Toward a formal synthesis of laureatin: Unexpected rearrangements involving cyclic ether nucleophiles

Article abstract of DOI:10.1021/jo301048z

Laureatin, a metabolite of the red algae Laurencia nipponica, has shown potent activity as a mosquito larvicide. The two previously published syntheses of laureatin involved an initial preparation of the 8-membered cyclic ether, followed by formation of the oxetane ring. Our strategy was the reverse, i.e., to utilize an oxetane as the framework to construct the larger ring. During this work, attempted Nbromosuccinimide (NBS)-mediated cyclization of oxetane alcohol 17, prepared from readily accessible 2-methyleneoxetane 12, yielded epoxytetrahydrofuran 19 rather than the expected laureatin core. Further derivatization of 19 yielded trans fused bistetrahydrofuran 32. The synthesis of 19 and 32, as well as structural and stereochemical elucidation studies, are described.

Full text of DOI:10.1021/jo301048z

Article
pubs.acs.org/joc
Toward a Formal Synthesis of Laureatin: Unexpected
Rearrangements Involving Cyclic Ether Nucleophiles
†
́
Santosh Keshipeddy, Isamir Martınez, Bernard F. Castillo, II, Martha D. Morton, and Amy R. Howell*
Department of Chemistry, The University of Connecticut, Storrs, Connecticut 06269-3060, United States
S
* Supporting Information
ABSTRACT: Laureatin, a metabolite of the red algae
Laurencia nipponica, has shown potent activity as a mosquito
larvicide. The two previously published syntheses of laureatin
involved an initial preparation of the 8-membered cyclic ether,
followed by formation of the oxetane ring. Our strategy was
the reverse, i.e., to utilize an oxetane as the framework to
construct the larger ring. During this work, attempted N-
bromosuccinimide (NBS)-mediated cyclization of oxetane alcohol 17, prepared from readily accessible 2-methyleneoxetane 12,
yielded epoxytetrahydrofuran 19 rather than the expected laureatin core. Further derivatization of 19 yielded trans fused bis-
tetrahydrofuran 32. The synthesis of 19 and 32, as well as structural and stereochemical elucidation studies, are described.
INTRODUCTION
■
Strained heterocycles possessing unique structural features
display interesting reactivity and have been shown to be
valuable in organic synthesis.1 We have pioneered research on
one member of this important class of heterocycles, 2-
methyleneoxetanes, and are exploiting them as synthetic
intermediates and in the synthesis of oxetane-containing
bioactive natural products.2 Recent preparations of psico-
nucleoside analogues further demonstrated the utility of 2-
methyleneoxetanes in the syntheses of natural product
analogues.3 With a desire to extend this work toward more
complex molecules, laureatin, a potent mosquito larvicide
isolated as a major metabolite of the red algae Laurencia
nipponica, was targeted.4
Laureatin has an oxetane embedded in an 8-membered cyclic
ether as well as two bromine atoms and a cis-alkene for a total
of eight stereogenic centers (Figure 1).5 Previous studies
suggested laureatin was most likely derived from (3Z,6S,7S)-
laurediol (Figure 1) via prelaureatin.6 Both compounds have
been isolated from L. nipponica. Laurediol has been converted
to prelaureatin, and prelaureatin has been converted to
laureatin (with less than 0.05% yield for both) by a partially
Figure 1. Proposed biosynthetic pathways for laureatin.
purified bromoperoxidase (BPO) from L. nipponica and by
scaffold to facilitate formation of the larger ring, a strategy that
would provide laureatin in fewer steps than the previously
published routes. We elected to complete a formal synthesis,
targeting advanced intermediate 2 from the Kim synthesis.8a
A key step in our approach to 2 was bromoetherification of
oxetane alcohol 3. This precursor for the 8-membered ring
would be prepared from readily accessible 2-methyleneoxetane
6 (Figure 3). The synthesis of 5 from the corresponding β-
lactone 7 and its conversion to the direct precursor (see 14 in
lactoperoxidase (LPO). An alternative pathway for the
biosynthesis of laureatin via oxetane 1 was proposed by
Kikuchi et al.,7 although no evidence was presented. However,
results from several groups and those presented herein suggest
that neither of these pathways may be predominant (vide
infra).
The two previously reported syntheses of laureatin took
inspiration from the biosynthetic pathway proposed by Murai
and built the 8-membered cyclic ether, followed by the oxetane
ring (Figure 2).8 Both routes encountered problems when
attempting bromoetherification to incorporate the oxetane
(vide infra). Our plan was to utilize a 2-methyleneoxetane as a
Received: May 24, 2012
Published: August 22, 2012
© 2012 American Chemical Society
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Scheme 1. Synthesis of Lactone 10
Attempts to establish the relative stereochemistry of the two
asymmetric centers using a combination of molecular
mechanics calculations and NOE studies on both diastereo-
meric sets did not provide a conclusive stereochemical
assignment. Cleavage of the silyl group and conversion of the
alcohol to the corresponding p-nitrobenzoyl ester 10a provided
a crystalline solid, which was used to establish the relative
stereochemistry of the ring carbon and the adjacent exocyclic
center (Scheme 2). Although this was not the relative
Figure 2. Key intermediates in previous syntheses of laureatin.
Scheme 2. Lactone Synthesis for X-ray Studies
Figure 3. Approach to the formal synthesis of laureatin.
Scheme 3) to oxetane aldehyde 4 would rely on methodology
we had previously developed.
RESULTS AND DISCUSSION
■
The formal synthesis of laureatin began with the preparation of
β-lactone 10, obtained in four steps from ethyl glyoxylate.
Heteroene reaction between this and 1-pentene gave the
required trans α-hydroxy ester in excellent yield using a
stoichiometric amount of SnCl4.9 Conversely, a catalytic
amount of SnCl4 provided a mixture of cis and trans isomers
in poor yield. Protection of the alcohol with tert-butyldiphe-
nylsilyl chloride provided 8 in 92% yield, and DIBAL-H
reduction of the ester gave aldehyde 9. Nelson’s asymmetric
acyl halide−aldehyde cyclocondensation (AAC) chemistry was
employed for the preparation of lactone ( )-10. This is an
efficient strategy to access β-lactones in high enantioselectivities
from achiral starting materials via a ketene−aldehyde cyclo-
addition.10 The reaction at −45 °C of acetyl bromide with
aldehyde 9 in the presence of chiral ligand 1111 and the Lewis
acid, dimethylaluminum chloride, provided lactone ( )-10 as a
single enantiomeric pair. At higher temperatures, varying
amounts of the alternate enantiomeric pair were also formed.
To our knowledge, the AAC reaction had not been previously
applied to aldehydes with α-oxygenation, and these results
further illustrate the power of this transformation.
stereochemistry needed for our planned formal synthesis, we
decided to move forward with 10 to evaluate the feasibility of
the critical steps.
The next key intermediate was oxetane aldehyde 15 (having
connectivity correspondence to 4 in Figure 3). On the basis of
our synthesis of epi-oxetin,2b the two steps where potential
problems were anticipated were the reductive cleavage of
dioxaspirohexane 13 and subsequent oxidation of the resultant
alcohol. Methylenation12 of 10 using dimethyltitanocene
proceeded smoothly in good yield (Scheme 3). The next step
was the chemoselective oxidation of 2-methyleneoxetane 12
with anhydrous, acetone-free DMDO.13 We had previously
shown that the oxidation of the enol ether moiety could be
accomplished in the presence of unactivated alkenes, and here
dioxaspirohexane 13 was obtained in quantitative yield with
good diastereoselectivity (8:1). It should be noted that the
diastereomeric ratio at the dioxaspirohexane stage does not
determine the relative stereochemistry at the next step. Our
previous studies involving ring-opening reactions that leave the
oxetane intact have supported a mechanism involving the
formation of an oxetane oxocarbenium ion.14
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Access to aldehyde 15 allowed us to test the feasibility of
another key step: bromoetherification. Compound 15 was
reacted with Grignard reagent 16 to yield key oxetane
intermediate 17. A single diastereomer was isolated in 42%
yield; no other significant product was seen. The relative
stereochemistry of the newly formed asymmetric carbon was
not deduced at this point. Alkenol 17 was then exposed to
NBS.8b No reaction was observed when CH2Cl2 or CCl4 was
used as the solvent; reaction did occur in acetonitrile. However,
instead of the desired bicyclic system 18, epoxytetrahydrofuran
19 was isolated as a single diastereomer in 51% yield (Scheme
4). No other significant product could be isolated. The use of
1,2,5,6-tetrabromooctane for the bromoetherification resulted
in a messier product distribution. The skeletal framework of 19
was confirmed by 2D-NMR studies. However, the relative
stereochemistries at C-3/C-4 and C-9/C-10 could not be
determined in CDCl3 because of overlapping signals (vide
infra).
Scheme 3. Synthesis of Oxetane Alcohol 17
The reductive ring-opening of 13 with DIBAL-H in CH2Cl2
proceeded in a moderate yield of 56% (42% of the desired
diastereomer) with modest diastereoselectivity (3:1). DIBAL-H
in hexane or toluene provided <20% of the diastereomeric
mixture. This lower diastereoselectivity in comparison to our
previously reported DIBAL-H reductions of dioxaspirohex-
anes2b,14 may be due to the fact that the ring substituent was
more remote (on opposite carbons, rather than neighboring
ones). The syn-relationship of the C-7 and C-9 oxetane
hydrogens (see Scheme 4 for numbering) of the major product
The unexpected formation of epoxytetrahydrofuran 19 can
be explained by reaction of the oxetane moiety, rather than the
alcohol, with the initially formed bromonium ion 20 (Figure 4).
Subsequent reaction of the alcohol group with oxonium ion 21
would provide 19.
Scheme 4. NBS-Mediated Skeletal Rearrangement of
Oxetane Alcohol 17
Figure 4. Proposed mechanism of NBS-mediated skeletal rearrange-
ment.
This outcome of a cyclic ether, rather than a free OH,
reacting with a bromonium ion, while unexpected, is not
without precedent. Indeed, this was observed in both previous
syntheses of laureatin. In a preliminary route of the synthesis by
Sugimoto et al.,8b an attempt to incorporate the oxetane moiety
via a bromoetherification of 22 failed. Tetrahydrofuranyl ketone
24, presumably formed through a transannular attack by the
furan oxygen, followed by a pinacol-type rearrangement of 23
(Figure 5a), was isolated instead. In the Kim synthesis it was
mentioned in passing that a direct bromoetherification route
was abandoned because of participation of the oxocene oxygen.
While this manuscript was in preparation, a clever exploitation
of bicyclic oxonium ions (e.g., 27) to make eight-membered
rings was reported by Snyder et al.16 Similar to the outcome
shown in Figure 5a, they observed an intramolecular
nucleophilic attack by a cyclic ether followed by a pinacol-
type rearrangement to give tetrahydrofuranyl ketone 25 (Figure
5b). Snyder and co-workers were also able to use bicyclic
oxonium ions to make eight membered rings, as shown in
Figure 5c. They developed a general strategy to access
Laurencia-type bromo ethers 28 by strategically placing a
nucleophile at C-3 of tetrahydrofuran 26, leading to 8- and 9-
membered cyclic ethers. Snyder also hypothesized that it is
was confirmed by NOESY experiments. Other reducing agents
were also explored. Diisobutylaluminum 2,6-di-tert-butyl-4-
methylphenoxide has been used for diastereoselective reduc-
tions, providing cleaner reactions than DIBAL-H in some
cases.15 However, this reducing agent did not provide the
desired product. Neither did Mg(OTf)2 in combination with
Et3SiH. When BH3·THF was used, the internal alkene in 13
was also reduced.
After successful synthesis of hydroxymethyloxetane 14, the
next step was oxidation of the alcohol moiety to the
corresponding aldehyde. Initial attempts using pyridinium
dichromate (PDC), tetra-n-propylammonium perruthenate
(TPAP), or the SO3·pyridine complex failed to provide desired
aldehyde 15. Gratifyingly, the Dess−Martin periodinane
oxidation did so in good yield. However, 15 proved to have
limited stability. A nonaqueous workup was employed, and no
column purification was done. Moreover, it was critical that
bath temperatures in the concentration of the reaction mixture
not exceed ca. 40 °C and that the aldehyde was always used
immediately after its preparation.
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Scheme 5. Derivatization of Epoxytetrahydrofuran 29
crystals for X-ray analysis. Trans stereochemistry of the epoxide
in 29 was tentatively deduced from the coupling constant
between the epoxide hydrogens (J = 1.9 Hz).18 Neither a p-
nitrobenzoyl ester nor naphthoyl ester 30 provided diffractable
crystals. However, the relative stereochemistries of the C-4 and
C-7 hydrogens in epoxytetrahydrofuran 30 were determined by
a combination of COSY and NOESY experiments (Scheme 5),
and the trans-stereochemistry of the epoxide protons was
confirmed (J = 2.2 Hz).
Knowing the relative stereochemistries of C-4 and C-7 and of
the epoxide protons allowed the assignment of the remaining
centers. If an SN2 attack on the bromonium is assumed, the C-4
and C-7 protons could not be trans if the bromonium had
formed on the opposite face (Figure 6). Also, the C-3 relative
stereochemistry is determined by the facial selectivity in the
formation of the bromonium. Similarly, the epoxide could not
have trans substituents if the stereochemistry at C-10 were the
opposite.
In another attempt to make a crystalline derivative of 29, it
was treated with Oct3P-CBr419 with an expectation that the free
OH would be converted to corresponding bromide 31.
However, trans-fused bis-tetrahydrofuran 32 was isolated in
65% yield (Scheme 5). To the best of our knowledge, the
transformation of epoxytetrahydrofurans to bis-tetrahydrofur-
ans has not been previously reported. There were no NOE
effects seen between C-6 and C-7,20 but this is not conclusive
proof of the trans-fusion. The assignment of a trans
stereochemistry is mainly based on what we believe the
pathway to be. We think that the first step in the process is the
reaction of the OH group in 29 with phosphonium
intermediate 33, followed by an intramolecular epoxide attack
leading to oxonium ion 34, which reacts with bromide to give
trans-fused bis-tetrahydrofuran 32 (Figure 7).
Figure 5. Cyclic ethers as nucleophiles in reactions with bromonium
ions.
likely that the biosynthesis of laurenan-type terpenes may
involve ethers as nucleophiles after initial bromoetherifications,
rather than multiple, simple haloetherifications. Our result with
oxetane 17 supports this. Interestingly, an epoxyfuranyl
terpene, laureoxolane (see Scheme 4), with the cyclic ethers
separated by a methylene spacer (as seen in 19) has been
isolated from Laurencia nipponica.17 An additional illustration of
the potential importance of ether nucleophiles in biosynthesis
came with our attempts to fully establish the relative
stereochemistry at all of the asymmetric carbons.
Assignment of the remaining stereochemical relationships in
epoxytetrahydrofuran 19 required further derivatization. As
noted above, single-crystal X-ray analysis of β-lactone 10a
allowed the assignment of the relative stereochemistry of the
hydrogen atoms on C-6 and C-7 (Scheme 2), and according to
our proposed mechanism, this relationship would remain
unchanged in the conversion of 10 to 19. However, further
NMR experiments on 19 did not reveal the relative
stereochemistries of the C-4 and C-7 tetrahydrofuran hydro-
gens (see Scheme 5) or of the C-9 and C-10 hydrogens, partly
because of issues with overlapping signals. Consequently, we
decided to cleave the TBDPS group so that the corresponding
alcohol 29 could be analyzed or derivatized, if needed. Upon
treatment with TBAF, epoxytetrahydrofuran 19 yielded the
corresponding deprotected alcohol 29 in 73% yield. The
relative stereochemistry of C-4 and C-7 in 29 could not be
unequivocally established using NOESY, and 29 did not give
Our argument that it is the OH (rather than the epoxide)
that reacts with phosphonium 33 is based on two literature
reports. First, under similar (PPh3/CCl4) conditions, Prinzbach
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Figure 8. Literature support for initial reaction of an OH with
phophonium salt in the presence of nucleophilic cyclic ethers.
Figure 6. Deduction of remaining relative stereochemistries for 19.
Figure 9. Natural, fused bis-tetrahydrofurans.
In conclusion, our attempts to access the natural product
laureatin led to the discovery of novel rearrangements involving
an oxetane alcohol and an epoxytetrahydrofuran. We believe
that these transformations are further illustrations of the
potential of cyclic ether nucleophiles for building molecular
complexity in a stereocontrolled fashion. The core structures of
the rearranged epoxytetrahydrofuran and trans-fused bis-
tetrahydrofuran are found in natural products. These results
also provide further support of the recent contention by
Snyder16 that some of the laurenan natural products may arise
from the oxonium ions formed from intramolecular reactions
by cyclic ether oxygens.
Figure 7. Postulated mechanism for the formation of trans-fused bis-
tetrahydrofuran 32.
and co-workers successfully converted an alcohol to a chloride
in the presence of an epoxide (Figure 8).21 Although the
second example does not involve an epoxide, when Fujiwara et
al.22 attempted bromination, using Oct3P-CBr4, of hydroxyox-
epane 35, all of the products isolated implied an initial reaction
between the free OH and the activated phosphine. Interest-
ingly, ring contraction product 36 (15%) and retention product
37 (23%) were presumed to have arisen from oxonium ion 38
(Figure 8). The formation of bis-fused tetrahydrofuran 32 is a
further illustration of the utility of cyclic ether nucleophiles in
building complexity and in accessing different ring sizes.
Moreover, such fused ring systems are seen in nature. For
example, kumausallene and compound 39 (Figure 9) have both
been isolated from red algae of the genus Laurencia.23 Although
these bis-tetrahydrofuran systems have cis-fusions, we believe
the stereochemical outcome in 32 is a result of the relative
stereochemistry of the tetrahydrofuranyl substituents in our
system.
EXPERIMENTAL SECTION
■
(4E)-2-Hydroxyhept-4-enoic Acid Ethyl Ester. 1-Pentene (4.80
mL, 44.1 mmol) was added to a stirred solution of ethyl glyoxylate
(5.90 mL, 29.4 mmol) in dry CH2Cl2 (225 mL) at −78 °C, followed
by the dropwise addition of tin(IV) chloride (SnCl4) (5.08 mL, 44.1
mmol) under N2. The reaction mixture was allowed to warm to rt and
stirred for 48 h. The resulting homogeneous solution was diluted with
CH2Cl2 (200 mL) and then washed with saturated aqueous NaHCO3
(200 mL) at 0 °C carefully, and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The
combined organic extracts were washed with H2O (100 mL), dried
(MgSO4), and concentrated to provide (4E)-2-hydroxyhept-4-enoic
acid ethyl ester as a pale yellow oil (4.05 g, 84%) which was used
without purification in the next reaction: IR (neat) 3461, 2963, 1731,
1199 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.60 (m, 1H), 5.39 (ddd, J
= 14.2, 7.1, 7.1 Hz, 1H), 4.23 (m, 3H), 3.03 (br s, 1H), 2.71 (d, J = 6.2
Hz, 1H), 2.50 (m, 1H), 2.38 (ddd, J = 15.0, 7.1, 7.1 Hz, 1H), 2.02 (m,
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2H), 1.30 (t, J = 6.1 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 174.5, 136.8, 122.4, 70.3, 61.5, 37.6, 25.6, 14.2, 13.7;
HRMS (ESI) calcd for C9H17O3 (M+ + H) m/z 173.1178, found
173.1164.
(3R*)-4-[(3E),(1R*)-1-(p-Nitrobenzoyloxy)hex-3-enyl]oxetan-
2-one (10a). TBAF (9.8 mL, 9.8 mmol) was added dropwise to a
stirred solution of (3R*)-4-[(3E),(1R*)-1-(tert-butyldiphenylsilany-
loxy)-hex-3-enyl]oxetan-2-one (10) (2.0 g, 4.9 mmol) in THF (15
mL) at 0 °C. After 2 h, the reaction mixture was concentrated in
vacuo. Purification by flash chromatography on silica gel (petroleum
ether/EtOAc 70:30) provided the deprotected lactone as a clear oil
(0.33 g). 4-Nitrobenzoyl chloride (0.77 g, 3.88 mmol), DMAP (0.24 g,
1.94 mmol), and NEt3 (0.54 mL, 3.88 mmol) were added to a stirred
solution of the lactone (0.33 g, 1.94 mmol) in CH2Cl2 (4 mL). After 1
h, the reaction mixture was concentrated in vacuo. Purification by flash
chromatography on silica gel (petroleum ether/EtOAc 80:20)
provided lactone 10a as a white solid (0.34 g, 26% over two steps):
(4E)-2-(tert-Butyldiphenylsilanyloxy)hept-4-enoic Acid Ethyl
Ester (8). (4E)-2-Hydroxyhept-4-enoic acid ethyl ester (7.70 g, 44.8
mmol), 4-dimethylaminopyridine (DMAP) (1.40 g, 11.2 mmol), and
imidazole (6.10 g, 89.6 mmol) were dissolved in dry DMF (45 mL)
under N2, followed by the addition of tert-butyldiphenylsilyl chloride
(TBDPSCl) (14.2 mL, 51.6 mmol). The reaction mixture was stirred
at rt overnight. The viscous solution was diluted with CH2Cl2 (400
mL) and poured into H2O (450 mL). The layers were separated, and
the aqueous layer was extracted with Et2O (3 × 150 mL). The
combined organic extracts were dried (MgSO4) and concentrated.
Purification by flash chromatography on silica gel (petroleum ether/
EtOAc 99:1) provided ester 8 as a clear oil (16.9 g, 92%): IR (neat)
1
mp 65−67 °C; H NMR (300 MHz, CDCl3) δ 8.34 (d, J = 8.8 Hz,
2H), 8.24 (d, J = 8.5 Hz, 2H), 5.68 (m, 1H), 5.41 (m, 2H), 4.79 (m,
1H), 3.59 (dd, J = 16.5, 6.1 Hz, 1H), 3.27 (dd, J = 16.4, 4.0 Hz, 1H),
2.59 (dd, J = 6.6, 6.6 Hz, 2H), 2.02 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).
(4R*)-4-[(3E,1R*)-1-(tert-Butyldiphenylsilanyloxy)hex-3-
enyl]-2-methyleneoxetane (12). A solution of dimethyltitanocene
(4.43 mL, 0.5 M in toluene) and (3R*)-4-[(3E),(1R*)-1-(tert-
butyldiphenylsilanyloxy)hex-3-enyl]oxetan-2-one (10) (0.60 g, 1.48
mmol) was stirred in the dark at 80 °C under N2 until the starting
material was consumed on the basis of TLC. The reaction was cooled
slowly to rt followed by the addition of petroleum ether (300 mL) and
stirred for 24 h. The resulting mixture was filtered through a pad of
Celite, which was then washed with petroleum ether until the filtrate
was colorless. The filtrate was concentrated in vacuo, and the residue
was purified by flash chromatography on silica gel (petroleum ether/
Et3N 96:4) to afford 12 as a clear yellow oil (0.45 g, 75%): IR (neat)
1
2961, 1753, 1473, 1428, 1112 cm−1; H NMR (400 MHz, CDCl3) δ
7.66 (m, 4H), 7.38 (m, 6H), 5.49 (m, 1H), 5.37 (m, 1H), 4.21 (dd, J =
5.8, 5.8 Hz, 1H), 3.93 (m, 2H), 2.40 (app t, J = 6.0 Hz, 2H), 1.98 (m,
2H), 1.09 (m, 12H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.6, 135.9, 135.8, 135.7, 133.5, 133.3, 129.6, 127.5, 127.5,
127.4, 123.3, 72.9, 60.2, 38.6, 26.8, 25.5, 19.3, 14.0, 13.5; HRMS
(FAB) calcd for C25H33O3Si (M+ − H) m/z 409.2199, found
409.2186.
(4E)-2-(tert-Butyldiphenylsilanyloxy)hept-4-enal (9). Diisobu-
tylaluminum hydride (DIBAL-H) (1.0 M in CH2Cl2, 11.6 mL, 11.6
mmol) was added dropwise to a solution of (4E)-2-(tert-
butyldiphenylsilanyloxy)hept-4-enoic acid ethyl ester (8) (2.40 g,
5.81 mmol) in dry CH2Cl2 (120 mL) under N2 at −78 °C. The
mixture was stirred for 3 h at −78 °C, followed by the dropwise
addition of MeOH (50 mL). The resulting mixture was warmed to rt.
The solution was poured into aqueous NaOH (0.5 M, 50 mL) and
diluted with CH2Cl2 (50 mL). The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The
combined organic extracts were washed with H2O (40 mL) and brine
(40 mL), dried (MgSO4), and concentrated. Purification by flash
chromatography on silica gel (petroleum ether/EtOAc 99:1) provided
aldehyde 9 as a colorless oil (2.02 g, 95%): IR (neat) 3072, 2963,
2863, 1738, 1428, 1112 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.57 (d,
J = 1.5 Hz, 1H), 7.67 (m, 4H), 7.42 (m, 6H), 5.51 (ddd, J = 15.5, 6.5,
6.5 Hz, 1H), 5.34 (ddd, J = 15.3, 7.0, 7.0 Hz, 1H), 4.07 (ddd, J = 5.9,
5.9, 1.5 Hz, 1H), 2.35 (dd, J = 6.4, 6.4 Hz, 2H), 1.99 (app qd, J = 7.2,
6.6 Hz, 2H), 1.14 (s, 9H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 203.8, 136.5, 136.1, 133.4, 133.3, 130.3, 130.2, 128.1,
128.0, 122.8, 78.3, 36.7, 27.2, 25.9, 19.6, 13.8; HRMS (FAB) calcd for
C23H31O2Si (M+ + H) m/z 367.2093, found 367.2076.
(3R*)-4-[(3E),(1R*)-1-(tert-Butyldiphenylsilanyloxy)hex-3-
enyl]oxetan-2-one (10). Dimethylaluminum chloride (1.0 M in
hexanes, 1.09 mL, 1.09 mmol) was added to a solution of (2S,6S)-4-
benzyl-1,7-ditriflic-2,6-diisopropyl-1,4,7-triazaheptane11 (11) (0.59 g,
1.09 mmol) in dry CH2Cl2 (40 mL) under N2 at rt. After the solution
was stirred for 1 h, diisopropylethylamine (3.23 mL, 18.5 mmol) was
added slowly via syringe. The reaction mixture was cooled to −45 °C,
followed by the addition of freshly distilled acetyl bromide (1.53 mL,
20.7 mmol) and (4E)-2-(tert-butyldiphenylsilanyloxy)hept-4-enal (9)
(4.01 g, 10.9 mmol), and the solution was stirred for 72 h at −45 °C.
The reaction was warmed to rt and filtered through a pad of silica with
CH2Cl2, and the filtrate was concentrated in vacuo. Purification by
flash chromatography on silica gel (petroleum ether/EtOAc 99:1)
provided β-lactone 10 as a clear oil (5.31 g, 90%): IR (neat) 3072,
2962, 2858, 1832, 1589, 1428, 1111 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.69 (app d, J = 7.1 Hz, 4H), 7.42 (m, 6H), 5.35 (m, 1H),
5.16 (ddd, J = 15.3, 7.6, 7.6 Hz, 1H), 4.49 (ddd, J = 4.6, 4.6, 4.6 Hz,
1H), 3.83 (ddd, J = 8.4, 4.4, 4.4 Hz, 1H), 3.28 (app d, J = 5.0 Hz, 2H),
2.27 (ddd, J = 13.8, 7.9, 7.9 Hz, 1H), 2.18 (m, 1H), 1.91 (m, 2H), 1.09
(s, 9H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.0, 136.4, 136.0, 135.9, 133.7, 133.0, 130.0, 129.9, 127.8, 127.7,
122.9, 73.1, 71.9, 39.2, 36.6, 27.0, 25.6, 19.5, 13.5; HRMS (FAB) calcd
for C25H33O3Si (M+ + H) m/z 409.2199, found 409.2214.
1
3072, 2963, 2861, 1694, 1473, 1428, 1389, 1362, 1112, 911 cm−1; H
NMR (400 MHz, CDCl3) δ 7.71 (m, 4H), 7.34 (m, 6H), 5.33 (m,
1H), 5.20 (m, 1H), 4.68 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), 4.10 (m, 1H),
3.85 (ddd, J = 6.3, 6.3, 6.3 Hz, 1H), 3.70 (m, 1H), 3.04 (m, 1H), 2.95
(m, 1H), 2.22 (ddd, J = 14.0, 7.1, 7.1 Hz, 1H), 2.10 (ddd, J = 13.7, 6.9,
6.9 Hz, 1H), 1.90 (m, 2H), 1.07 (s, 9H), 0.88 (t, J = 7.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 162.4, 136.0, 135.3, 134.2, 133.7, 129.6,
129.5, 127.5, 127.4, 123.7, 79.8, 79.4, 74.4, 35.5, 30.3, 26.9, 26.9, 25.4,
19.5, 13.5; HRMS (FAB) calcd for C26H35O2Si (M+ + H) m/z
407.2406, found 407.2397.
(4R*)-4-[(3E),(1R*)-1-(tert-Butyldiphenylsilanyloxy)]hex-3-
enyl-1,5-dioxaspiro[3.2]hexane (13). A solution of (4R*)-4-
[(3E,1R*)-1-(tert-butyldiphenylsilanyloxy)hex-3-enyl]-2-methyleneox-
etane (12) (0.39 g, 0.97 mmol) in dry CH2Cl2 (4 mL) under N2 was
cooled to 0 °C. A solution of DMDO (2.5 mL, 0.58 M in CH2Cl2) was
added dropwise, and the solution was stirred at 0 °C for 1 h. The
solution was then concentrated in vacuo and afforded 13 as a mixture
of diastereoisomers (88:12) in quantitative yield: Major diastereomer:
1H NMR (400 MHz, CDCl3) δ 7.72 (m, 4H), 7.40 (m, 6H), 5.32 (m,
1H), 5.18 (m, 1H), 4.62 (ddd, J = 10.1, 4.8, 4.8 Hz, 1H), 3.87 (ddd, J
= 9.4, 4.7, 4.7 Hz, 1H), 2.98 (dd, J = 12.4, 5.6 Hz, 1H), 2.93 (dd, J =
12.5, 7.7 Hz, 1H), 2.86 (d, J = 3.4 Hz, 1H), 2.65 (d, J = 3.4 Hz, 1H),
2.29 (ddd, J = 10.6, 7.9, 7.9 Hz, 1H), 2.14 (m, 1H), 1.90 (m, 2H), 1.07
(s, 9H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
136.3, 136.1, 135.7, 134.4, 133.8, 129.9, 129.8, 127.8, 127.7, 127.7,
123.9, 88.7, 75.5, 74.9, 51.5, 36.1, 30.7, 27.2, 25.7, 19.7, 13.7; HRMS
(FAB) calcd for C26H35O3Si (M+ + H) m/z 423.2355, found 423.2330.
(2R*,4S*)-2-[(3E,1R*)1-(tert-Butyldiphenylsilanyloxy)]hex-3-
enyl-4-hydroxymethyloxetane (14). DIBAL-H (1.0 M in CH2Cl2,
0.25 mL, 0.25 mmol) was added dropwise to a stirred solution of
(4R*)-4-[(3E),(1R*)-2-(tert-butyldiphenylsilanyloxy)]hex-3-enyl-1,5-
dioxaspiro[3.2]hexane (13) (80 mg, 0.19 mmol) in dry CH2Cl2 (2
mL) under N2 at −78 °C. After 2 h, the reaction mixture was diluted
with CH2Cl2 (10 mL) and allowed to warm to 0 °C. The reaction was
quenched with 15% NaOH (5 mL) and diluted with H2O (10 mL).
The resulting solution was extracted with CH2Cl2 (2 × 10 mL). The
organic extracts were combined, washed with H2O (10 mL), dried
(MgSO4), and concentrated. Purification by flash chromatography on
silica gel (petroleum ether/EtOAc 80:20) provided 14 as a mixture of
diastereomers (75:25). The required major diastereomer was isolated
as a colorless oil (34 mg, 42%): IR (CDCl3) 3539, 2925, 2854, 1109,
7888
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The Journal of Organic Chemistry
Article
1
704 cm−1; H NMR (400 MHz, CDCl3) δ 7.73 (m, 4H), 7.42 (m,
11H), 4.48 (s, 2H), 4.28 (m, 2H), 3.97 (ddd, J = 5.9, 2.9, 2.9 Hz, 1H),
3.83 (m, 1H), 3.54−3.42 (m, 2H), 2.78 (m, 1H), 2.66 (m, 1H), 2.10−
1.89 (m, 2H), 1.84 (m, 1H), 1.78−1.68 (m, 3H), 1.68−1.47 (m, 4H),
1.06 (s, 9H), 1.00 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
138.5, 136.0, 136.0, 134.0, 133.2, 130.1, 130.0, 128.6, 128.0, 127.9,
127.8, 127.7, 81.1, 80.0, 75.2, 73.1, 70.0, 62.9, 59.2, 56.8, 40.2, 33.4,
29.0, 28.7, 27.2, 26.4, 19.6, 12.2; HRMS (ESI) calcd for C36H48BrO4Si
(M+ + H) m/z 651.2500, found 651.2477.
6H), 5.28 (m, 2H), 4.65 (m, 2H), 3.75 (ddd, J = 6.6, 6.6, 5.1 Hz, 1H),
3.53 (ddd, J = 12.7, 2.7, 2.7 Hz, 1H), 3.28 (ddd, J = 12.3, 9.3, 2.9 Hz,
1H), 2.41 (ddd, J = 11.0, 7.7, 7.7 Hz, 1H), 2.32 (ddd, J = 11.0, 7.5, 7.5
Hz, 1H), 2.17 (ddd, J = 14.1, 6.7, 6.7 Hz, 1H), 2.01 (m, 1H), 1.92 (m,
2H), 1.57 (dd, J = 9.1, 3.9 Hz, 1H), 1.07 (s, 9H), 0.90 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 136.3, 136.3, 135.2, 134.6,
134.0, 129.9, 129.9, 127.7, 127.6, 124.1, 79.6, 77.6, 76.5, 64.9, 35.3,
27.3, 25.7, 23.9, 19.7, 13.8; HRMS (FAB) calcd for C26H35O3Si (M+ −
H) m/z 423.2355, found 423.2336.
(2R*,4S*)-2-[(3E,1R*)1-(tert-Butyldiphenylsilanyloxy)]hex-3-
enyl-4-formyloxetane (15). Dess−Martin periodinane (0.21 g, 0.49
mmol) was added to a stirred solution of (2R*,4S*)-2-[(3E,1R*)1-
(tert-butyldiphenylsilanyloxy)]hex-3-enyl-4-hydroxymethyloxetane
(14) (0.14 g, 0.33 mmol) in dry CH2Cl2 (4 mL) under N2 at 0 °C.
The reaction mixture was slowly warmed to rt. After 16 h, the reaction
mixture was concentrated in vacuo at 30 °C, and the residue was
washed with petroleum ether (3 × 10 mL). The combined organic
layers were concentrated in vacuo to afford 15 as a clear oil (0.12 g,
90%). The crude product was used directly in the next reaction
without further purification: IR (neat) 3070, 2931, 2857, 1730 cm−1;
1H NMR (400 MHz, CDCl3) δ 9.65 (d, J = 1.7 Hz, 1H), 7.71−7.69
(m, 4H), 7.42−7.35 (m, 6H), 5.25 (m, 1H), 5.13 (m, 1H), 4.79 (m,
2H), 3.71 (ddd, J = 7.5, 5.2, 5.2 Hz, 1H), 2.73 (ddd, J = 11.6, 8.0, 8.0
Hz, 1H), 2.49 (ddd, J = 11.6, 7.1, 7.1 Hz, 1H), 2.21 (ddd, J = 13.4, 6.4,
6.4, 1H), 1.99 (ddd, J = 12.2, 5.3, 5.3 Hz, 1H), 1.91−1.84 (m, 2H),
1.04 (s, 9H), 0.86 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 203.3,
136.2, 136.2, 135.6, 134.4, 133.7, 129.9, 129.8, 127.8, 127.7, 123.8,
81.8, 79.4, 76.0, 35.3, 29.9, 27.3, 27.2, 25.7, 25.6, 19.7, 13.8; HRMS
(ESI) calcd for C26H35O3Si (M+ + H) m/z 423.2350, found 423.2335.
Benzyloxy-3-propylmagnesium Bromide (16). Magnesium
chips (0.12 g, 5.1 mmol) were placed in a flame-dried flask fitted
with a reflux condenser under N2. Dry THF (0.5 mL), followed by
benzyl-3-bromopropyl ether (0.30 mL, 1.7 mmol), was added at rt.
After 15 min, the reaction mixture turned yellow. The concentration of
magnesium bromide 16 (0.24 M in THF) was determined by titration
using salicylaldehyde phenyl hydrazone as the indicator.24
(2R*,3R*,5S*)-2-[(2R*,3R*)3-(3-Benzyloxypropyl)oxiran-2-
yl)methyl]-3-hyd rox y-5-((1 R*)-1- bromopropyl)-
tetrahydrofuran (29). TBAF (1.0 M, 0.15 mL, 0.15 mmol) was
added to a solution of (2R*,3R*,5S*)-2-[(2R*,3R*)3-(3-
benzyloxypropyl)oxiran-2-yl)methyl]-3-[tert-butyldiphenylsilanyloxy]-
5-((1R*)-1-bromopropyl)tetrahydrofuran (19) (0.050 g, 0.076 mmol)
in THF (2 mL) at 0 °C, and stirring was continued at rt. After 3 h, the
reaction mixture was concentrated in vacuo and purified by flash
chromatography on silica gel (petroleum ether/EtOAc 70:30) to
1
afford 29 as a colorless oil (0.023 g, 73%): H NMR (500 MHz,
CDCl3) δ 7.34−7.23 (m, 5H), 4.49 (m, 2H), 4.39 (m, 1H), 4.27 (ddd,
J = 9.6, 6.0, 6.0 Hz, 1H), 4.12 (ddd, J = 8.6, 5.4, 2.9 Hz, 1H), 4.02
(ddd, J = 9.4, 6.0, 3.6 Hz, 1H), 3.49 (m, 2H), 2.86 (m, 1H), 2.77 (br s,
1H), 2.71 (m, 1H), 2.28 (dd, J = 13.9, 5.3 Hz, 1H), 2.17 (dd, J = 13.5,
6.0 Hz, 1H), 2.06 (m, 1H), 1.95 (m, 1H), 1.79−1.65 (m, 4H), 1.64−
1.54 (m, 1H), 1.43 (ddd, J = 14.1, 10.1, 10.1 Hz, 1H), 1.05 (t, J = 7.2,
3H); 13C NMR (100 MHz, CDCl3) δ 138.6, 128.6, 127.9, 127.8, 82.1,
80.2, 73.2, 73.2, 69.7, 63.4, 59.8, 56.1, 38.6, 32.7, 28.8, 28.7, 26.3, 12.4;
HRMS (ESI) calcd for C20H30BrO4 (M+ + H) m/z 413.1322, found
413.1313.
(2R*,3R*,5S*)-2-[(2R*,3R*)3-(3-Benzyloxypropyl)oxiran-2-
yl)methyl]-5-((1R*)-1-bromopropyl)tetrahydrofuran-3-yl-1-
naphthoate (30). (2R*,3R*,5S*)-2-[(2R*,3R*)3-(3-
Benzyloxypropyl)oxiran-2-yl)methyl]-3-hydroxy-5-((1R*)-1-
bromopropyl)tetrahydrofuran (29) (0.010 g, 0.024 mmol) was
dissolved in dry CH2Cl2 (2.0 mL) under N2 and cooled to 0 °C.
Triethylamine (0.0040 mL, 0.030 mmol) and DMAP (0.0029 g, 0.024
mmol) were added, followed by the addition of 1-naphthoylchloride
(0.0046 g, 0.024 mmol). After 6 h, the reaction mixture was
concentrated in vacuo and purified by flash chromatography on silica
gel (petroleum ether/EtOAc 80:20) to afford 30 as a clear oil (0.012 g,
86%): IR (neat) 2925, 2854, 1714 cm−1; 1H NMR (400 MHz, CDCl3)
δ 8.92 (d, J = 8.3 Hz, 1H), 8.16 (dd, J = 7.3, 1.2 Hz, 1H), 8.04 (d, J =
8.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 (m, 1H), 7.55−7.46 (m,
2H), 7.30−7.25 (m, 5H), 5.65 (dd, J = 3.9, 3.9 Hz, 1H), 4.48 (d, J =
12.9 Hz, 1H), 4.45 (d, J = 12.9 Hz, 1H), 4.36 (m, 2H), 3.98 (ddd, J =
10.5, 7.4, 3.3 Hz, 1H), 3.52−3.43 (m, 2H), 2.85 (ddd, J = 6.9, 4.4, 2.2
Hz, 1H), 2.70 (ddd, J = 5.7, 5.7, 2.2 Hz, 1H), 2.48 (dd, J = 14.7, 7.0
Hz, 1H), 2.32 (ddd, J = 14.0, 9.0, 4.8 Hz, 1H), 2.11−2.02 (m, 1H),
1.98 (ddd, J = 14.0, 9.4, 4.5 Hz, 1H), 1.82−1.65 (m, 4H), 1.64−1.54
(m, 2H), 1.07 (t, J = 7.2 Hz, 3H); 1H NMR (500 MHz, C6D6) δ 9.43
(d, J = 8.7 Hz, 1H), 8.23 (dd, J = 8.4, 1.3 Hz, 1H), 7.62 (d, J = 8.2 Hz,
1H), 7.55 (d, J = 8.1 Hz, 1H), 7.41 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H),
7.27−7.10 (m, 5H), 5.52 (dd, J = 3.8, 3.8 Hz, 1H), 4.32−4.29 (m,
1H), 4.27 (s, 2H), 4.15 (m, 1H), 3.66 (ddd, J = 10.9, 9.3, 3.1 Hz, 1H),
3.28−3.18 (m, 2H), 2.79 (ddd, J = 7.4, 4.0, 2.0 Hz, 1H), 2.48 (ddd, J =
6.0, 6.0, 2.0 Hz, 1H), 2.28 (dd, J = 14.4, 6.5 Hz, 1H), 2.03 (ddd, J =
13.7, 9.3, 4.1 Hz, 1H), 1.95 (ddd, J = 14.1, 9.0, 4.9 Hz, 1H), 1.90−1.82
(m, 1H), 1.69−1.54 (m, 5H), 1.54−1.43 (m, 3H), 0.94 (t, 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 138.7, 134.1, 134.1,
131.7, 130.6, 128.9, 128.6, 128.2, 127.8, 127.8, 126.7, 126.6, 125.9,
124.7, 80.4, 79.6, 76.4, 73.1, 69.9, 62.5, 59.2, 56.3, 38.6, 33.2, 29.0,
28.8, 26.4, 12.2; 13C NMR (125 MHz, C6D6) δ 166.6, 139.6, 134.6,
134.2, 132.5, 130.8, 129.1, 127.7, 127.4, 126.8, 126.6, 124.9, 80.6, 80.1,
76.7, 73.1, 70.0, 62.7, 58.9, 56.0, 39.1, 33.7, 29.4, 30.4, 29.1, 26.9, 12.2;
HRMS (ESI) calcd for C31H39BrNO5 (M+ + NH4) m/z 584.2012,
found 584.2001.
(2R*,4S*)-2-[(3E,1R*)1-(tert-Butyldiphenylsilanyloxy)]hex-3-
enyl-4-(1-hydroxy-4-benzyloxybutyl)oxetane (17). (2R*,4S*)-2-
[(3E,1R*)1-(tert-Butyldiphenylsilanyloxy)]hex-3-enyl-4-(formyl)-
oxetane (15) (0.040 g, 0.094 mmol) dissolved in dry THF (2 mL)
under N2 was added dropwise to the freshly prepared solution of
magnesium bromide (16) (0.24 M, 1.2 mL) at 0 °C. The reaction
mixture was allowed to warm to rt and stirred for 8 h. The reaction
was quenched with aqueous HCl (1.0 M, 1 mL) and diluted with H2O
(5 mL). The resulting solution was extracted with EtOAc (2 × 10
mL). The organic extracts were combined, washed with H2O (10 mL),
dried (MgSO4), and concentrated. Purification by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc 80:20) provided 17 as a
colorless oil (0.020 g, 42%): IR (neat) 3500, 2931, 1110 cm−1; H
1
NMR (400 MHz, CDCl3) δ 7.73−7.68 (m, 4H), 7.41−7.30 (m, 11H),
5.27−5.22 (m, 2H), 4.62 (ddd, J = 7.4, 7.4, 7.4 Hz, 1H), 4.49 (m, 1H),
4.46 (s, 2H), 3.72 (ddd, J = 6.2, 6.2, 6.2 Hz, 1H), 3.50 (m, 1H), 3.46−
3.40 (m, 2H), 2.35 (m, 1H), 2.21−2.06 (m, 3H), 2.00−1.85 (m, 3H),
1.68 (m, 1H), 1.59 (m, 1H), 1.24 (m, 2H), 1.05 (s, 9H), 0.87 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.7, 136.4, 136.3,
135.1, 134.7, 134.1, 129.9, 129.8, 128.6, 127.8, 127.8, 127.7, 127.6,
124.1, 80.0, 79.8, 76.5, 73.1, 71.5, 70.4, 35.3, 29.9, 27.4, 27.3, 26.0,
25.8, 19.7, 13.8; HRMS (ESI) calcd for C36H49O4Si (M+ + H) m/z
573.3390, found 573.3395.
(2R*,3R*,5S*)-2-[(2R*,3R*)3-(3-Benzyloxypropyl)oxiran-2-
yl)methyl]-3-[tert-butyldiphenylsilanyloxy]-5-((1R*)-1-
bromopropyl)tetrahydrofuran (19). N-Bromosuccinimide (0.019
g, 0.11 mmol) was added to a solution of (2R*,4S*)-2-[(3E,1R*)1-
(tert-butyldiphenylsilanyloxy)]hex-3-enyl-4-(1-hydroxy-4-
benzyloxybutyl)oxetane (17) (0.020 g, 0.036 mmol) in dry CH3CN (2
mL) under N2. After 16 h, the reaction mixture was concentrated in
vacuo. The residue was purified by flash chromatography on silica gel
(petroleum ether/EtOAc 90:10) to provide 19 as a colorless oil (0.012
g, 51%): 1H NMR (500 MHz, CDCl3) δ 7.62 (m, 4H), 7.44−7.25 (m,
(2R*,3aR*,5S*,6aS*)-2-[(1S*)-(4-(Benzyloxy)-1-bromobutyl)]-
5-[(1R*)-(1-bromopropyl)hexahydrofuro[3,2-b]furan (32). CBr4
(0.020 g, 0.061 mmol) and (trioctylphosphine) P(Oct)3 (0.0054 mL,
0.12 mmol), followed by pyridine (0.0060 mL), were added to a
solution of (2R*,3R*,5S*)-2-[(2R*,3R*)3-(3-benzyloxypropyl)oxiran-
7889
dx.doi.org/10.1021/jo301048z | J. Org. Chem. 2012, 77, 7883−7890

The Journal of Organic Chemistry
Article
2-yl)methyl]-3-hydroxy-5-((1R*)-1-bromopropyl)tetrahydrofuran
(29) (0.0050 g, 0.012 mmol) in dry toluene (2.0 mL) under N2 at rt.
The resulting mixture was stirred at 80 °C. After 6 h, the reaction
mixture was concentrated in vacuo and purified by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc 90:10) to afford 32 as a
(5) Kurosawa, E.; Furusaki, A.; Izawa, M.; Fukuzawa, A.; Irie, T.
Tetrahedron Lett. 1973, 14, 3857−3860.
(6) (a) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.; Fukuzawa,
A.; Murai, A. Tetrahedron 1997, 53, 8371−8382. (b) Ishihara, J.;
Kanoh, N.; Murai, A. Tetrahedron Lett. 1995, 36, 737−740.
(c) Fukuzawa, A.; Aye, M.; Takasugi, Y.; Nakamura, M.; Tamura,
M.; Murai, A. Chem. Lett. 1994, 2307−2310.
1
colorless oil (0.0038 g, 65%): IR (neat) 2925, 2854 cm−1; H NMR
(500 MHz, CDCl3) δ 7.35−7.25 (m, 5H), 4.75 (m, 2H), 4.49 (d, J =
12.0 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 4.19 (m, 1H), 4.15 (m, 1H),
3.96−3.91 (m, 2H), 3.52−3.45 (m, 2H), 2.33 (dd, J = 13.6, 5.6 Hz,
1H), 2.20 (dd, J = 13.5, 5.8 Hz, 1H), 1.97−1.88 (m, 6H), 1.75−1.66
(m, 2H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
138.6, 128.6, 127.9, 127.8, 84.9, 84.8, 82.6, 82.4, 73.2, 69.5, 62.2, 59.6,
39.1, 39.0, 32.5, 28.7, 28.2, 12.4; HRMS (ESI) calcd for
C20H28Br2NaO3 (M+ + Na) m/z 499.0278, found 499.0267.
(7) Kikuchi, H.; Suzuki, T.; Kurosawa, E.; Suzuki, M. Bull. Chem. Soc.
Jpn. 1991, 64, 1763−1775.
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1332−1335.
(10) Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121,
9742−9743.
ASSOCIATED CONTENT
■
(11) (a) Cernerud, M.; Adolfsson, H.; Moberg, C. Tetrahedron:
Asymmetry 1997, 8, 2655−2662. (b) Cernerud, M.; Skrinning, A.;
S
* Supporting Information
High-resolution 1H and 13C NMR spectra for new com-
pounds.X-ray data for compound 10a CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
́ ̀
Bergere, I.; Moberg, C. Tetrahedron: Asymmetry 1997, 8, 3437−3441.
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Rablen, P. R. J. Org. Chem. 2003, 68, 1480−1488. (b) Howell, A. R.;
Ndakala, A. J. Org. Lett. 1999, 1, 825−827.
AUTHOR INFORMATION
Corresponding Author
*E-mail: amy.howell@uconn.edu.
■
(15) Brunne, J.; Hoffmann, N.; Scharf, H.−D. Tetrahedron 1994, 50,
6819−6824.
Present Address
†Department of Chemistry, University of Nebraska, Lincoln,
NE 68588.
(16) Snyder, S. A.; Treitler, D. S.; Brucks, A. P.; Sattler, W. J. Am.
Chem. Soc. 2011, 133, 15898−15901.
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6536.
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(20) In CDCl3, the protons at the ring fusion had the same chemical
shift. In C6D6 and CD3OD there was a separation of ∼10 Hz for the
protons at the ring fusion. Nothing could be discerned from NOESY.
With difference NOE there did not appear to be enhancement, but this
interpretation is not clear cut because of the small difference in
chemical shifts.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This manuscript is based upon work supported by the National
Science Foundation (NSF) under Grant No. CHE-0809753.
We thank Yanke Liang, Prof. Scott Nelson (University of
Pittsburgh), and Prof. Marc Zimmer (Connecticut College) for
helpful discussions and Dr. Christopher Incarvito (Yale
University) for solving the crystal structure.
(21) Muller, K.-H.; Kaiser, C.; Pillat, M.; Zipperer, B.; Froom, M.;
̈
Fritz, H.; Hunkler, D.; Prinzbach, H. Chem. Ber. 1983, 116, 2492−
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