding 1,3-diols,[20] which were protected as benzyli-
dene derivatives and further reduced with DIBALH to yield
the mono-protected diols 4.[21] Oxidation to the aldehyde
and treatment with the appropriate lithium acetylide provid-
ed diastereomeric mixtures of propargylic alcohols 5.
When the Co2(CO)6 complex of 5 was submitted to the
usual acidic conditions of the Nicholas reaction (BF3·OEt2,
CH2Cl2, À208C), the reduction at the propargylic position
with concomitant benzyl cleavage occurred almost instantly
yielding, after cleavage of the complex, the stereochemically
defined bis-homopropargylic alcohol 6 (Table 1). If a THP
ether was present (Table 1, entry 4), the isolated product
showed that such a protecting group had been cleaved. The
When we tried to extend our study, locating the benzyloxy
group at the g-position, we found an unprecedented partici-
pation of this group that causes reduction at the propargylic
position. Thus, when the diastereomeric mixture 1 was sub-
mitted to the standard acidic conditions, the unprotected
bis-homopropargylic alcohol 2 was obtained in good yields
(Scheme 3).[17] It should be mentioned that the presence of
the benzyl group[18] is essential for achieving the reported
transformation since when the terminal hydroxy group was
either unprotected or protected as a silyl ether (TBDPS or
tert-butyldimethylsilyl (TBDMS)), the reduction did not
occur.
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Chirality Transfer in Protected Acetylenic Diols
FULL PAPER
Table 1. Representative examples of propargylic reduction in g-benzyl-
protected Co2(CO)6-a,g-acetylenic diols under Lewis acid treatment.
tion at the propargylic position. Our hypothesis to explain
such a process is based on a hydrogen transfer from the ben-
zylic methylene unit to the propargylic cation through a
chair-like transition state, followed by attack of water on the
benzylic oxonium ion, liberating benzaldehyde and the re-
duced bis-homopropargylic alcohol (Scheme 6).[22]
Entry
5
Yield [%][a]
1
2
3
4
5
6
7
5a R2 = n-C5H11
65 (70)
69 (78)
68 (75)
40 (46)[b]
77 (80)
69 (77)
46 (51)
5b R2 = (CH2)3OTBDPS
5c R2 = (CH2)3OTBS
5d R2 = (CH2)3OTHP
5e R2 = (CH2)3OBz
5 f R2 = CH2OTBDPS
5g R2 = (CH2)3OH
[a] Figures in parentheses denote the yield from the corresponding
Co2(CO)6–alkyne complex. [b] The product was isolated as a free diol
(6g).
procedure was also found to work in the presence of addi-
tional free hydroxy groups (Table 1, entry 7), albeit in mod-
erate yields. When the hydroxy groups were protected as
silyl ethers (TBDPS or TBDMS) (Table 1, entries 2, 3, and
6) or as an ester (Table 1, entry 5), satisfactory yields were
obtained regardless of the position of the protected hydroxy
group relative to the triple bond. In all cases, the Co2(CO)6-
bis-homopropargylic alcohols were satisfactorily decom-
plexed from the metal in the standard manner.
A very interesting feature of this process is that the rear-
rangement occurred with complete integrity of the stereo-
genic center at the secondary position at which the benzyl-
oxy group was located. To probe this fact, 6a (R2 = n-
C5H11) was prepared by an alternative process using stan-
dard conditions based on nucleophilic substitution
(Scheme 5); the specific rotation of the product thus ob-
tained, [a]2D5 = +5.26 (c = 2.3 in CHCl3), was found to be
essentially the same as that of the product obtained by the
propargylic reduction (Table 1, entry 1), [a]2D5 = +5.28 (c =
2.3 in CHCl3).
Scheme 6. Mechanistic proposal for propargylic reduction in g-benzyloxy
propargylic alcohols.
To obtain additional evidence about this plausible mecha-
nism based on the highly ordered transition state 7, we pro-
tected the g-hydroxy group as a MOM ether, assuming that
the methylene unit in this group may have similar properties
to those of the benzyl group in terms of hydride transfer
ability. However, when the diastereoisomeric mixture 8[23]
was submitted to the above-mentioned conditions,
a
1:0.8:0.7 mixture of 11, 12, and 13 was obtained in 85%
overall yield (Scheme 7). The expected bis-homopropargylic
alcohol 13 was contaminated with the acetal 11 and the for-
mate ester 12 resulting from attack of water on the cations 9
Scheme 5. Preparation of stereochemically defined bis-homopropargylic
alcohols from 2,3-epoxy alcohols following a classical route. HMPA=
hexamethylphosphoramide.
As mentioned above, the presence of the benzyl protect-
Scheme 7. Propargylic reduction in g-MOM-protected a,g-acetylenic
ing group at the g-position is essential to achieve the reduc-
diols.
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V. S. Martín et al.
Table 2. Diastereoselective propargylic reduction in g-benzyloxy tertiary
Co2(CO)6-propargylic alcohols.
and 10, respectively. Although the reaction was observed to
behave differently with this protecting group, the idea of a
six-membered transition state is reinforced.
Stereochemical course of the [1,5]-hydrogen rearrangement
in the acidic treatment of g-benzyloxy Co2(CO)6-propargylic
alcohols. Stereoselective synthesis of 2,4-disubstituted g-lac-
tones: Considering the mechanistic hypothesis outlined in
Scheme 6, we wondered whether the hydrogen rearrange-
ment could occur in a stereoselective manner. We anticipat-
ed that if the reaction implies a highly ordered transition
state, the newly created stereocenter at the propargylic
cation could be controlled by two major factors: the config-
uration of the benzyl-protected carbinol and the conforma-
tion of the cationic receptor. To probe this assumption, a
series of new compounds containing tertiary propargylic al-
cohol functions and having a well-defined stereochemistry
at the benzyloxy position was prepared (Scheme 8). Oxida-
Entry
15
17:18
Yield [%][a]
1
2
3
4
5
15a R3 = CH3
15b R3 = n-C5H11
15c R3 = Ph
100:1[b]
100:1[b]
100:1[b]
30:1
79 (89)
82(86)
84 (87)
72(81)
70 (79)
15d R3 = iPr
15e R3 = tBu
1:1
[a] Overall yield from 15 (in parentheses the yield from 16). [b] Within
the NMR detection limits, 18 was not detected.
in which complete chirality has been transmitted from the g-
position to the propargylic center. In addition, the stereo-
chemical course of the reaction proved insensitive to the ab-
solute configuration of the propargylic alcohol since inde-
pendent experiments with both diastereomers yielded the
same final reduced product (Scheme 9).
Scheme 8. Preparation of g-benzyloxy tertiary propargylic alcohols.
tion of the primary alcohol 4 to the corresponding aldehyde,
nucleophilic addition of the appropriate Grignard or lithium
reagent, and subsequent oxidation of the secondary alcohol
provided the ketones 14. These ketones were reacted with
the lithium acetylide of 1-heptyne to yield the diastereo-
meric tertiary alcohols 15. It should be pointed out that such
carbinols were prepared despite the bulkiness of the R3
group relative to the Co2(CO)6-acetylenic complex.
The Co2(CO)6-alkyne complexes 16 were smoothly pre-
pared in the standard manner. To our satisfaction, we found
that under the usual acidic conditions (BF3·OEt2) such com-
plexes provided, after demetalation, the desired sec-alkyl
bis-homopropargylic alcohols 17 and 18 (Table 2).[24] As can
be observed, the most interesting feature of this new trans-
formation is that, except in those cases where R3 is very
bulky, such as the tert-butyl group (Table 2, entry 5), the re-
action proceeded to yield exclusively one diastereoisomer.[25]
In fact, these experimental results reinforce the idea of a
chair-like transition state in which the bulkiest group be-
comes located at a pseudo-equatorial position (Scheme 6).
Thus, the obtained products are indicative of a new reaction
Scheme 9. Comparative experiment using both diastereoisomers at the
propargylic position.
We also proved that without the formation of the
Co2(CO)6 complex the transfer did not occur. Neither mi-
crowave nor acid treatment of 15c (R3 = Ph) under various
conditions yielded any reduced product. In most cases, the
material remained unaffected or small amounts of elimina-
tion products were detected.
To determine the stereochemistry at the newly created
stereocenter, we pondered the idea of transforming products
17 into the corresponding a,g-disubstituted g-lactones. If
successfully accomplished, this would achieve two goals si-
multaneously: to establish the relative stereochemistry of
the reduced acetylenic compound and the development of a
new and powerful synthetic method for the construction of
a commonly encountered structural unit in many bioactive
compounds. Thus, consecutively, 17a–d were hydrogenated
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Chirality Transfer in Protected Acetylenic Diols
FULL PAPER
under Lindlarꢁs conditions and acetylated to afford the (Z)-
acetate 19. RuO4 cleavage of the double bond, basic hydro-
lysis of the ester, and lactonization under acidic conditions
provided the corresponding g-lactones 20 (Table 3).[26] This
Table 3. Stereoselective synthesis of cis-a,g-butyrolactones.
Entry
17
19 Yield [%]
20 Yield [%]
1
2
3
4
17a R3 = CH3
17b R3 = n-C5H11
17c R3 = iPr
88
85
85
87
72
71
63
64
Scheme 10. Regioselective transfer of hydrogen in g,d-dibenzyloxy prop-
argylic alcohols.
17d R3 = Ph
To explore the full potential of the described reaction, we
speculated about the possibility of a double hydrogen trans-
fer in the same molecule. Our first attempt was applied to
the symmetrical Co2(CO)6-dipropargylic alcohol 31, offering
two sets of the necessary functional groups in the same sub-
strate. This compound was easily synthesized from the mon-
obenzyl ether of propanediol 29 (Scheme 11). When two
method was successful, except when R3 was a phenyl group.
In this case, the double bond fragmentation was performed
by way of the cis-diol (OsO4, NMO) and further oxidative
cleavage (KMnO4, K2CO3, NaIO4). Although the relative
stereochemistry was established by NOE studies, we pre-
pared the alternative trans-lactone 22 from 21 to avoid any
misinterpretation arising from conformational fluctuation of
the five-membered ring.[27] Alkylation of 21 under the usual
basic conditions provided the expected trans-lactone 22 as
the major product.[28] Comparative NOE studies permitted
us to establish unambiguously that the g-butyrolactones ob-
tained from the reduced acetylene have the cis relative ste-
reochemistry.
Regioselectivityand influence of additional substituents at-
tached to the linear chain: Another very important synthetic
feature of the described process is the complete regioselec-
tivity of the reaction. Only benzyl ethers located in the g-po-
sition relative to the triple bond undergo the hydrogen trans-
fer. Such behavior could be easily demonstrated using the
di-O-benzyl derivative 25, which was synthesized from the
known alcohol 23, in turn obtained from commercially avail-
able (S)-malic acid (Scheme 10).[29] The ether 24 was regio-
selectively reduced with a mixture of NaBH3(CN)/TMSCl to
afford 25; these conditions were used since the standard
benzylidene reduction using DIBALH led to the benzyl
ether being located at the primary position. The use of a se-
quence similar to that described above led to the diastereo-
meric mixture of tertiary carbinols 27. Finally, application of
the usual protocol for performing the hydrogen transfer led
to 28 as the only isolated product, with remarkable double
regio- and stereoselectivity.
Scheme 11. Competitive reactions in symmetrical dibenzyloxy propargylic
alcohols.
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V. S. Martín et al.
equivalents of Lewis acid were added, the complexed oxe-
pane 34 was the only product obtained and no traces of the
expected compound 32 were found. To characterize the
seven-membered ring, the cobalt complex was submitted to
the methodology developed by Isobe et al.[30] and further
catalytic hydrogenation. As indicated in Scheme 11, 34 was
formed by two consecutive processes: a hydrogen transfer
leading to 33 and an intramolecular Nicholas cyclization
leading to the corresponding cyclic ether (path b).[15] Further
reduction of 34 and subsequent hydrogenation yielded com-
pound 35, which unequivocally supports the previous forma-
tion of 34. Evidence for this two-stage mechanism was ob-
tained by treatment of 31 with just one equivalent of
BF3·OEt2 during a very short reaction time (ca. 1 min),
which led to a small amount of the mono-reduced alcohol
36.
In an attempt to avoid the cyclization product, we subject-
ed the dibenzyl ether of 4,6-decadiyne-1,3,8,10-tetraol 38 to
our synthetic protocol, considering that the presence of the
two consecutive triple bonds should strongly disfavor nine-
membered ring formation. Compound 38 was synthesized
by Eglinton coupling of the propargylic alcohol 37, which
was easily obtained from the benzyl ether of propanediol 29
(Scheme 12). Gratifyingly, when the corresponding di-
Co2(CO)6 complex 39 was submitted to the usual acidic con-
ditions, the expected reduced product 40 was obtained.
However, it should be pointed out that room temperature
and longer reaction times were necessary to accomplish the
entire process.
suitably predisposed to probe the double transfer concept
from the inner to the outer part of a molecule. The known
(E)-3-hexene-1,6-diol (41)[31] was consecutively di-protected
as the MOM ether, enantioselectively dihydroxylated, di-
benzylated, and submitted to MOM cleavage to afford the
diol 42. After unsuccessful attempts to simultaneously oxi-
dize both alcohol functions to the corresponding aldehydes,
homologation at both sides was performed in a stepwise
manner. Thus, after monoprotection as the THP derivative,
a sequence consisting of Swern oxidation, lithium acetylide
addition, acetylation, and removal of the THP ether provid-
ed 43. This primary alcohol was similarly homologated fol-
lowing a parallel series of reactions to provide, after remov-
al of the acetate, the desired dipropargylic diol 44. When
this diacetylenic diol was complexed with [Co2(CO)8] and
submitted to various conditions, varying the temperature
from À208C to ambient, instead of the expected diol 46 re-
sulting from the double transfer reaction, an approximately
1:1 diastereoisomeric mixture of tetrahydrofuran 45 was iso-
lated. This example shows the high propensity for cycliza-
tion as opposed to hydrogen transfer in those systems in
which the two competing reactions are possible
(Scheme 13).[32]
Once the possible competition between the newly de-
scribed hydrogen transfer and intramolecular cyclization
had been studied, we pondered the influence of additional
substituents located on the linear chain on both the stereo-
chemistry and the viability of the reaction itself. Especially
important for us was to study highly oxygenated systems,
mainly in view of their wide distribution in biological sys-
tems and the fact that under the reaction conditions we pre-
viously observed a competing elimination in a,b-dioxygenat-
ed acetylenes leading to homopropargylic ketones.[16] To
carry out our studies, we needed a molecular model of type
47 having the necessary g-benzyloxy group, the propargylic
alcohol function, and an additional b-substituent (alkyl or
alkoxy group) (Figure 1).[33]
Thus, we decided to prepare both stereoisomers with an
additional benzyloxy group located at the b-position. Previ-
ously prepared benzoate diol 48[34] was transformed into the
corresponding benzyloxy derivative 49. Mono-protection of
the primary hydroxy group permitted the formation of the
additional benzyl ether at the C-2carbon by simple William-
son-type alkylation followed by THP cleavage. Subjecting
50 to a similar protocol as that previously used to build a
propargylic system afforded 51. Finally, the sequence used
to induce the hydrogen transfer led to the expected product
52, although the reaction was sluggish and the yield was
slightly lower than in the absence of the b-substituent
(Scheme 14 and Table 4).
To study the stereochemical influence of the b-substituent,
we prepared the corresponding syn-b,g-dibenzyloxy isomer
53 (Scheme 15). (E)-2-Hexen-1-ol was protected as the cor-
responding THP ether, submitted to Sharpless asymmetric
dihydroxylation, and the resulting diol protected as the cor-
responding dibenzyl ether to afford, after acid THP cleav-
age, 53. Application of the sequence used above to construct
Scheme 12. Effective double hydrogen transfer.
In the above, we have described two processes in which
the double transfer is designed to take place from the
“outer” to the “inner” part of the molecules. Considering
the simplicity of the synthesis of the vicinal diol, we contem-
plated a symmetrical molecule having two benzyl-protected
alcohols as the central structural core and the necessary
propargylic alcohol functions located in suitable positions.
With this idea in mind, we synthesized the diol 44, which is
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Chirality Transfer in Protected Acetylenic Diols
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Scheme 13. Ring formation versus hydrogen transfer. MOM=methoxymethyl, DHP=3,4-dihydro-2H-pyran, DMAP=4-diaminopyridine.
the propargylic system afforded
54. Surprisingly, all attempts to
obtain 55 by the hydrogen
transfer were completely fruit-
less. This result indicates the
importance of the substituent at
the b-position, including with
regard to stereochemical con-
siderations. In the light of these
Figure 1. Substrates with possi-
ble competition affecting the
hydrogen transfer.
results, we prepared a library of
different substrates of type 47,
considering different oxygenat-
ed substituents, such as me-
thoxy and hydroxy groups, as
well as an alkyl group (methyl).
For the synthesis of b-methoxy-containing substrates, the
diol 49 was mono-THP protected, methylated at the secon-
dary carbinol, and then subjected to THP cleavage to afford
the anti-alcohol 56 (Scheme 16). Alternatively, 49 was fully
mesylated, treated with potassium acetate, and the acetate
groups were hydrolyzed to afford the syn-isomer 58.[35]
When 58 was submitted to a similar sequence as that ap-
plied to 49, the corresponding methoxy derivative 59 was
Scheme 14. Hydrogen transfer in anti-b,g-dibenzyloxy propargylic alco-
hols. PPTS=pyridinium 4-toluenesulfonate.
obtained. In the same manner as used to prepare the b-hy-
droxy-containing derivatives, we performed a similar se-
quence to introduce a p-methoxybenzyl group at the C-2po-
sition, with the understanding that such a protecting group
could be easily removed under oxidative conditions. Thus, a
simple variation of the sequence, using p-methoxybenzyl
chloride instead of methyl iodide, provided the PMB-pro-
tected alcohols 57 and 60 in a straightforward manner.
For the synthesis of the prototype 47 having a methyl
group as a b-substituent, we performed the sequence out-
lined in Scheme 17. The diol 49 was oxidatively cleaved and
the resulting aldehyde was subjected to Horner–Wads-
worth–Emmons[36] conditions to afford the (E)-unsaturated
ester 61. Reduction of 61 with in situ generated alane pro-
vided the allylic alcohol 62, which was successfully submit-
ted to Katsuki–Sharpless asymmetric epoxidation using both
enantiomers of diethyl tartrate. The resulting epoxides 63
and 65 were regioselectively opened at C-3 with AlMe3,
leading to the diols 64 and 66 as the major regioisomers.
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V. S. Martín et al.
Table 4. Influence of the substitution at the b-carbon on the hydrogen-transfer process.
cleaved by oxidative treatment
with CAN, giving the desired
propargylic alcohols 69 and 70.
Table 4 outlines the results
obtained (61, 52, 73–78) when
the above propargylic alcohols
were submitted to the whole se-
quence used to induce the hy-
drogen transfer. In general, the
substitution at the b-carbon
atom decreases the rates and
yields of the hydrogen transfer,
which are better when the sub-
stituents at the b- and g-carbon
atoms are in an anti configura-
tion.[33] Only with a hydroxy
group as the b-substituent did
the syn-isomer yield a faster re-
action (Table 4, entries 16–21).
The b-alkyl derivatives were
found to be more convenient
substrates for hydrogen transfer
than the b-alkoxy analogues,
presumably because of an inter-
action between the b-oxygenat-
ed center and the propargylic
cation in the latter. Neither b-
elimination products nor homo-
propargylic ketones were ob-
Entry
T [8C]
Time[a]
(Yield [%][b]
)
1
2
3
4
5
6
7
8
5a (R = H)
5a (R = H)
5a (R = H)
À20
0
RT
À2
0
RT
À2
0
RT
À2
0
RT
À2
0
RT
À2
0
RT
À2
0
RT
À20
0
5 min
1 min
1 min
61 (81)
61 (79)
61 (83)
052h(59)
52 (62)
52 (73)
51 (R = OBn) (S)
51 (R = OBn) (S)
51 (R = OBn) (S)
54 (R = OBn) (R)
54 (R = OBn) (R)
54 (R = OBn) (R)
67 (R = OMe) (S)
67 (R = OMe) (S)
67 (R = OMe) (S)
68 (R = OMe) (R)
68 (R = OMe) (R)
68 (R = OMe) (R)
69 (R = OH) (S)
69 (R = OH) (S)
69 (R = OH) (S)
70 (R = OH) (R)
70 (R = OH) (R)
70 (R = OH) (R)
71 (R = Me) (S)
71 (R = Me) (S)
71 (R = Me) (S)
72 (R = Me) (R)
72 (R = Me) (R)
72 (R = Me) (R)
0
0
0
0
0
0
2
9 h
3.5 h
44 h
3 h
–
–
2
13 h
9
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2
473h(43)
73 (55)
73 (72)
274 (35)
74 (62)
74 (69)
75 (6)
75 (32)
75 (41)
76h(38)
76 (47)
76 (65)
77 (73)
77 (79)
77 (82)
78 (41)
78 (57)
78 (68)
1 h
2min
2
h
5 h
40 min
30 h
32
18 h
45 min
14 h
30 min
70 min
15 min
4 min
0
2
RT
À2
0
35 h
3 h
RT
75 min
[a] Times refer to the hydrogen transfer over the corresponding Co2(CO)6-acetylenic complex until TLC shows
complete conversion. [b] Overall yield from propargylic alcohols.
Scheme 16. Stereocontrolled synthesis of 2-alkoxy-3-benzyloxy-1-alka-
nols.
Scheme 15. Failed attempt at hydrogen transfer in syn-b,g-dibenzyloxy
propargylic alcohols.
served at 08C or below, with minuscule amounts of these
side products only being detected in certain cases when the
reaction was carried out at room temperature. A dramatic
result was observed for the syn-(R)-b-benzyloxy derivative
54: after long periods of time, only an irresolvable mixture
of products of low polarity was obtained, along with remain-
ing starting material (Table 4, entries 7–9).
With alcohols 56, 57, 59, 60, 64, and 66 in hand, we incor-
porated the propargylic unit by oxidation or diol cleavage to
give the corresponding aldehyde followed by addition of the
appropriate lithium acetylide (Scheme 18). Finally, to obtain
the derivatives having a free hydroxy group, the PMB ether
functions in the products from 57 and 60 were efficiently
2600
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Chem. Eur. J. 2006, 12, 2593 – 2606

Chirality Transfer in Protected Acetylenic Diols
FULL PAPER
[1,5]-Hydrogen transfer in g-benzylamine propargylic al-
cohols: With an eye toward the application of this method-
ology to the synthesis of natural products, we decided to
assess whether the hydrogen transfer could be extended to
the corresponding g-nitrogenated systems. To probe this
idea, the g-benzylamino derivative 83 (Scheme 19) was con-
Scheme 17. Stereocontrolled synthesis of 3-methyl-4-benzyloxy-1,2-diols.
Scheme 19. Propargylic reduction in Co2(CO)6-g-benzylamino propargylic
alcohols. DCC=N,N’-dicyclohexylcarbodiimide.
veniently synthesized starting from benzylamine. DCC-cou-
pling with vinylacetic acid provided the corresponding
amide 79, which was reduced with alane to the secondary
amine 80. Boc-protection of the nitrogen center, dihydroxy-
lation of the terminal alkene, oxidative cleavage of the vici-
nal diol, and finally coupling with the appropriate lithium
acetylide yielded the propargylic alcohol 82. Acidic cleavage
of the Boc group provided the desired propargylic alcohol
83, which was submitted to the protocol for inducing the hy-
drogen transfer. Satisfyingly, the bis-homopropargylic amine
84 was formed, demonstrating the feasibility of application
of the described methodology to nitrogenated systems. It is
noteworthy that when the N-Boc-protected alcohol 82 was
submitted to the same conditions as 84 to perform the hy-
drogen transfer, the cyclized product 85 was exclusively ob-
Scheme 18. Synthesis of g-benzyloxy b-substituted propargylic alcohols 47
(R3 = Me, OMe).
Chem. Eur. J. 2006, 12, 2593 – 2606
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2601

V. S. Martín et al.
Table 5. Isotopic effect in the hydrogen transfer.
tained in very good yield as a result of intramolecular attack
of the Boc oxygen at the propargylic position.
Mechanistic considerations: Isotope effect in the hydrogen
transfer: To obtain additional mechanistic evidence, we de-
cided to perform an isotopic substitution at the benzylic po-
sition, looking for evidence of an isotope effect during the
transfer. Thus, the necessary deuterated propargylic alcohols
89 and 90 (Scheme 20) were prepared in the same manner
Entry
X
T [8C]
Time [min]
Conversion [%]
Yield [%]
1
2
3
4
5
6
H
D
H
D
H
D
À40
À40
À30
À30
À20
À20
5
15
3
6
1
41
20
8292
79
91
93
92
92
93
93
1
90
dence strongly supports the assumption that the breaking of
À
a C H(D) bond is involved in the process during the transi-
tion state.
Calculations: The structural complexity involved in the re-
ported hydrogen transfer warrants an initial theoretical
model based on a semiempirical treatment. PM3(tm) was
the chosen Hamiltonian as it is the only one existing to date
that possesses the necessary parameterization of the cobalt
atom. This Hamiltonian was used to optimize geometries for
the transformation of several a,b-substituted g-benzyloxy
propargylic cations complexed with [Co2(CO)8] into the cor-
responding reduced entities. To facilitate the calculations, 1-
hexyne was used as a base structure on which the different
substituents were located. We studied hypothetical transfor-
mations involving hydrogen transfer from both benzylic hy-
drogen atoms to both prochiral faces of the carbocation.
The most relevant energetic and structural features concern-
ing the stationary points are summarized in Table 6.
A model based on the results presented in Table 6 pre-
dicts endothermic processes with relatively large activation
energies (between 23.5 and 39.3 kcalmolÀ1), small discrimi-
nation in favor the transfer of the pro-R hydrogen (HR)
atom as opposed to the pro-S one (HS) in almost all cases
studied, and a preferential attack on the Re-face of the car-
bocation. Six-membered rings are involved in the transition-
state geometries, in which the transferred hydrogen adopts a
similar mode of binding to both the initial and final carbon
(C–H–C distances between 1.3 and 1.4 Š).
In addition, the results shown in Table 6 point to faster
[1,5]-hydrogen transfer if the b-chiral group is a methoxy,
methyl or benzyloxy group with the S configuration and an
easier rearrangement for the hydroxy group when the b-con-
figuration is R, in complete agreement with the experimen-
tal results.
Scheme 20. Stereoselective synthesis of deuterium-labeled methines and
methylenes.
as used to prepare the protonated analogues (Scheme 4 and
Scheme 8) but using a,a-[D2]benzyl bromide. Application of
the procedure for inducing the transfer to substrates 89 and
90 cleanly afforded the compounds 91 and 92, demonstrat-
ing the applicability of this methodology to the stereoselec-
tive synthesis of deuterium-labeled methines and methyl-
enes.
In spite of the high rate of the transfer at À208C, when
the reaction was carried out at À408C an isotope effect was
observed when the benzylic hydrogen atoms were replaced
with deuterium atoms (Table 5). This supports the rupture
of such a bond during the transition state. Thus, after a reac-
tion time of 15 min at À408C, the deuterated benzyl ether
(entry 2) provided only 20% conversion, while the reaction
using the protium derivative afforded 41% conversion in
only 5 min. Although this is only a qualitative study, the evi-
A chair-like transition state, as shown in Figure 2, can pro-
vide a very reasonable qualitative model for the global ki-
netic behavior and stereochemical outcome of our reaction.
The b-chiral substituents, when located anti relative to the
benzyloxy group, are placed equatorially in the ring, a more
favorable orientation than the obligatory axial position that
syn-substituents need to adopt. If we consider this effect to
be more important than the difference in stability between
the two diastereomeric starting products, we can anticipate
2602
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Chem. Eur. J. 2006, 12, 2593 – 2606

Chirality Transfer in Protected Acetylenic Diols
FULL PAPER
Table 6. Main energetic and geometric features for the semiempirical PM3(tm) treatment of hydrogen-transfer models.
TS description
[e]
[f]
Entry
R
Face[a]
H Tranf.[b]
A2[c]
TS2[c]
B2[c]
DH*[c]
DH3[c]
Imag. Freq.[d]
C(+) H
C(Bn) H
À
À
1
2
3
4
5
6
7
8
H
H
H
H
Si
Si
Re
Re
Si
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
HR
HS
À3482.9
À3482.9
À3482.9
À3482.9
À3525.5
À3525.5
À3525.5
À3525.5
À3529.1
À3529.1
À3529.1
À3529.1
À3518.2
À3518.2
À3518.2
À3518.2
À3518.8
À3518.8
À3518.8
À3518.8
À3490.2
À3490.2
À3490.2
À3490.2
À3486.6
À3486.6
À3486.6
À3486.6
À3490.1
À3490.1
À3490.1
À3490.1
À3489.7
À3489.7
À3489.7
À3489.7
À3451.8
À3456.8
À3458.4
À3457.5
À3487.1
À3489.4
À3495.3
À3492.8
À3489.8
À3493.0
À3495.4
À3495.3
À3481.9
À3486.6
À3486.9
À3485.4
À3484.4
À3488.3
À3488.6
À3489.6
À3461.4
À3456.8
À3457.6
À3456.2
À3460.8
À3463.1
À3463.0
À3463.4
À3455.5
À3460.2
À3460.4
À3457.6
À3456.2
À3456.2
À3459.6
À3461.8
À3477.3
À3477.3
À3477.3
À3477.3
À3520.4
À3520.4
À3520.4
À3520.4
À3515.6
À3515.6
À3515.6
À3515.6
À3514.0
À3514.0
À3514.0
À3514.0
À3508.9
À3508.9
À3508.9
À3508.9
À3479.6
À3479.6
À3479.6
À3479.6
À3474.0
À3474.0
À3474.0
À3474.0
À3488.4
À3488.4
À3488.4
À3488.4
À3483.8
À3483.8
À3483.8
À3483.8
31.1
26.1
24.5
25.4
38.4
36.1
30.2
32.7
39.3
36.1
33.7
33.8
36.3
31.6
31.3
32.8
34.4
30.5
5.6
5.6
5.6
5.6
5.1
5.1
5.1
5.1
1057.121.307
1057.12
1302.56
1286.83
1173.62
1315.91
1361.66
1312.57
1173.79
1406.22
1349.46
1334.04
1
1.42
1.431
1.405
1.423
1.361
1.440
1.418
1.405
1.340
1.416
1.404
1.403
1.376
1.394
1.371
1.407
1.357
1.397
1.396
1.446
1.401
1.390
1.385
OH (R)
OH (R)
OH (R)
OH (R)
OH (S)
OH (S)
OH (S)
S)
MeO (R)
MeO (R)
MeO (R)
MeO (R)
MeO (S)
MeO (S)
MeO (S)
MeO (S)
Si
Re
Re
Si
9
13.5
13.5
13.5
13.5
4.21191.86
774..82012
10
11
12OH (
13
14
15
16
17
18
19
20
2
Si
Re
Re
Si
1.371
1.452 1.353
1.396
1.391
Si
Re
Re
Si
Si
Re
Re
04..626132
1.391
1.446
1.344
1.422
4.2
9.9
9.9
1286.77
1208.71
1402.66
1.399
1.361
1.426
1.391
30.29.9 .71 1362
1.394
29.2
28.8
33.4
32.6
34.0
25.8
23.5
23.6
23.2
34.6
29.9
29.7
32.5
33.5
33.5
30.1
27.9
9.9
10.6
10.6
10.6
10.6
12.6
12.6
12.6
12.6
1.7
1.7
1.7
1.7
5.9
5.9
5.9
5.9
1320.37
1271.03
1154.43
1327.97
1312.57
979.65
1231.59
1304.78
1306.58
1185.01
1275.31
1311.47
1331.14
1173.921.339
1412.50
1368.91
1315.21
1.402
1.416
1.343
1.426
1.424
1.304
1.363
1.394
1.418
1.369
1.445
1.391
1.389
1.378
1.376
1.445
1.399
1.379
1.454
1.412
1.390
1.378
1.393
1.352
1.392
1.371
1
R) Me ( Si
22
2
2
Me (R)
3
4
Si
R) Me ( Re
R) Me ( Re
25
26
27
28
29
30
31
32BnO (
33
34
35
36
Me (S)
Si
Si
Re
Re
Si
Me (S)
Me (S)
Me (S)
BnO (R)
BnO (R)
BnO (R)
R)
BnO (S)
BnO (S)
BnO (S)
BnO (S)
Si
Re
Re
Si
Si
Re
Re
1.449
1.420
1.397
1.406
1.339
1.398
1.372
[a] Prochiral face of the carbocation assuming the Co2(CO)6-acetylenic group to be the highest ranking group in the Cahn–Ingold–Prelog system. [b] HR
= pro-R, HS = pro-S. [c] Energy in kcalmolÀ1. [d] Imaginary frequencies obtained in the harmonic vibrational frequency analysis. [e] Distance between
transferred H and propargylic cation, in Š. [f] Distance between transferred H and initial benzylic carbon, in Š.
ed by this model because the axial transition state is now
stabilized by
(Figure 3).
a
five-membered ring hydrogen bond
Figure 2. Chair-like transition-state geometry for pro-R-hydride transfers
and Re-attack on the carbocation.
Figure 3. Chair-like transition states in which substituents are placed in
the pseudo-equatorial position are preferred (A). With a b-hydroxy
group, an internal hydrogen bond permits stabilization of an axially locat-
ed group (B).
a faster reaction of the substituent when located anti, again
in complete agreement with the experimental results. The
only exception, the hydroxy group, can also be accommodat-
Chem. Eur. J. 2006, 12, 2593 – 2606
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2603

V. S. Martín et al.
J = 11.4 Hz, 1H), 4.64 (d, J = 11.4 Hz, 1H), 7.27–
2H), 4.49 (d,
Conclusion
7.35 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d = 14.2(q), 18.4 (t),
35.7 (t), 35.8 (t), 60.7 (t), 70.9 (t), 78.4 (d), 126.9 (d), 127.7 (d), 127.8 (d),
128.4 (d), 138.4 ppm (s); IR (film): n˜max = 3420, 2958, 2872, 1717, 1454,
1275, 1068 cmÀ1; MS: m/z (%): 208 [M]+ (0.5), 191 [M À CH3]+ (1), 147
(8), 107 (19), 91 (100); HRMS calcd. for C13H20O2: 208.14633; found
208.14683.
Herein, we have reported on a novel process of [1,3]-trans-
fer of chirality in g-benzyl-protected Co2(CO)6-a,g-acetylen-
ic diols under the Nicholas reaction conditions, in which a
benzylic hydrogen is stereoselectively transferred to the
propargylic cation. From the experimental results and semi-
empirical calculations, we can conclude that preferential
transfer of the benzylic pro-R hydride in a chair-like transi-
tion state favors b-substituents and a Co2(CO)6-acetylene
complex located at the equatorial positions. In addition, the
methodology offers a mild and general solution to the prob-
lem of controlling the stereochemistry in any alkyl group in-
troduced in a hydrocarbon chain, a relevant topic in the
field of the synthesis of natural products.[32,37]
General method for performing a [1,5]-hydrogen transfer in g-benzyloxy
propargylic alcohols: preparation of (4S)-11-(tert-butyldiphenylsilanyl-
oxy)undec-7-yn-4-ol (6b): SO3-Py complex (0.48 g, 3.00 mmol) was added
to a stirred mixture of 4 (R1
= n-C3H7) (200 mg, 0.96 mmol), Et3N
(0.68 mL, 4.8 mmol), dry DMSO (1.97 mL, 10.27 mmol), and dry CH2Cl2
(6 mL) at 08C. The mixture was stirred until TLC showed completion of
the reaction (ca. 2h). It was then diluted with further CH 2Cl2, washed
with brine, dried (MgSO4), filtered, and concentrated to provide the alde-
hyde in a sufficiently pure state for use in the next step without further
purification.
nBuLi (0.60 mL, 1.9m in hexanes, 1.12mmol) was added to a solution of
tert-butyl-pent-4-ynyloxy-diphenylsilane[39] (370.8 mg, 1.15 mmol) in dry
THF (2.7 mL) at À788C. After the addition, the mixture was allowed to
warm to room temperature over a period of 0.5 h. It was then cooled to
À788C once more and a solution of the aldehyde in dry THF (2.5 mL)
was added dropwise. The resulting mixture was stirred at À788C for 1 h,
and then the reaction was quenched with saturated NH4Cl solution and
Et2O. The organic layer was washed with brine, dried (MgSO4), filtered,
and concentrated to give the secondary alcohol 5b (405 mg, 80% overall
yield) as a mixture of diastereoisomers in which one slightly predominat-
ed (ca. 1.5:1).
Experimental Section
1
General methods and materials: H and 13C NMR spectra were recorded
at 258C on Bruker Avance-400 and/or 300 spectrometers with samples in
CDCl3 solution, and chemical shifts are reported relative to Me4Si. Low-
and high-resolution mass spectra were obtained by using a Micromass
Autospec spectrometer. Elemental analyses were performed on a Fisons
Instruments EA 1108 CHNS-O analyzer. Optical rotations were deter-
mined for solutions in chloroform or n-hexane with a Perkin–Elmer
model 241 polarimeter. Infrared spectra were recorded on a Bruker
IFS 55 spectrophotometer. Column chromatography was performed on
Merck silica gel, 60 Š and 0.2–0.5 mm. Spots were visualized under UV
light and/or by staining with phosphomolybdic acid in ethanol. All sol-
vents were purified by standard techniques.[38] Reactions requiring anhy-
drous conditions were performed under argon. Anhydrous magnesium
sulfate was used for drying solutions.
[Co2(CO)8] (341 mg, 0.90 mmol) was added to a solution of 5b in dry
CH2Cl2 (8 mL) at room temperature and the mixture was stirred until
TLC showed complete conversion to the hexacarbonyldicobalt complex
(ca. 1 h). The mixture was then filtered through a pad of silica gel and
concentrated to yield a brown solid, which was used directly in the next
step.
BF3·OEt2 (61 mL, 0.79 mmol) was slowly added to a stirred solution of
the crude Co2(CO)6 complex in dry CH2Cl2 (9 mL) at À208C. The reac-
tion mixture was stirred for 10 min and then poured into saturated aque-
ous NaHCO3 at 08C. The resulting mixture was vigorously stirred for
15 min and then extracted with CH2Cl2. The combined organic layers
were washed with brine, dried (MgSO4), filtered, and concentrated to
give the Co2(CO)6 complex, which was employed in the next step without
further purification.
General method for the preparation of enantiomeric 3-benzyl-protected
1,3-diols: preparation of (3S)-3-(benzyloxy)hexan-1-ol (4, R1 = n-C3H7):
Red-Al (27.8 mL, 3.4m solution in toluene, 94.6 mmol) was slowly added
to a solution of 3[19] (5.0 g, 43.0 mmol) in dry THF (215 mL) at 08C under
argon. The reaction mixture was stirred for 2.5 h, after which time TLC
showed no remaining epoxide. Water (20 mL) and HCl (5% w/v in
water) (30 mL) were then sequentially added, and the mixture was stirred
until clear phases were obtained (0.5 h). The phases were separated and
the aqueous phase was extracted with Et2O. The combined organic
phases were washed with saturated aqueous NaHCO3 and brine, dried
(MgSO4), filtered, and concentrated to afford the 1,3-diol as a colorless
oil.
CAN (1.72g, 0.56 mmol) was added in one portion to a stirred solution
of the complexed acetylene in dry acetone (9 mL) at 08C. The reaction
mixture was stirred at 08C until TLC showed completion of the reaction
(ca. 5 min). The mixture was then concentrated and the residue was dilut-
ed with water and extracted with Et2O. The combined organic phases
were dried (MgSO4), filtered, and concentrated. Flash column chroma-
tography yielded 6b as a colorless oil (223.7 mg, 69% yield overall). [a]D25
A catalytic amount of CSA (1.0 g, 4.3 mmol) and benzaldehyde dimethyl
acetal (7.8 mL, 51.6 mmol) were sequentially added to a stirred solution
of the crude 1,3-diol in dry CH2Cl2 (140 mL) at room temperature. The
reaction mixture was stirred for 1 h, after which time TLC showed com-
plete conversion to the benzylidene derivative. Et3N was then added
until pHꢀ7 was reached, and the mixture was stirred for 5 min and then
concentrated under reduced pressure.
1
= 4.15 (c = 2.12 in CHCl3); H NMR (400 MHz, CDCl3): d = 0.91 (t, J
= 6.9 Hz, 3H), 1.07 (s, 9H), 1.30–1.35 (m, 2H), 1.58 (brs, 4H), 1.65–1.75
(m, 2H), 2.24–2.32 (m, 4H), 3.73 (t, J = 5.9 Hz, 3H), 7.35–7.44 (m, 6H),
7.65–7.73 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d = 14.0 (q), 15.3
(t), 18.7 (t), 18.7 (t), 19.2 (s), 26.5 (q), 31.9 (t), 36.1 (t), 39.5 (t), 62.5 (t),
71.0 (d), 79.8 (s), 80.5 (s), 127.6 (d), 129.5 (d), 139.9 (s), 134.8 (s),
135.5 ppm (d); IR (film): n˜max = 3420, 2957, 2930, 2858, 1388, 1110 cmÀ1
;
DIBALH (172mL, 1 m solution in cyclohexane, 172mmol) was slowly
added to a solution of the aforementioned crude product in dry CH2Cl2
(140 mL) at 08C. After this addition, the mixture was allowed to warm to
room temperature over a period of 15 min with stirring, then diluted with
CH2Cl2 and aqueous HCl (5% w/v in water) was added. The resulting
mixture was extracted with CH2Cl2. The combined organic layers were
washed with saturated aqueous NaHCO3 and brine, dried, filtered, and
concentrated, and the product obtained was purified by column chroma-
tography to afford 4 (R1 = n-C3H7) as a colorless oil (6.61 g, 74% overall
yield): [a]2D5 = +20.7 (c = 1.9 in CHCl3); 1H NMR (400 MHz, CDCl3):
d = 0.93 (t, J = 7.2Hz, 3H), 1.34–1.39 (m, 2H), 1.48–1.56 (m, 1H),
1.62–1.67 (m, 1H), 1.76–1.83 (m, 2H), 3.63–3.66 (m, 1H), 3.73–3.81 (m,
MS: m/z (%): 421 [MÀ1]+ (0.1), 365 [MÀtBu]+ (5), 287 (100); elemental
analysis calcd (%) for C27H38O2Si: C 76.72, H 9.06; found: C 76.70, H
9.42.
General procedure for the preparation of enantiomeric b-benzyloxy ke-
tones: preparation of (S)-4-(benzyloxy)heptadecan-2-one (14a): PCC
(742mg, 3.44 mmol), powdered 4 Š molecular sieves, and
a small
amount of NaOAc (42mg, 0.51 mmol) were added sequentially to a solu-
tion of the alcohol 4 (R1 = n-C13H27) (600 mg, 1.72mL) in dry CH 2Cl2
(15 mL). The heterogeneous mixture was stirred for 4 h, filtered through
a pad of silica gel, and concentrated to provide the aldehyde, which was
sufficiently pure for use in the next step without further purification.
2604
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 2593 – 2606

Chirality Transfer in Protected Acetylenic Diols
FULL PAPER
MeMgCl (0.69 mL, 3m in THF, 2.06 mmol) was added dropwise to a solu-
tion of the crude aldehyde in THF (17 mL) at À788C. After the mixture
had been stirred for 0.5 h, saturated NH4Cl solution was added, and the
resulting slurry was extracted with Et2O. The combined organic extracts
were dried, filtered, and concentrated. The residual oil was used in the
next step without further purification.
1.25 (brs, 29H), 1.35–1.58 (m, 3H), 2.02 (d, J = 6.6 Hz, 3H), 2.44–2.49
(m, 1H), 4.11 (dd, J = 14.2, 7.1 Hz, 1H), 4.85–4.90 (m, 1H), 5.17 (t, J =
9.7 Hz, 1H), 5.26–5.30 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d =
14.0 (q), 21.0 (q), 21.2 (q), 22.5 (t), 22.6 (t), 25.2 (t), 27.3 (t), 28.5 (q),
29.3 (t), 29.5 (t), 29.6 (t), 31.5 (t), 31.9 (t), 34.3 (t), 41.8 (t), 72.9 (d), 128.5
(d), 135.3 (d), 170.7 ppm (s); IR (film): n˜max = 2929, 1740, 1464, 1374,
1260, 1095 cmÀ1; MS: m/z (%): 335 [MÀOAc]+ (22), 334 (80), 263 (42),
124 (75), 81 (100); elemental analysis calcd (%) for C26H50O2: C 79.12, H
12.77; found: C 79.35, H 12.94.
PCC (742mg, 3.44 mmol), powdered 4 Š molecular sieves, and a small
amount of NaOAc (42mg, 0.51 mmol) were added sequentially to a solu-
tion of the crude diastereomeric alcohols in dry CH2Cl2 (15 mL). The
heterogeneous mixture was stirred for 4 h, filtered through a pad of silica
gel, and concentrated. The resulting viscous oil was purified by flash
General procedure for the preparation of cis-a,g-disubstituted butyrolac-
tones: preparation of (3R,5S)-3-methyl-5-tridecyldihydrofuran-2-one
(20a): NaIO4 (160 mg, 0.75 mmol) and a catalytic amount of RuCl3 were
added to a solution of the acetate 19a (100 mg, 0.25 mmol) in a mixture
of CH3CN/CCl4/H2O (3:2:2) (2.5 mL). The mixture was vigorously stirred
for 30 min, after which time TLC analysis showed complete conversion
to the acid derivative. It was then diluted with Et2O and MgSO4 was
added. The mixture was stirred for 15 min, then filtered through a pad of
Celite and concentrated. The residue was dissolved in Et2O (1 mL) and a
solution of NaOH (30% w/v in water, saturated with NaCl) was added.
The resulting mixture was vigorously stirred for 1 h at room temperature.
After this time, concentrated HCl was added until pHꢀ2was attained,
and the acidified mixture was diluted with Et2O. Saturated aqueous NaCl
solution was added, and the resulting mixture was extracted with Et2O.
The combined organic phases were washed with saturated aqueous NaCl,
dried (MgSO4), filtered, and concentrated to afford the lactone 20a as a
white solid (50.7 mg, 72% yield). M.p. 43 8C; [a]2D5 = À8.6 (c = 1.91 in
CHCl3); 1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.4 Hz, 3H),
1.21–1.38 (brs, 22H), 1.38–1.62 (m, 5H), 1.72 (m, 1H), 2.48 (m, 1H), 2.65
(m, 1H), 4.31 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d = 13.8 (q),
14.0 (q), 22.2 (t), 22.4 (t), 22.6 (t), 25.2 (t), 29.3 (t), 29.4 (t), 29.5 (t), 29.6
(t), 31.9 (t), 35.5 (t), 35.9 (d), 37.3 (t), 78.7 (d), 179.6 ppm (s); IR (film):
n˜max = 3440, 2922, 2851, 1751, 1645 cmÀ1; MS: m/z (%): 283 [M+1]+ (3),
282 [M]+ (13), 265 [MÀOH]+ (1), 264 [MÀH2O]+ (6), 211 [MÀC5H11]+
(2), 205 (10), 149 (41), 111 (29), 99 (100); elemental analysis calcd (%)
for C18H34O2: C 76.54, H 12.13; found: C 76.89, H 11.85.
column chromatography to yield the ketone 14a as
a colorless oil
(377.7 mg, 61% overall yield). [a]2D5 +5.1 (c = 3.5 in CHCl3); 1H
=
NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.6 Hz, 3H), 1.26 (brs, 20H),
1.37–1.58 (m, 4H), 2.15 (s, 3H), 2.45 (dd, J = 15.8, 4.8 Hz, 2H), 2.73 (dd,
J = 15.7, 7.5 Hz, 1H), 3.91–3.95 (m, 1H), 4.49 (d, J = 4.7 Hz, 2H), 7.28–
7.45 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d = 14.1 (q), 22.6 (t),
25.1 (t), 29.3 (t), 29.5 (t), 29.6 (t), 31.1 (q), 31.9 (t), 34.3 (t), 48.6 (t), 71.8
(t), 75.6 (d), 127.6 (d), 127.8 (d), 128.3 (d), 138.4 (s), 207.7 ppm (s); IR
(film): n˜max = 2929, 2854, 1714, 1466, 1068 cmÀ1; MS (FAB): m/z (%):
361 [M+1]+ (14), 360 [M]+ (15), 359 [MÀ1]+ (11), 345 [MÀCH3]+ (14),
253 [MÀOBn]+ (100); elemental analysis calcd (%) for C24H40O2: C
79.94, H 11.18; found: C 80.02, H 11.32.
General procedure for the preparation of stereochemicallydefined a-
alkyl-bis-homoprogargylic alcohols: preparation of (4S,6R)-6-methyltri-
dec-7-yn-4-ol (17a): nBuLi (0.79 mL, 1.50 mmol, 1.9m in n-hexane) was
added dropwise to a solution of 1-heptyne (0.21 mL, 1.63 mmol) in dry
THF (13 mL) under argon at À788C. The reaction mixture was allowed
to warm to À208C and stirred for 15 min at this temperarure. It was then
cooled to À788C once more, whereupon a solution of the ketone 14a
(300 mg, 0.83 mmol) in dry THF (3 mL) was added. The reaction mixture
was stirred for 1 h, after which time TLC showed complete conversion.
The mixture was poured into saturated aqueous NH4Cl solution and di-
ethyl ether and the aqueous phase was extracted with further diethyl
ether. The combined organic solutions were dried over MgSO4 and con-
centrated and the crude product was used in the next step without purifi-
cation.
General procedure for the preparation of trans-a,g-disubstituted butyro-
lactones: preparation of (3S,5S)-3-methyl-5-tridecyldihydrofuran-2-one
(22): nBuLi (0.21 mL of a 1.9m solution in hexane, 0.39 mmol) was
slowly added to a solution of diisopropylamine (64 mL, 0.44 mmol) in
THF/HMPA (4:1) (3 mL) at À788C under argon. The mixture was stirred
for 15 min and then a solution of the lactone 21[40] (100 mg, 0.37 mmol) in
THF/HMPA (4:1) (0.5 mL) was added dropwise. The resulting mixture
was stirred for 20 min at À788C, whereupon a solution of MeI (24 mL,
0.44 mmol) in THF/HMPA (4:1) (0.5 mL) was added. The mixture was
allowed to warm to À408C, stirred for 3 h at this temperature, and then
treated with an aqueous solution of HCl (5% w/v) (2mL). It was then di-
luted with Et2O, saturated aqueous NaCl solution was added, and the re-
sulting mixture was extracted with Et2O. The combined organic phases
were washed with saturated aqueous NaCl, dried (MgSO4), filtered, and
concentrated to afford the lactone 22 as a colorless oil (80.3 mg, 77%
The tertiary carbinol thus obtained was subjected to the same procedure
as used above to obtain 6b from 5b, furnishing 17a as a colorless oil
1
(231 mg, 79% overall yield). [a]2D5 = À6.2( c = 0.32in CHCl ); H NMR
3
(400 MHz, CDCl3): d = 0.87 (t, J = 3.6 Hz, 3H), 0.88 (t, J = 3.7 Hz,
3H), 1.16 (d, J = 23.3 Hz, 3H), 1.25–1.36 (m, 26H), 1.43–1.51 (m, 4H),
1.54 (t, J
= 6.0 Hz, 2H), 2.14 (m, 3H), 2.51 (t, J = 7.3 Hz, 1H),
3.75 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d = 13.9 (q), 14.0 (q),
18.6 (t), 21.9 (q), 22.1 (t), 22.6 (t), 23.9 (d), 25.4 (t), 28.7 (t), 29.3 (t), 29.6
(t), 31.0 (t), 31.9 (t), 37.4 (t), 44.7 (t), 71.3 (d), 82.0 (s), 84.5 ppm (s); IR
(film): n˜max = 3346, 2929, 2856, 1462 cmÀ1; MS: m/z (%): 351 [M+1]+
(25), 350 [M]+ (32), 333 [MÀOH]+ (53), 332[ MÀH2O]+ (26), 295 (51),
238 (45), 210 (80), 199 (100); elemental analysis calcd (%) for C24H46O:
C 82.21, H 13.22; found: C 82.27, H 13.01.
1
yield). [a]2D5 = +10.4 (c = 4.66 in CHCl3); H NMR (400 MHz, CDCl3):
General procedure for the preparation of stereochemicallydefined a-
alkyl-(Z)-bis-homoallylic esters: preparation of (1S,3R,4Z)-acetic acid 3-
d = 0.87 (t, J = 5.6 Hz, 3H), 1.25–1.36 (brs, 22H), 1.36–1.44 (m, 1H),
1.67–1.69 (m, 1H), 1.97–2.07 (m, 1H), 2.08–2.11 (m, 1H), 2.70 (dd, J =
6.5, 5.6 Hz, 1H), 4.50 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d =
14.1 (q), 15.9 (q), 22.7 (t), 25.3 (t), 29.3 (t), 29.5 (t), 29.6 (t), 31.9 (t), 34.0
(d), 35.4 (t), 78.4 (d), 180.1 ppm (s); IR (film): n˜max = 3440, 2920, 2849,
1751, 1645 cmÀ1; MS: m/z (%): 283 [M+1]+ (5), 282 [M]+ (16), 265
[MÀOH]+ (2), 264 [MÀH2O]+ (10), 211 [MÀC5H11]+ (3), 205 (10), 99
(100); elemental analysis calcd (%) for C18H34O2: C 76.54, H 12.13;
found: C 76.82, H 12.23.
methyl-1-tridecyl-dec-4-enyl ester (19a):
A mixture of 17a (200 mg,
0.57 mmol) and Lindlarꢁs catalyst (5 mg) in dry EtOAc (6 mL) was stir-
red at room temperature under a H2 atmosphere (ca. 1 atm). After 2h,
TLC analysis showed the reaction to be complete. The solution was fil-
tered through a pad of Celite and the pad was washed with EtOAc. The
combined organic phases were concentrated, and the crude product thus
obtained was used in the next step without purification.
At 08C under argon, DMAP (83 mg, 0.68 mmol) and acetic anhydride
(65 mL, 0.68 mmol) were added sequentially to a solution of the alkene
obtained as described above in dry CH2Cl2 (5 mL). The reaction mixture
was allowed to warm to room temperature and stirred for 1 h, and then
quenched with brine and extracted with CH2Cl2. The combined organic
layers were washed with brine, dried (MgSO4), filtered, and concentrated.
Flash column chromatography yielded 19a as a colorless oil (197.6 mg,
Acknowledgements
The authors thank the MYCT (PPQ2002–04361-C04–02) of Spain and
the Canary Islands Government for supporting this research. D. D. D.
thanks the Spanish MECD (Ministerio de Educación, Cultura y Deportes
88% overall yield). [a]D25
= +3.9 (c =
0.8 in CHCl3); 1H NMR
(400 MHz, CDCl3): d = 0.88–0.92(m, 6H), 0.95 (d, J = 7.1 Hz, 3H),
Chem. Eur. J. 2006, 12, 2593 – 2606
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2605

V. S. Martín et al.
de EspaÇa; Secretaría de Estado de Educación y Universidades) for a
postdoctoral fellowship co-financed by the Fondo Social Europeo. Many
thanks are also due to Dr. T. Martín, Dr. J. M. Betancort, F. R. P. Crisós-
tomo, and J. Gallagher for helpful discussions, suggestions, and/or valua-
ble assistance.
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Received: September 12, 2005
Published online: January 9, 2006
2606
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 2593 – 2606