Iron(III) catalyzed direct synthesis of cis -2,7-disubstituted oxepanes. the shortest total synthesis of (+)-isolaurepan

Article abstract of DOI:10.1021/ol3028016

Prins cyclization of bis-homoallylic alcohols with aldehydes catalyzed by iron(III) salts shows excellent cis selectivity and yields to form 2,7-disubstituted oxepanes. The iron(III) is able to catalyze this process with unactivated olefins. This cyclization was used as the key step in the shortest total synthesis of (+)-isolaurepan.

Full text of DOI:10.1021/ol3028016

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iron(III) Catalyzed Direct Synthesis
of cis-2,7-Disubstituted Oxepanes. The
Shortest Total Synthesis of (þ)-Isolaurepan
†
Martın A. Purino, Miguel A. Ramırez, Antonio H. Daranas, Vıctor S. Martın, and
†
†
†
´
Juan I. Padron*
´
´
´
,†,‡
ꢀ
ꢀ
´
Instituto Universitario de Bio-Organica “Antonio Gonzalez”, Departamento de Quımica
ꢀ
ꢀ
´
Organica, Universidad de La Laguna, C/Astrofısico Francisco Sanchez 2,
38206 La Laguna, Tenerife, Spain, and Instituto de Productos Naturales y Agrobiologıa,
ꢀ
´
´
ꢀ
CSIC, C/Astrofısico Francisco Sanchez 3, 38206 La Laguna, Tenerife, Spain
jipadron@ipna.csic.es
Received October 15, 2012
ABSTRACT
Prins cyclization of bis-homoallylic alcohols with aldehydes catalyzed by iron(III) salts shows excellent cis selectivity and yields to form
2,7-disubstituted oxepanes. The iron(III) is able to catalyze this process with unactivated olefins. This cyclization was used as the key step in the
shortest total synthesis of (þ)-isolaurepan.
Seven-membered oxacycles (oxepanes) are a common
structural unit present and widespread in many bioactive
marine natural products.1 The common structural features
are the 2,7-disubstituted oxepanes, with different halide
atoms atthe side chainsinthe case of the simpler Laurencia
acetogenin metabolites (Figure 1),2 or being part of highly
complex natural compounds such as the marine polycyclic
toxins.3
The development of new methodologies togain access to
this type of oxacycle has steadily increased in recent years
mainly focusing on two major strategies of cyclization:
through CꢀC and CꢀO bond formation.4 However
Figure 1. Some representative lauroxepanes and (þ)-isolaure-
pan, the fully saturated core of (þ)-isolaurepinnacin.
† IUBO, Universidad de La Laguna.
‡ IPNA, CSIC.
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48 and preceding
issues. (b) Basu, S.; Ellinger, B.; Rizzo, S.; Deraeve, C.; Schurmann, M.;
Preut, H.; Arndt, H.-D.; Waldmann., H. Proc. Natl. Acad. Sci. U.S.A. 2011,
108, 6805–6810. (c) Alonso, E.; Fuwa, H.; Vale, C.; Suga, Y.; Goto, T.;
simple, direct construction of oxepanes is not an easy task.
Ideally, such methodology should use accessible starting
€
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Tetrahedron 2012, 68, 6999–7018.
r
10.1021/ol3028016
XXXX American Chemical Society

materials, achieving stereochemical control (usually cis) of
the (R,R0)-substituents adjacent to the oxygen atoms.
With our research group’s experience in the synthesis of
oxacycles of various sizes,4f we now focused on developing
a simple and direct methodology to gain access to medium-
size-ring oxacycles in a sustainable metal catalysis con-
text,5 using nontoxic, abundant, and biologically relevant
iron(III).6 We decided to use Prins cyclization,7 in the
direct synthesis of oxepanes considering the few precedents
found in the literature.8 The seminal work of Overman
et al. was based on the indirect cyclization of mixed acetals
derived from silyl activated 4-alken-1-ols and promoted
by an excess of Lewis acid.9 Herein we report studies of
Prins cyclization, with unactivated olefins, in the direct
synthesis of oxepanes and its utility in the total synthesis of
(þ)-isolaurepan.
Table 1. Prins Cyclization of Oxepanes Using Stoichiometric
Amounts of Iron(III) Chloridea
yieldd
yieldd
entry
R1
R2
(3)(%)
(5)(%)
1
2
H
H
H
H
H
i-Bu
3a, 5a
3b
56
60
70
32
15
42
75
43
63
45
41
0
c-C6H11
3
t-Bu
3c
0
4
n-C6H13
CH2=CH(CH2)2
i-Bu
3d, 5b
3e, 5c
3f, 5d
3g
37
21
33
0
5
Prins cyclization of 4-alken-1-ol (1, R1 = H) and iso-
valeraldehyde was initially performed in dry CH2Cl2
using stoichiometric amounts of FeCl3. The desired all
cis-disubstituted oxepane 3a was obtained in 56% yield
contaminated with 41% of the monosubstituted tetra-
hydrofuran (THF) 5a (Table 1, entry 1). The oxepanes
3b and 3c were obtained exclusively, without the presence
of the corresponding THFs, using more hindered aldehydes
(Table 1, entries 2 and 3).
6
n-C6H13
n-C6H13
n-C6H13
CH2Ph
CH2Ph
7
t-Bu
8
CH2=CH(CH2)2
i-Bu
3h, 5e
3i, 5f
3j, 5g
37
35
42e
9
10
CH2=CH(CH2)2
a Reaction conditions: 1 (1.0 mmol), R2CHO (1.1 mmol), and FeCl3
(1.0 equiv) in dry CH2Cl2 (10 mL) at rt in an open atmosphere for 15 h.
b The cis stereochemistry of the oxepanes was assigned by NOE experi-
ments. c The relative stereochemistry of the THFs was determined by
NMR studies on 5g (see the Supporting Information (SI)). d Yields
of products after purification by silica gel column chromatography.
e Reaction time was 3 h; otherwise the final products are decomposed
Next, we tested this cyclization using secondary bis-
homoallylic alcohols (1, R1 ¼ H) under the same reaction
conditions (Table 1). The all cis-2,4,7-trisubstituted oxe-
panes were obtained as the major compounds (Table 1,
entries 6ꢀ10, 3fꢀ3j). Again, with a hindered aldehyde as
pivalaldehyde, the oxepane 3g was formed exclusively in
good yield (Table 1, entry 7). At this point, we had very
good overall yields from the cyclization process but with
high yields of THF derivatives (Table 1, 5bꢀ5g). There-
fore, we applied our previously described catalytic system
formed from iron(III) salts and trimethylsilyl chloride in
the synthesis of oxepanes (Table 2).6c
Table 2. Iron(III)/TMSCl System Catalyzes the Direct Synthesis
of Substituted Oxepanesa
FeCl3 Fe(acac)3 ratiod
To our delight, the application of such a catalytic system
to the Prins cyclization led, with very good yields, to the
mixtures of oxepanes (3 and 4) without the presence of
THF derivatives 5 (Table 2). Withbis-homoallylic alcohols
1, the iron sources FeCl3 and Fe(acac)3 catalyzed the
yieldc
yieldc
(3:4)
entry
R1
R2
(%)
(%)
(%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
i-Bu
3a,4a
3b,4b
3c,4c
3d,4d
99
99
75
80
40
90
ꢀ
85
92
60
80
70
85
90
ꢀ
55:45
73:27
72:28
58:42
59:41
60:40
67:33
71:29
58:42
56:44
60:40
c-C6H11
t-Bu
n-C6H13
(5) Plietker, B. Synlett 2010, 14, 2049–2058.
(6) (a) Miranda, P. O.; Ramırez, M. A.; Martın, V. S.; Padron, J. I.
´ ´
CH2=CH(CH2)2 3e,4e
n-C6H13 i-Bu
n-C6H13 t-Bu
n-C6H13 t-Bu
3f, 4f
3g,4g
3g,4g
ꢀ
Org. Lett. 2006, 8, 1633–1636. (b) Miranda, P. O.; Leon, L. G.; Martı
´
n,
ꢀ
ꢀ
V. S.; Padron, J. I.; Padron, J. M. Bioorg. Med. Chem. Lett. 2006, 16,
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´
3135–3138. (c) Miranda, P. O.; Carballo, R. M.; Martın, V. S.; Padron,
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Chem. 2007, 11, 925–957. (e) Pastor, I. M.; Yus, M. Curr. Org. Chem.
2012, 16, 1277–1312.
(7) (a) Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Tetra-
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2007, 11, 925–957. (c) Pastor, I. M.; Yus, M. Curr. Org. Chem. 2012, 16,
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(8) (a) Coppi, L.; Ricci, A.; Taddei, M. J. Org. Chem. 1988, 53, 913–
915. (b) Lolkema, L. D. M.; Hiemstra, H.; Mooiweer, H. H.; Speckamp,
W. N. Tetrahedron Lett. 1988, 29, 6365–6368. (c) Furman, B.; Dziedzic,
M.; Justyniak, I. Tetrahedron 2008, 64, 3103–3110.
n-C6H13 CH2=CH(CH2)2 3h,4h 90
85
95
97
10 CH2Ph i-Bu
3i,4i
95
95
11 CH2Ph CH2=CH(CH2)2 3j,4j
a Reaction conditions: 1 (1.0 mmol), R2CHO (1.1 mmol), and FeCl3
(0.1 mmol)/TMSCl (1.1 mmol) in dry CH2Cl2 (10 mL) at rt in an open
atmosphere for 15 h. b The relative stereochemistry of the oxepanes was
assigned by NOE experiments (see the SI). c Yields of products after
purification by silica gel column chromatography. d The ratios were
determined by 1H NMR spectroscopy.
~
(9) (a) Overman, L. E.; Castaneda, A.; Blumenkopf, T. A. J. Am.
~
Chem. Soc. 1986, 108, 1303–1304. (b) Castaneda, A.; Kucera, D. J.;
Overman, L. E. J. Org. Chem. 1989, 54, 5695–5707. (c) Berger, D.;
Overman, L. E.; Renhowe, P. A. J. Am. Chem. Soc. 1997, 119, 2446–
2452.
cyclization, affording, in both cases, a mixture of cis-2,7-
dialkyl-oxepanes differing in the stereochemistry of the
B
Org. Lett., Vol. XX, No. XX, XXXX

Cl-atom at C-4. Prins cyclization of 4-alkenol and isova-
leraldehyde led to a 55:45 mixture of substituted oxepanes
(3a/4a) withexcellentyield (Table2, entry 1). The yieldsare
very good with both iron(III) sources, being slightly higher
with FeCl3. However, Fe(acac)3 shows better results with
aldehydes bearing functionalized groups as double bonds
when R1 = H (Table 2, entry 5). It should be emphasized
that the excellent yields obtained with functionalized alde-
hydes with both iron(III) sources(Table2, entries 9 and 11)
led the waytootherfunctionalgroups. Prinscyclizationled
to 60:40 mixtures of oxepanes 3/4 except when a bulky
aldehyde was used (Table 2, entries 2, 3, 7, and 8).10
It must be noted that, from a synthetic point of view, the
absence of stereochemical control at the Cl-substituted
carbon is not a limitation for the effective synthesis of the
oxepane ring. The Cl-atom can be easily removed, yielding
a single cis-2,7-disubstituted oxepane. To test the stereo-
chemical behavior of the process and advance further
synthetic applications, we decided to explore this cycliza-
tion using enantiomerically enriched secondary bis-homo-
allylic alcohols (Scheme 1).
enriched bis-homoallylic alcohol 10 incorporating the
n-hexyl group which was obtained in one step. Regio-
selective ring opening of the known epoxide (ꢀ)-911 with
allyl magnesium bromide in the presence of CuI afforded
the desired 10 in 90% yield (>99 ee).12
Scheme 2. Total Synthesis of (þ)-Isolaurepan through the Prins
Cyclization
Prins cyclization with the commercially available
(S)-hex-5-en-2-ol (6) and isovaleraldehyde led to oxepanes
7 in excellent yield using both iron(III) sources, FeCl3 and
Fe(acac)3. The oxepane 8 was obtained in 85% yield after a
subsequent dehalogenation reaction using n-Bu3SnH and
AIBN. We observed parallel results starting from the
corresponding enantiomer of the bis-homoallylic alcohol
6 (Scheme 1). The overall yield to generate enantiomeri-
cally enriched cis-2,7-disubstituted oxepanes was in the
76ꢀ83% range.
Prins cyclization of 10 with butyraldehyde was per-
formed under standard reaction conditions, using Fe(acac)3
as the iron(III) source,13 to generate the desired oxepane 11
in 95% yield.14 A final dehalogenation step led to formation
of (þ)-isolaurepan ([R]D25 = þ1.5 (c 0.97, CHCl3)) in 90%
yield. From the enantiomerically enriched epoxide 9, we
have accomplished the shortest and most efficient total
synthesis of (þ)-isolaurepan with a 77% overall yield.15
Furthermore with this total synthesis, we have shown that
the cyclization proceeds without a loss in enantiopurity.
To gain insight into the reaction mechanism, mechan-
istic oriented experiments were performed. We propose
thatthe reactionof the secondary bis-homoallylic alcohol 1
Scheme 1. Synthesis of Enantiomerically Enriched
cis-2,7-Disubstituted Oxepanes
(12) The epoxide (ꢀ)-9 was prepared via hydrolytic kinetic resolu-
tion: (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gouul, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307–1315. (b) Nielsen, L. P. C.; Stevenson, C. P.;
Backmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360–
1362.
(13) The Prins cyclization with the racemic alcohol 10 and FeCl3 as the
catalyst led to the desired oxepane 11 as a cis/trans 60:40 mixture in 90%
yield. However, this cyclization was improved using Fe(acac)3 as the
catalyst, and it was applied in the total synthesis of the (þ)-isolaurepan in
Scheme 2.
(14) The oxepane 11 was obtained as a cis/trans 60:40 mixture, with
respect to the atom of chlorine. These isomers were isolated and
characterized. See the SI.
(15) Synthesis of isolaurepan; (þ)-isolaurepan: (a) Kotsuki, H.;
24
Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem. 1989, 54, 5153–5161
(36% overall yield, [R]D = þ1.5 (c 0.97, CHCl3)). (b) Tripathi, D.;
25
Kumar, P. Tetrahedron Lett. 2008, 49, 7012–7014 (30% overall yield,
[R]D = þ1.5 (c 0.97, CHCl3)). (c) Pazos, G.; Perez, M.; Gandara, Z.;
With all these data in hand, we concentrated our efforts
toward the total synthesis of (þ)-isolaurepan using the de-
scribed Prins cyclization as the key reaction step (Scheme 2).
We planned this synthesis from the enantiomerically
ꢀ
ꢀ
ꢀ
Gomez, G.; Fall, Y. Tetrahedron Lett. 2009, 50, 5285–5287 (11.5%
overall yield, [R]D20 = þ1.7 (c 0.94, CHCl3)). (d) Tripathi, D.; Kumar,
24
S.; Kumar, P. Tetrahedron 2009, 65, 2226–2231 (34% overall yield,
~
[R]D = þ1.5 (c 0.97, CHCl3)). Formal synthesis: (e) Carreno, M. C.;
Mazery, R. D.; Urbano, A.; Colobert, F.; Solladie, G. Org. Lett. 2004, 6,
297–299 (31% overall yield at intermediate of Kotsuki). (ꢀ)-Isolaur-
epan: (f) Prasad, K.; Anbarasan, P. Tetrahedron: Asymmetry 2007, 18,
1419–1427 (60% overall yield at intermediate of Kotsuki). Racemic
synthesis: (g) Davies, M. J.; Moody, C. J. Synlett 1990, 95–96 (58%
overall yield). (h) Carling, R. W.; Clark, J. S.; Holmes, A. B. J. Chem.
Soc., Perkin Trans. 1 1992, 83–94 (<1%). (i) Ebine, M.; Suga, Y.;
Sasaki, M. Org. Biomol. Chem. 2010, 8, 39–42 (29% overall yield).
(10) When this cyclization was performed using Fe(acac)3 and iso-
valeraldehyde, in the presence of air and moisture, the target product
was obtained in a remarkable 85% yield (scaled up to 3 g).
(11) (a) Miller, K. M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison,
T. F. J. Am. Chem. Soc. 2004, 126, 4130–4131. (b) Berkessel, A.;
€
Rollmann, C.; Chamouleau, F.; Labs, S.; May, O.; Groger, H. Adv.
Synth. Catal. 2007, 349, 2697–2704.
Org. Lett., Vol. XX, No. XX, XXXX
C

and analdehyde 2 catalyzed by ferricchloride generates the
oxocarbenium ion 12, which can also be generated from
the acetal 13 which was isolated and characterized.16 The
intermediate 12 evolves to the corresponding oxepanes 3
and 4 via the carbocation 14, explaining the ratio between
the oxepanes 3 and 4. THFs 5 and 17 could be generated
from the corresponding bicycles 15 and 16 (Scheme 3).
Scheme 4. Experiments Performed to Contrast the Mechanistic
Proposal
Scheme 3. Mechanistic Proposal in the Synthesis
of 2,7-Disubtituted Oxepanes Catalyzed by Iron(III)
proposal of Scheme 3.18 In the oxepane 4, the oxygen of the
ether participates in a transannular cyclization through
an SN2 due to the optimal spatial requirement with the
Cl-atom (internal angle OꢀCꢀCl, 166.7°), leading to 15.
The leaving group nature of the Cl-ion is enhanced by
coordination with FeCl3. The attack of the chloride to the
carbon adjacent to the oxonium, with R2 as the substitu-
ent, led to the thermodynamically more stable THF 5.
In the case of bulky substituents at this position (R2 =
c-C6H11 and t-Bu) this attack is unfavorable, with the pres-
ence of THF 5 undetected (Table 1, entries 2, 3 and 7).
However, in the oxepane 3, the transannular cyclization is
unfavorable because the oxygen and chlorine (internal
angle OꢀCꢀCl, 141.7°) did not meet the spatial require-
ment to form the bicycle 16 and therefore the tetrahydro-
furan 17.
In summary, we successfully developed an efficient Prins
cyclization of bis-homoallylic alcohols with aldehydes
catalyzed by iron(III) salts. The reaction provides a direct
entry to cis-2,7-disubstituted oxepanes with excellent yields.
Using this approach as a key step, we performed the shortest
and most efficient total synthesis of (þ)-isolaurepan, thus
demonstrating the value of this methodology which uses
unactivated olefins. The suitable experiments allowed us to
propose a rational mechanism in the synthesis of 2,7-
disubstituted oxepanes.
We have developed a general and useful route to the
synthesis of a wide variety of functionalized cis-2,7-disub-
stituted oxepanes. Further application of this methodology
to the total synthesis of natural products (more complex
oxepanes) and computational studies are underway.
However, we have only observed oxepanes 3 and 4
and THF 5 as products of this reaction and suspected
that oxepane 4 was being transformed into the THF 5
(Tables 1 and 2).
Next, to confirm that the trisubstituted oxepane 4 is
transformed into THF 5, we decided to run a Prins cycliza-
tion using the commercially available bis-homoallylic
alcohol 6 enantiomerically enriched. We used 1.0 equiv
of iron(III) chloride to obtain the THF ring in addition
to the oxepane rings (Scheme 4). All the products were
isolated and fully characterized.16
The oxepane 7-cis was stable upon treatment with catalytic
amounts of iron(III) chloride during 24 h at rt (Scheme 4).
However, treatment of the oxepane 7-trans under the condi-
tions mentioned above afforded a mixture of the THF 18
with the starting oxepane 7-trans (Scheme 4). Longer reaction
times led exclusively to the THF 18 as the final product.17
All these experimental results show the bicycle 15 as an
intermediate to the THF 5 and support the mechanistic
Acknowledgment. This research was supported by the
Spanish MINECO, cofinanced by the European Regional
Development Fund (ERDF) (CTQ2011-28417-C02-01/
BQU).
Supporting Information Available. 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) For more details, see the SI.
(17) The relative stereochemistry of the tetrahydrofuran 18 was
determined by NMR studies. See the SI.
(18) Our mechanistic proposal completes the Overman studies in the
synthesis of 2,7-disubstituted oxepanes from mixed acetals derived from
4-penten-1-ol (see ref 8b).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX