Concise substrate-controlled asymmetric total syntheses of dioxabicyclic marine natural products with 2,10-dioxabicyclo-[7.3.0]dodecene and 2,9-dioxabicyclo[6.3.0]undecene skeletons

Article abstract of DOI:10.1021/ja310249u

We report a completely substrate-controlled approach to the asymmetric total synthesis of representative dioxabicyclic bromoallene marine natural products with either a 2,10-dioxabicyclo[7.3.0]dodecene or 2,9-dioxabicyclo[6.3. 0]undecene skeleton from commercially available glycidol as a common starting material. The former include (-)-isolaurallene (1), the enantiomeric form of natural (+)-neolaurallene (2), and (+)-itomanallene A (3c), and the latter are (+)-laurallene (4) and (+)-pannosallene (5a). In addition, our first syntheses of 3c and 5a established the structure and absolute stereochemistry of both natural products. Our general approach to establish the α,α′- relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the AS2-type ring conformation.

Full text of DOI:10.1021/ja310249u

Article
pubs.acs.org/JACS
Concise Substrate-Controlled Asymmetric Total Syntheses of
Dioxabicyclic Marine Natural Products with 2,10-Dioxabicyclo-
[7.3.0]dodecene and 2,9-Dioxabicyclo[6.3.0]undecene Skeletons
Mi Jung Kim,† Te-ik Sohn,† Deukjoon Kim,*,† and Robert S. Paton‡
†The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
‡Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United
Kingdom
S
* Supporting Information
ABSTRACT: We report a completely substrate-controlled
approach to the asymmetric total synthesis of representative
dioxabicyclic bromoallene marine natural products with either a
2,10-dioxabicyclo[7.3.0]dodecene or 2,9-dioxabicyclo[6.3.0]-
undecene skeleton from commercially available glycidol as a
common starting material. The former include (−)-isolaurallene
(1), the enantiomeric form of natural (+)-neolaurallene (2), and
(+)-itomanallene A (3c), and the latter are (+)-laurallene (4)
and (+)-pannosallene (5a). In addition, our first syntheses of 3c
and 5a established the structure and absolute stereochemistry of
both natural products. Our general approach to establish the
α,α′-relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious
pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled
or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was
achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these
dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate
conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an
alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the AS2-type ring conformation.
and the bromoallene unit could not be determined, 3a and 3b
were proposed for the possible structures of itomanallene A.
On the other hand, (+)-laurallene (4) and (+)-pannosallene
(5) are representative members of the Laurencia C15
acetogenins with a 2,9-dioxabicyclo[6.3.0]undecene skeleton
(Figure 1). (+)-Laurallene (4) was isolated from L. nipponica by
Fukuzawa and Kurosawa in 1979,6 and Suzuki and co-workers
isolated 5 from L. pannosa in 1996.7 The structure of 4 was
determined from its physical and chemical properties.6 The
relative stereochemistry of the pannosallene bicyclic skeleton
was defined by NOESY correlations, including the α,α′-cis
relative stereochemistry in the tetrahydrofuran ring. The
stereochemistry of the bromine on the C(12) side-chain was
deduced from biosynthetic considerations.7 Furthermore, as
INTRODUCTION
■
Species of the red algal genus Laurencia (Rhodomelaceae,
Ceramiales) have been a prolific source of halogenated C15
acetogenins based on diverse skeletons such as 2,10-
dioxabicyclo[7.3.0]dodecene and 2,9-dioxabicyclo[6.3.0]-
undecene.1 Since Kurata and co-workers first reported the
isolation of isolaurallene (1) from the red alga L. nipponica in
1982,2 new C15 acetogenins with the 2,10-dioxabicyclo[7.3.0]-
dodecene skeleton have been isolated (Figure 1). Examples
include (+)-neolaurallene (2), which was isolated by Kurosawa
and co-workers from L. okamurai in 1984,3 and (+)-itoma-
nallene A that was subsequently isolated by the Suzuki group
from L. intricata in 2002.4 The structure and absolute
configuration of both isolaurallene (1) and neolaurallene (2)
were firmly established on the basis of X-ray crystallographic
studies.2,3 Unlike isolaurallene and neolaurallene, itomanallene
A was initially presumed to possess an α,α′-cis-tetrahydrofuran
moiety. The relative stereochemistry of the bicyclic skeleton in
itomanallene A was established by extensive spectroscopic
studies.4 Judging from the strongly positive rotation of
above,5 the strongly positive optical rotation {[α]26 +64.3 (c
D
0.070, CHCl3)} led to the bromoallene moiety in pannosallene
being assigned as S. However, because the relative stereo-
chemistry of C(3) and C(4) was yet undetermined, 5a and 5b
were proposed as potential structures for (+)-pannosallene.
itomanallene A {[α]22 +99 (c 0.44, CHCl3)}, its bromoallene
D
moiety would be assigned as S by application of Lowe’s rule.5
Received: October 17, 2012
Since the relative stereochemistry between the bicyclic skeleton
© XXXX American Chemical Society
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Figure 1. Representative dioxabicyclic bromoallene marine natural products with 2,10-dioxabicyclo[7.3.0]dodecene and 2,9-dioxabicyclo[6.3.0]-
undecene skeletons.
Scheme 1. General Synthetic Strategy
Owing to their exquisite structures, these medium-ring
dioxabicyclic bromoallene marine natural products have
received considerable attention from synthetic chemists.
Among the marine natural products with a 2,10-
dioxabicyclo[7.3.0]dodecene skeleton, only isolaurallene with
an α,α′-cis-oxonene skeleton had yielded to total synthesis prior
to our work, wherein the Crimmins group exploited dual
synergistic gauche effects to guide the course of their nine-
membered ether ring-closing metathesis.8 We recently
disclosed the first asymmetric total synthesis of (+)-itoma-
nallene A,9 in which the structure of this compound was revised
to 3c with an α,α′-trans-tetrahydrofuran instead of the initially
presumed α,α′-cis. In addition, we have also achieved an
asymmetric synthesis of ent-neolaurallene (ent-2). Likewise,
synthetic efforts toward marine natural products with a 2,9-
dioxabicyclo[6.3.0]undecene skeleton have culminated in
several total and formal syntheses of laurallene (4).10 However,
(+)-pannosallene has not been synthesized to date.
This article gives a detailed account of our completely
substrate-controlled approach to these medium-ring bromoal-
lene marine natural products using the commercially available
glycidol as a common starting material. This sequence features
our protecting-group-dependent intermolecular amide enolate
alkylation and either our intramolecular amide enolate (IAEA)
or nitrile anion alkylation (INAA) to establish both sets of
relative α,α′-oxymethine configurations in the natural products.
Application of this approach offers optional access to any of
these dioxabicyclic bromoallene marine natural products.
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Scheme 2. Synthesis and Structure Revision of Itomanallene A, and Synthesis of ent-Neolaurallene
More specifically, our “chemoselective chelation-controlled”
intermolecular amide enolate alkylation [7 → 8] and
intramolecular nitrile anion alkylation were utilized to establish
the α,α′-trans-oxonene and α,α′-trans-tetrahydrofuran stereo-
chemistry in itomanallene A and ent-neolaurallene, respectively.
On the other hand, the intermolecular dianion alkylation
strategy [9 → 10] and intramolecular nitrile anion alkylation
provided access to the respective α,α′-cis-oxonene skeleton and
α,α′-trans-tetrahydrofuran for the synthesis of isolaurallene. In
addition, the use of an allyl halide electrophile in place of ethyl
halide for the intermolecular dianion alkylation [9 → 11]
enabled us to construct the α,α′-trans-oxocene skeleton in
laurallene and pannosallene. The α,α′-trans- and α,α′-cis-
tetrahydrofuran stereochemistry in laurallene and pannosallene
were established through INAA and IAEA, respectively.
Asymmetric Total Synthesis and Structure Revision of
Itomanallene A, and Synthesis of ent-Neolaurallene.
Scheme 2 presents a summary of our recently published9
synthesis and structure revision of (+)-itomanallene A and
synthesis of ent-neolaurallene, with particular emphasis on the
most salient stereo-, regio-, and chemoselective steps. The
critical α,α′-anti stereochemistry in α-alkoxyamide 8 was
successfully addressed via the chemoselective chelation-
controlled intermolecular amide enolate alkylation of 7 with
ethyl iodide, probably via attack on the convex face of the cup-
shaped chelated enolate intermediate A.9,11 Here, the PMB-
protected alkoxy group participates in the chelation in
preference to the TIPS-protected alkoxy group, which is
known to be a poor coordinating group. The inefficiency in the
ring-closure metathesis reaction of the C(6)/C(7)-syn, α,α′-
anti, C(12)/C(13)-syn bis-alkene 12, which produced the
RESULTS AND DISCUSSION
■
As shown in Scheme 1, our general synthetic strategy was
designed to encompass any arbitrary relative α,α′-oxymethine
configurations in any of these dioxabicyclic bromoallene marine
natural products without recourse to the use of any chiral
auxiliary. Our entirely substrate-controlled sequence employs
the commercially available glycidol (6) (or its enantiomer) as a
common starting material. Our general approach to establish
the α,α′-relative stereochemistry of the medium-ring (oxonene
or oxocene) and tetrahydrofuran, respectively, involved the
judicious pairing of our protecting-group-dependent intermo-
lecular amide enolate alkylation (either chemoselective
chelation-controlled or dianion alkylation) with either our
intramolecular amide enolate or nitrile anion alkylation.
Application of this approach would offer us optional access to
any of these dioxabicyclic bromoallene marine natural products.
In addition to our approach for installing the proper relative
stereochemistry, our plan takes advantage of the versatility of
the α-alkoxy N,N-dimethylamide functionality. Addition of
organometallics such as Grignard or alkyllithium reagents to the
α-alkoxydimethylamide gave the corresponding ketone directly
in a highly reliable manner. The L-selectride reduction of this
type of ketone is known to proceed in a highly stereoselective
fashion, as rationalized by a Felkin−Ahn model. In addition, the
dimethyl amide could be converted to the corresponding
aldehyde or primary alcohol by addition of an ate complex or
superhydride, respectively. The requisite bromoallene could be
elaborated via the stereoselective Overman protocol, which
would be applied to either a propargylic alcohol or its
diastereomer obtained via a Mitsunobu inversion.
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corresponding oxonene 13 in less than 20% yield, was
overcome by modifying the synthetic route to incorporate the
tetrahydrofuran ring earlier on to benefit from the associated
conformational bias. Gratifyingly, tetrahydrofuranyl dienes 14
and 14′ underwent ring-closing metathesis with Grubbs’ second
generation catalyst to produce key bicyclic oxonenes 15 and
15′, respectively, in reasonably good yield; this selectivity is
rationalized on the basis of computational studies described
below. Most importantly, the first asymmetric total synthesis
and consequent structure revision of (+)-itomanallene A
provides a versatile strategy for the synthesis of both α,α′-cis-
and α,α′-trans-tetrahydrofurans in such dioxabicyclic marine
natural products and related structures through the judicious
choice between an amide enolate and nitrile anion, respectively,
for the intramolecular alkylation. A rationale for the stereo-
selectivity observed during the INAA is provided in our
synthesis of isolaurallene (vide infra).
Computational Studies on Oxonene Formation via
RCM. The relative stereochemistry of the incipient cyclic ether
oxygen atom with respect to each of the adjacent oxygen
substituents as well as the α,α′-relative stereochemistry can
exert a subtle conformational effect on the rate of ring-closing
metathesis to give oxonenes.8,9,12 To gain insight into these
conformational effects, we embarked on computational studies
on RCM of the eight possible diastereomers of 12.13
calculations required to study these species for such flexible
systems are computationally intractable. Thus, we focused
instead on the relative stabilities of diastereomeric reactants and
cyclized products to give values for ΔΔErxn: this enables us to
rank the systems in terms of thermodynamic favorability. This
energetic driving force provides quantitative insight into
reactivity.
A 10 000 step Monte Carlo conformational search was
performed, and energies were evaluated separately with MMFF
and OPLSAA force fields, as shown in Figure 3. Open chain
reactant energies all lie within 0.5 kcal/mol of each other, since
the reactants are flexible and may adopt a number of
conformations. Following RCM, the cyclized product stability,
however, is more variable, and it is this energy that dictates
ΔΔErxn. With the exception of I, all the systems (i.e., II−VIII)
show a preference for the asymmetric AS2 conformation.
Values of ΔΔErxn are shown relative to II, which is predicted to
have the most favorable ΔΔErxn. Diastereomer VII, which
corresponds to the stereochemistry of 12, has less favorable
reaction energy in comparison with other diasteromers, and this
analysis is consistent with the fact that the attempted RCM on
12 proceeded in <20% yield. However, we also modeled the
furanyl-containing 14′ (which has the same stereochemistry as
12) in which the alkoxy side chains are tethered together. This
tethered form is computed to cyclize with a more favorable
reaction energy by 3−4 kcal/mol than is the case for 12. This is
in agreement with experiment where RCM of 14 and 14′
proceeded in 70% and 57% yield, respectively, after tethering
the side chain.
We located low-lying conformations of (Z)-2,3,4,7,8,9-
hexahydrooxonin with a 10 000 step Monte Carlo conforma-
tional search and MMFF force-field; all conformers within 5
kcal/mol of the global minimum were then reoptimized at the
wB97XD/6-31G(d) level of DFT (Figure 2). Following on the
In the AS2 conformation preferentially adopted by the ring,
one of the dihedral angles is partially eclipsing, as shown in
Figure 3. In nearly all of these, a β-alkoxy group points away
from the ring, presumably to avoid destabilization from an
eclipsing CCCO interaction. In the one diastereomer that this
is not possible, α,α′-cis-disubstituted I, the ring adopts a less
stable boat−chair conformation to avoid this clash. In α,α′-
trans-disubstituted VII, the eclipsing CCCO interaction is
present and results in the destabilization of this structure and
retardation of ring closure. It is notable that the most stable
diastereomers do not benefit from the double gauche C−O
alignment. In fact, these bonds are trans-aligned in the most
stable diastereomer II, so that evidently torsional strain in these
cyclic systems overrides stereoelectronic effects. Synthetic
intermediates with a stereochemistry corresponding to that of
diastereomer IV have been observed experimentally to undergo
RCM with good yields.8 This has previously been attributed to
a reinforcing double gauche effect. The reaction energy is
computed to be the second most favorable, however, and this is
predominantly due to the minimization of torisonal strain, as
discussed previously, while benefitting from a single gauche
effect. In fact, although diastereomer II does not benefit from
any gauche C−O interactions, it was computed to be the most
stable ring-closed product. We have synthesized 19′, with the
same stereochemistry as in model II and found that it readily
underwent RCM [(Cy3P)2Cl2Ru=CHPh, CH2Cl2, reflux, 6.5 h,
80%; unoptimized]. More importantly, diene 19′ reacted faster
than 19 (corresponding to IV) in a parallel RCM experiment
[(Cy3P)2Cl2Ru=CHPh (10 mol %), CH2Cl2 (0.003 M), reflux,
1.5 h: product/starting material = 2.7:1, 73% conversion for 19′
Figure 2. Lowest energy conformations for (Z)-2,3,4,7,8,9-hexahy-
drooxonin. Energetics with MMFF and wB97XD/6-31G(d) opti-
mizations in kilocalories per mole.
work of Favini and Furusaki,14 conformers are classified as
either asymmetric, boat−chair, or chair−chair. The relative
conformer stabilities show good agreement across both levels of
theory studied.
Stabilities of open chain (i.e., with terminal alkenes) and ring-
closed forms (following RCM) of the eight possible
diastereomers of 12 (modeling protecting groups as Me
groups) were calculated in an attempt to gauge the effect of
stereochemistry on the energetics of RCM. The mechanism of
ring closure involves Ru-alkylidene and metallocycle inter-
mediates and transition states, but the quantum-chemical
1
by 600 MHz H NMR; product/starting material =1:1.1, 48%
conversion for 19]. This experimental result thus supports our
computational prediction of greater stability of diastereomer II
and our new rationalization of reactivity based on the
D
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Figure 3. Global minimum energy conformations for the eight possible diastereomers (plus ring-tethered form of diastereomer XII) following RCM.
MMFF and OPLSAA energies in kilocalories per mole.
minimization of torsional strain in the preferred AS2 ring
conformation.
Scheme 3. Retrosynthetic Plan for (−)-Isolaurallene
Asymmetric Total Synthesis of (−)-Isolaurallene (1).
As shown in our retrosynthetic plan (Scheme 3), we envisioned
that isolaurallene (1) could be synthesized from key bicyclic
nitrile 16 through installation of the requisite bromoallene unit.
Unlike its congeners 2 and 3c, 1 possesses an α,α′-cis-
disubstituted oxonene skeleton. Our previous experiences led
to initial confidence that the critical α,α′-cis-oxonene stereo-
chemistry could be established by applying our dianion
alkylation protocol to hydroxy N,N-dimethyl amides with any
protected hydroxymethyl group at C(6), such as in 9 (vide
infra).15 The other crucial stereochemical problem, preparation
of the α,α′-trans-tetrahydrofuran 17, was to be solved by an
intramolecular nitrile anion alkylation of tosyl nitrile 18. This
tactic was based on the insights acquired during our
itomanallene A synthesis, which drew inspiration from the
pioneering work by Stork and co-workers16 and subsequent
investigations by Fleming et al.17 Notably, the MOM group in
19 serves a dual function as a protecting group and as a highly
efficient precursor for cyanomethylation to prepare the INAA
substrate.
This sequence began with the preparation of key
intermolecular dianion alkylation substrate 9 from known
TIPS-protected (S)-glycidol (20)18 by the four-step sequence
shown in Scheme 4. In this scheme, we were concerned that the
TIPS group, which is essential for high stereoselectivity in the
planned intermolecular dianion alkylation (vide infra), might
E
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a
silyl group migration were borne out in the Williamson ether
synthesis [21 → 22] under the usual conditions (NaH, N,N-
dimethyl chloro- or bromoacetamide, THF or DMF) because
the desired product was accompanied by an inseparable TIPS-
migrated alkylation product (ca. 15−20%). After some
experimentation, we were pleased to find that O-alkylation of
allylic alcohol 21 could be accomplished without migration of
the TIPS group by treatment with NaH and N,N-dimethyl
iodoacetamide in CH2Cl2 to produce the desired α-
alkoxyamide 22 in nearly quantitative yield (96%). One-pot
cleavage of alkene 22 by a modified Lemieux−Johnson
oxidation,20 followed by Keck allylation21 of the resultant α-
alkoxyaldehyde 23, gave the desired syn-homoallylic alcohol 9
(77% yield for the two steps, syn/anti = 7:1) and set the stage
for the pivotal dianion alkylation.
Scheme 4. Intermolecular Dianion Alkylation
Dianion alkylation of hydroxy α-alkoxy amides with various
substituents {R = CH2CH3, CH2CH2OBn, CH2CH2CH2OBn,
or CH2CH(OCH2CH2O)} at C(6) in intermediate 9 offers
serviceable syn/anti stereoselectivity (ca. 6−9 to 1), and has
been utilized as a key step for our substrate-controlled total
synthesis of medium-ring oxacyclic natural products.15a,c The
observed stereoselectivity could be rationalized by invoking our
empirical model B with the electrophile approaching from the
least hindered side in the H,H-eclipsed conformation, as
depicted in the scheme.
a
Reagents and conditions: (a) (CH3)3SI, n-BuLi, THF, −10 °C to rt, 2
h, 95%; (b) NaH, ICH2CONMe2, CH2Cl2, rt, 40 min, 96%; (c) OsO4,
NMO, H2O/acetone (2:1), rt, 3 h, then NaIO4, rt, 30 min; (d)
allyltributyltin, MgBr2·Et2O, CH2Cl2, −78 °C to rt, 3 h, 77% total yield
for two steps, syn/anti = 7:1; (e) LiHMDS, ethyl iodide, THF, −40
°C, 30 min, 91% total yield, syn/anti = 37:1; (e′) LiHMDS, ethyl
iodide, THF, −40 °C, 2 h, 54% total yield, syn/anti = 1.1:1.
migrate at some stage of the synthesis. In the event, TIPS-(S)-
glycidol (20) was converted to allylic alcohol 21 in excellent
yield (95%) by methylenation of the epoxide according to the
Falck−Mioskowski protocol.19 Our initial concerns regarding
However, dianion alkylation of 9′ (R = CH2OPMB), an
intermediate for our synthesis of (+)-itomanallene A,9 gave very
disappointing stereoselectivity (syn/anti = 1.1:1) and chemical
a
Scheme 5. Cyanomethylation, INAA, and Completion of the Synthesis
a
Reagents and conditions: (a) MOMCl, N,N-diisopropylethylamine, CH2Cl2, 0 °C to rt, 5 h, 98%; (b) CH2CHCH2MgCl, THF, −78 °C, 30 min;
(c) L-Selectride, THF, −78 °C, 2 h, 80% total yield for two steps, syn/anti = 7:1; (d) NaH, BnBr, DMF, 0 °C to rt, 2 h, 95%; (e) Me2BBr, n-
Bu4NCN, CH2Cl2, −78 °C, 20 min, 88%; (f) TBAF, THF, rt, 30 min, 98%; (g) TsCl, DMAP, Et3N, CH2Cl2, 0 °C to rt, 3 h, 97%; (h) see Table 1;
(i) (H2IMes)(Cy3P)Cl2RuCHPh, CH2Cl2, reflux, 2 h, then DMSO, rt, 12 h, 96%; (j) DDQ, CH2Cl2/pH 7.4 buffer solution (9:1), 40 °C, 12 h,
93%; (k) CBr4, n-Oct3P, 1-methylcyclohexene, toluene, 70 °C, 7 h, 68%; (l) DIBAL-H, toluene, −78 °C, 30 min; (m) TMS−acetylene, n-BuLi,
ClTi(Oi-Pr)3, Et2O, −78 °C to rt, 12 h, 76% total yield for two steps, S/R = 7.4:1; (n) p-bromobenzoic acid, PPh3, DIAD, THF, 0 °C to rt, 2 h, 79%;
(o) K2CO3, MeOH, rt, 20 min, 98%; (p) TrisCl, DMAP, CH2Cl2, reflux, 1 h, 98%; (q) LiCuBr2, THF, reflux, 19 h, 71% total yield, R/S = 5.6:1.
F
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yield (54%). Although the use of 9′ in this sequence would
simplify our general approach to these targets, the virtual
absence of stereoselectivity forced us to employ an alternative
protecting group at the C(6) hydroxymethyl group, even
though this required an earlier divergence in our overall
scheme. We reasoned that use of the corresponding TIPS-
protected alkoxy group might avoid any potential interference
by the PMB-alkoxy group in 9′ due to chelation, since TIPS
ethers are known to be poor coordinating groups. We were
delighted to find that the application of our protocol to TIPS-
protected hydroxy α-alkoxy amide 9 (R = CH2OTIPS) proved
successful, and treatment with LiHMDS in the presence of
ethyl iodide furnished the desired α,α′-syn-hydroxyamide 10
with excellent stereoselectivity (91% total yield; syn/anti =
37:1). We are still developing a rationale to explain this
relatively high degree of stereoselectivity.
Table 1. Intramolecular Nitrile Anion Alkylation
c
d
entry
no.
temp
time
yield %
(total)
ratio
a
b
solvent
THF
base
(°C)
(min)
(trans/cis)
1
2
3
4
5
6
7
LiHMDS in
THF
−10
−30
−78
−10
−30
−10
5
13
40
10
40
40
75
75
93
88
85
83
89
2.4:1
THF
THF
Et2O
Et2O
LiHMDS in
THF
3.1:1
4.0:1
5.6:1
5.8:1
4.3:1
4.9:1
LiHMDS in
THF
LiHMDS in
THF
LiHMDS in
THF
toluene LiHMDS in
THF
toluene LiHMDS in
−20
81
THF
a
b
c
d
1
0.005 M. 1.0 M sol. (3 equiv). Bath temp. By H NMR.
With the critical α,α′-syn stereochemistry installed, attention
turned to the preparation of key INAA substrate 18 for the
construction of the desired α,α′-trans-tetrahydrofuranyl nitrile
17, as outlined in Scheme 5. MOM protection of 10 (98%),
followed by elaboration of the α-alkoxydimethylamide moiety
in the resultant 24 via our direct ketone synthesis/L-Selectride
reduction sequence,22 furnished diene 19 with the desired
C(12)/C(13)-syn relative stereochemistry in 67% overall yield
for the three steps after benzylation. The chemoselective
cyanomethylation of MOM ether 19 was readily accomplished
in good yield (88%) upon exposure to n-Bu4NCN in the
presence of Me2BBr according to Morton and Guindon,23
which made gram quantities of cyanomethyl ether 25 available
with relative ease. With an efficient cyanomethylation protocol
established, removal of the TIPS group and tosylation led to
key INAA substrate 18, setting the stage for the intramolecular
nitrile anion alkylation.
Many of the extant applications of this intramolecular nitrile
anion alkylation methodology have involved the stereoselective
construction of a quaternary center by taking advantage of the
relatively small size and powerful nucleophilicity of the nitrile
function.16,17 The presence of an acidic proton in α-
unsubstituted cases, such as the present one, raises a concern
regarding a potential loss of stereochemical integrity of the
cyclization.
Given the relevance to defining a broader scope for this
methodology, we investigated the stereochemical effects in the
intramolecular nitrile anion alkylation of 18 by varying the
solvent, base, leaving group, and temperature. Ideally, we
sought to identify parallel routes to obtain either the α,α′-trans
or α,α′-cis isomer, analogous to what has been demonstrated by
Stork and co-workers.16 Unfortunately, our system did not
prove amenable to this sort of dramatic stereochemical
dichotomy based on reaction conditions. However, we were
able to secure the desired α,α′-trans-tetrahydrofuran 17 as the
major isomer upon exposure of nitrile tosylate 18 to LiHMDS.
As is evident from Table 1, the lower the polarity of the solvent,
from tetrahydrofuran through diethyl ether to toluene, the
slower the reaction proceeded. The best conditions for optimal
yield, stereoselectivity, and procedural ease were 40 min at −30
°C in ether. An equilibration experiment to probe the relative
stability of the isomers showed that the α,α′-trans isomer is
more stable than the corresponding cis by a 2 to 1 margin,
which is in good agreement with the computed energy
difference (0.4 kcal/mol) between these isomers.13 Further-
more, from a deuterium incorporation study as well as
resubjection of the isolated isomers separately to the reaction
conditions, we were able to establish that this 5.8:1 selectivity
ratio (entry 5) arises from a kinetically controlled process under
the cyclization conditions. The internal alkylation of the linear,
N-metalated nitrile anion generated under the reaction
conditions furnishes the desired α,α′-trans-tetrahydrofuran as
the major product.17 We reason that the intermediate passes
through transition state geometry D (Scheme 5), which
benefits from stereoelectronic stabilization by placing the C−
CN bond anti-periplanar to the oxygen lone pair on the ether
oxygen.24,25b To the best of our knowledge, the examples that
appear in the present study constitute the first construction of a
tetrahydrofuran via an intramolecular α-alkoxynitrile alkyla-
tion.25 It is both highly significant and fortunate that the α-
alkoxynitrile affords stereoselection that is complementary to
that obtained with the corresponding α-alkoxy N,N-dimethy-
lamide (vide infra).
To complete the synthesis, tetrahydrofuranyl nitrile 17 was
converted to the desired bicyclic bromoaldehyde 26 by a four-
step sequence (1. ring-closing metathesis; 2. deprotection of
benzyl group; 3. bromination with inversion of configuration; 4.
DIBAL-H reduction of nitrile). With key bromoaldehyde 26 in
hand, we turned our attention to installation of the bromoallene
unit on the basis of the well-established Overman protocol.26
Thus, addition of titanium TMS-acetylide to aldehyde 26 with
Felkin−Ahn-type stereoselectivity,26,27 followed by adjustment
of the propargylic alcohol configuration of the resultant TMS-
propargylic alcohols 27 via a Mitsunobu-saponification
sequence,28 led to (R)-propargylic alcohol 28, the structure
of which was confirmed by X-ray crystallography.29 Finally,
trisylation of (R)-propargylic alcohol 28, followed by copper-
catalyzed anti-SN2′ reaction of the corresponding trisylate,26,30
gave rise to give a 5.6:1 mixture of (−)-isolaurallene (1) and
epi-isolaurallene in 71% total yield. Of note here is that ring-
closing metathesis of bis-alkene 17, which has the same
stereochemistry as that of IV in Figure 3, proceeded with the
anticipated high efficiency (96%). The spectral characteristics
and optical rotation of our synthetic material 1 were in good
agreement with those reported for both the natural and
synthetic isolaurallene: [α]25D −107.2 (c 0.38, CHCl3) [natural:
lit.2 [α]D −113.9 (c 1.00, CHCl3); synthetic: lit.8a [α]24
−117.8 (c 0.09, CHCl3)].
D
In summary, an asymmetric total synthesis of (−)-isolaur-
allene (1) was accomplished in 22 steps from readily available
TIPS-protected (S)-glycidol (20). In our completely substrate-
controlled synthesis, an intermolecular dianion alkylation or
G
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a
intramolecular nitrile anion alkylation sequence provided access
to the α,α′-cis-oxonene skeleton or α,α′-trans-tetrahydrofuran,
respectively. In addition, we have developed a highly efficient
protocol where the MOM group serves a dual function,
alternately as a protecting group and as a precursor for the
cyanomethylation to prepare the INAA substrate.
Scheme 7. Synthesis of (+)-Laurallene (4)
Asymmetric Total Synthesis of (+)-Laurallene (4).
(+)-Laurallene (4) possesses a cis-fused 2,9-dioxabicyclo[6.3.0]-
undecene skeleton that includes an α,α′-trans-oxocene and
α,α′-trans-tetrahydrofuran. As shown in Scheme 6, we
Scheme 6. Retrosynthetic Plan for (+)-Laurallene (4)
a
Reagents and conditions: (a) LiHMDS, allyl bromide, THF, −40 °C,
2 h, 90% total yield, anti/syn = 33:1; (b) MOMCl, N,N-
diisopropylethylamine, CH2Cl2, 0 °C to rt, 3 h, 96%; (c) EtMgBr,
THF, 0 °C, 1 h, 96%; (d) L-Selectride, THF, −78 °C, 1 h, 96% total
yield, syn/anti = 28:1; (e) BnBr, NaH, DMF, 0 °C to rt, 5 h, 98%; (f)
Me2BBr, n-Bu4NCN, CH2Cl2, −78 °C, 30 min; (g) TBAF, THF, rt, 20
min, 85% (2 steps); (h) TsCl, DMAP, Et3N, CH2Cl2, 0 °C to rt, 2.5 h,
98%; (i) LiHMDS (1.0 M sol. in THF), Et2O, −30 °C, 40 min, 80%
total yield, trans/cis = 9.1:1; (j) (H2IMes)(Cy3P)Cl2RuCHPh,
CH2Cl2, reflux, 2 h, then DMSO, rt, 12 h, 84%; (k) DDQ, CH2Cl2/pH
7.4 buffer solution (9:1), 40 °C, 12 h, 93%; (l) CBr4, n-Oct3P, 1-
methylcyclohexene, toluene, 70 °C, 2 h, 88%; (m) DIBAL-H, toluene,
−78 °C, 30 min; (n) TMS−acetylene, n-BuLi, ClTi(Oi-Pr)3, Et2O,
−78 °C to rt, 12 h, 64% total yield for two steps, S/R = 5.5:1; (o)
TBAF, THF, rt, 10 min, 94%; (p) TrisCl, DMAP, CH2Cl2, reflux, 2.5
h, 97%; (q) LiCuBr2, THF, reflux, 18 h, 76% total yield, S/R = 15:1.
INAA substrate 31 (83% over 3 steps). Tosylate 31 was
subjected to INAA (LiHMDS/ether/−30 °C/40 min) to give
the desired α,α′-trans-tetrahydrofuran 30 (80% total yield; α,α′-
trans/cis = 9.1:1). Finally, α,α′-anti-bis-alkene 30 underwent
RCM with the second-generation Grubbs’ Ru catalyst, followed
by debenzylation and introduction of the bromine atom at
C(13) with inversion of configuration to give rise to key
intermediate 29, the structure of which was validated by X-ray
crystallography.29
envisioned that the critical α,α′-anti stereochemistry in bis-
alkene 11 could be established by an intermolecular dianion
alkylation of α-alkoxyamide 9 with allyl halide in this case. By
contrast, our earlier described synthesis of isolaurallene
employed ethyl iodide as the electrophile in the dianion
alkylation of α-alkoxyamide 9. Our strategy is adaptable in that
use of either ethyl or allyl halide as the electrophile for the
dianion alkylation leads to an α,α′-cis-oxonene or α,α′-trans-
oxocene product, respectively. We further envisioned that the
intermolecular dianion allylation product 11 could be
elaborated using a pathway parallel to the isolaurallene
sequence up to key dioxabicyclic intermediate 29.
Our synthesis began with the preparation of α,α′-anti-bis-
alkene 11 (Scheme 7) using our dianion alkylation protocol. As
anticipated, treatment of TIPS-protected α-alkoxyamide 9 with
LiHMDS in the presence allyl bromide furnished the desired
α,α′-anti-diene 11 with excellent stereoselectivity (90% total
yield; anti/syn = 33:1).31 After MOM protection of the
secondary hydroxyl group in diene 11 (96%), the α-
alkoxydimethylamide function in the resulting intermediate
was elaborated to append the C(12) side chain without
incident via a three-step sequence (direct ketone synthesis, L-
Selectride reduction, benzylation) to furnish diene 32 in 87%
overall yield. Conversion of MOM ether 32 to the
corresponding cyanomethyl ether,23 followed by removal of
the TIPS group and subsequent tosylation, yielded the key
The completion of the (+)-laurallene synthesis employed a
pathway analogous to that described earlier for isolaurallene (1)
except that the step in which the propargylic alcohol
configuration was adjusted was unnecessary. The spectral
characteristics and optical rotation of our synthetic material 4
were in good agreement with those reported for both natural
and synthetic laurallene: [α]26 +159.1 (c 0.24, CHCl3)
D
[natural: lit.6 [α]D +173.6 (c 1.13, CHCl3); synthetic: lit.10b
[α]24 +161.1 (c 0.28, CHCl3)]. In addition, this work
D
confirmed that the structure and absolute stereochemistry of
(−)-epi-laurallene are identical to those of (−)-nipponallene,
recently isolated from L. nipponica.32
In summary, a highly stereoselective and efficient 21-step
synthesis of laurallene (4) has been accomplished in an entirely
substrate-controlled fashion starting from the known TIPS-
protected (S)-glycidol (20). Our strategy is highly adaptable in
that either an α,α′-cis-oxonene or α,α′-trans-oxocene product
can be accessed by employing either ethyl or allyl halide as the
electrophile for the dianion alkylation, respectively.
H
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Asymmetric Total Synthesis and Structure Determi-
nation of (+)-Pannosallene. For the sake of simplicity in
determining the relative stereochemistry of C(3) and C(4) in
pannosallene, we set out to synthesize 5a and ent-5b instead of
the originally proposed structures 5a and 5b (Scheme 8), an
Scheme 9. Protecting-Group-Free Sequence to 33 from 11
and Completion of the Synthesis
a
Scheme 8. Retrosynthetic Plan for 5a and ent-5b
arbitrary decision that turned out to be fortuitous. We were
confident that the necessary α,α′-cis-tetrahydrofuran ring in 33
could be constructed in a stereoselective manner via IAEA on
tosyl amide 34,9,33 which in turn could be elaborated from
oxocene intermediate 35. The eight-membered cyclic ether 35
could then be formed by RCM of bis-alkene 11, a key common
intermediate used earlier in the synthesis of laurallene (4). As
we formulated a plan for this particular synthesis, a considerable
amount of effort was directed to streamlining the sequence by
minimizing the use of protecting groups, an effort that was well
rewarded (vide infra).
Our synthesis began with preparation of oxocene 35
(Scheme 9), which was obtained in 75% yield via RCM of
α,α′-anti-bis-alkene 11 with the second-generation Grubbs’ Ru
catalyst. The C(12) side chain appendage was elaborated as
before (direct ketone synthesis/L-Selectride reduction),22 with
conversion of α-alkoxyamide 35 to diol 36 without protection
of the C(7) hydroxyl group in a highly stereoselective fashion
in 65% overall yield [73% BRSM] for the two steps.
Gratifyingly, chemoselective monoalkylation at the C(7)
hydroxyl group of diol 36 with N,N-dimethyl chloroacetamide
produced an 83% yield of α-alkoxyamide 37 along with a small
amount of the corresponding dialkylated product (8%). DFT
calculations indicated that in the preferred conformation, E, of
diol 36 (and in all other low-energy conformers), the C(13)
alcohol in the side chain forms a weak interaction with the
oxygen of the silyl protecting group. We posit that the C(7)
hydroxyl in the ring is more exposed and, hence, is alkylated
preferentially.13 Bromination of secondary alcohol 37 with
inversion of configuration, followed by removal of the TIPS
group and subsequent tosylation, led to the key IAEA substrate
34 in 66% overall yield for the three steps. Treatment of tosyl
amide 34 with LiHMDS in the presence of the C(13) bromide
functionality gave rise to the desired α,α′-cis-tetrahydrofuran 33
(94% total yield; α,α′-cis/trans = 17:1), presumably via “H-
eclipsed” transition-state geometry F.
a
Reagents and conditions: (a) (H2IMes)(Cy3P)Cl2RuCHPh,
CH2Cl2, reflux, 12 h, then DMSO, rt, 6 h, 75%; (b) EtMgBr, THF,
0 °C to rt, 1.5 h, 70% [79% BRSM]; (c) L-Selectride, THF, −78 °C, 30
min, 93%; (d) ClCH2CONMe2, NaH, THF, 0 °C to rt, 2 h, 83%; (e)
CBr4, n-Oct3P, pyridine, toluene, 60 °C, 3 h; (f) TBAF, THF, rt, 10
min, 78% for two steps; (g) TsCl, DMAP, Et3N, CH2Cl2, reflux, 12 h,
84%; (h) LiHMDS, THF, −78 °C, 30 min, 94% total yield, cis/trans =
17:1; (i) DIBAL-H/n-BuLi (1/1), THF, 0 °C, 10 min, 89%; (j) TMS−
acetylene, n-BuLi, ClTi(Oi-Pr)3, Et2O, −78 to −10 °C, 12 h, 83% total
yield, R/S = 6.7:1; (k) p-bromobenzoic acid, PPh3, DIAD, THF, rt, 1
h, 73%; (l) K2CO3, MeOH, rt, 30 min, 96%; (m) TrisCl, DMAP,
CH2Cl2, reflux, 1.5 h, 92%; (n) LiCuBr2, THF, reflux, 18 h, 91% total
yield, S/R = 4:1.
A significant advantage in this approach is that the
chemoselective Williamson ether synthesis of diol 36 as well
as the highly efficient IAEA of bromo tosylate 34 enabled us to
secure the dioxabicyclic compound 33 without additional
protecting-group manipulations.
For the completion of the synthesis, the bromoallene
endgame sequence was implemented as for the earlier
described synthesis of isolaurallene (1), except that in this
case, the aldehyde intermediate was derived from the
dimethylamide function by reduction with the ate complex of
DIBAL-H and n-BuLi,34 to produce a 4:1 mixture of 5a and ent-
5b in 91% yield. The spectral and optical rotation data for our
synthetic material 5a were in good agreement with those of the
natural product, which enabled us to confirm the structure and
absolute configuration as depicted in 5a: [α]25 +87.5 (c 0.20,
D
CHCl3) [natural: lit.7 [α]26 +64.3 (c 0.070, CHCl3)].35
D
In summary, this first asymmetric total synthesis and
structure confirmation of (+)-pannosallene was accomplished
in a substrate-controlled fashion in 19 steps from readily
available TIPS-protected (S)-glycidol (20). Our concise
synthesis of this C15 acetogenin containing the rare α,α′-cis-
tetrahydrofuran moiety features highly stereoselective inter-
I
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molecular and intramolecular amide enolate alkylations as key
steps to establish both sets of relative α,α′-oxymethine
configurations in the natural product.
ACKNOWLEDGMENTS
■
We thank Professors M. Suzuki (Hokkaido University), V. A.
Stonik (the Russian Academy of Sciences), and J. Ishihara
(Nakasaki University) for providing the reference spectra. We
are also very grateful to Professor F. F. Fleming (Duquesne
University) for helpful discussions. This work was supported by
the NRF grant funded by the MEST, Korea (No.
20120000847), the Oxford University Press John Fell fund,
and the Royal Society (RG110617).
CONCLUSION
■
We have developed a completely substrate-controlled approach
to the asymmetric total synthesis of representative dioxabicyclic
bromoallene marine natural products with either a 2,10-
dioxabicyclo[7.3.0]dodecene or 2,9-dioxabicyclo[6.3.0]-
undecene skeleton from commercially available glycidol as a
common starting material. The former include (−)-isolaur-
allene (1), the enantiomeric form of natural (+)-neolaurallene
(2), and (+)-itomanallene A (3c), and the latter are
(+)-laurallene (4) and (+)-pannosallene (5a). In addition,
our first syntheses of (+)-itomanallene A (3c) and (+)-pan-
nosallene (5a) have established the structure and absolute
stereochemistry of both natural products. Furthermore, we
report spectral data for the bromoallene diastereomers of the
natural products for reference to aid in identification when they
are isolated from natural sources in the future.
REFERENCES
■
(1) (a) Vairappan, C. S.; Suzuki, M. Curr. Top. Phytochem. 2005, 7,
1−34. (b) Bonney, K. J.; Braddock, D. C. J. Org. Chem. 2012, 77,
9574−9584 and references therein.
(2) Kurata, K.; Furusaki, A.; Suehiro, K.; Katayama, C.; Suzuki, T.
Chem. Lett. 1982, 1031−1034.
(3) Suzuki, M.; Kurosawa, E.; Furusaki, A.; Katsuragi, S.; Matsumoto,
T. Chem. Lett. 1984, 1033−1034.
(4) Suzuki, M.; Takahashi, Y.; Mitome, Y.; Itoh, T.; Abe, T.; Masuda,
M. Phytochemistry 2002, 60, 861−867.
In addition, a computational analysis was performed to
investigate conformational effects on the rate of oxonene
formation via RCM, a key step in these approaches. The results
suggested an alternative rationale for reactivity based on the
avoidance of eclipsing torstional interactions in the AS2-type
ring conformation. A prediction was made of the most reactive
diastereomer, and this was subsequently verified experimentally.
We identify several useful contributions of this work that
should be of keen interest in the field of organic synthesis. Our
general approach to establish the α,α′-relative stereochemistry
of the medium ring (oxonene or oxocene) and tetrahydrofuran,
respectively, involved the judicious pairing of our protecting-
group-dependent intermolecular amide enolate alkylation
(either chemoselective chelation-controlled or dianion alkyla-
tion) with either our intramolecular amide enolate or nitrile
anion alkylation. Remarkable selectivity was achieved through
the use of the appropriate alkylation steps, and this approach
offered us optional access to any of these dioxabicyclic
bromoallene marine natural products. We note that our
“protecting-group-dependent” alkylation−RCM strategy for
medium ring construction is related to the Crimmins
asymmetric alkylation−RCM strategy,8,10b,12 but in our case
is executed with complete substrate-based control. These
syntheses feature a number of stereo-, regio-, and chemo-
selective transformations that enabled us to achieve concise and
efficient syntheses, routes that are competitive with or surpass
existing approaches in terms of brevity and selectivity.
(5) Lowe, G. J. Chem. Commun. 1965, 411−413.
(6) Fukuzawa, A.; Kurosawa, E. Tetrahedron Lett. 1979, 30, 2797−
2800.
(7) Suzuki, M.; Takahashi, Y.; Matsuo, Y.; Masuda, M. Phytochemistry
1996, 41, 1101−1103.
(8) (a) Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123,
1533−1534. (b) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L.
Tetrahedron 2002, 58, 1817−1834.
(9) Jeong, W.; Kim, M. J.; Kim, H.; Kim, S.; Kim, D.; Shin, K. J.
Angew. Chem., Int. Ed. 2010, 49, 752−756.
(10) (a) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.; Fukuzawa,
A.; Murai, A. Tetrahedron 1997, 53, 8371−8382. (b) Crimmins, M. T.;
Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473−5476. (c) Saitoh, T.;
Suzuki, T.; Sugimoto, M.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett.
2003, 44, 3175−3178. (d) Sasaki, M.; Hashimoto, A.; Tanaka, K.;
Kawahata, M.; Yamaguchi, K.; Takeda, K. Org. Lett. 2008, 10, 1803−
1806. (e) Sasaki, M.; Oyamada, K.; Takeda, K. J. Org. Chem. 2010, 75,
3941−3943.
(11) (a) Kim, B.; Cheon, G.; Park, J.; Lee, H.; Kim, H.; Kim, S.; Kim,
D. Heterocycles 2007, 74, 171−175. (b) Chemoselective chelation-
controlled alkylation of 7 with allyl bromide instead of ethyl iodide
proceeded in a highly stereoselective fashion (96%, syn/anti = 99:1)
under comparable conditions (LiHMDS, allyl bromide, THF, −40 °C,
2 h), which enables entry to α,α′-cis-oxocene natural products.
(12) Crimmins, M. T.; Powell, M. T. J. Am. Chem. Soc. 2003, 125,
7592−7595; diastereomer VI corresponds to the stereochemistry of
intermediates leading to obtusenyne.
(13) DFT calculations were performed using Gaussian 09. Frisch, M.
J.; et al. Gaussian 09, revision A.02; Gaussian, Inc.: Wallingford, CT,
2009, and molecular mechanics calculations with Macromodel.
Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J.
Comput. Chem. 1990, 11, 440−467.
ASSOCIATED CONTENT
■
S
* Supporting Information
(14) (a) Favini, G.; Buemei, G.; Raimondi, M. J. Mol. Struct. 1968, 2,
137−148. (b) Buemi, G.; Favini, G.; Zuccarello, F. J. Mol. Struct. 1970,
5, 101−110. (c) Zuccarello, F.; Buemi, G.; Favini, G. J. Mol. Struct.
1973, 18, 295−302. (d) Furusaki, A.; Katsuragi, S.-I.; Suehiro, K.;
Matsumoto, T. Bull. Chem. Soc. Jpn. 1985, 58, 803−809.
(15) (a) Park, J.; Kim, B.; Kim, H.; Kim, S.; Kim, D. Angew. Chem.,
Int. Ed. 2007, 46, 4726−4728. (b) Kim, B.; Sohn, T.; Kim, S.; Kim, D.;
Lee, J. Heterocycles 2011, 82, 1113−1118. (c) Dyson, B. S.; Burton, J.
W.; Sohn, T.; Kim, B.; Bae, H.; Kim, D. J. Am. Chem. Soc. 2012, 134,
11781−11790.
Experimental procedures; spectroscopic and analytical data for
all new compound including copies of NMR spectra; X-ray
crystallographic data; computational details; full reference 13.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
E-mail: deukjoon@snu.ac.kr
(16) (a) Stork, G.; Gardner, J. O.; Boeckman, R. K., Jr.; Parker, K. A.
J. Am. Chem. Soc. 1973, 95, 2014−2016. (b) Stork, G.; Boeckman, R.
K. J. Am. Chem. Soc. 1973, 95, 2016−2017.
Notes
The authors declare no competing financial interest.
J
dx.doi.org/10.1021/ja310249u | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(17) For recent reviews on nitrile anion cyclizations, see:
(a) Fleming, F. F.; Wei, Y.; Liu, W.; Zhang, Z. Tetrahedron 2008,
64, 7477−7488. (b) Fleming, F. F.; Gudipati, S. Eur. J. Org. Chem.
2008, 5365−5374.
(18) Laine, D.; Fujita, M.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1999,
1, 1639−1645.
(19) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Gall, T.
L.; Shin, D.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449−5452.
(20) (a) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
Org. Chem. 1956, 21, 478−479. (b) VanRheenen, V.; Kelly, R. C.; Cha,
D. Y. Tetrahedron Lett. 1976, 17, 1973−1976.
(21) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265−268.
(22) Kim, H.; Choi, W. J.; Jung, J.; Kim, S.; Kim, D. J. Am. Chem. Soc.
2003, 125, 10238−10240 and references therein.
(23) Morton, H. E.; Guindon, Y. J. Org. Chem. 1985, 50, 5379−5382.
(24) Rychnovsky, S. D.; Takaoka, L. R. Angew. Chem., Int. Ed. 2003,
42, 818−820.
(25) (a) For synthesis of dihydrobenzofurans via a 5-exo-tet
cyclization of epoxide, see: Nicolaou, K. C.; Snyder, S. A.; Huang, X.;
Simonsen, K. B.; Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004, 126,
10162−10173. (b) For synthesis of 2-cyanotetrahydropyrans via an
electrophile-induced ether transfer/base-mediated cyclization se-
quence, see: Kartika, R.; Taylor, R. E. Heterocycles 2007, 74, 447−459.
(26) Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org. Chem.
1993, 58, 2468−2477.
(27) (a) Tabisa, F.; Yamada, T.; Suzuki, K.; Mukaiyama, T. Chem.
Lett. 1984, 405−408. (b) Krause, N.; Seebach, D. Chem. Ber. 1987,
120, 1845−1851.
(28) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380−2382.
(29) CCDC-905679 (for 29), 905680 (for 28), and 905681 (for SI-
A-24) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data-request/
cif; see also the Supporting Information.
(30) (a) Montury, M.; Gore, J. Synth. Commun. 1980, 10, 873−879.
(b) Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W. J. Org. Chem.
1985, 50, 364−367. (c) Jian, Y.-J.; Wu, Y. Synlett 2009, 3303−3306.
(31) Dianion alkylation of 9′ under the comparable conditions
(LiHMDS, allyl bromide, THF, −40 °C, 2 h) produced the
corresponding α,α′-anti-diene, with much inferior stereoselectivity
(85% total yield, anti/syn = 1.8:1).
(32) Lyakhova, E. G.; Kalinovsky, A. I.; Dmitrenok, A. S.;
Kolesnikova, S. A.; Fedorov, S. N.; Vaskovsky, V. E.; Stonik, V. A.
Tetrahedron Lett. 2006, 47, 6549−6522.
(33) Kim, H.; Lee, H.; Kim, J.; Kim, S.; Kim, D. J. Am. Chem. Soc.
2006, 128, 15851−15855 and references therein.
(34) Kim, S.; Ahn, K. H. J. Org. Chem. 1984, 49, 1717−1724.
(35) The structures of laurallene and pannosallene could be
correlated. Thus, epimerization of α,α′-trans-tetrahydrofuranyl nitrile
30, a key intermediate for synthesis of laurallene (Scheme 7), gave the
corresponding α,α′-cis-tetrahydrofuranyl nitrile. This was then taken
on via a pathway parallel to the laurallene sequence up to the bicyclic
α,α′-cis-tetrahydrofuranyl aldehyde intermediate in the pannosallene
synthesis (see the Supporting Information). This correlation firmly
established that these two natural products are epimeric at C(4).
K
dx.doi.org/10.1021/ja310249u | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX