Radical cyclization of α-bromo aluminum acetals onto alkenes and alkynes (radic[al] process): A simple access to γ-lactols and 4-methylene-γ-lactols

Article abstract of DOI:10.1002/chem.201100049

An efficient preparation of γ-lactols and methylene-γ-lactols is described. Highly acid-sensitive lactols are prepared in a concise manner by using a radical cyclization of aluminum acetals. The precursors for the radical reactions are readily prepared fr

Full text of DOI:10.1002/chem.201100049

FULL PAPER
DOI: 10.1002/chem.201100049
Radical Cyclization of a-Bromo Aluminum Acetals onto Alkenes and
Alkynes (Radic[Al] Process): A Simple Access to g-Lactols and
4-Methylene-g-Lactols
Anne Boussonniꢀre, Romain Bꢁnꢁteau, Nicolas Zimmermann, Jacques Lebreton,* and
Fabrice Dꢁnꢀs*[a]
Abstract: An efficient preparation of g-lactols and methylene-g-lactols is de-
scribed. Highly acid-sensitive lactols are prepared in a concise manner by using a
radical cyclization of aluminum acetals. The precursors for the radical reactions
are readily prepared from allyl or propargyl alcohols and a-bromo acids. Function-
alization of the resulting g-lactols and methylene-g-lactols can be achieved follow-
ing isolation, leading to synthetically useful building blocks, such as 1,4-diols, 1,4-
dienes, g-lactones, and polysubstituted tetrahydrofurans.
Keywords: aluminum
bond-forming reactions · cycliza-
tion · lactols · radical reactions
acetals
·
Introduction
ular, radical cyclizations have proven very successful for the
preparation of five-membered rings. However, as a result of
conformational constraints the radical cyclization of O-allyl-
and O-propargyl a-haloesters under reducing conditions to
form g-lactones and methylene-g-lactones, respectively, is
not an efficient process. Although some isolated examples
have been reported,[2] no general method is available to ach-
ieve the radical cyclization of a-haloesters, especially when
the reaction has to be carried out at a low temperature and
under reducing conditions (Scheme 1a). The cyclization of
g-Lactols represent versatile intermediates that can be easily
converted into the corresponding lactones. They can be re-
garded as masked aldehydes and thus transformations in-
volving the reactivity of the carbonyl group (e.g., Wittig ole-
fination, nucleophilic addition, etc.) can be achieved, leading
to the corresponding ring-opening products. Moreover, sub-
stitution of the hydroxyl group can be conveniently achieved
by using various nucleophiles (e.g., allylsilanes, silicon hy-
drides, thiols or selenols, etc.), thus delivering the corre-
sponding tetrahydrofuran derivatives and giving an entry to
sugar and nucleoside chemistry. The versatility of saturated
g-lactols has been extensively exploited in the past, whereas
the functionalization of related 4-methylene-g-lactols has
not been, thus far, the subject of intensive studies. The ab-
sence of general methods allowing an easy access to this
highly acid-sensitive class of compounds might be responsi-
ble for this apparent lack of interest. We report herein a
new access to g-lactols and 4-methylene-g-lactols based on a
one-pot sequence involving the radical cyclization of ther-
mally labile a-bromo aluminum acetals.
Radical reactions have been intensively investigated
during the last three decades.[1] The new synthetic methods
that arose from this work are characterized by their mild-
ness and their complementarity to ionic processes. In partic-
Scheme 1. Radical cyclization of a-bromo esters (a) and a-bromo ace-
tals (b).
a-haloacetals (the Ueno–Stork reaction),[3] developed inde-
pendently by Ueno[4] and Stork[5] in the 1980s, has become a
very popular approach to solve the problems encountered in
the cyclization of related a-bromo esters under reductive
conditions (Scheme 1b).[6] The resulting cyclic acetals have
proven to be useful precursors for the corresponding lactols
and lactones, though these transformations imply the use of
Brçnsted or Lewis acidic conditions, which constitutes a lim-
[a] A. Boussonniꢀre, R. Bꢁnꢁteau, N. Zimmermann,
Prof. Dr. J. Lebreton, Dr. F. Dꢁnꢀs
Universitꢁ de Nantes, CEISAM UMR 6230
UFR des Sciences et des Techniques
2 rue de la Houssiniꢀre BP 92208, 44322 Nantes Cedex 3 (France)
Fax : (+33)251-12-54-02
E-mail: Fabrice.Denes@univ-nantes.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100049.
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itation for this approach in the case of substrates possessing
highly acid-sensitive functionalities.[7]
Accordingly, by performing the radical cyclization at
À788C, the competitive process could be suppressed and the
desired cyclic acetal 2 was obtained in 50% yield (unopti-
mized). Unfortunately, the hydrolysis of acetal 2 into the
corresponding g-lactols proved to be, in our hands, unsuc-
cessful. These observations clearly indicate that, even at rel-
atively high concentrations in tin hydride (initially
10À1 molLÀ1 in our case), side reactions are to be expected
when conducting the radical cyclization of a-bromo acetals
or a-bromo esters onto carbon–carbon triple bonds at tem-
peratures allowing the vinyl radical intermediate to undergo
rearrangements. Moreover, the presence of acid-sensitive
functionalities on the substrate (a O-TBDMS (TBDMS=
tert-butyldimethylsilyl) silyl ether in compound 2) severely
limits the reaction conditions to choose from to access g-lac-
tols from cyclic acetals and calls for a new synthetic method.
Ideally, the latter should allow one to perform the radical
cyclization at low temperature from simple precursors and
would deliver the desired g-lactols without the need for an
additional step. These observations prompted us to develop
a more practical approach to g-lactols, starting from a-
bromo esters the preparation of which under classical
esterification conditions is well documented, by using a one-
pot reaction involving the formation of an a-bromo alumi-
num acetal and its cyclization under reductive radical condi-
tions at low temperature (Scheme 4).[11]
Results and Discussion
During the course of our research on the synthesis of biolog-
ically relevant macrocyclic compounds from marine sources,
we were in need for diol 1 as a key intermediate. The de-
sired diol 1 was expected to be obtained from cyclic acetal 2
by hydrolysis into the corresponding g-lactol, followed by
ring-opening in the presence of a metal hydride. We decided
to then investigate the cyclization of bromo acetal 3 under
Ueno–Stork conditions to form the cyclic acetal
(Scheme 2).
2
Scheme 2. Retrosynthetic analysis for the preparation of key-intermedi-
ate 1.
Attempts at cyclizing a-bromo acetal 3 (Scheme 3) at
room temperature in toluene, in the presence of nBu3SnH
and by using Et3B/O2 as a radical initiator, led to a complex
mixture the origin of which was attributed to the formation
of a highly reactive vinyl radical intermediate 4. Indeed,
Scheme 4. Aim of the work.
Aluminum acetals are well-known intermediates com-
monly obtained from carboxylic acid esters by reduction
with aluminum hydrides. When di-iso-butylaluminum hy-
dride (DIBAL-H) is used as a reducing agent, the aluminum
acetal intermediates have proven to be stable at low temper-
ature, thus allowing the selective reduction of carboxylic
acid esters into the corresponding aldehydes with limited
over-reduction into the alcohols.[12,13] Since the 1980s, alumi-
num acetals have found some applications in organic synthe-
sis. In particular, they have been trapped with electrophiles,
such as silyl triflates and silyl imidazole or acetic anhydride
and acid fluorides to give the corresponding monosilyl ace-
tals[14–16] and a-acetoxy acetals,[17,18] respectively. The latter
were found to be very efficient for the generation of oxacar-
benium ions, which could engage further in Prins[19] and
oxonia-Cope[20] rearrangements or could be trapped by vari-
ous nucleophiles.[21,22] Despite the aforementioned applica-
tions of aluminum acetals in ionic processes, their use as in-
termediates in radical reactions was unknown until very re-
cently, since our group reported a convenient radical cycliza-
tion of O-allyl-a-bromo esters leading to g-lactols.[11]
Scheme 3. Radical cyclization of a-bromo acetal 3 under classical Ueno–
Stork conditions.
such vinyl radicals are known to undergo 1,5-hydrogen
transfer,[8] a rearrangement facilitated in the case of 4 by
both a geminal effect of the substituents[9] and by the stabili-
zation of the resulting radical species 5. Although 1,5-hydro-
gen transfer in vinyl radicals is usually favored at higher
temperatures, examples of translocation at room tempera-
ture have also been reported.[10]
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A Simple Access to g-Lactols and 4-Methylene-g-Lactols
FULL PAPER
Cyclization of O-allyl-a-bromo esters: a-Bromo esters 6a–i
were easily prepared in high yields from allylic alcohols 8a–i
and a-bromo acids by using standard procedures for esterifi-
cation (see the Supporting Information for details). We
started a feasibility study in which various a-bromo alumi-
num acetals were generated by DIBAL-H reduction of the
parent a-bromo esters and subsequently subjected to radical
cyclization conditions according to (Scheme 5).
8d. Mono- and disusbtitution at the terminal position of the
alkene also led to the g-lactols in high yields (82–99%). As
illustrated by the cyclization of esters 6h and 6i, which both
contain labile protecting groups, such as benzyloxy methyl
(BOM) or trityl (Tr), the method tolerates acid-sensitive
functionalities, the corresponding g-lactols 7h and 7i being
isolated in good to high yields.
Disregarding the hemiacetal center, the stereoselectivity
of the cyclization reaction leading to 7a–d and 7h–i (C4–C5
selectivity) was in all cases over 95:5. For clarity, the selec-
tivity reported in Scheme 5 does not take into account the
hemiacetal center.
Cyclization of O-propargyl-a-bromo esters: We then turned
our attention to the more challenging formation of 4-meth-
ylene-g-lactols. The radical cyclization of a-halo acetals onto
the carbon–carbon triple bond has been found to be an effi-
cient process since the early development of this methodolo-
gy (Scheme 6).[23] Nevertheless, the hydrolysis of the cyclic
acetal generally results in the aromatization into the furan
derivatives instead of delivering the desired methylene-g-
lactols.[24–27]
Scheme 6. Radical cyclization of a-bromo acetals onto carbon–carbon
triple bonds under classical Ueno–Stork conditions.
We envisioned that our strategy could be applicable to
the cyclization of O-propargyl-a-bromo esters, allowing a
more practical approach to highly acid-sensitive methylene-
g-lactols, by starting from easily available a-bromo esters. A
series of representative a-bromo esters were prepared by
using standard protocols for esterification and they engaged
in the tandem Radic[Al] reaction, according to Scheme 7.
Scheme 5. Preparation of g-lactols by sequential one-pot reduction–cycli-
zation of a-bromo esters (Radic[Al] process).
a-Bromo ester 6a, which has a substituent at the allylic
position, was converted into the corresponding aluminum
acetal by reduction with DIBAL-H in toluene at À788C.
After complete disappearance of the starting material (ca.
15–30 min, TLC monitoring indicates formation of alcohol
8a), tri-n-butyltin hydride (1.1–1.3 equiv) and Et3B (0.3-
1 equiv, 1m in hexane) were simultaneously introduced at
À788C, followed by air (ca. 1 mL). The conversion was
monitored by TLC analysis, which allowed the disappear-
ance of alcohol 8a to be observed. Gratifyingly, the desired
g-lactol 7a was obtained in 90% yield, following aqueous
workup and purification by flash chromatography over silica
gel (Scheme 5). Similarly, substrate 6b led to the desired g-
lactol 7b in 95% yield. Substituents at the carboxylic acid
moiety were also tolerated, as illustrated by the cyclization
to 7c–f. In most cases, only trace amounts of over-reduction
products 8a–i could be detected but for 6d, which gave the
expected g-lactol 7d in somewhat lower yield (59%) togeth-
er with a significant amount (ca. 40%) of recovered alcohol
Scheme 7. Preparation of 4-methylene-g-lactols by sequential one-pot re-
duction–cyclization of a-bromo esters (Radic[Al] process).
The reduction/cyclization sequence was examined first
with a-bromo esters 9a–e containing a terminal alkyne. The
results are collected in Table 1. In most cases, the tandem
reaction proved successful, with the acid-sensitive methyl-
ene-g-lactols being isolated in good to high yields. For in-
stance, cyclization of 9a led to the corresponding methyl-
ene-g-lactols 10a in 67% yield (Table 1, entry 1). The latter,
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F. Dꢁnꢀs, J. Lebreton et al.
Table 1. Synthesis of 4-methylene-g-lactols by using the reduction–cycli-
zation sequence.
ed alkynyl moiety, gave the corresponding lactol 10j in 94%
yield (E/Z 31:69, Table 2, entry 5). Arylidene-g-lactols 10k
and 10l were obtained in 88 and 91% yields, respectively,
from esters 9k and 9l, which both present a phenyl-substi-
tuted alkynyl side chain (Table 2, entries 6 and 7). It is
worthy of note that under our reaction conditions (À788C,
initial concentration of nBu3SnH of 1.1ꢃ10À1 mol.lÀ1) com-
pound 10l could be isolated in high yield without any traces
of bicyclic products resulting from a 6-exo-trig cyclization
onto the pendant alkenyl side chain. Accordingly, the cycli-
zation of 9m and 9n led to 10m and 10n in moderate to
high yields (Table 2, entries 8 and 9) with high levels of dia-
stereoselectivity (E/Z>95:5 and E/Z=5:95, respectively).
As previously observed for 9e and 9h, the reduction of the
sterically demanding a-bromo ester 9m was better achieved
in the presence of two equivalents of DIBAL-H.
As illustrated by the cyclization of some representative
substrates and/or lactols presented in Table 2, the method
tolerates the presence of acid-sensitive functionalities. For
instance, under the previously described reaction conditions,
a-bromo esters 9o and 9p afforded the corresponding lac-
tols 10o and 10p in satisfactory yields (72 and 74%, respec-
tively) without cleavage of the O-trityl bond (Table 2, en-
tries 10 and 11). Similarly, the O-benzyloxymethyl-protected
arylidene-g-lactol 10q could be obtained in 69% yield from
9q (Table 2, entry 12). Under the same reaction conditions,
the cyclization of 9r led to methylene-g-lactol 10r in 78%
yield, without ring-opening of the cyclopropylvinyl radical
intermediate (Table 2, entry 13).[28]
Entry
1
Substrate[a]
Product[b]
Yield [%][c]
67
2
3
4
5
82
77[d]
79[e]
57[e]
[a] All reactions were carried out with a-bromo esters (2 mmol) in tolu-
ene (see the Supporting Information for details), by using DIBAL-H
(1.1 equiv) at À788C, then nBu3SnH (1.1 equiv) and Et3B (0.3–1.1 equiv),
unless otherwise stated. [b] Lactols were isolated as mixture of diastereo-
isomers. [c] Yields of isolated products. [d] Diastereoselectivity C3–C5:
d.r.=62:38. [e] Two equivalents of DIBAL-H were used for the reduc-
tion.
however, was found to be particularly unstable and could
not be stored for a prolonged period of time. Similar results
were obtained with 9b and 9c, which afforded 10b and 10c
in 82 and 77% yields, respectively (Table 1, entries 2 and 3).
a-Bromo esters 9d presenting a gem-disubstituted position,
which could prevent aromatization into the corresponding
furans, led to the expected methylene-g-lactols 10d in 79%
yield (Table 1, entry 4). It is worthy of note that the reduc-
tion of 9d required the use of two equivalents of DIBAL-H
to reach complete conversion. Similarly, reduction of the
more hindered a-bromo esters 9e also required the use of
an excess of DIBAL-H. In this case, the radical cyclization
led to the expected lactol 10e in only 57% yield (Table 1,
entry 5).
Mechanistic considerations: The following mechanistic ra-
tional can be proposed to account for the results obtained in
both series (O-allyl- and O-propargyl esters). Aluminum
acetal 12, obtained by reduction of the a-bromo ester with
DIBAL-H, undergoes halogen abstraction by the tin-cen-
tered radical, generated from nBu3SnH in the presence of
Et3B/O2 as a radical initiator, to form the corresponding
carbon-centered radical 13, which undergoes a 5-exo-trig or
5-exo-dig radical cyclization to give 14 (Scheme 8). Hydro-
gen-atom abstraction from the tin hydride reagent by the cy-
clized carbon-centered radical 14 gives the cyclic aluminum
With these promising results in hands, we then turned our
attention to the preparation of alkylidene- and arylidene-g-
lactols. The results are presented in Table 2. Under the same
reaction conditions, a-bromo ester 9 f gave the correspond-
ing alkylidene-g-lactol 10 f in 78% yield and with a moder-
ate E/Z selectivity in favor of the E isomer (E/Z 71:29,
Table 2, entry 1). The diastereoselectivity could be slightly
increased by using a bulkier alkyl substituent (vide infra,
Table 2, entry 4). Cyclization of 9g, containing a gem-disub-
stitution at the propargylic position, led to 10g in excellent
yield (Table 2, entry 2). On the other hand, gem-disubstitut-
ed a-bromo ester 9h was converted into lactol 10h in mod-
erate yield (Table 2, entry 3). Alkylidene-g-lactol 10i was
obtained in 74% yield from 9i as a 82:18 mixture of E/Z
isomers (Table 2, entry 4). The reduction/cyclization se-
quence carried out with 9j, which presents a TMS-substitut-
Scheme 8. Mechanistic proposal for the cyclization of a-bromo esters by
using the Radic[Al] process.
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A Simple Access to g-Lactols and 4-Methylene-g-Lactols
FULL PAPER
Table 2. Synthesis of alkylidene- and arylidene-g-lactols by using the reduction–cyclization sequence (Radic[Al] process).
Entry
a-Bromo ester[a]
Product[b]
d.r.[c]
Yield [%][d]
Entry
a-Bromo ester[a]
Product[b]
d.r.[c]
Yield [%][d]
58[e]
1
71:29
78
8
>95:5
2
3
4
5
63:37
62:38
82:18
31:69
99[e]
50[e]
74
9
5:95
94[e]
10
11
12
37:63
17:83
26:74
72
74
94
69
6
7
26:74
22:78
88
91
13
52:48
78
[a] Unless otherwise stated, all reactions were carried out with a-bromo esters (2 mmol) in toluene (see the Experimental Section for details), by using
DIBAL-H (1.1 equiv) at À788C, then nBu3SnH (1.1–1.3 equiv), Et3B (0.3–1.1 equiv), and air (ca. 1 mL). [b] Major E/Z isomer shown. [c] E/Z selectivity
determined by NMR spectroscopic analysis after reduction into the corresponding diols with NaBH4 or LiAlH4 (see below and the Supporting Informa-
tion for details). For clarity reasons, the selectivity reported in Table 2 does not take into account the hemiacetal center. [d] Yields of isolated products.
[e] Two equivalents of DIBAL-H were used for the reduction.
acetal 15, which leads to the g-lactol upon aqueous workup.
To the best of our knowledge, this is the first report of a re-
action involving a radical aluminum acetal species.
The cyclization of aluminum acetals onto internal alkynes
led to a mixture of E and Z isomers. The nature of the sub-
stituent at the terminal position of the alkyne and the pres-
ence of side chains on the lactol ring showed a strong influ-
ence on the diastereoselectivity. The reverse E/Z selectivity
observed for 10k and 10l relative to 10 f and 10i (Table 2,
entries 6 and 7, vs. entries 1 and 4) is in agreement with pre-
vious studies, which have demonstrated that sp-hybridized
phenyl-substituted vinyl radicals, such as 17 (Scheme 9), are
trapped under kinetic control from the less hindered side
and thus lead to the less stable Z olefins, whereas sp2-hydri-
dized vinyl radicals, such as 16 (Scheme 9), preferentially ab-
stract a hydrogen atom from the more hindered side (except
for 10h), leading to the more stable E olefin.[29–31] Accord-
ingly, the cyclization of 9m and 9n into 10m and 10n
(Table 2, entries 8 and 9) occurred with high levels of diaste-
reoselectivity (E/Z>95:5 and E/Z 5:95, respectively).
Interestingly, the radical cyclization onto 1-TMS-alkynes
also led to the more sterically demanding Z olefin, thus sup-
Scheme 9. Hydrogen abstraction from nBu3SnH by the alkenyl radical in-
termediate under kinetic control. Stereoselectivity outcome depending
upon the nature of the alkenyl radical and the substituents.
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F. Dꢁnꢀs, J. Lebreton et al.
porting previous reports in which alkenyl radicals substitut-
ed with a silyl group are believed to be sp-hybridized.[32] The
nature of the protecting group of the hydroxyl functionality
in 9o, 9p, and 9q also played a role in the control of the
carbon–carbon double bond configuration. Indeed, while no
significant changes have been observed in the cyclization of
aryl-substituted alkynes 9k, 9l, and 9q, the E/Z selectivity
was either reversed (71:29 and 37:63, for 10 f and 10o, re-
spectively), or increased (from 31:69 to 17:83 for 10j and
10p, respectively) by using a bulky triphenylmethyl protect-
ing group.
Functionalization of g-lactols and 4-methylene-g-lactols:
The versatility of the resulting g-lactols was illustrated by
various transformations. For instance, reaction with allyltri-
methyl silane,[33,34] thiophenol, or Et3SiH[33] in the presence
of BF3·Et2O gave the corresponding tetrahydrofurans 18–20
in good yields (>80% from 7b, Scheme 10).
Scheme 11. Illustration of the versatility of g-lactols by using their reac-
tivity as masked aldehydes.
90% yield, respectively) under very mild conditions
(Scheme 12). Note that the latter transformations could not
be achieved directly from cyclic acetals obtained by the clas-
sical Ueno–Stork reaction.
Scheme 10. Illustration of the versatility of g-lactols by using their reac-
tivity as oxonium ion precursors.
Oxidation of g-lactol 7b could be achieved by the use of
Ac-2,2,6,6-tetramethylpiperidine N-oxide (Ac-TEMPO) in
the presence of N-chlorosuccinimide (NCS) under phase-
transfer conditions, or alternatively in the presence of pyri-
dinium chlorochromate (PCC), leading to lactone 21 in
quantitative yield (Scheme 11). Olefination with three
equivalents of a stabilized phosphorous ylide was carried
out in THF at room temperature and gave 22 in 87% yield
as an 89:11 mixture of E/Z isomers. Ring-opening of lactol
7b could also be achieved under mild conditions either with
sodium borohydride in THF/MeOH or by the use of a vinyl
Grignard reagent, following metallation with nBuLi, to give
1,4-diols 23b and 24, respectively.
More interestingly, PCC oxidation of 7i, for which the hy-
droxyl group was protected as a highly acid-sensitive triphe-
nylmethyl ether, gave lactone 25 in high yield as a single
diastereoisomer. Reduction of g-lactols 7h and 7i, which
both possess an acid-sensitive protecting group for the hy-
droxyl moiety, into the corresponding mono-protected triols
23h and 23i could also be achieved in high yields (99 and
Scheme 12. Oxidation and reduction of g-lactols possessing acid-sensitive
functionalities.
The reactivity of 4-methylene-g-lactols with various nucle-
ophiles was then investigated. We first turned our attention
to the ring-opening of methylene-, alkylidene-, and aryli-
dene-g-lactols with hydrides. Gratifyingly, lactols 10a–r were
efficiently converted into the corresponding 1,4-diols 26a–r
under mild reaction conditions, according to Scheme 13. In
the case of alkylidene- and arylidene-g-lactols, the diols
were obtained as an E/Z mixture of diastereoisomers, thus
allowing E/Z ratio (for lactols 10 f–r) and the diastereomeric
C2–C4 ratio (for lactols 10c) to be determined at this stage.
The results are presented in Table 3.
The reduction of 4-methylene-g-lactols 10a–d (Table 3,
entries 1–4) could be easily achieved at room temperature
by using sodium borohydride in THF/MeOH, leading to the
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A Simple Access to g-Lactols and 4-Methylene-g-Lactols
FULL PAPER
such as alkylidene- and arylidene-4-methylene-g-lactols 10h
and 10m (Table 3, entries 8 and 13) required the use of
LiAlH4 for the reduction into the corresponding diols 26h
and 26m (99 and 85% yields, respectively), whereas nonhin-
dered alkylidene- and arylidene-4-methylene-g-lactols 10 f,
10g, 10i–l, 10n, 10o, 10q, and 10r could be reduced in good
to high yields with the use of a milder reducing agent
(Table 3, entries 6, 7, 9–12, 14, 15, 17, and 18). In the case of
the highly acid-sensitive g-lactols 26p, the best results were
obtained with sodium bis(2-methoxyethoxy)aluminumhy-
dride (Red-Al) in CH2Cl2.
Interestingly, 4-methylene-g-lactol 10l could be conven-
iently converted into lactol 27 in a three-step sequence in-
volving the ring-opening of 10l with sodium borohydride to
give diol 26l, followed by selective protection of the primary
hydroxyl group and oxidative cleavage of the two carbon–
carbon double bonds with ozone. The resulting g-hydroxy al-
Scheme 13. Reduction of 4-methylene-g-lactols into 1,4-diols.
desired 1,4-diols 26a–d in good to high yields (67–99%). On
the other hand, compound 10e containing a gem-dimethyl
substitution next to the hemiacetal center proved to be un-
reactive under similar reaction conditions.
In this case, a more powerful reducing agent, such as lithi-
um aluminum hydride was needed to give diol 26e in high
yield (Table 3, entry 5). Similarly, other hindered lactols,
Table 3. Reduction of g-lactols 10a–r into 1,4-diols with hydrides.
Entry
Substrate[a]
Product
Yield [%][b]
d.r.[c]
Entry
10
Substrate[a]
Product
Yield [%][b]
82
d.r.[c]
1
99
–
31:69
2
92
–
11
91
26:74
3
4
5
67
62:38[d]
12
13
14
93
85[e]
94
28:72
>95:5
5:95
99
–
–
99[e]
6
7
8
9
97
71:29
33:67
62:38
82:18
15
16
17
18
78
37:63
17:83
26:74
53:47
91
67[f]
99[e]
87
99
80
[a] All reactions were carried out with NaBH4 in MeOH/THF at room temperature, unless otherwise stated. [b] Yields of isolated products. [c] Selectivity
E/Z determined by NMR spectroscopy (NOE measurements). [d] d.r. C2–C4. [e] LiAlH4 was used. [f] Red-Al was used.
Chem. Eur. J. 2011, 17, 5613 – 5627
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5619

F. Dꢁnꢀs, J. Lebreton et al.
dehyde spontaneously cyclized into lactol 27 (72% yield for
the three steps) giving an entry to 2,5-disubstituted tetrahy-
drofuran derivatives (Scheme 14).
Scheme 16. Base-mediated Michael cyclization of diene 28a.
dene-g-lactols could engage in new carbon–carbon bond-
forming reactions, as illustrated by the highly diastereoselec-
tive allylation of (Z)-10k by using allyltrimethylsilane in the
presence of BF3·Et2O, which led to the corresponding poly-
substituted tetrahydrofuran 30 with a complete control of
the stereochemistry (Scheme 17).
Scheme 14. Three-step sequence for the preparation of lactol 27 from
lactol 10l. TBDPS=tert-butyldiphenylsilyl.
The reactivity of alkylidene- and arylidene-g-lactols under
Wittig–Horner conditions was then investigated. Olefination
reactions proved successful, as illustrated by the reaction of
10a–b and (Z)-10k with a stabilized phosphorous ylide de-
livering 1,4-dienes 28a–b and 28k in high yields, without mi-
gration of the double bond (Scheme 15). Whilst 5-substitut-
Scheme 17. Functionalization of (Z)-10k with allyltrimethylsilane.
Conclusion
We have reported herein that thermally labile a-bromo alu-
minum acetal species derived from O-allyl-a-bromo esters
by reduction with DIBAL-H are very useful intermediates,
which are stable enough at low temperature to engage in
radical cyclization at a low temperature in the presence of
nBu3SnH and Et3B/O2. This one-pot process led to g-lactols
in good to excellent yields. The scope of this reaction could
be extended to include the related O-propargyl-a-bromo
esters, giving access to polysubstituted methylene g-lactols, a
class of highly acid-sensitive compounds the preparation of
which by using the classical Ueno–Stork approach proved to
be rather difficult. This one-pot procedure appears quite
general and efficient, especially when disubstituted alkynyl
side chains are employed as radical acceptors. This very
simple approach tolerates substitution at the different posi-
tions of the starting a-bromo ester derivatives with a high
flexibility. Relative to the classical cyclization of a-halo ace-
tals, several advantages of the approach reported here can
be highlighted. First, the precursors are easily prepared in
high yields by simple esterification of allylic or propargylic
alcohols with a-bromo acids by using standard procedures.
The mild reaction conditions are compatible with acid-sensi-
tive functionalities, such as labile hydroxy protecting groups.
Finally, the versatility of saturated and unsaturated g-lactols
produced by this reaction makes them particularly attractive
for further transformations. The classical radical cyclization
of a-halo acetals pioneered by Ueno and Stork produces
cyclic acetals. The latter represent a protected form of the
corresponding aldehyde moiety and are unreactive under
basic conditions. On the contrary, the g-lactols obtained by
using the Radic[Al] process could engage directly in reduc-
Scheme 15. Olefination of 4-methylene-g-lactols by using stabilized phos-
phorous ylides.
ed-g-lactols 10a and (Z)-10k led to the desired 1,4-dienes in
good to high yields but with only moderate levels of diaste-
reoselectivity in favor of the E isomer (E/Z ca. 90:10), the
olefination reaction from 10b proved to be highly stereose-
lective, the corresponding diene 28b being obtained exclu-
sively as the E isomer with no traces of the Z isomer detect-
ed by NMR spectroscopic analysis of the crude reaction
mixture.
Gratifyingly, attempts at cyclizing diene 28a under basic
conditions (1.1 equiv of tBuOK) revealed the desired meth-
ylene-tetrahydrofurans 29a without migration of the exocy-
clic carbon–carbon double bond (Scheme 16).
Contrary to saturated lactols, such as 7b, functionalization
of 4-methylene-g-lactols, such as 10a, in the presence of
Lewis acids proved thus far unsuccessful. The high sensitivi-
ty to acidic media of this class of lactols might account for
this observation. On the other hand, more stable 4-aryli-
5620
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5613 – 5627

A Simple Access to g-Lactols and 4-Methylene-g-Lactols
FULL PAPER
er 9a (0.57 g, 2 mmol). Flash chromatography (petroleum ether/Et2O
70:30) gave 10a (0.27 g, 67%) as
tion reactions with hydrides under mild conditions, as well
in carbon–carbon bond-forming reactions, thus complement-
ing nicely the classical approach. The application of this
methodology for the total synthesis of macrolides is current-
ly underway in our laboratory.
a
colorless oil. 1H NMR (C6D6,
300 MHz; mixture of two isomers at the hemiacetal center): d=7.33–7.15
(m, 10H; two isomers), 5.55 (brs, 1H; major isomer), 5.47 (brs, 1H;
minor isomer), 4.96 (s, 1H; major isomer), 4.92 (s, 1H; minor isomer),
4.84 (s, 1H; major isomer), 4.79 (s, 1H; minor isomer), 4.76 (brs, 1H;
major isomer), 4.47 (brd, J=9.0 Hz, 1H; minor isomer), 3.67 (brs, 2H;
OH, two isomers), 3.09–2.76 (m, 4H; two isomers), 2.61–2.47 (m, 4H;
two isomers), 2.23–1.83 ppm (m, 4H; two isomers); 13C NMR (C6D6,
75 MHz; mixture of two isomers at the hemiacetal center): d=149.8 (C,
minor isomer), 149.6 (C, major isomer), 142.44 (C, minor isomer), 142.40
(C, major isomer), 128.9 (2CHAr), 128.8 (2CHAr), 128.7 (4CHAr), 126.1
(2CHAr), 105.5 (CH2, minor isomer), 105.4 (CH2, major isomer), 97.7
(CH, minor isomer), 97.3 (CH, major isomer), 80.3 (CH, minor isomer),
78.7 (CH, major isomer), 41.0 (CH2, minor isomer), 40.6 (CH2, major
isomer), 39.4 (CH2, minor isomer), 37.7 (CH2, major isomer), 32.6 (CH2,
minor isomer), 31.9 ppm (CH2, major isomer); IR (neat): n˜ =3403, 3025,
2933, 2860, 1668, 1605, 1495, 1453, 1177, 1028, 889, 700 cmÀ1; MS (ESI+):
m/z: for C13H16O2: 227 [M+Na]+; HRMS (ESI+): m/z: calcd for
C13H16O2: 227.1043 [M+Na]+; found: 227.1032; TLC: Rf =0.48 (petro-
leum ether/Et2O 50:50).
Experimental Section
General considerations: All reactions were performed under an argon at-
mosphere. THF and toluene were distilled from sodium/benzophenone
and sodium, respectively. DIBAl-H and n-tributyltin hydride were pur-
chased from Acros Organics and Et3B (1m in hexanes) from Aldrich.
Flash column chromatography (FC): SDS-CarloErba Silica gel 60 ACC
(40–63 mm). TLC: Merck silica gel 60 F254 analytical plates; detection
either with UV (254 nm) or dipping in a solution of KMnO4 (3 g), K2CO3
(20 g), NaOH 5% (5 mL) in H2O (300 mL) or in a solution of vanillin
1
(1 g), H2SO4 96% (2 mL) in EtOH (200 mL) and subsequent heating. H
and 13C NMR spectra were recorded on a BRUKER ARX300 (1H=300,
3-Butyl-4-methylenetetrahydro-2-furanol (10b): The title compound was
prepared according to the general procedure GP1 from a-bromoester 9b
(1.17 g, 5 mmol). Flash chromatography (petroleum ether/Et2O 70:30)
gave 10b (0.64 g, 82%) as a colorless oil. 1H NMR (CD3OD, 300 MHz;
mixture of two isomers at the hemiacetal center): d=5.41 (d, J=4.8 Hz,
1H; minor isomer), 5.16 (d, J=0.9 Hz, 1H; major isomer), 5.00–4.97 (m,
2H; major isomer), 4.95–4.90 (m, 2H; minor isomer), 4.51–4.33 (m, 4H;
two isomers), 2.56–2.37 (m, 2H; two isomers), 1.70–1.18 (m, 12H; two
isomers), 1.02–0.87 ppm (m, 6H; two isomers); 13C NMR (CD3OD,
75 MHz; mixture of two isomers at the hemiacetal center): d=151.7 (C,
major isomer), 151.2 (C, minor isomer), 105.6 (CH2, major isomer), 104.2
(CH, major isomer), 103.9 (CH2, minor isomer), 99.6 (CH, minor
isomer), 70.5 (CH2, minor isomer), 70.3 (CH2, major isomer), 52.4 (CH,
major isomer), 49.2 (CH, minor isomer), 33.3 (CH2, major isomer), 31.2
(CH2, minor isomer), 30.4 (CH2, major isomer), 27.5 (CH2, minor
isomer), 24.1 (CH2, minor isomer), 23.8 (CH2, major isomer), 14.4 ppm
(2CH3, two isomers); IR (neat): n˜ =3404, 2956, 2930, 2859, 1456, 1436,
1027, 931, 885 cmÀ1; MS (CI+): m/z: for C9H16O2: 157 [M+H]+; HRMS
(CI+): m/z: calcd for C9H16O2: 157.1229 [M+H]+; found: 157.1227; TLC:
Rf =0.64 (petroleum ether/Et2O 50:50).
13C=75 MHz) and
a
BRUKER Avance3 (1H=400, 13C=100 MHz);
chemical shifts (d) are reported in parts per million (ppm) and coupling
constants (J) in Hertz (Hz); chemical shifts in ppm relative to tetrame-
1
thylsilane (d=0 ppm) or CHCl3 for H (d=7.26 ppm) and CDCl3 for 13C
(d=77.16 ppm) for spectra recorded in CDCl3; chemical shift in ppm rel-
ative to benzene (d=7.16 ppm) for 1H (d=7.16 ppm) and C6D6 for 13C
(d=128.02 ppm) for spectra recorded in C6D6. LRMS: Thermo-Finnigan
DSQII quadripolar spectrometer (coupled with a TraceUltra GC appara-
tus); chemical ionization (CI) and electronic impact (EI, 70 eV) m/z
(%); instrument Thermo-Finnigan LCQ Advantage; electrospray ioniza-
tion (ESI). HRMS: instruments Thermo-Finnigan MAT 95 XL spectrom-
eter or BRUCKER microTOF QII; ionizations (CI, ESI, and EI, 70 eV).
IR spectra were recorded on a BRUKER Vector 22 spectrometer; fre-
quencies are reported in cmÀ1. Melting points (m.p.) were determined on
a Stuart Scientific apparatus 7SMP3.
General procedure GP1 for the preparation of g-lactols: DIBAl-H
(4.2 mL, 1.2m in toluene, 5.0 mmol) was added dropwise to a solution of
a-bromoester (5.0 mmol) in toluene (40 mL) under argon at À788C.
After complete disappearance of the starting material (15 min, TLC
monitoring), Et3B (2.5 mL, 1m in hexanes, 2.5 mmol), nBu3SnH
(1.34 mL, 5.0 mmol), and air (ca. 1 mL) were simultaneously added drop-
wise at À788C. The mixture was kept at À788C until complete disappear-
ance of alcohol (TLC monitoring, vanillin revelation). The cold bath was
removed and the reaction mixture quenched by a saturated aqueous solu-
tion of NaF. The reaction mixture was stirred vigorously overnight, then
placed in a separatory funnel and diluted with CH2Cl2 without agitating.
The organic phase was collected and the procedure repeated twice. The
aqueous phase was then extracted several times with CH2Cl2. The result-
ing organic phase was dried over Na2SO4, filtered, concentrated in vacuo,
and the residue was purified by flash chromatography.
3-Butyl-4-methylene-5-phenethyltetrahydro-2-furanol (10c): The title
compound was prepared according to the general procedure GP1 from
a-bromoester 9c (0.68 g, 2 mmol). Flash chromatography (petroleum
ether/Et2O 70:30) gave 10c (0.40 g, 77%) as a colorless oil. 1H NMR
(C6D6, 300 MHz; mixture of four isomers): d=7.25–7.05 (m, 20H), 5.47–
5.15 (m, 4H), 4.88–4.42 (m, 12H), 3.64–2.45 (m, 12H, 4H; OH), 2.15–
1.80 (m, 8H), 1.76–1.13 (m, 24H), 0.92–0.81 ppm (m, 12H); 13C NMR
(C6D6, 75 MHz; mixture of four isomers): d=154.4 (C), 154.1 (C), 153.7
(C), 153.5 (C), 142.52 (CAr), 142.47 (CAr), 142.43 (CAr), 142.37 (CAr),
128.9 (4CHAr), 128.8 (4CHAr), 128.7 (8CHAr), 126.1 (4CHAr), 105.5
(CH2), 105.4 (CH2), 104.1 (CH2), 103.8 (CH2), 102.8 (CH), 102.2 (CH),
98.2 (CH), 97.8 (CH), 80.2 (CH), 80.1 (CH), 79.6 (CH), 79.2 (CH), 52.2
(CH), 52.0 (CH), 49.0 (CH), 48.5 (CH), 39.5 (CH2), 39.3 (CH2), 38.6
(CH2), 38.2 (CH2), 33.4 (CH2), 32.8 (CH2), 32.60 (CH2), 32.57 (CH2), 32.2
(CH2), 31.9 (CH2), 30.4 (CH2), 30.2 (CH2), 30.0 (CH2), 29.5 (CH2), 27.1
(CH2), 26.6 (CH2), 23.4 (CH2), 23.0 (2CH2), 23.0 (CH2), 14.3 (CH3), 14.3
(CH3), 14.2 ppm (2CH3); IR (neat): n˜ =3403, 3026, 2930, 2858, 1496,
1456, 1029, 888, 748, 699 cmÀ1; MS (ESI+): m/z: for C17H24O2: 283
[M+Na]+; HRMS (ESI+): m/z: calcd for C17H24O2: 283.1669 [M+Na]+;
found: 283.1661; TLC: Rf =0.79 (petroleum ether/Et2O 50:50).
General procedure GP2 for the preparation of g-lactols: DIBAL-H
(8.4 mL, 1.2m in toluene, 10.0 mmol) was added dropwise to a solution of
a-bromoester (5.0 mmol) in toluene (40 mL) under argon at À788C.
After complete disappearance of the starting material (15 min, TLC
monitoring), Et3B (2.5 mL, 1m in hexanes, 2.5 mmol) and nBu3SnH
(1.34 mL, 5.0 mmol) were simultaneously added dropwise at À788C. The
mixture was kept at À788C until complete disappearance of alcohol
(TLC monitoring, vanillin revelation). The cold bath was removed and
the reaction mixture quenched by a saturated aqueous solution of NaF.
The reaction mixture was stirred vigorously overnight, then placed in a
separatory funnel and diluted with CH2Cl2 without agitating. The organic
phase was collected and the procedure repeated twice. The aqueous
phase was then extracted twice with CH2Cl2. The resulting organic phase
was dried over Na2SO4, filtered, concentrated in vacuo, and the residue
was purified by flash chromatography.
3-Butyl-5,5-dimethyl-4-methylenetetrahydro-2-furanol (10d): The title
compound was prepared according to the general procedure GP2 from
a-bromoester 9d (653 mg, 2.5 mmol). Flash chromatography (petroleum
ether/Et2O 80:20) gave 10d (365 mg, 79%) as a colorless oil. 1H NMR
(C6D6, 300 MHz; mixture of two isomers at the hemiacetal center): d=
5.36 (dd, J=3.7, 3.9 Hz, 1H), 5.23 (brs, 1H), 4.81–4.75 (m, 4H), 3.63 (d,
J=2.8 Hz, 1H; OH), 3.30 (d, J=2.2 Hz, 1H; OH), 2.70 (t, J=7.0 Hz,
4-Methylene-5-phenethyltetrahydro-2-furanol (10a): The title compound
was prepared according to the general procedure GP1 from a-bromoest-
Chem. Eur. J. 2011, 17, 5613 – 5627
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5621

F. Dꢁnꢀs, J. Lebreton et al.
1H), 2.59–2.55 (m, 1H), 1.71–1.18 (m, 12H), 1.55 (s, 3H), 1.52 (s, 3H),
1.31 (s, 3H), 1.30 (s, 3H), 0.89 (t, J=7.0 Hz, 3H), 0.83 ppm (t, J=6.9 Hz,
3H); 13C NMR (C6D6, 75 MHz; mixture of two isomers at the hemiacetal
center): d=159.6 (C), 158.8 (C), 104.6 (CH2), 103.1 (CH2), 102.0 (CH),
97.4 (CH), 83.4 (C), 83.1 (C), 52.5 (CH), 48.4 (CH), 33.4 (CH2), 31.6
(CH3), 30.6 (CH3), 30.4 (CH3), 30.2 (CH2), 30.1 (CH3), 29.8 (CH2), 26.8
(CH2), 23.4 (CH2), 23.0 (CH2), 14.3 (CH3), 14.2 ppm (CH3); IR (neat):
n˜ =3403, 2957, 2871, 1662, 1460, 1190, 1000, 885 cmÀ1; MS (ESI+): m/z:
for C11H20O2: 207 [M+Na]+; HRMS (ESI+): m/z: calcd for C11H20O2:
207.1356 [M+Na]+; found: 207.1361; TLC: Rf =0.68 (petroleum ether/
Et2O 50:50).
(m, 4H; two isomers), 1.29 (s, 3H; E isomer), 0.83 (t, J=7.3 Hz, 3H; E
isomer), 0.83 ppm (t, J=7.3 Hz, 3H;
Z
isomer); 13C NMR (C6D6,
75 MHz; 63:37 mixture of E/Z isomers): d=145.7 (C, E isomer), 143.9
(C, Z isomer), 121.3 (CH, Z isomer), 119.8 (CH, E isomer), 97.0 (CH, E
isomer), 96.5 (CH, Z isomer), 83.1 (C, E isomer), 82.1 (C, Z isomer), 42.7
(CH2, Z isomer), 37.5 (CH2, E isomer), 32.0 (CH2, E isomer), 30.9 (CH2,
E isomer), 30.5 (CH3, Z isomer), 29.9 (CH3, Z isomer), 29.8 (CH3, E
isomer), 28.3 (CH3, Z isomer), 23.5 (CH2, Z isomer), 22.9 (CH2, E
isomer), 13.9 (CH3, Z isomer), 13.8 ppm (CH3, E isomer); IR (neat): n˜ =
3406, 2963, 2930, 2871, 1456, 1360, 1142, 1071, 967, 827 cmÀ1; MS (ESI+):
m/z: for C10H18O2: 193 [M+Na]+; HRMS (ESI+): m/z: calcd for
C10H18O2: 193.1191 [M+Na]+; found: 193.1199; TLC: Rf =0.54 (petro-
leum ether/Et2O 50:50).
3,3-Dimethyl-4-methylene-5-phenethyltetrahydro-2-furanol (10e): The
title compound was prepared according to the general procedure GP2
from a-bromoester 9e (618 mg, 2 mmol). Flash chromatography (petro-
leum ether/Et2O 80:20) gave 10e (270 mg, 57%) as a colorless oil.
1H NMR (CD3OD, 300 MHz; mixture of two isomers at the hemiacetal
center): d=7.28–7.12 (m, 10H; two isomers), 5.01 (s, 1H; major isomer),
4.93 (s, 1H; minor isomer), 4.91 (d, J=15.7 Hz, 1H; major isomer), 4.90
(d, J=15.7 Hz, 1H; major isomer), 4.86 (d, J=17.1 Hz, 1H; minor
isomer), 4.85 (d, J=17.1 Hz, 1H; minor isomer), 4.63–4.58 (m, 1H;
major isomer), 4.47–4.41 (m, 1H; minor isomer), 2.93–2.64 (m, 4H; two
isomers), 2.03–1.77 (m, 4H; two isomers), 1.12 (s, 3H; major isomer),
1.10 (s, 3H; major isomer), 1.09 (s, 3H; minor isomer), 1.08 ppm (s, 3H;
minor isomer); 13C NMR (CD3OD, 75 MHz; mixture of two isomers at
the hemiacetal center): d=160.9 (C, major isomer), 160.6 (C, minor
isomer), 143.6 (CAr, minor isomer), 143.4 (CAr, major isomer), 129.52
4-Butylidene-3,3-dimethyl-5-phenethyltetrahydro-2-furanol (10h): The
title compound was prepared according to the general procedure GP2
from a-bromoester 9h (0.70 g, 2 mmol). Flash chromatography (petro-
leum ether/Et2O 60:40) gave 10h (0.28 g, 50%) as
a colorless oil.
1H NMR (C6D6, 300 MHz; mixture of four isomers): d=7.27–7.05 (m,
20H), 5.14–4.35 (m, 12H), 3.09–2.75 (m, 10H), 2.74 (d, J=3.5 Hz, 1H;
OH), 2.65 (d, J=3.3 Hz, 1H; OH), 2.24–1.67 (m, 16H), 1.36 (s, 3H),
1.33–1.21 (m, 8H), 1.25 (s, 3H), 1.174 (s, 3H), 1.167 (s, 3H), 1.13 (s, 3H),
1.12 (s, 3H), 1.06 (s, 3H), 1.03 (s, 3H), 0.87–0.76 ppm (m, 12H);
13C NMR (C6D6, 75 MHz; mixture of four isomers): d=150.0 (C), 148.6
(C), 148.2 (C), 147.9 (C), 142.7 (2CAr), 142.6 (CAr), 142.4 (CAr), 129.0
(2CHAr), 128.95 (2CHAr), 128.91 (2CHAr), 128.85 (2CHAr), 128.7
(8CHAr), 126.14 (2CHAr), 126.07 (2CHAr), 121.5 (CH), 121.2 (CH), 119.9
(CH), 119.7 (CH), 105.7 (CH), 105.5 (CH), 105.2 (CH), 104.4 (CH), 80.1
(CH), 79.8 (CH), 78.42 (CH), 78.37 (CH), 46.6 (C), 46.5 (C), 46.0 (C),
45.9 (C), 39.8 (CH2), 39.3 (CH2), 39.0 (CH2), 38.4 (CH2), 33.2 (CH2), 33.1
(CH2), 32.7 (CH2), 32.5 (CH2), 30.9 (2CH2), 29.8 (CH2), 29.6 (CH2), 28.2
(CH3), 27.7 (CH3), 26.7 (CH3), 25.5 (CH3), 23.6 (2CH2), 23.2 (2CH2),
22.0 (CH3), 21.9 (CH3), 21.6 (CH3), 21.2 (CH3), 14.0 (2CH3), 13.89 (CH3),
13.85 ppm (CH3); IR (neat): n˜ =3403, 3025, 2958, 2870, 1496, 1464, 1456,
1029, 748, 699 cmÀ1; MS (ESI+): m/z: for C18H26O2: 297 [M+Na]+;
HRMS (ESI+): calcd for C18H26O2: 297.1825 [M+Na]+; found: 297.1824;
TLC: Rf =0.72 (petroleum ether/Et2O 50:50).
(4CHAr, major isomer), 129.42 (4CHAr, major isomer), 126.8 (CHAr
,
major isomer), 126.7 (CHAr, minor isomer), 105.3 (CH, major isomer),
105.2 (CH, minor isomer), 103.6 (CH2, major isomer), 103.4 (CH2, minor
isomer), 80.0 (CH, major isomer), 79.8 (CH, minor isomer), 47.7 (C,
major isomer), 47.5 (C, minor isomer), 40.2 (CH2, minor isomer), 39.5
(CH2, major isomer), 33.4 (CH2, minor isomer), 33.2 (CH2, major
isomer), 28.5 (CH3, major isomer), 27.1 (CH3, minor isomer), 21.7 (CH3,
major isomer), 21.2 ppm (CH3, minor isomer); IR (neat): n˜ =3396, 3026,
2959, 2928, 2868, 2521, 1496, 1454, 1030, 992, 699 cmÀ1; MS (ESI+): m/z:
for C15H20O2: 255 [M+Na]+; HRMS (ESI+): m/z: calcd for C15H20O2:
255.1356 [M+Na]+; found: 255.1350; TLC: Rf =0.76 (petroleum ether/
Et2O 50:50).
4-(2,2-Dimethylpropylidene)-5-phenethyltetrahydro-2-furanol (10i): The
title compound was prepared according to the general procedure GP1
from a-bromoester 9i (1.68 g, 5 mmol). Flash chromatography (petro-
leum ether/Et2O 50:50) gave 10i (0.96 g, 74%, E/Z 82:18) as a colorless
oil.
4-Butylidene-5-phenethyltetrahydro-2-furanol (10 f): The title compound
was prepared according to the general procedure GP1 from a-bromoest-
er 9 f (1.61 g, 5 mmol). Flash chromatography (petroleum ether/Et2O
60:40) gave 10 f (0.96 g, 78%, E/Z 71:29) as a colorless oil. 1H NMR
(CD3OD, 300 MHz; mixture of four diastereoisomers): d=7.34–7.11 (m,
20H), 5.57–5.23 (m, 8H), 4.73–4.32 (m, 4H), 2.90–2.32 (m, 16H), 2.11–
1.69 (m, 16H), 1.48–1.32 (m, 8H), 0.95–0.87 ppm (m, 12H); 13C NMR
(CD3OD, 75 MHz; mixture of four diastereoisomers): d=143.7 (C), 143.6
(C), 143.4 (2C), 141.4 (CAr), 141.15 (CAr), 141.10 (CAr), 140.08 (CAr),
129.59 (2CHAr), 129.53 (2CHAr), 129.49 (2CHAr), 129.47 (4CHAr), 129.38
(4CHAr), 129.35 (2CHAr), 126.81 (2CHAr), 126.76 (CHAr), 126.71 (CHAr),
123.5 (CH), 122.7 (CH), 121.9 (CH), 121.8 (CH), 99.2 (CH), 98.8 (CH),
98.1 (CH), 97.7 (CH), 81.3 (CH), 79.5 (CH), 79.3 (CH), 78.1 (CH), 42.1
(CH2), 41.4 (CH2), 40.6 (CH2), 39.9 (CH2), 38.7 (CH2), 38.4 (2CH2), 38.3
(CH2), 33.13 (CH2), 33.05 (CH2), 32.96 (CH2), 32.89 (CH2), 32.41 (CH2),
32.35 (CH2), 32.2 (CH2), 32.1 (CH2), 23.9 (2CH2), 23.7 (2CH2), 14.22
(2CH3), 14.17 ppm (2CH3); IR (neat): n˜ =3403, 3025, 2956, 1603, 1495,
1454, 1177, 1029, 698 cmÀ1; MS (ESI+): m/z: for C16H22O2: 269 [M+Na]+;
HRMS (ESI+): m/z: calcd for C16H22O2: 269.1512 [M+Na]+; found:
269.1521; TLC: Rf =0.33 (major isomer), 0.28 (minor isomer) (petroleum
ether/Et2O 60:40).
Major isomer: 1H NMR (C6D6, 300 MHz; E isomer, mixture of two iso-
mers at the hemiacetal center): d=7.25–7.04 (m, 10H), 5.47 (d, J=
5.0 Hz, 1H; major isomer), 5.40 (brs, 1H; minor isomer), 5.17 (dd, J=
2.2, 4.7 Hz, 1H; major isomer), 5.11 (dd, J=2.4, 4.5 Hz, 1H; minor
isomer), 4.69 (brd, J=7.9 Hz, 1H; major isomer), 4.40 (brd, J=9.5 Hz,
1H; minor isomer), 3.03–2.39 (m, 10H; two isomers), 2.18–1.74 (m, 4H;
two isomers), 0.99 (s, 9H; major isomer), 0.97 ppm (s, 9H; minor
isomer); 13C NMR (C6D6, 75 MHz; E isomer, mixture of two isomers at
the hemiacetal center): d=142.7 (2C, E isomer), 137.5 (CAr, E isomer),
136.9 (CAr, E isomer), 131.21 (CH, E isomer), 131.18 (CH, E isomer),
129.0 (2CHAr), 128.9 (2CHAr), 128.7 (4CHAr), 126.1 (2CHAr, E isomer),
99.0 (CH, E isomer), 97.9 (CH, E isomer), 82.2 (CH, E isomer), 80.0
(CH, E isomer), 40.5 (CH2, E isomer), 38.4 (CH2, E isomer), 37.7 (CH2,
E isomer), 37.6 (CH2, E isomer), 33.0 (CH2, E isomer), 32.9 (C, E
isomer), 32.8 (C, E isomer), 32.0 (CH2, E isomer), 30.5 ppm (6CH3, E
isomer); IR (neat): n˜ =3406, 3025, 2953, 2864, 1495, 1455, 1212, 1028,
878, 746, 699 cmÀ1; MS (ESI+): m/z: for C17H24O2: 283 [M+Na]+; HRMS
(ESI+): m/z: calcd for C17H24O2: 283.1669 [M+Na]+; found: 283.1671;
TLC: Rf =0.51 (major isomer) (petroleum ether/Et2O 50:50).
Relevant signals for the minor isomer: 1H NMR (C6D6, 300 MHz; Z
isomer, mixture of two isomers at the hemiacetal center): d=5.24 (brs,
1H), 5.07–5.02 (m, 2H), 4.87 (brd, J=10.6 Hz, 1H), 0.94 (s, 9H),
0.90 ppm (s, 9H); 13C NMR (C6D6, 75 MHz; mixture of four isomers):
d=142.5 (C, Z isomer), 142.3 (C, Z isomer), 137.5 (CAr, Z isomer), 135.9
(CAr, Z isomer), 133.3 (CH, Z isomer), 131.7 (CH, Z isomer), 126.2
(2CHAr, Z isomer), 97.4 (CH, Z isomer), 96.1 (CH, Z isomer), 77.4 (CH,
Z isomer), 76.0 (CH, Z isomer), 43.4 (CH2, Z isomer), 42.5 (CH2, Z
4-Butylidene-5,5-dimethyltetrahydro-2-furanol (10g): The title compound
was prepared according to the general procedure GP2 from a-bromoest-
er 9g (0.74 g, 3 mmol). Flash chromatography (petroleum ether/Et2O
60:40) gave 10g (0.50 g, 99%, E/Z 63:37) as a pale-yellow oil. 1H NMR
(C6D6, 300 MHz; 63:37 mixture of E/Z isomers): d=5.59 (d, J=4.6 Hz,
1H; E isomer), 5.49 (d, J=4.6 Hz, 1H; Z isomer), 5.15–5.05 (m, 2H; two
isomers), 4.54 (brs, 1H; OH, E isomer), 4.46 (brs, 1H; OH, Z isomer),
2.74–2.48 (m, 4H; two isomers), 2.02–1.75 (m, 4H; two isomers), 1.68 (s,
3H; Z isomer), 1.56 (s, 3H; E isomer), 1.37 (s, 3H; Z isomer), 1.35–1.21
5622
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5613 – 5627

A Simple Access to g-Lactols and 4-Methylene-g-Lactols
FULL PAPER
isomer), 39.8 (CH2, Z isomer), 39.1 (CH2, Z isomer), 33.9 (C, Z isomer),
33.8 (C, Z isomer), 32.9 (CH2, Z isomer), 32.3 (CH2, Z isomer), 30.7 ppm
(6CH3, Z isomer); IR (neat): n˜ =3406, 3025, 2953, 2864, 1495, 1455, 1212,
1028, 878, 746, 699 cmÀ1; MS (ESI+): m/z: for C17H24O2: 283 [M+Na]+;
HRMS (ESI+): m/z: calcd for C17H24O2: 283.1669 [M+Na]+; found:
283.1671; TLC: Rf =0.42 (minor isomer) (petroleum ether/Et2O 50:50).
696 cmÀ1; MS (ESI+): m/z: for C15H18O2: 253 [M+Na]+; HRMS (ESI+):
m/z: calcd for C15H18O2: 253.1199 [M+Na]+; found: 253.1197; TLC: Rf =
0.45 (Z isomer), 0.51 (E isomer) (petroleum ether/Et2O 50:50).
3,3-Dimethyl-5-phenethyl-4-[(E)-1-phenylmethylidene]tetrahydro-2-fura-
nol (10m): The title compound was prepared according to the general
procedure GP2 from a-bromoester 9m (1.92 g, 5 mmol). Flash chroma-
tography (petroleum ether/Et2O 70:30) gave 10m (0.89 g, 58%, E/Z>
5-Phenethyl-4-(1-trimethylsilylmethylidene)tetrahydro-2-furanol
(10j):
1
95:5) as a colorless oil. H NMR (C6D6, 300 MHz; mixture of two isomers
The title compound was prepared according to the general procedure
GP1 from a-bromoester 9j (3.53 g, 10 mmol). Flash chromatography (pe-
troleum ether/Et2O 80:20) gave 10j (2.6 g, 94%, E/Z 31:69) as a colorless
at the hemiacetal center): d=7.27–6.93 (m, 20H; two isomers), 6.28 (d,
J=1.9 Hz, 1H; major isomer), 6.24 (d, J=2.0 Hz, 1H; minor isomer),
4.80–4.75 (m, 2H; two isomers), 4.69 (d, J=4.9 Hz, 1H; major isomer),
4.48 (ddd, J=2.3, 3.1, 9.6 Hz, 1H; minor isomer), 3.10–2.52 (m, 4H),
2.20–1.93 (m, 6H), 1.18 (s, 3H; major isomer), 1.05 (s, 3H; minor
isomer), 1.01 (s, 3H; minor isomer), 1.00 ppm (s, 3H; major isomer);
13C NMR (C6D6, 75 MHz; mixture of two isomers at the hemiacetal
center): d=151.19 (C), 151.15 (C), 142.6 (CAr), 142.4 (CAr), 137.9 (CAr),
137.8 (CAr), 129.3 (4CHAr), 129.0 (4CHAr), 128.9 (4CHAr), 128.7
(4CHAr), 126.8 (2CHAr), 126.2 (2CHAr), 122.2 (CH), 122.0 (CH), 106.0
(CH), 105.6 (CH), 81.0 (CH), 80.1 (CH), 47.2 (C), 46.8 (C), 39.8 (2CH2),
32.8 (2CH2), 28.2 (CH3), 26.0 (CH3), 21.2 (CH3), 20.9 ppm (CH3); IR
(neat): n˜ =3395, 3024, 2931, 1601, 1495, 1454, 1029, 699 cmÀ1; MS (ESI+):
m/z: for C21H24O2: 331 [M+Na]+; HRMS (ESI+): m/z: calcd for
C21H24O2: 331.1674 [M+Na]+; found: 331.1674; TLC: Rf =0.53 (petro-
leum ether/Et2O 60:40).
1
oil. H NMR (C6D6, 300 MHz; mixture of four isomers): d=7.29–7.04 (m,
20H), 5.63–5.27 (m, 8H), 4.90–4.86 (m, 1H), 4.72–4.69 (m, 1H), 4.64–
4.60 (m, 1H), 4.41–4.36 (m, 1H), 4.28 (d, J=3.3 Hz, 1H; OH), 4.16–4.10
(m, 3H; OH), 3.07–2.43 (m, 16H), 2.40–1.75 (m, 8H), 0.10 (s, 9H), 0.08
(s, 9H), 0.03 (s, 9H), 0.02 ppm (s, 9H); 13C NMR (C6D6, 75 MHz; mix-
ture of four isomers): d=159.1 (C), 158.5 (C), 158.3 (C), 158.0 (C), 142.5
(2CAr), 142.3 (CAr), 142.2 (CAr), 129.1 (4CHAr), 128.96 (2CHAr), 128.93
(2CHAr), 128.83 (2CHAr), 128.77 (2CHAr), 128.71 (4CHAr), 126.22
(CHAr), 126.17 (CHAr), 126.12 (2CHAr), 120.9 (CH), 120.0 (CH), 118.5
(CH), 118.3 (CH), 98.4 (CH), 98.1 (CH), 97.6 (CH), 97.0 (CH), 82.5
(CH), 80.7 (CH), 80.0 (CH), 78.3 (CH), 44.7 (CH2), 44.0 (CH2), 40.6
(CH2), 40.5 (CH2), 40.3 (CH2), 39.6 (CH2), 39.4 (CH2), 37.8 (CH2), 32.83
(CH2), 32.78 (CH2), 32.2 (CH2), 32.0 (CH2), 0.03 (6CH3), À0.08 (3CH3),
À0.43 ppm (3CH3); IR (neat): n˜ =3403, 3025, 2951, 1637, 1496, 1453,
1248, 1029, 858, 699 cmÀ1; MS (ESI+): m/z: for C16H24O2Si: 299 [M+Na]+;
HRMS (ESI+): m/z: calcd for C16H24O2Si: 299.1443 [M+Na]+; found:
299.1443; TLC: Rf =0.57 (major isomer), 0.68 (minor isomer) (petroleum
ether/Et2O 50:50).
5,5-Dimethyl-4-[(Z)-1-phenylmethylidene]tetrahydro-2-furanol
(10n):
The title compound was prepared according to the general procedure
GP2 from a-bromoester 9n (1 g, 3.55 mmol). Flash chromatography (pe-
troleum ether/Et2O 60:40) gave 10n (0.69 g, 94%, E/Z 5:95) as a white
powder. 1H NMR (C6D6, 300 MHz): d=7.21–7.04 (m, 5H), 6.43 (brs,
1H), 5.51–5.49 (m, 1H), 4.19 (brs, 1H; OH), 2.82 (ddd, J=2.4, 4.3,
15.3 Hz, 1H), 2.69 (dt, J=1.3, 15.3 Hz, 1H), 1.54 (s, 3H), 1.37 ppm (m,
3H); 13C NMR (C6D6, 75 MHz): d=147.2 (C), 138.1 (CAr), 129.2
(2CHAr), 128.2 (2CHAr), 126.9 (CHAr), 122.1 (CH), 96.0 (CH), 82.5 (C),
43.6 (CH2), 30.0 (CH3), 29.5 ppm (CH3); IR (KBr): n˜ =3385, 3077, 2992,
5-Phenethyl-4-(1-phenylmethylidene)tetrahydro-2-furanol (10k): The
title compound was prepared according to the general procedure GP1
from a-bromoester 9k (3.75 g, 10.5 mmol). Flash chromatography (petro-
leum ether/Et2O 80:20) gave 10k (2.6 g, 88%, E/Z 26:74) as a white
powder. 1H NMR (C6D6, 300 MHz; mixture of four isomers): d=7.25–
7.17 (m, 40H), 6.24–6.09 (m, 4H), 5.62–5.52 (m, 4H), 5.31 (brd, J=
8.5 Hz, 1H), 5.01 (brd, J=9.4 Hz, 1H), 4.88 (brd, J=6.2 Hz, 1H), 4.53
(brd, J=9.2 Hz, 1H), 4.04 (d, J=2.0 Hz, 2H; OH), 3.97 (d, J=3.8 Hz,
1H; OH), 3.85 (d, J=2.5 Hz, 1H; OH), 2.95–2.51 (m, 16H), 2.07–
1.63 ppm (m, 8H); 13C NMR (C6D6, 75 MHz; mixture of four isomers):
d=143.3 (2C), 142.4 (2C), 142.3 (2C), 141.8 (2C), 137.9 (2C), 137.2
(2C), 129.3 (4CHAr), 129.1 (4CHAr), 129.0 (4CHAr), 128.9 (4CHAr), 128.7
(4CHAr), 128.62 (4CHAr), 128.60 (4CHAr), 128.55 (4CHAr), 126.9
(2CHAr), 126.7 (2CHAr), 126.2 (2CHAr), 126.1 (2CHAr), 122.6 (CH),
121.7 (CH), 121.41 (CH), 121.36 (CH), 98.9 (CH), 97.9 (CH), 97.3 (CH),
96.5 (CH), 82.2 (CH), 80.2 (CH), 78.4 (CH), 77.0 (CH), 42.7 (2CH2), 39.8
(CH2), 39.3 (CH2), 39.2 (CH2), 38.0 (CH2), 36.3 (CH2), 34.9 (CH2), 32.6
(CH2), 32.5 (CH2), 31.99 (CH2), 31.95 ppm (CH2); IR (neat): n˜ =3417,
2929, 1439, 1361, 1069, 1022, 966, 706 cmÀ1 MS (ESI+): m/z: for
;
C13H16O2: 227 [M+Na]+; HRMS (ESI+): m/z: calcd for C13H16O2:
227.1034 [M+Na]+; found: 227.1043; TLC: Rf =0.42 (petroleum ether/
Et2O 50:50); m.p. 69–718C.
4-Butylidene-5-trityloxymethyltetrahydro-2-furanol (10o): The title com-
pound was prepared according to the general procedure GP1 from a-
bromoester 9o (1.47 g, 3 mmol). Flash chromatography (petroleum ether/
Et2O 50:50) gave 10o (0.89 g, 72%, E/Z 37:63) as
a colorless oil.
1H NMR (C6D6, 300 MHz; mixture of four isomers): d=7.65–7.61 (m,
24H), 7.17–6.99 (m, 36H), 5.66–5.60 (m, 4H), 5.28–5.08 (m, 4H), 5.03–
4.62 (m, 4H), 4.36 (d, J=6.7 Hz, 1H; OH), 4.07 (d, J=6.8 Hz, 1H; OH),
3.67–3.21 (m, 10H), 2.73–2.40 (m, 8H), 1.86–1.53 (m, 8H), 1.29–0.97 (m,
8H), 0.80–0.66 ppm (m, 12H); 13C NMR (C6D6, 75 MHz; mixture of four
isomers): d=144.8 (3CAr), 144.7 (3CAr), 144.3 (6CAr), 137.9 (C), 137.7
(C), 137.5 (C), 137.0 (C), 129.34 (12CHAr), 129.28 (12CHAr), 128.14
(12CHAr), 128.07 (12CHAr), 127.3 (6CHAr), 127.2 (6CHAr), 123.6 (CH),
123.0 (CH), 122.2 (CH), 121.8 (CH), 98.9 (CH), 98.7 (CH), 98.2 (CH),
97.8 (CH), 87.7 (2C), 87.0 (2C), 80.9 (CH), 79.5 (CH), 79.3 (CH), 78.2
(CH), 68.0 (CH2), 67.6 (CH2), 67.4 (CH2), 66.6 (CH2), 41.5 (2CH2), 38.4
(CH2), 37.5 (CH2), 32.2 (CH2), 32.1 (CH2), 31.5 (CH2), 31.4 (CH2), 23.0
(2CH2), 22.8 (CH2), 22.7 (CH2), 13.92 (2CH3), 13.89 ppm (2CH3); IR
(neat): n˜ =3406, 3022, 2956, 2870, 1596, 1490, 1448, 1222, 1074, 957,
705 cmÀ1; MS (ESI+): m/z: for C28H30O3: 437 [M+Na]+; HRMS (ESI+):
m/z: calcd for C28H30O3: 437.2087 [M+Na]+; found: 437.2087; TLC: Rf =
0.43 (major isomer), 0.50 ppm (minor isomer) (petroleum ether/Et2O
40:60).
3022, 2940, 1602, 1496, 1242, 1069, 667 cmÀ1 MS (ESI+): m/z: for
;
C19H20O2: 303 [M+Na]+; HRMS (ESI+): m/z: calcd for C19H20O2:
303.1361 [M+Na]+; found: 303.1360; TLC: Rf =0.54 (minor isomer), 0.39
(major isomer) (petroleum ether/Et2O 50:50); m.p. 70–728C.
5-(3-Butenyl)-4-(1-phenylmethylidene)tetrahydro-2-furanol (10l): The
title compound was prepared according to the general procedure GP1
from a-bromoester 9l (1.22 g, 4 mmol). Flash chromatography (petro-
leum ether/Et2O 70:30) gave 10l (0.84 g, 91%, E/Z 22:78) as a colorless
1
oil. H NMR (C6D6, 300 MHz; mixture of four isomers): d=7.20–6.96 (m,
20H), 6.25–6.13 (m, 4H), 5.96–5.65 (m, 4H), 5.47–4.50 (m, 16H), 3.11
(dd, J=1.3, 3.4 Hz, 1H; OH), 3.04 (d, J=3.3 Hz, 1H; OH), 3.00 (d, J=
3.8 Hz, 1H; OH), 2.92 (dd, J=1.1, 3.2 Hz, 1H; OH), 2.78–2.17 (m, 16H),
2.01–1.43 ppm (m, 8H); 13C NMR (C6D6, 75 MHz; mixture of four iso-
mers): d=143.7 (C), 142.8 (C), 142.7 (C), 142.5 (C), 138.70 (CH), 138.67
(CH), 138.31 (CH), 138.26 (CH), 138.0 (CAr), 137.8 (CAr), 137.5, (CAr),
137.4 (CAr), 128.61 (4CHAr), 128.58 (8CHAr), 128.54 (4CHAr), 126.8
(4CHAr), 122.6 (CH), 121.8 (CH), 121.4 (2CH), 115.3 (CH2), 115.2
(CH2), 115.0 (CH2), 114.9 (CH2), 98.8 (CH), 97.8 (CH), 97.3 (CH), 96.5
(CH), 82.4 (CH), 80.3 (CH), 78.9 (CH), 77.3 (CH), 42.71 (CH2), 42.67
(CH2), 39.4 (CH2), 39.3 (CH2), 37.3 (CH2), 35.3 (CH2), 34.3 (CH2), 32.6
(CH2), 30.7 (CH2), 30.6 (CH2), 30.0 (CH2), 29.9 ppm (CH2); IR (neat):
n˜ =3396, 3024, 2974, 2940, 2850, 1750, 1494, 1447, 1118, 1073, 749,
4-(1-Trimethylsilylmethylidene)-5-trityloxymethyltetrahydro-2-furanol
(10p): The title compound was prepared according to the general proce-
dure GP1 from a-bromoester 9p (4.35 g, 8.35 mmol). Flash chromatogra-
phy (petroleum ether/Et2O 80:20) gave 10p (2.75 g, 74%, E/Z 17:83) as a
white powder. 1H NMR (CD3OD, 300 MHz; mixture of four isomers):
d=7.53–7.41 (m, 24H), 7.29–7.17 (m, 36H), 5.69–5.36 (m, 8H), 4.86–4.42
(m, 4H), 3.59–2.37 (m, 16H), 0.11 (s, 9H), 0.10 (s, 9H), À0.17 (s, 9H),
À0.22 ppm (s, 9H); 13C NMR (CD3OD, 75 MH
Chem. Eur. J. 2011, 17, 5613 – 5627
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5623

F. Dꢁnꢀs, J. Lebreton et al.
z; mixture of four isomers): d=156.8 (C), 156.7 (C), 156.3 (C), 155.9 (C),
145.42 (6CAr), 145.35 (6CAr), 130.1 (6CHAr), 130.0 (18CHAr), 128.8
(18CHAr), 128.7 (6CHAr), 128.1 (9CHAr), 128.0 (3CHAr), 122.9 (CH2),
122.8 (CH2), 121.2 (CH2), 120.4 (CH2), 99.5 (CH), 99.0 (CH), 98.8 (CH),
98.0 (CH), 87.7 (4C), 83.4 (CH), 82.5 (CH), 81.7 (CH), 80.2 (CH), 70.3
(CH2), 69.3 (CH2), 68.9 (CH2), 67.6 (CH2), 46.0 (CH2), 45.0 (CH2), 41.5
(CH2), 41.4 (CH2), À0.07 (3CH3), À0.18 (3CH3), À0.35 (3CH3),
À0.41 ppm (3CH3); IR (neat): n˜ =3413, 3058, 3032, 2950, 1652, 1490,
1448, 1248, 1075, 836, 705 cmÀ1; MS (ESI+): m/z: for C28H32O2Si: 467
[M+Na]+; HRMS (ESI+): m/z: calcd for C19H20O2Si: 467.2013 [M+Na]+;
found: 467.1994; TLC: Rf =0.58 (petroleum ether/Et2O 50:50); m.p. 57–
598C.
HRMS (EI+): m/z: calcd for C13H18O: 190.1353 [M]+; found: 190.1357;
TLC: Rf =0.37 (petroleum ether/Et2O 95:5).
(2S*,3R*,5S*)-5-Allyl-3-methyl-2-phenetyltetrahydrofuran
(19):
BF3·Et2O (390 mL, 3 mmol) was added dropwise to a solution of lactol 7b
(310 mg, 1.5 mmol) and allyltrimethylsilane (730 mL, 4.5 mmol) in CH2Cl2
(22 mL) under argon at À788C. After completion of the reaction (TLC
monitoring), the mixture was allowed to reach À308C and a saturated so-
lution of NaHCO3 was added. The aqueous phase was extracted with
CH2Cl2 (ꢃ2) and the resulting organic phase was dried over Na2SO4, fil-
tered, and concentrated in vacuo. Flash chromatography (petroleum
ether/Et2O 98:2) gave 19 (0.30 g, 86%, d.r.=85:15) as a colorless oil.
Major isomer: 1H NMR (CDCl3, 300 MHz): d=7.30–7.13 (m, 5HAr),
5.83 (tdd, J=7.0, 10.2, 17.1 Hz, 1H), 5.13–5.03 (m, 2H), 4.05–3.95 (m,
1H), 3.37 (dt, J=4.1, 7.4 Hz, 1H), 2.82 (ddd, J=5.5, 10.6, 13.7 Hz, 1H),
2.66 (ddd, J=6.2, 10.4, 13.7 Hz, 1H), 2.43–2.32 (m, 1H), 2.28–2.14 (m,
1H), 1.95–1.73 (m, 4H), 1.63–1.54 (m, 1H), 0.99 ppm (d, J=6.4 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d=142.6 (CqAr), 135.3 (C), 128.5 (2CAr),
128.4 (2CAr), 125.8 (CAr), 116.8, 85.8, 77.2, 41.0, 39.3, 38.2, 36.6, 32.7,
17.8 ppm; IR (neat): n˜ =3063, 2955, 2870, 1641, 1454, 1108, 1031, 913,
699 cmÀ1; MS (CI+): m/z: for C16H22O: 248 [M+NH4]+, 231 [M+H]+;
HRMS (EI+): m/z: calcd for C16H22O: 230.1671 [M]+: found: 230.1670;
TLC: Rf =0.57 (petroleum ether/Et2O 95:5).
5-Benzyloxymethoxymethyl-4-(1-phenylmethylidene)tetrahydro-2-furanol
(10q): The title compound was prepared according to the general proce-
dure GP1 from a-bromoester 9q (0.92 g, 2.27 mmol). Flash chromatogra-
phy (petroleum ether/Et2O 70:30) gave 10q (0.51 g, 69%, E/Z 24:74) as
a white gum. 1H NMR (C6D6, 300 MHz; mixture of four isomers): d=
7.32–6.95 (m, 40H), 6.31–6.14 (m, 4H), 5.65–4.71 (m, 8H), 4.71–3.49 (m,
28H), 2.82–2.49 ppm (m, 8H); 13C NMR (C6D6, 75 MHz; mixture of four
isomers): d=140.0 (2C), 139.8 (2C), 138.5 (CAr), 138.2 (CAr), 137.7 (CAr),
137.6 (CAr), 137.2 (4CAr), 128.7 (8CHAr), 128.5 (16CHAr), 128.2 (8CHAr),
127.7 (2CHAr), 127.6 (2CHAr), 127.0 (2CHAr), 126.9 (2CHAr), 123.7
(CH), 123.2 (CH), 122.2 (2CH), 99.2 (CH), 98.5 (CH), 97.5 (CH), 96.9
(CH), 94.8 (CH2), 94.6 (2CH2), 94.5 (CH2), 82.1 (CH), 80.5 (CH), 79.2
(CH), 78.1 (CH), 71.0 (CH2), 69.4 (CH2), 69.3 (2CH2), 69.1 (3CH2), 68.6
(CH2), 43.8 (CH2), 42.9 (CH2), 40.4 (CH2), 39.4 ppm (CH2); IR (KBr):
n˜ =3446, 3033, 2955, 2880, 1652, 1495, 1448, 1026, 749, 697 cmÀ1; MS
(ESI+): m/z: for C20H22O4: 349 [M+Na]+; HRMS (ESI+): m/z calcd for
C20H22O4: 349.1410 [M+Na]+; found: 349.1409; TLC: Rf =0.27 (Z
isomer), 0.32 (E isomer) (petroleum ether/Et2O 40:60).
(2S*,3R*,5R*)- + (2S*,3R*,5R*)-3-Methyl-2-phenetyl-5-phenylsulfanyl-
tetrahydrofuran (20): BF3·Et2O (390 mL, 3 mmol) was added dropwise to
a solution of lactol 7b (310 mg, 1.5 mmol) and thiophenol (460 mL,
4.5 mmol) in CH2Cl2 (20 mL) under argon at À788C. After completion of
the reaction (TLC monitoring), the mixture was allowed to reach À308C
and a saturated solution of NaHCO3 was added. The aqueous phase was
extracted with CH2Cl2 (ꢃ2) and the resulting organic phase was dried
over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography
(petroleum ether/Et2O 98:2) gave 20 (0.36 g, 81%, d.r.=65:35) as a col-
orless oil.
4-(1-Cyclopropylmethylidene)-5-phenethyltetrahydro-2-furanol
(10r):
The title compound was prepared according to the general procedure
GP1 from a-bromoester 9r (1.61 g, 5 mmol). Flash chromatography (pe-
troleum ether/Et2O 50:50) gave 10r (0.95 g, 78%, E/Z 52:48) as a color-
less oil. 1H NMR (C6D6, 300 MHz; mixture of four isomers): d=7.28–
7.04 (m, 20H), 5.60–5.49 (m, 4H), 5.02–4.38 (m, 8H), 3.71 (brd, J=
3.0 Hz, 1H; OH), 3.53 (brd, J=2.9 Hz, 1H; OH), 3.49 (brs, 1H; OH),
3.47 (brs, 1H; OH), 3.07–2.35 (m, 16H), 2.33–1.73 (m, 8H), 1.18–0.89
(m, 4H), 0.57–0.37 (m, 8H), 0.24–0.09 ppm (m, 8H); 13C NMR (C6D6,
75 MHz; mixture of four isomers): d=142.70 (C), 142.66 (2C), 142.63
(C), 138.6 (CAr), 138.5 (CAr), 138.4 (CAr), 137.6 (CAr), 129.0 (4CHAr),
128.8 (4CHAr), 128.7 (8CHAr), 126.3 (CH), 126.1 (4CHAr), 125.5 (CH),
124.8 (CH), 124.7 (CH), 98.6 (CH), 98.4 (CH), 97.7 (CH), 97.4 (CH),
80.8 (CH), 79.2 (CH), 78.9 (CH), 77.8 (CH), 41.1 (CH2), 40.7 (CH2), 39.9
(CH2), 38.9 (CH2), 38.0 (CH2), 37.83 (CH2), 37.78 (CH2), 37.4 (CH2), 32.7
(CH2), 32.63 (CH2), 32.1 (CH2), 31.9 (CH2), 12.1 (CH), 12.0 (CH), 11.23
(CH), 11.19 (CH), 7.5 (CH2), 7.4 (CH2), 7.0 (CH2), 6.9 (2CH2), 6.8 (CH2),
6.71 (CH2), 6.66 ppm (CH2); IR (neat): n˜ =3396, 3025, 3001, 2929, 1652,
1495, 1454, 1354, 1028, 957, 699 cmÀ1; MS (ESI+): m/z: for C16H20O2: 267
[M+Na]+; HRMS (ESI+): m/z: calcd for C16H20O2: 267.1356 [M+Na]+;
found: 267.1348; TLC: Rf =0.52 (E isomer), 0.46 (Z isomer) (petroleum
ether/Et2O 50:50).
Major isomer: 1H NMR (C6D6, 300 MHz): d=7.69 (d, J=7.2 Hz, 2H;
Ar), 7.18–6.95 (m, 8H; Ar), 5.55 (dd, J=6.3, 6.6 Hz, 1H), 3.65 (dt, J=
3.0, 8.3 Hz, 1H), 2.85 (ddd, J=5.2, 9.8, 14.0 Hz, 1H), 2.66 (ddd, J=7.1,
9.6, 14.0 Hz, 1H), 2.30–2.18 (m, 1H), 1.81–1.60 (m, 2H), 1.51–1.34 (m,
2H), 0.68 ppm (d, J=6.1 Hz, 3H); 13C NMR (C6D6, 75 MHz): d=142.3
(CqAr), 137.5 (CqAr), 131.0 (2CAr), 129.0 (2CAr), 128.8 (2CAr), 128.6
(2CAr), 126.7 (CAr), 126.1 (CAr), 86.1, 83.2, 41.9, 38.8, 35.2, 33.0,
15.9 ppm; IR (neat): n˜ =3024, 2928, 2869, 1583, 1453, 1090, 1026, 741,
699 cmÀ1; MS (CI+): m/z: for C19H22OS: 316 [M+NH4]+; HRMS (EI+):
m/z: calcd for C19H22OS: 298.1391 [M]+; found: 298.1391; TLC: Rf =0.58
(major isomer) (petroleum ether/Et2O 95:5).
Minor isomer: 1H NMR (C6D6, 300 MHz): d=relevant signals 7.67 (d,
J=7.3 Hz, 2H; Ar), 5.51 (dd, J=3.0, 6.3, 7.2 Hz, 1H), 3.41 (dt, J=3.6,
8.7 Hz, 1H), 0.65 ppm (d, J=6.4 Hz, 3H); 13C NMR (C6D6, 75 MHz): d=
142.5 (CqAr), 136.9 (CqAr), 131.4 (2CAr), 129.0 (2CAr), 128.8 (2CAr),
128.6 (2CAr), 126.8 (CAr), 126.0 (CAr), 87.1, 86.4, 41.9, 38.4, 37.5, 33.1,
16.9 ppm; IR (neat): n˜ =3024, 2928, 2869, 1583, 1453, 1090, 1026, 741,
699 cmÀ1; MS (CI+): m/z: for C19H22OS: 316 [M+NH4]+; HRMS (EI+):
m/z: calcd for C19H22OS: 298.1391 [M]+; found: 298.1391; TLC: Rf =0.50
(minor isomer) (petroleum ether/Et2O 95:5).
ACHTUNGTRENNUNG
AHCTUNGTERG(NNUN 4R*,5R*)-4-Methyl-5-phenetyltetrahydro-2-furanone (21): To a solution
a
of lactol 7b (0.573 g, 2.8 mmol) in CH2Cl2 (28 mL) were successively
added a solution of NaHCO3/K2CO3 (0.5 molLÀ1/H2O, 28 mL), tBu4NCl
(0.078 g, 0.28 mmol), N-chlorosuccinimide (0.742 g, 5.6 mmol), and Ac-
TEMPO (0.209 g, 1.0 mmol) at room temperature. The reaction mixture
was stirred vigorously at room temperature until completion (NMR spec-
troscopic monitoring, ca. 36 h). The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (ꢃ3). The combined organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo. Flash column
chromatography on silica gel (petroleum ether/Et2O 60:40) gave 21
(0.535 g, 94%, d.r.> 95:5) as a colorless oil. 1H NMR (C6D6, 300 MHz):
d=7.18–7.00 (m, 5H; Ar), 3.37 (dt, J=7.6, 4.9 Hz, 1H), 2.71–2.62 (m,
1H), 2.48 (dt, J=13.9, 8.5 Hz, 1H), 2.06 (dd, J=16.8, 7.9 Hz, 1H), 1.53–
1.28 (m, 4H), 0.33 ppm (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d=176.6, 141.0, 128.6 (2C), 128.5 (2C), 126.2, 86.4, 37.2, 36.3, 35.9, 32.1,
17.3 ppm; IR (neat): n˜ =3061, 3026, 2932, 1774, 1602, 1495, 1454, 1383,
1.5 mmol) and triethylsilane (720 mL, 4.5 mmol) in CH2Cl2 (20 mL) under
argon at À788C. After completion of the reaction (TLC monitoring), the
mixture was allowed to reach À308C and
a saturated solution of
NaHCO3 was added. The aqueous phase was extracted with CH2Cl2 (ꢃ2)
and the resulting organic phase was dried over Na2SO4, filtered, and con-
centrated in vacuo. Flash chromatography (petroleum ether/Et2O 95:5)
1
gave 18 (0.24 g, 82%) as a colorless oil. H NMR (CDCl3, 300 MHz): d=
7.23–7.07 (m; 5H; Ar), 3.83–3.71 (m, 2H), 3.25 (dt, J=3.5, 8.1 Hz, 1H),
2.77 (ddd, J=5.2, 10.7, 13.7 Hz, 1H), 2.58 (ddd, J=6.2, 10.5, 13.7, 1H),
2.07–1.96 (m, 1H), 1.85–1.59 (m, 3H), 1.52–1.40 (m, 1H), 0.94 ppm (d,
J=6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d=142.6 (CqAr), 128.5
(2CAr), 128.4 (2CAr), 125.8 (CAr), 85.4, 66.9, 39.2, 36.4, 34.9, 33.0,
17.4 ppm; IR (neat): n˜ =3025, 2927, 2870, 1603, 1453, 1107, 1039, 746,
699 cmÀ1
;
MS (CI+): m/z: C13H18O: 208 [M+NH4]+, 191 [M+H]+;
5624
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5613 – 5627

A Simple Access to g-Lactols and 4-Methylene-g-Lactols
FULL PAPER
1360, 1330, 1305, 1257, 1203, 1144, 1027, 937, 751, 701 cmÀ1; MS (CI+):
m/z: for C13H16O2: 222.1 [M+NH4]+, 205.1 [M+H]+; HRMS (CI+): m/z:
calcd for C13H16O2: 205.1223 [M+H]+; found: 205.1219; TLC: Rf =0.31
(petroleum ether/Et2O 60:30).
lution of lactol 7b (206 mg, 1 mmol) in THF (15 mL) at À788C. The solu-
tion was stirred for 30 min and vinylmagnesium bromide (3 mL, 1m/THF,
3 mmol) was added dropwise. The solution was allowed to warm to room
temperature. After 3 h at room temperature, the mixture was quenched
with NH4Cl saturated solution and extracted with CH2Cl2. The organic
phase was dried over Na2SO4, filtered, and concentrated in vacuo. Flash
chromatography (petroleum ether/Et2O 50:50) gave 24 (0.16 g, 67%,
d.r.=56:44) as a colorless oil. 1H NMR (C6D6, 300 MHz; mixture of two
isomers): d=7.21–7.03 (m, 10H; Ar, two isomers), 5.89–5.73 (m, 2H; two
isomers), 5.23 (dt, J=1.5, 17.2 Hz, 1H; major isomer), 5.22 (dt, J=1.5,
17.1 Hz, 1H; minor isomer), 5.00 (dt, J=1.5, 10.3 Hz, 1H; minor
isomer), (dt, J=1.5, 10.4 Hz, 1H; major isomer), 4.19–4.06 (m, 2H; two
isomers), 3.97 (brs, 2H; OH minor isomer), 3.71 (brs, 2H; OH, major
isomer), 3.39–3.27 (m, 2H; two isomers), 2.95–2.82 (m, 2H; two isomers),
2.73–2.59 (m, 2H; two isomers), 1.85–1.06 (m, 10H; two isomers), 0.87
(d, J=6.7 Hz, 3H; minor isomer), 0.81 ppm (d, J=6.8 Hz, 3H; major
isomer); 13C NMR (C6D6, 75 MHz; mixture of two isomers): d=143.0
(CqAr, major isomer), 142.9 (CqAr, minor isomer), 142.6 (Cb, major
isomer), 142.0 (Cb, minor isomer), 128.9 (4CAr, two isomers), 128.7
(4CAr, two isomers), 126.0 (2CAr, two isomers), 114.1 (minor isomer),
113.5 (major isomer), 75.8 (major isomer), 74.8 (minor isomer), 71.5
(major isomer), 70.0 (minor isomer), 41.9 (major isomer), 39.7 (minor
isomer), 36.9 (2C, minor isomer and major isomer), 36.5 (major isomer),
35.9 (minor isomer), 32.8 (minor isomer), 32.5 (major isomer), 17.1
(minor isomer), 17.0 ppm (major isomer); IR (neat): n˜ =3352, 3025, 2930,
2873, 1495, 1453, 1038, 921, 699 cmÀ1; MS (CI+): m/z: for C15H22O2: 252
[M+NH4]+, 235 [M+H]+, 217 [MÀH2O+H]+; HRMS (ESI+): m/z: calcd
for C15H22O2 [M+Na]+: 257.1517; found: 257.1515; TLC: Rf =0.32 (petro-
leum ether/Et2O 50:50).
(E)-(5R*,6S*)-6-Hydroxy-5-methyl-8-phenyl-2-octenoic ethyl ester ((E)-
22): (Carbethoxymethylene)triphenylphosphorane (1.04 g, 3 mmol) was
added to a solution of lactol 7b (206 mg, 1 mmol) in CH2Cl2 (20 mL) at
room temperature. The solution was stirred at room temperature until
completion (NMR spectroscopic monitoring, 16 h). The solvent was re-
moved under reduced pressure. Flash column chromatography on silica
gel (petroleum ether/Et2O 60:40) gave 22 (0.24 g, 87%, d.r. (E/Z)=
89:11) as a colorless oil. 1H NMR (CDCl3, 300 MHz): d=7.32–7.17 (m,
5H; Ar), 6.93 (ddd, J=6.9, 8.1, 15.3 Hz, 1H), 5.82 (dt, J=1.3, 15.3 Hz,
1H), 4.18 (q, J=7.1 Hz, 2H), 3.51–3.44 (m, 1H), 2.93–2.80 (m, 1H),
2.71–2.61 (m, 1H), 2.47–2.38 (m, 1H), 2.13–2.02 (m, 1H), 1.88–1.65 (m,
3H), 1.50 (brs, 1H; OH), 1.29 (t, J=7.1 Hz, 3H), 0.92 ppm (d, J=6.9 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d=166.7, 148.1, 142.1 (CqAr), 128.6
(2CAr), 128.5 (2CAr), 126.0 (CAr), 122.8, 74.9, 60.3, 38.7, 35.8, 35.2,
32.4, 15.8, 14.4 ppm; IR (neat): n˜ =3464, 3026, 2930, 1718, 1701, 1496,
1454, 1269, 1043, 700 cmÀ1; MS (CI+): m/z: for C17H24O3: 294 [M+NH4]+
,
277 [M+H]+; HRMS (ESI+): m/z: calcd for C17H24O3: 299.1623
[M+Na]+; found: 299.1621; TLC: Rf =0.26 (petroleum ether/Et2O 60:40).
(Z)-(5R*, 6S*)-6-Hydroxy-5-methyl-8-phenyl-2-octenoic ethyl ester ((Z)-
22): 1H NMR (CDCl3, 300 MHz): d=7.33–7.15 (m, 5H; Ar), 6.28 (ddd,
J=7.3, 9.1, 11.5 Hz, 1H), 5.82 (dt, J=1.3, 11.5 Hz, 1H), 4.18 (q, J=
7.1 Hz, 2H), 3.44–3.38 (m, 1H), 2.93–2.77 (m, 2H), 2.70–2.58 (m, 2H),
1.92–1.64 (m, 3H), 1.60 (brs, 1H; OH), 1.29 (t, J=7.1 Hz, 3H), 0.94 ppm
(d, J=7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d=167.1, 148.7, 142.6
(CqAr), 128.6 (2CAr), 128.5 (2CAr), 125.8 (CAr), 121.0, 74.6, 60.3, 39.6,
35.9, 32.4, 32.0, 16.1, 14.4 ppm.
AHCTUNGTERG(NNUN 4R*,5R*)-4-Methyl-5-trityloxymethyltetrahydro-2-furanone (25): Molec-
ular sieves (4 ꢄ) and PCC (325 mg, 1.5 mmol) were added to a solution
of lactol 7h (375 mg, 1 mmol) in CH2Cl2. The mixture was stirred at
room temperature until completion of the reaction (TLC monitoring,
KMnO4) and then filtered through Celite. The solvent was removed
under reduced pressure. Flash column chromatography on silica gel (pe-
troleum ether/Et2O 60:40) gave 25 (0.37 g, 98%) as a white powder.
1H NMR (C6D6, 300 MHz): d=7.53 (d, J=7.7 Hz, 6H), 7.16–6.99 (m,
9H), 3.59 (ddd, J=3.3, 4.8, 6.6 Hz, 1H), 3.20 (dd, J=3.3, 10.5 Hz, 1H),
2.98 (dd, J=4.8, 10.5 Hz, 1H), 2.24 (dd, J=8.3, 16.9 Hz, 1H), 1.77–1.63
(m, 1H), 1.54 (dd, J=8.2, 16.9 Hz, 1H), 0.35 ppm (d, J=6.7 Hz, 3H);
13C NMR (C6D6, 75 MHz): d=175.1, 144.2 (3Cq), 129.0 (6C), 128.3 (6C),
127.4 (3C), 87.4, 84.9, 64.8, 36.6, 32.0, 17.7 ppm; IR (KBr): n˜ =3448,
3050, 2937, 2868, 1766, 1487, 1446, 1217, 1106, 775 cmÀ1; MS (ESI+): m/z:
calcd for C25H24O3: 395 [M+Na]+; HRMS (ESI+): m/z: calcd for
C25H24O3: 395.1623 [M+Na]+; found: 395.1623; m.p. 140–1418C; TLC:
Rf =0.33 (petroleum ether/Et2O 60:40).
ACHTUNGTRENNUNG(3R*,4S*)-3-Methyl-6-phenylhexane-1,4-diol (23b): According to the
general procedure GP3 from lactol 7b (0.50 g, 2.4 mmol). Flash chroma-
tography (petroleum ether/Et2O 20:80) gave 23b (0.47 g, 90%, d.r.>
95:5) as a colorless oil. 1H NMR (CDCl3, 300 MHz): d=7.27–7.12 (m,
5H), 3.74 (ddd, J=4.9, 6.5, 10.9 Hz, 1H), 3.62 (ddd, J=5.1, 6.9, 10.9 Hz,
1H), 3.44 (ddd, J=3.6, 5.7, 9.0 Hz, 1H), 3.06 (s, 2H; OH), 2.85 (ddd, J=
5.6, 9.8, 13.8 Hz, 1H), 2.65 (ddd, J=6.7, 9.7, 13.8 Hz, 1H), 1.88–1.55 (m,
5H), 0.93 ppm (d, J=6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d=142.4,
128.6 (2C), 128.5 (2C), 125.9, 75.2, 60.4, 36.8, 36.4, 35.4, 32.4, 16.6 ppm;
IR (neat): n˜ =3330, 3025, 2932, 2876, 1603, 1454, 1055, 748, 699 cmÀ1; MS
(CI+): m/z: for C13H20O2: 226 [M+NH4]+, 209 [M+H]+; HRMS (CI+):
m/z: calcd for C13H20O2: 209.1542 [M+H]+; found: 209.1542; TLC: Rf =
0.46 (petroleum ether/Et2O 10:90).
ACHTUNGTRENNUNG(3R*,4R*)-5-Benzyloxymethoxy-3-methyl-1,4-pentanediol (23h): Accord-
ing to the general procedure GP3 from lactol 7h (0.15 g, 0.6 mmol).
Flash chromatography (Et2O) gave 23h (0.15 g, 99%, d.r.>95:5) as a col-
orless oil. 1H NMR (CDCl3, 300 MHz): d=7.40–7.25 (m, 5H), 4.79–4.77
(m, 2H), 4.61 (s, 2H), 3.76–3.68 (m, 2H), 3.63–3.50 (m, 3H), 3.51 (brs,
2H; OH), 1.85–1.67 (m, 2H), 1.61–1.49, (m, 1H), 0.92 ppm (d, J=6.8 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d=137.6 (Cq), 128.5 (2C), 127.9 (2C),
127.8, 95.1, 74.4, 71.2, 69.7, 60.3, 36.1, 33.8, 16.5 ppm; IR (neat): n˜ =3386,
2931, 2880, 1652, 1454, 1381, 1114, 1047, 739, 698 cmÀ1; MS (ESI+): m/z:
for C14H22O4: 277 [M+Na]+; HRMS (ESI+): m/z: calcd for C14H22O4:
277.1416 [M+Na]+; found: 277.1415; TLC: Rf =0.25 (Et2O).
2-(2-tert-Butyldiphenylsilyloxyethyl)-1-phenyl-hepta-1,6-dien-3-ol: Et3N
(210 mL, 1.5 mmol), tert-butyldiphenylsilyl chloride (0.418 g, 1.5 mmol),
and DMAP (0.012 g, 0.1 mmol) were successively added to a solution of
diol 26l (0.235 g, 1.0 mmol) in CH2Cl2 (8 mL) at room temperature. The
reaction mixture was stirred at room temperature for 9 h, then quenched
with a saturated aqueous solution of NaHCO3 (10 mL). The aqueous
phase was extracted with Et2O (ꢃ3). The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography (petroleum ether/toluene/Et2O 50:40:10)
gave the title compound as a mixture of two diastereoisomers (0.446 mg,
93%, E/Z 23:77) as a colorless oil.
Major isomer: 1H NMR (CDCl3, 400 MHz): d=7.72–7.68 (m, 4H), 7.46–
7.22 (m, 11H), 6.44 (s, 1H), 5.77 (ddt, J=6.6, 10.2, 16.9 Hz, 1H), 4.95
(dq, J=1.7, 17.0 Hz, 1H), 4.91–4.88 (m, 1H), 4.67 (dt, J=5.4, 8.1 Hz,
1H), 3.92 (dt, J=5.1, 10.0, 1H), 3.80 (dt, J=4.6, 9.1 Hz, 1H), 3.32 (d, J=
5.3 Hz, 1H), 2.64 (ddd, J=5.3, 9.2, 14.2 Hz, 1H), 2.32 (ddt, J=1.1, 4.6,
14.2 Hz, 1H), 2.16–1.97 (m, 2H), 1.83–1.75 (m, 1H), 1.64–1.55 (m, 1H),
1.08 ppm (s, 9H); 13C NMR (CDCl3, 100 MHz): d=142.1, 138.5, 137.3,
135.8, 133.11, 133.08, 130.03, 129.99, 129, 97, 129.0, 128.3, 127.96, 127.94,
126.8, 69.0, 65.9, 35.5, 34.6, 30.2, 27.0, 19.2 ppm; IR (film): n˜ =3430, 3072,
3052, 2931, 2857, 1491, 1471, 1444, 1428, 1217, 1112, 1073, 1046, 918, 861,
757, 700 cmÀ1; MS (CI+): m/z: for C31H38O2Si: 453 [MÀH2O+H]+, 470
ACHTUNGTRENNUNG(3R*,4R*)-3-Methyl-5-trityloxy-1,4-pentanediol (23i): According to the
general procedure GP3 from lactol 7i (0.37 g, 1 mmol). Flash chromatog-
raphy (petroleum ether/Et2O 10:90) gave 23i (0.34 g, 90%, d.r.>95:5) as
a white gum. 1H NMR (C6D6, 300 MHz): d=7.68 (d, J=7.6 Hz, 6H),
7.30–7.10 (m, 9H), 3.76–3.54 (m, 5H), 3.46 (dd, J=3.0, 9.0 Hz, 1H), 3.35
(dd, J=6.9, 9.0 Hz, 1H), 2.00–1.86 (m, 1H), 1.80–1.69 (m, 1H), 1.58–1.45
(m, 1H), 0.81 ppm (d, J=6.8 Hz, 3H); 13C NMR (C6D6, 75 MHz): d=
144.6 (3Cq), 129.2 (6C), 128.3 (6C), 127.3 (3C), 87.1 (Cq), 75.3, 66.7,
60.4, 36.3, 34.2, 16.7 ppm; IR (neat): n˜ =3374, 2969, 2878, 1490, 1448,
1050, 763, 706 cmÀ1; MS (ESI+): m/z: for C25H28O3: 399 [M+Na]+, 774
[2M+Na]+; HRMS (ESI+): m/z: calcd for C25H28O3: 399.1936 [M+Na]+;
found: 399.1938; TLC: Rf =0.62 (Et2O).
(3R*,5R*,6S*)-
+
(3S*,5R*,6S*)-5-Methyl-8-phenyl-oct-1-ene-3,6-diol
(24): nBuLi (0.4 mL, 2.5m/hexanes, 1 mmol) was added dropwise to a so-
Chem. Eur. J. 2011, 17, 5613 – 5627
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5625

F. Dꢁnꢀs, J. Lebreton et al.
[M+H]+; HRMS (ESI+): m/z: calcd for C31H38O2Si: 493.2533 [M+Na]+;
found: 493.2523; TLC: Rf =0.41 (petroleum ether/Et2O 80:20).
J=7.1 Hz, 3H), 0.88 ppm (t, J=6.9 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d=166.7, 151.3, 149.2, 120.9, 110.5, 64.3, 60.3, 45.4, 32.3, 29.4,
22.5, 14.1, 13.8 ppm; IR (film): n˜ =3500, 2957, 2931, 2871, 2860, 1720,
1640, 1466, 1392, 1334, 1304, 1267, 1213, 1175, 1134, 1096, 1043, 988, 904,
868, 811, 788, 731 cmÀ1; MS (CI+): m/z: for C13H22O3: 244 [M+NH4]+,
227 [M+H]+; HRMS (ESI+): m/z: calcd for C13H22O3: 249.1461
[M+Na]+; found: 249.1464; TLC: Rf =0.45 (petroleum ether/Et2O
40:60).
Minor isomer: 1H NMR (CDCl3, 400 MHz): d=7.65–7.59 (m, 4H), 7.44–
7–23 (m, 8H), 7.19–7.14 (m, 3H), 6.60 (s, 1H), 5.86 (ddt, J=6.6, 10.2,
16.9 Hz, 1H), 5.05 (dq, J=1.7, 17.1 Hz, 1H), 5.00–4.96 (m, 1H), 4.22–
4.18 (m, 1H), 3.80–3.71 (m, 1H), 3.13 (d, J=4.4 Hz, 1H), 2.62–2.58 (m,
2H), 2.25–2.07 (m, 2H), 1.83–1.65 (m, 2H), 1.04 ppm (s, 9H); 13C NMR
(CDCl3, 100 MHz): d=142.1, 138.6, 137.5, 135.8, 133.15, 133.09, 129.96,
129.91, 128.82, 128.6, 128.4, 127.91, 127.88, 126.8, 76.6, 63.7, 35.49, 30.36,
30.26, 26.9, 19.2 ppm; TLC: Rf =0.38 (petroleum ether/Et2O 80:20).
Ethyl 2-(4-methylene-5-phenethyl-tetrahydrofuran-2-yl)acetate (29a):
tBuOK (0.123 g, 1.1 mmol) was added to a solution of diene 28a (274 mg,
1 mmol) in THF (6 mL) at À788C. The solution was stirred at À788C for
3 h. The reaction mixture was quenched with a saturated aqueous solu-
tion of NH4Cl (10 mL) and the aqueous phase was extracted with Et2O
(ꢃ3). The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. Flash column chromatogra-
phy on silica gel (petroleum ether/Et2O 80:20) gave 29a (219 mg, 80%,
d.r.=70:30) as a colorless oil.
Major isomer: 1H NMR (CDCl3, 300 MHz): d=7.22–7.08 (m, 5H), 4.93–
4.90 (m, 1H), 4.79–4.77 (m, 1H), 4.28–4.16 (m, 1H), 4.21 (dq, J=6.5,
9.1 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 2.78–2.58 (m, 3H), 2.64 (dd, J=6.7,
15.1 Hz, 1H), 2.46 (dd, J=6.6, 15.3 Hz, 1H), 2.34–2.19 (m, 1H), 1.90
(dddd, J=3.8, 6.5, 10.4, 17.5 Hz, 1H), 1.82–1.68 (m, 1H), 1.20 ppm (t, J=
7.1 Hz, 3H); 1H NMR (CDCl3, 75 MHz): d=171.16, 151.0, 142.4, 128.6
(2C), 128.4 (2C), 125.83, 105.6, 80.3, 74.3, 160.6, 40.7, 39.3, 37.2, 31.5,
14.3 ppm; IR (film): n˜ =3083, 3061, 3025, 2981, 2862, 1734, 1496, 1454,
1433, 1399, 1368, 1312, 1259, 1242, 1193, 1146, 1093, 1042, 885, 749,
700 cmÀ1; MS (CI+): for C17H22O3: 292 [M+NH4]+, 275 [M+H]+; HRMS
(ESI+): m/z: calcd for C13H22O3: 297.1461 [M+Na]+; found: 297.1459;
TLC: Rf =0.57 (petroleum ether/Et2O 80:20).
Minor isomer: 1H NMR (CDCl3, 300 MHz): d=7.22–7.08 (m, 5H), 4.96–
4.94 (m, 1H), 4.82–4.80 (m, 1H), 4.44 (quint., J=6.6 Hz, 1H), 4.39–4.31
(m, 1H), 4.10 (q, J=7.1 Hz, 2H), 2.78–2.58 (m, 3H), 2.57 (dd, J=7.0,
15.2 Hz, 1H), 2.38 (dd, J=6.8, 15.2 Hz, 1H), 2.34–2.19 (m, 1H), 1.82–
1.68 (m, 2H), 1.20 ppm (t, J=7.1 Hz, 3H); 1H NMR (CDCl3, 75 MHz):
d=171.20, 150.66, 142.2 (minor isomer), 128.6 (2C), 128.4 (2C), 125.85,
104.9, 79.3, 73.8, 160.6, 40.4, 38.6, 37.3, 31.8, 14.3 ppm; IR (film): n˜ =
3083, 3061, 3025, 2981, 2862, 1734, 1496, 1454, 1433, 1399, 1368, 1312,
1259, 1242, 1193, 1146, 1093, 1042, 885, 749, 700 cmÀ1; MS (CI+): m/z: for
C17H22O3: 292 [M+NH4]+, 275 [M+H]+; HRMS (ESI+): m/z: calcd for
C13H22O3: 297.1461 [M+Na]+; found: 297.1459; TLC: Rf =0.57 (petro-
leum ether/Et2O 80:20).
3-(tert-Butyldiphenylsilyloxy)-1-(5-hydroxytetrahydrofuran-2-yl)-propan-
1-one (27): O3 was introduced to a solution of 2-(2-tert-butyldiphenylsilyl-
oxyethyl)-1-phenyl-hepta-1,6-dien-3-ol (0.300 g, 0.63 mmol) in CH2Cl2/
MeOH (9:1, 40 mL) until persistence of
a deep-blue coloration at
À788C. The excess of ozone was removed under a flow of argon and
Me2S (0.5 mL, 6.8 mmol) was added at À788C. The reaction mixture was
stirred overnight while the temperature was allowed to slowly reach
room temperature. The solvent and the excess of Me2S were removed
under reduced pressure. Flash chromatography (petroleum ether/Et2O
50:50) gave 27 (0.21 g, 84%) as a colorless oil.
Major isomer: 1H NMR (C6D6, 300 MHz): d=7.93–7.83 (m, 4H; Ar),
7.37–7.25 (m, 8H; Ar), 5.40–5.34 (m, 1H), 4.30 (t, J=7.9 Hz, 1H), 4.13–
4.07 (m, 2H), 2.90 (brs, 1H; OH), 2.79 (dt, J=6.1, 16.9 Hz, 1H), 2.72–
2.64 (m, 1H), 2.16–2.0 (m, 1H), 1.76–1.66 (m, 1H), 1.52–1.39 (m, 2H),
1.26 ppm (s, 9H); 13C NMR (C6D6, 75 MHz): d=209.9, 136.0, 133.9,
130.0, 128.1, 99.81, 84.4, 59.6, 41.2, 33.6, 27.0, 26.3, 19.34 ppm; IR (film):
n˜ =3434, 3072, 3052, 2958, 2931, 2888, 2857, 1719, 1487, 1472, 1462, 1428,
1390, 1361, 1112, 823, 786, 701 cmÀ1; MS (CI+): m/z: for C23H30O4Si: 416
[M+NH4]+; HRMS (ESI+): m/z: calcd for C23H30O4Si: 421.1813
[M+Na]+; found: 421.1813; TLC: Rf =0.21 (petroleum ether/Et2O
50:50).
Minor isomer: 1H NMR (C6D6, 300 MHz): d=7.93–7.25 (m, 10H; Ar),
5.40–5.34 (m, 1H), 4.54 (dd, J=5.2, 8.9 Hz, 1H), 4.13–4.07 (m, 2H),
2.70–2.64 (m, 2H), 2.26 (brs, 1H; OH), 2.16–2.00 (m, 1H), 1.93–1.83 (m,
1H), 1.76–1.53 (m, 2H), 1.25 ppm (s, 9H); 13C NMR (C6D6, 75 MHz): d=
208.3, 136.0, 133.9, 130.0, 128.1, 99.75, 83.0, 59.4, 41.3, 32.5, 27.0, 26.5,
19.36 ppm; IR (film): n˜ =3434, 3072, 3052, 2958, 2931, 2888, 2857, 1719,
1487, 1472, 1462, 1428, 1390, 1361, 1112, 823, 786, 701 cmÀ1; MS (CI+):
m/z: for C23H30O4Si: 416 [M+NH4]+; HRMS (ESI+): m/z: calcd for
C23H30O4Si: 421.1813 [M+Na]+; found: 421.1813; TLC: Rf =0.21 (petro-
leum ether/Et2O 50:50).
A
ethyl
(2E)-5-(1-Hydroxy-3-phenylpropyl)-2,5-hexadienoic ethyl ester (28a):
(Carbethoxymethylene)triphenylphosphorane (1.04 g, 3 mmol) was added
to a solution of lactol 10a (204 mg, 1 mmol) in CH2Cl2 (20 mL) at room
temperature. The solution was stirred at room temperature for 16 h.
Silica was added and the solvent was removed under reduced pressure.
Flash column chromatography on silica gel (petroleum ether/Et2O 60:40)
gave 28a (210 mg, 77%, d.r. (E/Z) ca. 87:13) as a colorless oil. 1H NMR
(C6D6, 300 MHz): d=7.26–7.04 (m, 5H; Ar+1H), 5.87 (dt, J=1.4,
15.6 Hz, 1H), 4.95 (s, 1H), 4.71 (s, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.84–
3.76 (m, 1H), 2.74–2.49 (m, 4H), 1.73–1.55 (m, 2H+1H; OH), 0.99 ppm
(t, J=7.1 Hz, 3H); 13C NMR (C6D6, 75 MHz): d=166.2, 149.0, 146.7,
142.3, 128.8, 128.7, 126.1, 123.2, 112.0, 74.0, 60.2, 37.3, 34.2, 32.2,
14.3 ppm; IR (film): n˜ =3500, 3084, 3061, 3025, 2981, 2935, 2863, 1717,
1652, 1583, 1495, 1453, 1368, 1310, 1271, 1206, 1160, 1041, 987, 911, 865,
806, 749, 699 cmÀ1; MS (CI+): m/z: for C17H22O3: 292 [M+NH4]+, 275
[M+H]+; HRMS (ESI+): m/z: calcd for C17H22O3: 297.1461 [M+Na]+;
found: 297.1457; TLC: Rf =0.33 (petroleum ether/Et2O 50:50).
ester (28k): (Carbethoxymethylene)triphenylphosphorane (1.04 g,
3 mmol) was added to a solution of lactol (Z)-10k (280 mg, 1 mmol) in
CH2Cl2 (20 mL) at room temperature. The solution was stirred at room
temperature for 16 h. Silica was added and the solvent was removed
under reduced pressure. Flash column chromatography on silica gel (pe-
troleum ether/Et2O 60:40) gave 29 (322 mg, 92%, d.r. (E/Z)=92:8) as a
colorless oil. 1H NMR (CDCl3, 300 MHz): d=7.30–7.00 (m, 10H; Ar+
1H), 6.35 (s, 1H), 4.95 (dt, J=1.4, 15.5 Hz, 1H), 4.77 (dd, J=4.3, 9.1 Hz,
1H), 4.21 (q, J=7.1 Hz, 2H), 3.25 (ddt, J=1.4, 7.0, 16.4 Hz, 1H), 3.08
(ddt, J=1.2, 7.4, 16.4 Hz, 1H), 2.81–2.59 (m, 2H), 2.11–1.79 (m, 2H),
1.94 (brs, 1H; OH), 1.30 ppm (t, J=7.1 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d=166.7, 147.7, 141.6, 141.3, 136.6, 129.3, 128.7 (2CAr), 128.6,
(2CAr), 128.5 (2CAr), 128.3 (2CAr), 126.9 (CAr), 126.0 (CAr), 122.9, 68.7,
60.4, 36.9, 33.4, 32.1, 14.4 ppm; IR (neat): n˜ =3445, 3024, 2979, 2938,
1717, 1494, 1453, 1267, 1039, 699 cmÀ1; MS (CI+): m/z: for C23H26O3: 368
[M+NH4]+, 350 [MÀH2O+NH4]+, 333 [MÀH2O+H]+; HRMS (ESI+):
m/z: calcd for C23H26O3: 373.1780 [M+Na]+; found: 373.1770; TLC: Rf =
0.24 (petroleum ether/Et2O 70:30).
(2E)-4-Butyl-5-(1-hydroxymethyl)-2,5-hexadienoic ethyl ester (28b):
(Carbethoxymethylene)triphenylphosphorane (1.04 g, 3 mmol) was added
to a solution of lactol 10b (156 mg, 1 mmol) in CH2Cl2 (20 mL) at room
temperature. The solution was stirred at room temperature for 16 h.
Silica was added and the solvent was removed under reduced pressure.
Flash column chromatography on silica gel (petroleum ether/Et2O 60:40)
gave 28b (210 mg, 93%, d.r. (E/Z)>95:5) as a colorless oil. 1H NMR
(CDCl3, 300 MHz): d=6.84 (dd, J=15.6, 8.5 Hz, 1H), 5.82 (dd, J=15.6,
1.0 Hz, 1H), 5.19 (d, J=0.9 Hz, 1H), 5.00 (brs, 1H), 4.18 (q, J=7.1 Hz,
2H), 4.07 (brs, 2H), 2.87 (q, J=6.0 Hz, 2H), 1.63–1.19 (m, 6H), 1.29 (t,
5-Allyl-2-phenethyl-3-[(Z)-1-phenylmethyliden]tetrahydrofuran
(30):
BF3·Et2O (255 mL, 2 mmol) was added dropwise to a solution of lactol
(Z)-10k (280 mg, 1 mmol) and allyltrimethylsilane (480 mL, 3 mmol) in
CH2Cl2 (15 mL) under argon at À788C. After completion of the reaction
(TLC monitoring), the mixture was allowed to reach À308C and a satu-
rated solution of NaHCO3 was added. The aqueous phase was extracted
with CH2Cl2 (ꢃ2) and the resulting organic phase was dried over Na2SO4,
filtered, and concentrated in vacuo. Flash chromatography (petroleum
5626
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5613 – 5627

A Simple Access to g-Lactols and 4-Methylene-g-Lactols
FULL PAPER
ether/Et2O 97:3) gave 30 (210 mg, 68%, d.r. (cis/trans)>5:95) as a color-
less oil. H NMR (CDCl3, 300 MHz): d=7.24–7.00 (m, 10H; Ar), 6.25 (q,
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1
J=1.9 Hz, 1H), 5.90 (tdd, J=7.0, 10.5, 17.2 Hz, 1H), 5.15–5.06 (m, 3H),
4.04 (quint., J=6.6 Hz, 1H), 2.86–2.81 (m, 2H), 2.61 (tdd, J=1.9, 6.6,
15.8 Hz, 1H), 2.49–2.40 (m, 1H), 2.32–2.17 (m, 2H), 1.96–1.70 ppm (m,
2H); 13C NMR (CDCl3, 75 MHz): d=145.6, 141.9 (CqAr), 137.4 (CqAr),
135.2, 129.2 (2CAr), 128.6 (2CAr), 128.5 (4CAr), 126.6 (CAr), 126.1 (CAr),
121.4, 117.0, 77.2, 75.0, 40.4, 40.0, 33.7, 32.5 ppm; IR (neat): n˜ =3024,
2923, 2858, 1641, 1601, 1495, 1453, 1043, 913, 697 cmÀ1; MS (CI+): m/z:
for C22H24O: 322 [M+NH4]+, 305 [M+H]+; TLC: Rf =0.70 (petroleum
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Acknowledgements
This work was supported by the French Ministry of Science (MESR
grant for A.B.), ANR JCJC (grant ANR-10-JCJC-0712 for R.B.), CNRS,
and ꢅregion Pays-de-la-Loireꢆ (grant for N. Z.). The authors thank N.
Henriques, C. Duchamp, and Dr. D. Bouchu (Centre Commun de Spec-
troscopie de Masse-Universitꢁ Claude Bernard Lyon 1 - France) for
HRMS measurements and V. Sylvestre (CEISAM) for assistance in NOE
measurements (structure determination).
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Received: January 5, 2011
Published online: April 6, 2011
Chem. Eur. J. 2011, 17, 5613 – 5627
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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