Stereoselective Synthesis of Highly Substituted Tetrahydropyrans through an Evans Aldol-Prins Strategy

Article abstract of DOI:10.1021/acs.joc.8b01182

A direct and general method for the synthesis of naturally occurring 2,3,4,5,6-pentasubstituted tetrahydropyrans has been developed, employing β,γ-unsaturated N-acyl oxazolidin-2-ones as key starting materials. The combination of the Evans aldol addition and the Prins cyclization allowed the diastereoselective and efficient generation of the desired oxacycles in two fashions: a one-pot Evans aldol-Prins protocol, in which five new σ bonds and five contiguous stereocenters were straightforwardly generated, and a two-step version, which additionally permitted the isolation of β,γ-unsaturated alcohol precursors bearing an N-acyl oxazolidin-2-one in the α position. From these alcohols were also obtained halogenated pentasubstituted tetrahydropyrans as well as 2,3,4,5-tetrasubstituted tetrahydrofurans, shedding light on the mechanism of the process. Computational studies were consistent with the experimental findings, and this innovative Evans aldol-Prins strategy was performed for the preparation of a battery of more than 30 densely substituted tetrahydropyrans, unprecedentedly fused to a 1,3-oxazinane-2,4-dione ring, both in a racemic fashion and in an enantiomeric fashion. These novel molecules were successfully submitted to several transformations to permit simple access to a variety of differently functionalized tetrahydropyrans. Most of these unique molecules were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria and the yeast Candida albicans, and some structure-activity relationships were established.

Full text of DOI:10.1021/acs.joc.8b01182

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Article
Stereoselective Synthesis of Highly Substituted
Tetrahydropyrans through an Evans Aldol-Prins Strategy
Sergio J. Álvarez-Méndez, Marta Fariña-Ramos, María Luisa Villalba, Marcelle D.
Perretti, Celina Garcia, Laila Moujir Moujir, Miguel A. Ramírez, and Victor S. Martin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01182 • Publication Date (Web): 23 Jul 2018
Downloaded from http://pubs.acs.org on July 24, 2018
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Stereoselective Synthesis of Highly Substituted Tetrahydropyrans through
an Evans AldolꢀPrins Strategy
†
*
†
‡
Sergio J. Álvarez-Méndez , Marta Fariña-Ramos , María Luisa Villalba , Marcelle D.
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Perretti , Celina García , Laila M. Moujir , Miguel A. Ramírez , and Víctor S. Martín
†
Instituto Universitario de BioꢀOrgánica “Antonio González” (IUBOꢀAG), Centro de
Investigaciones Biomédicas de Canarias (CIBICAN), Departamento de Química
Orgánica, Universidad de La Laguna (ULL), Avda. Astrofísico Francisco Sánchez 2,
38206 San Cristóbal de La Laguna (Tenerife), Spain.
‡
Laboratorio de Investigación y Desarrollo de Bioactivos (LIDeB), Departamento de
Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata,
Argentina, 47 & 115, B1900AJI La Plata, Buenos Aires, Argentina.
§
Departamento de Bioquímica, Microbiología, Biología Celular y Genética, Facultad de
Farmacia, Universidad de La Laguna (ULL), Avda. Astrofísico Francisco Sánchez s/n,
38206 San Cristóbal de La Laguna (Tenerife), Spain.
* E-mails: salvmen@ull.edu.es, vmartin@ull.edu.es
ABSTRACT GRAPHIC
*
Sergio J. ÁlvarezꢀMéndez’s current address: Sección de Ingeniería Agraria, Escuela Politécnica
Superior de Ingeniería, Universidad de La Laguna (ULL), Carretera San Miguel de Geneto 2, 38296 San
Cristóbal de La Laguna (Tenerife), Spain.
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ABSTRACT
A direct and general method for the synthesis of naturally occurring 2,3,4,5,6ꢀ
pentasubstituted tetrahydropyrans has been developed, employing β,γꢀunsaturated Nꢀ
acyl oxazolidinꢀ2ꢀones as key starting materials. The combination of the Evans aldol
addition and the Prins cyclization allowed the diastereoselective and efficient generation
of the desired oxacycles in two fashions: a oneꢀpot Evans aldolꢀPrins protocol, in which
five new σ bonds and five contiguous stereocenters were straightforwardly generated,
and a twoꢀsteps version, which additionally permitted the isolation of precursors β,γꢀ
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unsaturated alcohols bearing an Nꢀacyl oxazolidinꢀ2ꢀone in the α position. From these
alcohols were also obtained halogenated pentasubstituted tetrahydropyrans as well as
2,3,4,5ꢀtetrasubstituted tetrahydrofurans, shedding light on the mechanism of the
process. Computational studies were consistent with the experimental findings, and this
innovative Evans aldolꢀPrins strategy conducted to the preparation of a battery of more
than 30 densely substituted tetrahydropyrans, unprecedentedly fused to a 1,3ꢀoxazinaneꢀ
2,4ꢀdione ring, both in a racemic and in a enantiomeric fashion. These novel molecules
were successfully submitted to several transformations to permit a simple access to a
variety of differently functionalized tetrahydropyrans. Most of these unique molecules
were evaluated for their antimicrobial activity against Gramꢀpositive and Gramꢀnegative
bacteria and the yeast Candida albicans and some structure/activity relationships were
established.
INTRODUCTION
The tetrahydropyran (THP) motif is commonly found in biologically active secondary
metabolites isolated from marine and terrestrial sources, such as those shown in Figure
1
1, as well as being part of complex cyclic polyether systems. For example, 2,3,5ꢀ
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trisubstituted THPs can be found in morinols A and B, isolated in 1999 from Morina
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chinensis, a plant employed in the traditional Chinese medicine. Morinols and some
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derivatives show antiproliferative, antimicrobial and antifungal activity. Higher
substituted THPs can be found in clavosolides A and B, which exhibit two 2,3,4,6ꢀ
tetrasubstituted THPs in their structures. They were isolated from the cytotoxic extract
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of the sponge Myriastra clavosa from the Philippines. The same substitution and
stereochemical pattern appears in the tetrasubstituted THP bore by the family of toxins
polycavernosides, isolated from the red alga Gracilaria edulis (also known as
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Polycavernosa tsudai). Kendomycin, which was isolated from several Streptomyces
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strains, shows a 2,3,4,5,6ꢀpentasubstituted THP with the substituent at C adopting an
axial disposition. This compound acts as an endothelin receptor antagonist and it also
exhibits cytotoxicity against multiple human cell line and antiosteoporotic and antibiotic
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activities. Phorboxazoles A and B were isolated from Indian Ocean sponge Phorbas sp.
9
and show antitumor activity and antifungal activity against Candida albicans. Four
THPs rings appear in their structures, underlining the presence of the THP labelled as B
(Figure 1) with substituents in all its positions and the same substitution pattern found in
kendomycin. Besides being part of bioactive natural products, it has been demonstrated
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that the THP ring can even improve the efficacy of antiviral drugs, and it can show
1
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bioactivity itself, such as antinociceptive activity, serotonin and norepinephrine
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transporter inhibitory activity, antimicrobial activity by the inhibition of bacterial
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topoisomerase and antiproliferative activity.
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Figure 1. Examples of natural products containing nonꢀfused densely substituted THPs.
The number of natural products containing a THP ring has encouraged the
development and application of many synthetic strategies to achieve its obtaining, such
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as Pdꢀcatalyzed oxaheterocyclization, PetasisꢀFerrier union/rearrangement tactic,
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N
Michaelꢀlike reactions, S ꢀmediated and metalꢀpromoted cyclizations, ester enolate
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Claisen rearrangement,
ring expansion of tetrahydrofurans, 1,5ꢀcyclization,
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iodolactonization, epoxide openingꢀring closure reactions, and so on. Among the
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existing tactics, the Prins cyclization has emerged for the last years as a handy tool
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that affords the access to desired THPs. Throughout the last decade, our research
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group, has taken advantage of the Prins cyclization to synthesize differently substituted
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sixꢀ and sevenꢀmembered oxaꢀ and azaꢀheterocycles. Nevertheless, the application of
the Prins cyclization to access challenging 2,3,4,5,6ꢀpentasubstituted THPs has not been
systematically studied. On the one hand, there are only a few examples as part of
methodological works oriented to the obtaining of THPs with a less populated
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22e,23ꢀ26
substitution design.
On the other hand, Rychnovsky and coꢀworkers have
employed Prins cyclization to build pentasubstituted THPs to synthesize some natural
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products.
This absence of a general method encouraged us to propose a strategy based in
the combination of the wellꢀknown Evans aldol addition, as a powerful tool to construct
the necessary homoallylic alcohol, and the Prins cyclization to yield the target highly
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substituted THPs (Scheme 1). Thus, this Evans aldolꢀPrins (EAP) protocol suggests
that a 2,3,4,5,6ꢀpentasubstituted THP 1 could be accessed via the Prins cyclization of an
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aldehyde R CHO and the synꢀaldol 2. β,γꢀUnsaturated alcohols 2 bear a Nꢀacyl
oxazolidinꢀ2ꢀone moiety at α position. This auxiliary is the key for introduction of the
stereochemistry in the aldol and, therefore, in the subsequent THP 1. Evans aldol
addition was proposed as the diastereoselective pathway to get the aldol 2 starting from
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a generic aldehyde R CHO and β,γꢀunsaturated Nꢀacyl oxazolidinꢀ2ꢀone 3.
Compounds 3 may be prepared from the appropriate oxazolidinꢀ2ꢀone via an Nꢀ
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acylation of β,γꢀunsaturated carboxylic acids 4. Several of these acids are
commercially available, though they also can be readily synthesized via a modified
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2
Knoevenagel condensation starting from aldehydes R CH CHO. Thus, the envisioned
tactic should allow the stereoselective access to an enormous structural complexity by
the consecutive combining of three different aldehydes in four reaction steps. Prior to
establish an asymmetric strategy, nonꢀchiral oxazolidinꢀ2ꢀone were firstly selected as
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Evans auxiliary to evaluate its influence in this unprecedented process. In this report, we
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expand the results previously published in order to exhaustively detail all the studies
that led us to establish a protocol to yield 2,3,4,5,6ꢀpentasubstituted THPs in a general
and diastereoselective fashion. A special emphasis has been giving herein to the
different reaction conditions screenings and to the identification of all the byꢀproducts
and minor stereoisomers associated to the EAP protocol. We have also delved into
mechanistic studies, the enantiomeric approach and the derivatization and biological
evaluation of the novel family of compounds synthesized.
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Scheme 1. Retrosynthetic Analysis to Access 2,3,4,5,6-Pentasubstituted THPs via
an Evans Aldol-Prins Strategy
RESULTS AND DISCUSSION
As shown in Scheme 1, our synthetic approach firstly requires the preparation of a set of
Nꢀacyl oxazolidinꢀ2ꢀones 3 employing carboxylic acids 4 as starting materials (Table 1).
Acids 4a-4c were commercially available, whereas acids 4d-4f were straightforwardly
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obtained via a solventꢀfree condensation/decarboxylation sequence. Acids 4 were
differently activated prior to their subsequent treatment with the lithiated oxazolidinꢀ2ꢀ
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one to yield 3. Both systems DMF/oxalyl chloride and DCC/DMAP proved to be
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efficient, albeit we eventually selected TEA/pivaloyl chloride as reagents due to the
compatibility with the multigram synthesis of 3a (Table 1, entry 1). With these
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conditions in hand, nonꢀchiral Nꢀacyl oxazolidinꢀ2ꢀones 3b-3f (entries 2ꢀ6) and chiral
Nꢀacyl oxazolidinꢀ2ꢀones 3g-3i (entries 7ꢀ9) were efficiently synthesized with yields
ranging from 60 to 90%, except when the starting acid bore a terminal double bond (4b,
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R = H), since undesired Eꢀα,βꢀ3b was also obtained as consequence of the
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isomerization of the double bond (entry 2). NꢀAcyl oxazolidinꢀ2ꢀones 3aꢀ3c were
submitted to the Evans protocol to gain access to various synꢀaldols 2 with good yields
and showing an excellent tolerance to aromatic groups and both linear and branched
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aliphatic chains (entries 10ꢀ17). Similarly, chiral aldols 2iꢀ2m were obtained from
Nꢀacyl oxazolidinꢀ2ꢀones 3gꢀ3i (entries 18ꢀ22). As expected, in all the cases synꢀaldols
were exclusively obtained except when a nonꢀproperly stored nꢀBu
2
BOTf solution was
employed (entry 10), due to the diastereoselectivity of the aldol addition may be
3
8
sensitive to the concentration of that reagent. Isolation of traces of antiꢀ2a invited us
to try the efficient and selective access to that aldol, although the employment of the
3
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methods previously published by Evans and Hoye were unsuccessful. Additionally,
when Nꢀacyl oxazolidinꢀ2ꢀone 3c, bearing a double bond with a Z geometry, was
selected as starting material, it was observed a partial isomerization of the double bond
in the final product, leading to desired 2g with a moderate yield (entry 16).
Table 1. Synthesis of the N-Acyl Oxazolidin-2-ones 3 and Aldols 2
Nꢀacylation
Evans aldol addition
1
2
c
Entry Acid
R
R’
R’’
3 (%)
Entry
3
R
2 (%)
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d
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4a
4b
4c
4d
4e
4f
Et
H
H
H
H
H
H
H
H
H
3a (68)
3b (39)
3c (75)
3d (60)
3e (90)
3f (60)
3g (90)
3h (83)
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15
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17
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19
3a iꢀBu
3a Me
3a Bu
2a (81)
b
H
H
2b (75)
2c (84)
2d (81)
2e (81)
2f (76)
(Z)ꢀMe
H
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PhCH
2
H
3a Ph
nꢀpentyl
H
3a PhCH
3b Me
3c iꢀBu
2 2
CH
BnOCH
2
CH
2
H
e
4a
4a
4a
Et
Et
Et
(R)ꢀBn
(S)ꢀiꢀPr
2g (48)
2h (59)
3a 4ꢀBrꢀPh
3g Me
f
(R)ꢀMe (S)ꢀPh 3i (87)
2i (75)
2j (60)
f
3g PhCH
3h Me
2 2
CH
g
20
21
22
2k (86)
g
3h PhCH CH2 2l (69)
2
f
3i
Bu
2m (64)
a
b
7.7 grams of product were obtained from 7 grams of 4a. It was isolated a 54% of an inseparable 2.5/1
c
mixture of the desired product β,γꢀ3b and its positional isomer Eꢀα,βꢀ3b. Only synꢀaldols were detected
1
d
by H NMR analysis of the reaction crudes, unless noted otherwise. Traces of its diastereoisomer,
e 1
2
antiꢀ2a, were also isolated when a nonꢀproperly stored nꢀBu BOTf was employed. H NMR analysis of
the crude revealed that aldol 2g was obtained as a 2/1 mixture of the Zꢀ and Eꢀisomers due to an
isomerization of the double bond, although the yield given corresponds exclusively to the desired Zꢀ
f
g
isomer. (2S,3R). (2R,3S).
With aldols 2 in hand, we decided to test the Prins cyclization conditions
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previously optimized in our research group, employing the system Fe(acac) /TMSCl as
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2
2d
promoter. 4ꢀChloroꢀTHP 1a-Cl was selected as target molecule and aldol 2a and
isovaleraldehyde as starting materials (Scheme 2). The presence of each iꢀBu in
positions 2 and 6 of the ring should avoid the obtaining of undesired THPs as a
consequence of the side chain exchange due to the 2ꢀoxoniaꢀCope rearrangement, a
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2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
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0
1
2
3
4
5
6
7
8
9
0
41
[
3,3]ꢀsigmatropic rearrangement concomitant to the Prins cyclization. Aldol 2a
yielded two products after 30 min, one of them more nonpolar than the substrate and the
1
other one more polar and UVꢀvisible. Regarding the nonpolar product, H NMR
analysis confirmed the presence of a THP ring with the expected side chains. However,
mass analysis revealed that the molecule did not own a chlorine atom. Fortunately, Xꢀ
ray crystallography unambiguously determined that the product was 5a, in which the
THP ring appeared fused to a 1,3ꢀoxazinaneꢀ2,4ꢀdione ring (Scheme 2). Thus, bicycle
5
a was obtained as a mixture of two diastereoisomers (85:15 dr) in 43% total yield. The
4
2
43
Xꢀray analysis, together with the Jꢀcoupling over 9 Hz and GOESY experiments,
allowed us to establish an allꢀtrans configuration in the major diastereoisomer. GOESY
experiments also revealed that the minor diastereoisomer was the C ꢀepimer (Scheme
). On the other hand, the polar product was obtained in 7% yield and identified as
alcohol 6a, a skeletal isomer of aldol 2a, obtained on account of the 2ꢀoxoniaꢀCope
5
2
4
1
rearrangement (Scheme 2). Once the products of the reaction were identified, we
directed our attention to the unprecedented synthesis of the bicycle 5. Rearrangements
of Nꢀacyl oxazolidinꢀ2ꢀones to yield this kind of heterocycles had been previously
4
4
reported, though, to the best of our knowledge, this was the first example in which the
,3ꢀoxazinaneꢀ2,4ꢀdione ring was fused with a THP. Additionally, it should be
remarked that both heterocycles usually are related with varied biological activities such
1
45
46
11
as antiꢀepileptic, analgesic and antiproliferative. A synergistic biological activity
might be expected from these structures. Despite of its unexpected bicyclic structure,
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5
5
5
5
5
5
5
6
compound 5a is a 2,3,4,5,6ꢀpentasubstituted THP, so it consequently satisfies our initial
synthetic goal (Scheme 1). Additionally, the uniqueness of this bicyclic core encouraged
us to delve into the synthesis of this kind of compounds.
0
1
2
3
4
5
6
7
8
9
0
1
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3
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7
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Fe-Based Prins Cyclization of Aldol 2a to Yield Unexpected Bicycle 5a
We first screened a series of Lewis acids (LAs) to pursue better yields in the
obtaining of bicycles 5. We chose alcohol 2b and MeCHO as the most simple starting
materials to access to a 2,3,4,5,6ꢀpentasubstituted THP (Table 2). Firstly, those reagents
were submitted to the previously published conditions with Fe(acac)
3
/TMSCl (Scheme
), obtaining the expected bicycle 5b as an only diastereoisomer with a similar yield
to that of 5a (38% vs 43%), together with traces of the undesired rearrangement isomer
6b (Table 2, entry 1). A higher presence of Fe(acac) improved the yield of 5b and
avoided the formation of 6b (entries 2 vs 3). Nevertheless, when Fe(acac) and TMSCl
were employed separately as catalysts, the cyclization did not occur after 5 h of
reaction. The yield of 5b did not improve when an excess of FeCl was employed as an
22d
2
3
3
3
alternative source of Fe(III) (entry 4), although a supraꢀstoichiometric quantity of InCl3
led to 5b with an interesting 61% yield (entry 5). When 0.1 equiv of those iron and
indium compounds were tested, unaltered starting material was recovered. Other
47
3
promoters were tested until we discovered that BF ·THF allowed the synthesis of 5b
1
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with a remarkable 70% yield, although with a higher proportion of 6b (entry 6). To our
delight, a better yield was obtained when BF ·OEt was chosen as the LA, and 6b was
3
2
not detected (entry 7). Almost the same yield was obtained when a larger amount of
BF ·OEt was employed (entry 8), but when the amount of the LA was progressively
3
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reduced, the yield of 5b decreased in favor of an increase in the yield of nonꢀdesired 6b
and longer reaction time (entries 9 and 10). Then, we decided to evaluate the combined
effect of BF ·OEt with TMSCl as promoter of the EAP cyclization (entries 11ꢀ12). We
3
2
3 2
repeated the reaction shown in the entry 10 (0.05 equiv of BF ·OEt ) including 2.5
equiv of TMSCl in the set of reagents. Surprisingly, under these conditions the main
product of the reaction was the halogenated bicycle 7b-Cl instead of the bicycle 5b
(entry 11). Additionally, it was also observed the obtaining of the rearranged alcohol 6b
together with part of the unreacted starting material. When the amount of the BF ·OEt2
3
was increased to 0.5 equiv, the starting aldol was consumed, yielding a 67% of 7b-Cl
along with traces of 6b (entry 12). By contrast, when 2.5 equiv of TMSCl were
employed as sole promoter, a practically equimolar mixture of the halogenated product
7b-Cl and the starting material was detected after 44 h (entry 13). Next, we decided to
check the influence of the halogen in this process. When TMSI was employed as
promoter, full conversion of aldol 2b was observed after only 10 min, and two products
were identified (entry 14): the expected halogenated bicycle 7b-I (58%) and the 4ꢀ
iodineꢀTHP 1b-I (17%), with the originally pursued structure (Scheme 1). In the same
vein, TMSBr allowed the access to 7b-Br (46%) and 1b-Br (30%) after 3 h of reaction
4
8
(
entry 15). We eventually tested the EAP cyclization employing FeBr both as a LA
3
and as a bromide source. The reaction was complete after 30 min yielding the 4ꢀbromoꢀ
THP 1b-Br (23%), the hydroxylated bicycle 5b (34%) and the rearranged alcohol 6b
(9%), but no traces of the halogenated bicycle 7b-Br were detected (entry 16).
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4
4
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5
5
5
5
5
5
5
5
5
6
Table 2. Screening of Lewis Acids (LAs)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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0
a
a
b
a
Entry LA
Equiv
X
ꢀ
1b-X (%) 5b (%) 6b (%) 7b-X (%)
1
2
3
4
5
6
7
8
9
1
Fe(acac) /TMSCl 0.1/1.5
ꢀ
38
59
28
41
61
70
78
79
68
58
ꢀ
1
ꢀ
ꢀ
3
c
Fe(acac)
3
/TMSCl 0.5/1.5
ꢀ
ꢀ
ꢀ
d
Fe(acac)
3
/TMSCl 0.02/1.5 ꢀ
ꢀ
3
2
15
13
ꢀ
ꢀ
FeCl
InCl
BF ·THF
3
1.5
1.5
2.5
2.5
5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3
ꢀ
ꢀ
ꢀ
ꢀ
3
BF
BF
BF
BF
3
3
3
3
·OEt
·OEt
·OEt
·OEt
2
2
2
2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1
ꢀ
3
7
10
6
6
ꢀ
ꢀ
d
d,e
f
0
0.05
ꢀ
ꢀ
11
12
BF ·OEt /TMSCl 0.05/2.5 Cl
ꢀ
46
67
45
58
46
3
2
BF
3
·OEt
2
/TMSCl 0.5/2.5 Cl
ꢀ
ꢀ
g
h
i
b
13
14
15
TMSCl
TMSI
2.5
2.5
2.5
Cl
I
ꢀ
ꢀ
17
30
ꢀ
TMSBr
Br
ꢀ
ꢀ
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1
6
FeBr3
2.5
Br
23
34
9
ꢀ
a
1
b
Isolated yield, unless noted otherwise; >95:5 dr (determined by H NMR spectroscopy). Calculated by
1
c
H NMR spectroscopy. The employment of 1 equiv of Fe(acac)
3
lead to a decrease in the yield of 5b and
d
e
to the obtaining of traces of 7b-Cl. The reaction was stopped after 20 h. It was recovered a 44% of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
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4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
g
unreacted starting material. The reaction was stopped after 2 h. The reaction was stopped after 44 h and
h
i
it was found a 49% of unreacted starting material. The reaction was stopped after 20 min. The reaction
was stopped after 3 h.
Once verified the benefits of BF ·OEt as promoter of the EAP cyclization, it
3
2
was studied the effect of the solvent (Table 3). Bicycle 5c was obtained as a sole
diastereoisomer in 66% yield from aldol 2c and nꢀpentanal employing DCM as solvent
(
entry 1). Secondly, the reaction was repeated several times replacing DCM by solvents
such as acetonitrile, benzene and toluene, although the yield did not improve (entries 2ꢀ
1
4
). The crudes of those reactions were thoroughly studied by H NMR to check that no
4
9
50
byꢀproducts associated to competitive PrinsꢀRitter or PrinsꢀFriedelꢀCrafts processes
(
both associated to nucleophilic solvents) were obtained. The selection of Et O as
2
solvent led to the poorest yield (entry 5). Interestingly, when acetic acid was employed
as solvent, bicycle 5c was obtained as its Oꢀacetylated derivative (entry 6). However,
3 2
keeping the acetic acid as solvent and leaving out the BF ·OEt as promoter, the
reaction did not take place. It was also tested the Prins cyclization between aldol 2b and
nꢀpentanal employing DCM as solvent to access to bicycle 5d in 69% yield (entry 7).
There was a drop in yield when the reaction was repeated in the presence of CHCl
hexane as solvents (entries 8ꢀ9).
3
or nꢀ
Table 3. Screening of Solvents
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0
a
Entry Aldol Solvent
DCM
Acetonitrile 5c
Bicycle Yield (%)
1
2
3
4
5
6
7
8
9
2c
2c
2c
2c
2c
2c
2b
2b
2b
5c
66
55
52
43
21
71
69
50
31
Benzene
Toluene
5c
5c
5c
Et O
2
b
Acetic acid 5c-Ac
DCM
CHCl
5d
5d
5d
3
nꢀhexane
a
1
b
Isolated yield; >95:5 dr (determined by H NMR spectroscopy). Bicycle was obtained as its Oꢀ
acetylated derivative.
The studies described above allowed us to conclude that the optimized
conditions for the EAP cyclization imply the use of 2.5 equiv of BF ·OEt and DCM as
3
2
5
1
solvent at rt. This EAP cyclization has proven to be a diastereoselective fashion to
synthesize 2,3,4,5,6ꢀpentasubstituted THPs with an allꢀtrans stereochemistry, placing
their substituents in equatorial positions. The substituents at C and C of the THP adopt
2
6
a preferred syn stereochemistry to minimize the 1,3ꢀdiaxial interaction in the chairꢀlike
52
transition state (Scheme 3, equation 1). The position of the oxygen atom linked to C
4
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is a consequence of the position adopted by the oxazolidinꢀ2ꢀone in the transition state,
as will be discussed in the mechanistic discussion section (Scheme 7). Regarding the
stereochemistry of C
3
and C
5
, it is controlled by the stereochemistry of the starting
31
alcohol. On the one hand, the trans disposition of the substituents of the synꢀaldol
leads to the trans orientation of the substituents at C and C
contrast, an antiꢀaldol should conduct to a cis orientation of those substituents (equation
). On the other hand, an Eꢀgeometry of the olefin conducts to the equatorial position of
the substituent at C (equations 1 and 2), whereas a Zꢀgeometry should favor the axial
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
(equation 1 and 3); by
2
5
26
position (equation 3). A further mechanistic discussion will be given in Scheme 7. As
we had obtained a small amount of antiꢀ2a (Table 1, entry 7), we decided to evaluate it
in the EAP cyclization to synthesize the bicycle 5e with the substituent at C in an axial
3
position (Scheme 3, equation 2). Thus, antiꢀ2a was submitted to each reactions
3 3 2
employing FeCl (method A) and BF ·OEt (method B) as Lewis acids. In both cases,
the main product was the expected bicycle 5e, whose relative stereochemistry was
confirmed by GOESY analysis. However, the employment of the antiꢀ2a as starting
material yielded the synthesis of two undesired minor diastereoisomers in 3/1
proportion: the main one was identified as the allꢀtrans bicycle 5a, whereas the other
5
3
5
one was its C ꢀepimer. When synꢀaldol 2g, bearing a Zꢀolefin, was submitted to the
optimized EAP cyclization conditions, the desired bicycle 5f was diastereoselectively
obtained in 76% yield (Scheme 3, equation 3). As bicycles 5e and 5f, bearing axial
substituents, can be accessed via the EAP cyclization, it therefore constitutes an
interesting tool to access to the core of natural products such as kendomycin or
phorboxazols (Figure 1).
Scheme 3. Synthesis of Bicycles with Different Stereochemical Patterns
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
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9
0
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8
9
0
Afterwards, we selected synꢀaldol 2b as starting material to check the robustness
of the optimized conditions (BF
3
·OEt
Table 4). Entries 1 and 2 collect the previously described synthesis of bicycles 5b
Table 2, entry 7) and 5d (Table 3, entry 7), respectively. Besides these linear chains,
position of the THP yielding a
70% of 5g (entry 3). Hexꢀ5ꢀynal and pentꢀ4ꢀynal were synthesized through a PCCꢀ
2
/DCM/rt) by broadening the scope of aldehydes
(
(
the bulkier iꢀBu was successfully introduced at the C
6
5
4
mediated oxidation of the corresponding commercial alcohols, and they were
employed in the Prins cyclization without further purification, yielding bicycles 5h and
5
i respectively (entries 4 and 5). Together with 5i, it was detected a small amount of
bicycle 5b because of the release of MeCHO to the medium as result of the
4
1
2
ꢀoxoniaꢀCope rearrangement. We also chose octꢀ2ꢀynal to test an α,βꢀunsaturated
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aldehyde, and bicycle 5j was obtained in 46% yield (entry 6). It should be noted that
octꢀ2ꢀynal protected as its diethylacetal led to the same product with a slightly inferior
39% yield. Cyclopropanecarbaldehyde is an apparently problematic aldehyde due to
55
presence of an acidꢀsensitive motif, but to our delight it reacted properly to yield 5k in
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
63% yield (entry 7). Cyclohexanone was also tested as carbonylic compound in the
5
6
EAP cyclization to study the obtaining of spirotetrahydropyrans, providing 5l in 23%
yield although with excellent diastereoselectivity (entry 8). The low yield is a
consequence of the influence of the 2ꢀoxoniaꢀCope rearrangement, which leads to the
obtaining of bicycle 5b as the main product. Additionally, the 2,3,4,5,5ꢀpentasubstituted
tetrahydrofuran (THF) 8l was isolated as a 4/1 mixture of the epimers at C
4
in 19%
yield. It is proposed that THF 81 is a consequence of a 5ꢀexoꢀtrig attack of the olefin on
5
7
the oxocarbenium ion, instead of the 6ꢀendoꢀtrig attack conducive to the bicycle 5.
Afterwards, benzaldehyde (entry 9) and several electronꢀpoor aromatic aldehydes
(entries 10ꢀ12) were evaluated. An electronꢀrich aromatic aldehyde carrying a MeO
group in paraꢀ position also provided a similar good yield (entry 13), though a drop in
the yield was observed when the same donor group was located in the ortoꢀ position
58
(
(
(
entry 14). As occurred when cyclohexanone was employed as carbonylic compound
entry 8), the corresponding 2,3,4,5ꢀtetrasubstituted THFs 8 were generally identified
entries 9ꢀ11 and 13ꢀ14), unlike the results found when aliphatic aldehydes were used as
starting materials.
Table 4. Synthesis of Differently Substituted THPs
1
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5
5
5
5
5
5
5
6
1
2
3
a
b
c
Entry 2
R
R
R
5 (%)
5b (%) 8 (%)
1
2
3
4
5
6
7
2b Et
2b Et
2b Et
2b Et
2b Et
2b Et
2b Et
Me
Me
Me
Me
Me
Me
Me
Me
5b (78)
5d (69)
5g (70)
5h (65)
5i (60)
78
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Bu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
iꢀBu
ꢀ
HC≡C(CH
2
2
)
3
2
ꢀ
HC≡C(CH
)
10
ꢀ
d,e
nꢀC H C≡C 5j (46)
5
11
cꢀPr
5k (63)
ꢀ
O
8
2b
Et
Me
5l (23)
45
8l (19)
9
1
2b Et
2b Et
2b Et
2b Et
2b Et
2b Et
2a Et
2c Et
2c Et
Me
Me
Me
Me
Me
Me
Ph
5m (72)
ꢀ
8m (4)
f
0
3ꢀFꢀPh
2ꢀClꢀPh
4ꢀBrꢀPh
4ꢀ(MeO)ꢀPh
2ꢀ(MeO)ꢀPh
iꢀBu
5n (64)
5o (60)
5p (68)
5q (63)
5r (20)
5a (75)
5c (66)
5s (50)
ꢀ
8n (8)
11
12
1
3
12
10
ꢀ
8o (16)
ꢀ
1
1
1
3
4
5
8q (10)
8r (20)
g
g
iꢀBu
Bu
-
-
-
16
Bu
ꢀ
17
Bu
iꢀBu
ꢀ
1
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d
1
1
2
2
8
9
0
1
2d Et
2h Et
2e Et
Ph
Me
5t (35)
55
6
ꢀ
-
-
-
-
-
-
4ꢀBrꢀPh
Me
5u (43)
d
PhCH
2
CH
2
Me
5v (54)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
h
i
2f
2f
2f
H
H
H
Me
Me
5w (38)
ꢀ
d
22
Me
Ph
5x (39)
ꢀ
j
2
3
Me
3,4ꢀ(MeO)
2
Ph 5y (41)
ꢀ
a
1
b
Isolated yield; >95:5 dr, unless noted otherwise (determined by H NMR spectroscopy). Calculated by
1
c
H NMR spectroscopy, except in entry 1, where 5b is the expected product. Isolated yield; 80:20 dr,
1
d
1
unless noted otherwise (determined by H NMR spectroscopy). 90:10 dr (determined by H NMR
e
f
spectroscopy). A 39% yield was obtained when aldehyde was employed protected as diethylacetal.
1
g
h
8
5:15 dr (determined by H NMR spectroscopy). Reaction performed at 0 ºC. 40% of 6b was also
i
isolated; when nꢀhexane (0.05 M) was employed as solvent, 50% of 5w and 30% of 6b were isolated. 6x
1
j
(
35%) and 5w (14%, >95:5 dr) were calculated by H NMR spectroscopy. 6y (10%) and 5w (14%, >95:5
1
dr) were calculated by H NMR spectroscopy.
Once the effectiveness of the Prins cyclization between the simplest secondary
2
3
aldol 2b (R = Me) and several aldehydes R CHO was demonstrated, we decided to
2
3
2
3
modify both substituents R and R (Table 5). As illustrated in entry 15, when R = R =
iꢀBu, bicycle 5a was efficiently synthesized as a sole diastereoisomer performing the
reaction at 0 ºC (traces of the C ꢀepimer were obtained when the reaction was carried
5
out at rt). Entry 16 gathers the previously discussed synthesis of bicycle 5c (Table 3,
entry 1). When the synthesis of bicycle 5s was addressed, it was essential performing
the reaction at 0 ºC to avoid the obtaining of traces of the bicycles 5a and 5c, as
consequence of the processes associated to the 2ꢀoxoniaꢀCope rearrangement (entry
41
2
17). However, when MeCHO was combined with 2d (R = Ph), the presence of an
aromatic group directly attached to the hydroxy group of the aldol led us inevitably to a
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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5
5
5
5
5
5
5
5
5
6
mixture of the desired bicycle 5t (35%) and side chains exchanged byꢀproduct 5b (55%)
2
as main product (entry 18). This phenomenon can be explained considering that if R is
an aromatic group, it stabilizes by resonance the intermediate oxocarbenium obtained
59
after the 2ꢀoxoniaꢀCope rearrangement. As expected, the presence of an electron
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
withdrawing group in the aromatic moiety of aldol 2h (R = 4ꢀBrꢀPh) conducted to a
decrease of the undesired byꢀproduct 5b and yielded bicycle 5u diastereoselectively
6
0,61
(entry 19).
The presence of a twoꢀunit methylene bridge between the aromatic and
2
the hydroxy groups of the aldol 2e (R = PhCH
2
CH
2
) allowed likewise an improvement
of the yield in the synthesis of bicycle 5v (entry 20). Then we tested the EAP
1
cyclization employing aldol 2f (R = H) as starting material. When it was combined
with MeCHO, the absence of an aliphatic chain attached to the olefin led to the bicycle
5w in 38% yield (entry 21), significantly lower than the 78% obtained during the
1
1
synthesis of 5b (R = Et, entry 1). Moreover, the 2ꢀoxoniaꢀCope byꢀproduct 6c (R = H,
3
R = Me) was also isolated in 40% yield, the highest one of all the examples shown up
6
2
to now. This result will be addressed again at the end of the mechanistic section
Scheme 7). Similar results were found when aldol 2f was combined with aromatic
(
aldehydes to yield bicycles 5x and 5y, and in these cases traces of bicycle 5w (entries 22
and 23) were also isolated. In spite of the low yield, it should be remarked that 2,3,4,6ꢀ
tetrasubstituted THPs 5w, 5x and 5y bear their substituents in equatorial positions,
hence they share the same core shown by natural products such as polycavernosides and
clavosolides (Figure 1), which enhance the synthetic utility of the EAP protocol.
Summarizing, this EAP protocol allows the twoꢀsteps conversion of Nꢀacyl
oxazolidinꢀ2ꢀones 3 into bicycles 5 via the formation of aldols 2. During the first step,
the Evans aldol methodology permits the generation of a σ CꢀC bond and two
stereocenters in a diastereoselective fashion. The Prins cyclization of those aldols
2
0
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implies the creation of four σ bonds (three CꢀO and one CꢀC) and the insertion of three
stereocenters (Scheme 4, new bonds are highlighted in bold and the stereocenters with
asterisks). Therefore, starting from a molecule with no chiral centers such as 3a, a high
structural complexity may be straightforwardly generated: bicycle 5b was obtained in
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
59% yield as a single diastereoisomer after just two steps. Nevertheless, we wondered if
an even simpler alternative could be performed, by combining both Evans aldol and
Prins cyclization in a oneꢀpot process. Thus, Nꢀacyl oxazolidinꢀ2ꢀone 3a and MeCHO
were submitted to the Evans protocol to yield 2b; once TLC analysis showed that the
reaction was complete, another portion of MeCHO and 2.5 equiv of BF
added to the reaction medium (Scheme 4). To our delight, bicycle 5b was obtained in
4% yield, comparable to that obtained in the twoꢀsteps process. It should be
3 2
·OEt were
5
empathized that this is a truly excellent yield for a method in which five contiguous
stereocenters are diastereoselectively installed and five σ bonds are generated, meaning
an average yield for each bond of 88%. Additionally, this simplified protocol avoids the
workꢀup and purification of aldol 2b, with the consequent saving of organic solvents
and time.
Scheme 4. Two-steps EAP Cyclization vs One-pot EAP Cyclization
The efficacy of the oneꢀpot EAP protocol in the synthesis of 5b encouraged us to
expand the scope by combining several Nꢀacyl oxazolidinꢀ2ꢀones 3 and diverse
aldehydes (Table 5). Entry 1 gathers the result previously shown in Scheme 4. Nꢀacyl
2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
oxazolidinꢀ2ꢀone 3a also yielded bicycles 5 bearing different aliphatic and aromatic
groups at C and C (entries 2ꢀ5). Entry 6 shows that this oneꢀpot EAP protocol was
2
6
perfectly compatible with a multigram synthesis, allowing the preparation of 5.3 g of
bicycle 5a from 3a with no loss of yield and enhancing the synthetic utility of this
methodology. The oneꢀpot EAP protocol was also efficient starting from Nꢀacyl
oxazolidinꢀ2ꢀones bearing an aromatic group (entry 7) and longer linear aliphatic chain
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entries 8 and 9). When a benzyl ether was present at starting material 3f, the
corresponding bicycle was achieved in 54% overall yield, as a 1.3/1 mixture of the
benzylated/nonꢀbenzylated product (entry 10).
Table 5. Synthesis of 2,3,4,5,6-Pentasubstituted THPs via the One-pot EAP
Cyclization
1
2
3
a
b
Entry
Substrate R
R
R
Bicycle Yield (%)
Yieldav (%)
1
2
3
4
5
6
3a
3a
3a
3a
3a
3a
Et
Me
Me
Me
Me
Me
Ph
5b
54
22
41
42
31
60
88
74
84
84
79
90
c
Et
Et
Et
Et
Et
4ꢀBrꢀPh
5u
nꢀC13
iꢀBu
Bu
H
27
5z
5aa
5ab
d
e
iꢀBu
iꢀBu 5a
2
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1
3d
3e
3e
3f
PhCH2
Bu
Me
Bu
Me
Bu
Bu
Me
Me
5ac
5ad
5ae
32
31
30
54
80
79
79
88
nꢀpentyl
nꢀpentyl
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
0
BnOCH
2
CH
2
5af
a
1
b
Isolated yield; >95:5 dr, unless noted otherwise (determined by H NMR spectroscopy). Average yield
c
of each one of the five new σꢀbonds generated during the oneꢀpot EAP cyclization. It was also isolated
d
1
e
5
b (4%, >95:5 dr). 90:10 dr (determined by H NMR spectroscopy). 5.3 grams were obtained with
f
8
5:15 dr. Obtained as a 1.3/1 mixture of the benzylated/nonꢀbenzylated THPs.
In summary, both in the twoꢀsteps and the oneꢀpot versions, the EAP protocol
rises up as a powerful tool for the synthesis of valuable 2,3,4,5,6ꢀpentasubstituted THPs
with the general structure 5. However, in spite of its contrasted efficacy, we still kept in
mind our original aim of accessing to densely substituted 4ꢀhaloꢀTHPs 1 (Scheme 1).
During the aboveꢀrelated studies through the understanding of the EAP cyclization, the
isolated synthesis of such 4ꢀhaloꢀTHPs (Table 2, entries 14ꢀ16) really grabbed our
attention, because those were the only examples in which the oxazolidinꢀ2ꢀone moiety
acted as a mere spectator instead of undergoing a rearrangement to form the bicyclic
structure. For this reason, we were interested in studying the influence of the nature of
the substituent directly attached to the carbonyl group in the aldol employed as starting
material in the Prins cyclization (Scheme 5).
Scheme 5. Influence of the Nature of the Substituent Directly Attached to the
Carbonyl Group
2
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Thus, we devised a variation of the aldolꢀPrins cyclization with aldols 9a and 9b,
whose structures are identical to Evans aldols 2a and 2b except for the substitution of
the oxazolidinꢀ2ꢀone moiety for an ester group. synꢀAldol 9a was combined with
iꢀBuCHO in a Prins cyclization promoted by FeCl
7% yield (equation 1, top). The isolation of a small amount of homoallylic alcohol 11
7%) demonstrated that the Prins cyclization was competing with the 2ꢀoxoniaꢀCope
rearrangement. Fortunately, the generation of this undesired byꢀproduct was suppressed
3
to produce 4ꢀchloroꢀTHP 10a in
4
(
when the promoter system was replaced by Fe(acac) /TMSCl, allowing the synthesis of
3
10a in 70% yield (equation 2, bottom). antiꢀAldol 9a was also submitted to this Feꢀ
based Prins cyclization to evaluate the influence of the stereochemistry present in the
starting material (equation 2). The reaction was firstly stopped at 20 min and the
nonpolar product analysed by NMR, revealing the expected 4ꢀchloroꢀTHP 10b (17%),
2
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the C ꢀepimer of 10a, whose stereochemistry was unequivocally assigned based on the
3
GOESY analysis and the Jꢀcoupling values found (equation 2, top). When the presumed
remaining starting material was checked by NMR, we surprisingly discovered that it
was actually a mixture of the unreacted antiꢀaldol 9a (44%) and the δꢀlactone 12 (26%).
When the reaction time was increased to 4 h it was obtained a similar yield of THP 10b
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
20%), although a higher proportion of lactone 12 (42%) regarding the unreacted
starting aldol (10%) was detected (equation 2, middle). Eventually, when the system
Fe(acac) /TMSCl was employed as promoter and the reaction time was set at 21 h, the
3
starting material was completely consumed and lactone 12 was isolated in 62% yield,
63
although the yield of THP 10b did not improve (equation 2, bottom). Next, we
decided to evaluate the efficacy of Feꢀbased Prins cyclization for synthesizing THPs
with different chains at the positions 2 and 6. Thus, synꢀaldol 9b was combined with
3
BuCHO and treated with Fe(acac) /TMSCl (equation 3). Unfortunately, expected THP
10c was obtained with a poor 20% yield together with a 16% of THP 10d, in which a
side chains exchange occurred as consequence of the 2ꢀoxoniaꢀCope rearrangement.
synꢀAldol 9b was also submitted to the Prins cyclization mediated by 2.5 equiv of
3 2
BF ·OEt pursuing the synthesis of the 4ꢀhydroxyꢀTHP 13 (equation 4). In contrast to
the efficient synthesis of 5b achieved when the analogous synꢀaldol 2b was treated
under the same conditions (78% and >95:5 dr, see Table 4, entry 1), herein the desired
4
THP 13 was obtained in 12% yield and as an 1/1 epimeric mixture at C . Thus,
according to these results, the oxazolidinꢀ2ꢀone moiety directly attached to the carbonyl
group of the aldol seems to be crucial, not only to guarantee the prevalence of the Prins
cyclization product facing the 2ꢀoxoniaꢀCope byꢀproducts, but also to achieve the THPs
with good yields and diastereoselectivities.
2
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Prins cyclizations illustrated in Scheme 5 constitute an unsuccessful pathway to
yield desired 2,3,4,5,6ꢀpentasubstituted THPs differently functionalized at C and C ,
3
4
which are interesting intermediates for the synthesis of THPꢀcontaining natural
products. However, the EAP protocol provides an efficient and robust access to this
kind of THPs, although fused to a 1,3ꢀoxazinaneꢀ2,4ꢀdione ring (5). Thus, the removal
of this second heterocycle should be an alternative way to access to highly substituted
nonꢀbicyclic THPs, such as those commonly found in natural products (Figure 1).
Bicycle 5a was chosen as starting material, and the cleavage of the nitrogenated
heterocycle was tackled through different transformations (Scheme 6). Firstly, 5a was
refluxed with a HCl aqueous solution for 4 h; under these conditions, the bicyclic
structure remained stable, although a chlorine atom replaced the terminal hydroxy
group, yielding the haloꢀbicycle 7a-Cl in 57% yield. The homologous product 7b-Cl
had been previously obtained with a similar yield when aldol 2a was submitted to the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3 2
Prins cyclization mediated by the system BF ·OEt /TMSCl (67%, see Table 2, entry
12). Similarly, when 5a was refluxed with a HBr aqueous solution, the haloꢀbicycle 7a-
Br was obtained in 81% yield. Bicycle 5a was also submitted to an elimination reaction
by treatment with KHMDS in order to obtain the dihydropyran 14 with an amide at
6
4
C
3
.
That elimination reaction allowed the release of a CO
2
molecule to permit the
cleavage of the bicyclic structure. Another protocol to transform bicycle 5a into an
6
5
amide was tested, affording a simple access to the βꢀhydroxy amide 15. Afterwards, a
6
6
basic hydrolysis protocol was tried to yield a THP embedded in a βꢀhydroxy acid.
Thus, treatment of 5a with freshly prepared lithium hydroperoxide yielded the THP 16
with a carboxylic acid at C and a carbamate at C , which was successfully hydrolyzed
3
4
at reflux with LiOH to allow the access to the βꢀhydroxy acid 17. Eventually, several
reductive protocols with DIBALꢀH were analysed, observing noteworthy differences
2
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according to the reagent nature and the addition order. When bicycle 5a was added over
an iceꢀcooled DIBALꢀH solution, 4ꢀhydroxy THP 18, bearing a tertiary amine, was
obtained because of the total reduction of both carbonyl groups. However, when
DIBALꢀH was dropwise added to a solution of bicycle 5a in THF and then refluxed,
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diol 19 was obtained. The employment of NaBH
4
as the source of hydride led to
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carbamate 20, whose hydrolysis yielded diol 19. The conclusion deduced from this
derivatization screening is that bicycles 5, easily obtained via our EAP protocol,
constitute a versatile platform to access to a substantial family of highly substituted
THPs bearing various functional groups.
Scheme 6. Derivatization of Bicycles 5
A mechanistic model for the Prins cyclization using the Eꢀ and Zꢀhomoallylic
alcohols 2 obtained from the Evans aldol addition is outlined below. Considering that
the variation of the reaction temperature almost did not affect the diastereoselectivity of
51
the reaction and only modified the reaction time, a kinetically controlled mechanism
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would be expected. In addition, from the experimental results, it seems that the
oxazolidinꢀ2ꢀone group is not a mere spectator in the process, since the reaction fails
when it is replaced by an ester group (Scheme 5). We carried out DFT calculations to
delve into the complete diastereoselectivity of the aboveꢀdescribed Lewis acidꢀcatalyzed
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Prins cyclization. In this regard, we computed the reaction profile (SCRF(CH
2 2
Cl )ꢀ
B3LTP/6ꢀ31g(d) level) involving the oxocarbenium resulting of the condensation of
1
2
simple allylic alcohol 2b (R = Et, R = Me) for both Eꢀ and Zꢀisomers (E-INT1 and
Z-INT1) in the presence of BF as the Lewis acid (Scheme 7). We speculate the
formation of trifluorohydroxyborate from the BF used, a species which will be
3
3
important during the overall mechanism conducting to the final tetrahydropyran.
Relative enthalpies ∆G (298 K) and bond distances are given in kcal/mol and angstrom,
respectively. Numbering of the figures is arbitrary and used for discussion. Only
representative hydrogens are shown. DFT calculations, in gas phase, were performed at
the B3LYP/6ꢀ31G (d) level, punctual corrected to include solvation in DCM, using the
SCRF method, used by default in Gaussian. The transition states were confirmed with
the corresponding force calculations, ensuring the presence of a single imaginary
frequency in all cases. For the determination of the E-INT3 and Z-INT3 complexes, the
Basis Set Superposition Error was taken into account using the “counterpoise” method.
Scheme 7. Computed Reaction Profile for the Cyclization of Oxonium E-INT1 and
Oxonium Z-INT1
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We first discuss the cyclization for the Eꢀisomer of the double bond at the
homoallylic alcohol. As depicted in Scheme 7, oxonium ion E-INT1 evolves
exothermically (∆E
r
= –15.3 kcal/mol) to carbocation E-INT2 through double bond
= +5.4 kcal/mol) adopts a chairꢀlike
nucleophilic attack. The transition state E-TS1 (∆E
r
conformation caused by the arrangement of the Nꢀacyl oxazolidinꢀ2ꢀone bearing in the
substrate. In this transition state, all substituents are located in the equatorial position
5 6
setting the relative configurations of C and C in the product. The obtained carbocation,
via E-TS1, allows the carbonyl nucleophilic equatorial attack of the oxazolidinꢀ2ꢀone
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