Studies toward brevisulcenal F via convergent strategies for marine ladder polyether synthesis

Article abstract of DOI:10.1016/j.tet.2018.01.039

Shortly after the initial isolation of marine ladder polyether natural products, biomimetic epoxide-opening cascade reactions were proposed as an efficient strategy for the synthesis of these compounds. However, difficulties in assembling the cascade precursors have limited the realization of these cascades. In this report, we describe strategies that provide convergent access to cascade precursors via regioselective allylation and efficient fragment coupling. We then investigate epoxide-opening cascades promoted by strong bases for the formation of fused tetrahydropyrans. These strategies are evaluated in the context of the synthesis of rings CDEFG of brevisulcenal F.

Full text of DOI:10.1016/j.tet.2018.01.039

Tetrahedron xxx (2018) 1e12
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies toward brevisulcenal F via convergent strategies for marine
ladder polyether synthesis
Matthew H. Katcher, Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Shortly after the initial isolation of marine ladder polyether natural products, biomimetic epoxide-
opening cascade reactions were proposed as an efficient strategy for the synthesis of these com-
pounds. However, difficulties in assembling the cascade precursors have limited the realization of these
cascades. In this report, we describe strategies that provide convergent access to cascade precursors via
regioselective allylation and efficient fragment coupling. We then investigate epoxide-opening cascades
promoted by strong bases for the formation of fused tetrahydropyrans. These strategies are evaluated in
the context of the synthesis of rings CDEFG of brevisulcenal F.
Received 28 July 2017
Accepted 20 January 2018
Available online xxx
Keywords:
Natural products
Cascade reactions
Epoxide openings
Polyethers
© 2018 Elsevier Ltd. All rights reserved.
Oxygen heterocycles
1. Introduction
a convergent strategy for ladder polyether synthesis in which
skipped polyenes can be readily constructed and coupled with
The marine ladder polyether natural products have attracted the
interest of chemists and biologists since their initial discovery.1 For
most of these compounds, the dearth of available material has
hampered investigations of biological activity and mechanism of
action. In addressing this concern, our group has sought to develop
efficient syntheses of marine ladder polyethers by emulating their
proposed biosynthesis,2 which is postulated to occur by a cascade
of epoxide ring opening reactions to form the fused cyclic ether
skeleton.1,3 Previous work has illustrated that such cascades can be
carried out under aqueous conditions,4 with acidic5 or basic6 pro-
motion, using oxidative conditions,7 or via rhodium catalysis.8
Despite successes observed in model systems, these endo-se-
lective, epoxide-opening cascade reactions have seen limited ap-
plications in target-oriented synthesis.9 Many challenges presented
by these cascades arise from difficulties in constructing the cascade
precursors in a convergent fashion. Once the polyepoxide substrate
is assembled (ideally by exhaustive epoxidation of a polyene), the
reaction conditions appropriate to the cascade substrate must also
be identified. In considering these challenges, we drew inspiration
from brevisulcenal F (1), which was isolated in 2012 as part of an
effort to determine the bioactive compounds responsible for fish
kills off the coast of New Zealand (Fig. 1).10 In this paper, we present
other fragments. After elaboration of the polyene to a polyepoxide
cascade precursor, we investigate base-mediated epoxide-opening
cascade reactions for the construction of fused tetrahydropyrans.
This work represents the first reported efforts toward the synthesis
of brevisulcenal F.
2. Results and discussion
2.1. Retrosynthetic analysis and design plan
Our efforts focused on the synthesis of rings CDEFG of brevi-
sulcenal F. This portion of the molecule contains four methyl groups
at ring junctions, which have previously been shown to complicate
the synthesis of cascade precursors as well as the cascades them-
selves.11 Our proposed route incorporates a late-stage epoxide-
opening cascade to construct the CDE rings from triepoxide 3
(Scheme 1). In a convergent fashion, triepoxide 3 would arise from
the coupling of triene 4 and bicyclic aldehyde 5. Triene 4 would
result from sequential allylation events of allylic bromide 7 with
vinyl Grignard reagent 6, while bis-tetrahydropyran 5 would be
assembled by a base-mediated epoxy alcohol cyclization of 8.
Overall, this strategy would enable rapid assembly of the polyene
fragment prior to its union with the FG fragment.
* Corresponding author.
E-mail address: tfj@mit.edu (T.F. Jamison).
https://doi.org/10.1016/j.tet.2018.01.039
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
synthesis, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.039

2
M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
Fig. 1. Proposed structure of brevisulcenal F. Absolute stereochemistry unknown. Relative stereochemistry unknown between each contiguous ring fragment and where indicated.
isomerization. Furthermore, a more reactive nucleophile should
increase the relative rate of selective carbonecarbon bond forma-
tion. Toward this end, we adapted conditions for the copper-
catalyzed allylation of vinylmagnesium bromide from a report by
Falck, Mioskowski, and co-workers.14 Our approach was facilitated
by a known, one-step procedure to generate versatile Grignard
reagent 6.15 In the event, known allylic bromide 716 reacted with 6
to deliver diene 9 as a single isomer (Scheme 2). Although the yield
for this transformation is moderate (58%), utilizing 6 directly in the
coupling reaction avoided several protecting group manipulations.
Bromination of allylic alcohol 9 then afforded bromide 10, which
underwent a second Cu-catalyzed allylation with 6. Again, high
selectivity (20:1) was obtained for the formation of the desired
triene (11), from which the primary alcohol was protected as the
MOM ether. We anticipate that this allylation strategy, which per-
mits the synthesis of triene 4 in seven linear steps, could apply to
the construction of other skipped polyenes with variable substi-
tution patterns.
2.3. Synthesis of aldehyde 5 via base-mediated epoxy alcohol
cyclization
Our focus next turned to the assembly of aldehyde 5, which we
sought to synthesize through cyclization of epoxy alcohol 8. To
arrive at 8, known tetrahydropyran 1217 was first converted to
exocyclic olefin 13 via ozonolysis/reduction, iodination, and elimi-
Scheme 1. Retrosynthetic analysis of rings CDEFG of brevisulcenal F.
MOM ¼ methoxymethyl, TBS ¼ tert-butyldimethylsilyl.
nation (Scheme 3). B-Alkyl Suzuki coupling with vinyl triflate 1418
then furnished trisubstituted olefin 15 in 86% yield.19,20 This
a,b-
unsaturated ester was elaborated to epoxy alcohol 8 via reduction
with diisobutylaluminum hydride (DIBAL), Sharpless asymmetric
epoxidation,21 and silyl deprotection.
For the cyclization of 8, we looked to identify conditions that
could be employed not only in this reaction but also in cascade
2.2. Triene synthesis via sequential allylation
We began with the synthesis of triene 4. Our design plan dic-
tates that this fragment must include a handle to facilitate coupling
with fragment 5; we chose a vinyl bromide due to its relative sta-
bility, ease of synthesis, and versatility in coupling reactions. To
construct the trisubstituted olefins, controlling the regio- and
stereoselectivity of the proposed allylation was necessary to avoid
complex mixtures of isomers. Although regioselective allylations
with carbon nucleophiles have been extensively investigated,
limited studies have employed a vinyl bromide as a trisubstituted
electrophilic partner.12 We initially attempted the allylation via
palladium-catalyzed Negishi couplings, as these reactions have
found success for the construction of skipped dienes with trisub-
stituted partners.13 For our system, we obtained the desired
regioselectivity (SN2 vs. SN20) with Negishi conditions but were
unable to maintain the desired olefin geometry.
Scheme 2. Reagents and conditions: a) CuBr, THF, ꢀ50 to ꢀ30 ꢁC, 58%, >20:1 selec-
tivity; b) PBr3, Et2O, 0 ꢁC, 93%, 20:1 selectivity; c) 6, CuBr, THF, ꢀ50 to ꢀ30 ꢁC, 60%, 20:1
selectivity; d) MOMCl, i-Pr2NEt, CH2Cl2, rt, 82%. selectivity ¼ ratio of desired isomer to
all other isomers, THF ¼ tetrahydrofuran.
To overcome this problem, we reasoned that performing the
reaction at cryogenic temperatures would limit unproductive
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M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
3
substitution stems from the fact that electronic effects generally
govern regioselectivity when epoxides are activated by Brønsted or
Lewis acids.22
We envisioned that activation of the nucleophile with a strong
base would offer an alternative strategy to provide complementary
selectivity (Scheme 4c). Upon alkoxide formation, steric consider-
ations should promote endo-selective cyclization of a proximally
substituted epoxy alcohol to provide the desired tetrahydropyran
product.22 Strong bases have been used sparingly for endo-selective
epoxy alcohol cyclizations23 and, to the best of our knowledge, have
never been applied to a cascade reaction with multiple epoxides.24
Although Nakata and co-workers previously demonstrated
endo-selective cyclizations of epoxy alcohols with proximal methyl
substitution using NaH in DMSO, these reactions require a styrene
substituent on the epoxide to achieve high regioselectivity.23c For
our purposes, we found that treatment of 8 with potassium bis(-
trimethylsilyl)amide (KHMDS), followed by in situ protection as the
bis-methyl ether, provided bis-tetrahydropyran 16 in 84% yield and
17:1 endo/exo selectivity (Scheme 3).25 Notably, this cyclization
occurs in the presence of an unprotected primary alcohol,26 and the
stereochemical outcome suggests that a Payne rearrangement does
not precede tetrahydropyran formation.27 Acetal 16 was then
converted to aldehyde 5 in four steps, including protecting group
manipulations28 and ParikheDoering oxidation.
Scheme 3. Reagents and conditions: a) O3; then NaBH4, CH2Cl2/MeOH, ꢀ78 ꢁC to rt,
90%; b) I2, PPh3, imidazole, THF, ꢀ40 ꢁC to rt, 96%; c) KOt-Bu, THF, 0 ꢁC, 99%; d) 13, 9-
BBN dimer, THF, rt; then 14, PdCl2(dppf)ꢂCH2Cl2, aq. NaHCO3, DMF, rt, 86%; e) DIBAL,
CH2Cl2, e78 ꢁC, 85%; f) TBHP, Ti(Oi-Pr)4, D-(-)-DET, CH2Cl2, e20 ꢁC, 91%, 10:1 dr; g)
TBAF, THF, rt, quant.; h) KHMDS; then NaH, MeI, THF, 0 ꢁC to rt, 84%, 17:1 endo/exo; i) p-
TsOH, CH2Cl2/MeOH, rt, 79%; j) TBSCl, imidazole, DMF, 50 ꢁC; k) ( )-CSA, CH2Cl2/MeOH,
0 ꢁC, 85% (over 2 steps); l) SO3$pyridine, DMSO, Et3N, CH2Cl2, rt, 83%. 9-BBN ¼ 9-
borabicyclo[3.3.1]nonane, CSA ¼ 10-camphorsulfonic acid, DET ¼ diethyl tartrate,
2.4. Fragment coupling and epoxide opening cascades
DIBAL ¼ diisobutylaluminum
DMSO ¼ dimethyl sulfoxide,
hydride,
DMF ¼ N,N-dimethylformamide,
With fragments 4 and 5 in hand, coupling and elaboration to the
key triepoxide were then pursued. Treatment of aldehyde 5 with
the vinylzinc reagent derived from vinyl bromide 4 afforded allylic
alcohol 20 in 78% yield (Scheme 5). Although this reaction pro-
duced the undesired configuration at the newly formed stereo-
center, the stereochemistry could be inverted via an oxidation-
reduction sequence to provide 21.9d Alternate reactions, including
vinylmagnesium addition or NozakieHiyamaeKishi coupling,
afforded lower yields of the allylic alcohol and inseparable mixtures
of diastereomers 20 and 21.
dppf ¼ 1,10-ferrocenediyl-bis(diphenylphosphine),
dr ¼ diastereomeric ratio, HMDS ¼ bis(trimethylsilyl)amide, TBAF ¼ tetra-n-buty-
lammonium fluoride, TBHP ¼ tert-butyl hydroperoxide.
reactions with multiple epoxides. It has proven especially difficult
to incorporate the proximal methyl substitution pattern into endo-
selective, epoxide-opening cascade reactions (Scheme 4a). For the
sole example in the literature, cyclization of diepoxide 17 provides a
1:1 mixture of 6-endo/6-endo bis-tetrahydropyran 18 and unde-
sired 5-exo tetrahydrofuran 19 (Scheme 4b).11a The difficulty of
achieving selective endo cyclization with proximal methyl
To prepare the desired triepoxide cascade precursor, we initially
attempted to epoxidize all three olefins in one reaction utilizing Shi
Scheme 5. Reagents and conditions: a) 4, t-BuLi, Et2O, ꢀ78 ꢁC; then ZnBr2, 0 ꢁC; then
5, toluene, 0 ꢁC to rt, 78%, >20:1 dr; b) DMP, NaHCO3, CH2Cl2, rt; c) NaBH4, CeCl3$7H2O,
MeOH, ꢀ40 ꢁC, 76%, >10:1 dr (over 2 steps); d) TBHP, Ti(Oi-Pr)4, L-(-)-DET, CH2Cl2,
e20 ꢁC, 92%, >20:1 dr; e) 22, Oxone, (n-Bu)4NHSO4, K2CO3, pH 10.5, DMM/CH3CN, 0 ꢁC,
85%, 5:1 dr; f) BnBr, Ag2O, TBAI, rt, 81%; g) TBAF, THF, rt, 83%. DMM ¼ dimethoxy-
methane, DMP ¼ Dess-Martin periodinane, TBAI ¼ tetra-n-butylammonium iodide.
Scheme 4. Epoxy alcohol cyclizations and cascade reactions. Proximal and distal refer
to the relationship of epoxide substituents to the internal nucleophile.
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4
M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
asymmetric epoxidation conditions,29 but the olefin proximal to
the tetrahydropyran rings was minimally reactive under these
conditions. Therefore, we opted for a two-step sequence of
Sharpless, and then Shi, asymmetric epoxidations that generated
23 in higher yield and diastereoselectivity in comparison to the
one-step Shi protocol. From triepoxide 23, the free alcohol was
protected as a benzyl ether,30 and desilylation then furnished
cascade precursor 3.
Having prepared this triepoxide, we investigated the epoxide-
opening cascade to form rings C, D, and E. Using the optimal con-
ditions for the cyclization of epoxy alcohol 8, the cascade was
initially attempted with KHMDS as base (Table 1, entry 1). Although
these conditions did not provide desired product 2, we were
pleased to find that the first epoxide opening occurred as expected
to provide a mixture of diepoxide 25 and diol 26. In addition to
extensive 2D NMR studies, the structure of 25 was also confirmed
by X-ray crystallography.31 The hindered nature of the tertiary
alkoxide in this intermediate likely impedes attack of this nucleo-
phile on the second epoxide; elimination and subsequent epoxide
opening would lead to diol 26.32 This result prompted us to hy-
pothesize that the size of the alkoxide counterion could influence
the rate of the second epoxide opening relative to the rate of this
undesired pathway. With NaHMDS as base, a higher temperature
was required to achieve reactivity, but the reaction still provided a
mixture of 25 and 26 (entry 2).
2 are expected to be similar, important differences in the 13C NMR
shifts between des-benzyl 27 and the analogous portion of the
natural product indicated that 2 had not been formed.32 Further-
more, the coupling constants of the methylene protons on putative
ring C were consistent with the formation of a tetrahydrofuran
rather than a tetrahydropyran.33
In these studies, we observed that the outcome of the cascade
cyclizations under basic conditions is dependent on the metal
counterion. We hypothesize that this cation may coordinate to the
substrate in different ways to cause conformational changes, which
have previously been shown to affect the rate and selectivity of
epoxy alcohol cyclizations.34 Murai and co-workers have also
shown that coordination of a Lewis acid to the substrate can in-
fluence the regioselectivity of epoxide-opening cascades.5a In our
case, coordination of the cation with the MOM ether and its
neighboring epoxide may be responsible for the undesired exo
cyclization. Attempts to disfavor or alter cation coordination in our
system were unsuccessful; we attempted reactions of 3 and
LiHMDS with hexamethylphosphoramide (HMPA) as an additive
and reactions of substrates containing other protecting groups in
place of the MOM ether. In these cases, we obtained either intrac-
table mixtures or the same product ratio as in the reaction of
Table 1, entry 3.35
3. Conclusion
With lithium as counterion, the treatment of triepoxide 3 with
LiHMDS at 80 ꢁC led to formation of a new product, 27, which did
not appear to contain any epoxides by initial NMR analysis (entry
3). Additional 2D NMR studies indicated that, unfortunately, the
final ring had cyclized in a 5-exo fashion to form pentad 27.
Although the NMR spectra for this product and the desired product
In the context of the natural product brevisulcenal F, we have
explored new strategies for marine ladder polyether synthesis. We
first applied a copper-catalyzed allylation to the efficient con-
struction of skipped polyenes. The polyene fragment was then
readily coupled with a preformed tetrahydropyran to convergently
access the precursor for a polyepoxide cascade reaction. Basic
promoters were investigated for this cascade, for which the reac-
tion outcome exhibited a counterion dependence. We expect that
these strategies will prove valuable for the optimization of cascade
reactions in marine ladder polyether synthesis and to enable effi-
cient construction of these molecules in a biomimetic fashion.
Table 1
Effect of metal counterion on triepoxide cascade cyclization.
4. Experimental section
All reactions were performed under an atmosphere of argon
with anhydrous conditions, unless otherwise noted. Dichloro-
methane, tetrahydrofuran (THF), diethyl ether, benzene, dioxane,
acetonitrile, dimethylformamide (DMF), pyridine, dimethylsulf-
oxide (DMSO) and triethylamine were purified via an SG Water USA
solvent column system. Unless otherwise noted, all reagents were
commercially obtained and used without further purification. So-
lutions of potassium bis(trimethylsilyl)amide, sodium bis(-
trimethylsilyl)amide, and lithium bis(trimethylsilyl)amide were
prepared fresh prior to use from solid stored in a nitrogen-filled
glovebox (these reagents were purchased from Sigma-Aldrich).
Analytical thin layer chromatography (TLC) was performed using
EM Science silica gel 60 F254 plates, visualizing with a UV lamp
(254 nm), potassium permanganate, p-anisaldehyde, or ceric
ammonium molybdate. Liquid chromatography was performed
using forced flow (flash chromatography) of the indicated solvent
system on Silicycle silica gel (230e400 mesh) or Biotage® Isolera
flash purification system on SNAP KP, HP, and Ultra silica gel col-
umns. NMR spectra were acquired on a Bruker Avance (operating at
400 MHz for 1H and 101 MHz for 13C), Varian Inova 500 spec-
trometer (operating at 500 MHz for 1H and 126 MHz for 13C), or
JEOL Resonance ECZ 500R (operating at 500 MHz for 1H and
126 MHz for 13C). Chemical shifts (1H and 13C) are reported in parts
Entrya
Base
Temp. (ꢁC)
2/25/26/27b
1
KHMDS
NaHMDS
LiHMDS
0 to rt
80
80
0:3:1:0
0:2:1:0
0:0:1:9
2
3c
a
10 equiv base, 0.01 M in THF.
b
c
Determined by 1H NMR of crude reaction mixtures.
per million relative to TMS (
d
¼ 0.00 ppm) and were referenced to
57% isolated yield of 27.
the residual solvent peak (CDCl3, 7.26 ppm for 1H NMR, CDCl3,
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M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
5
77.16 ppm for 13C NMR; C6D6, 7.16 ppm for 1H NMR, C6D6,
128.06 ppm for 13C NMR; pyridine-d5, 7.21 ppm for 1H NMR, pyri-
dine-d5, 125.8 ppm for 13C NMR).36 The following designations are
used to describe multiplicities: s (singlet), d (doublet), t (triplet), q
(quartet), br (broad), app (apparent). IR spectra were obtained on
an Agilent Cary 630 FT-IR spectrometer equipped with an ATR
(attenuated total reflectance) accessory. MS (low resolution) was
performed on an Agilent 5973N gas chromatograph/mass spec-
trometer. Exact masses (high resolution mass spectra) were ob-
tained on a Bruker Daltonics APEX IV 4.7T FTICR mass spectrometer
operating with electrospray ionization (ESI) in positive ion mode or
direct analysis in real time (DART) ionization in positive ion mode
at the MIT Department of Chemistry Instrumentation Facility. Op-
tical rotations were measured using an Anton Paar MCP500
modular circular polarimeter at 589 nm and calculated using the
1.72 (d, J ¼ 1.4 Hz, 3H, 3H*). 13C NMR (101 MHz, CDCl3)
d
140.42,
128.52, 121.61, 121.30, 39.10, 28.81, 23.24, 16.13. FT-IR (ATR, cmꢀ1):
2976, 2917, 2853, 1654, 1426, 1379, 1200, 1098, 1063, 996, 944, 908,
892, 847, 765. MS (EIþ, m/z): calculated for C8H12Br2 ([M]þ): 268,
found: 268.
4.3. (2E,5E,8E)-9-bromo-3,6-dimethyldeca-2,5,8-trien-1-ol (11)
To a solution of Grignard reagent 6 (32.9 mL, 0.85 M in THF,
62.5 mmol) at ꢀ50 ꢁC, copper(I) bromide (402 mg, 2.8 mmol) was
added. The reaction mixture was allowed to stir under argon
at ꢀ50 ꢁC for 30 min before adding a solution of allylic bromide 10
(3.01 g, 11.2 mmol) in THF (23 mL) dropwise via cannula. The re-
action mixture was then transferred to a bath at ꢀ30 ꢁC. After
stirring at this temperature for 19 h, the reaction mixture was
quenched with aqueous ammonium chloride (saturated, 75 mL)
at ꢀ30 ꢁC. After warming to room temperature, the aqueous layer
was extracted with diethyl ether (4 ꢃ 100 mL). The combined
organic extracts were washed with brine, dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by Biotage column chromatography (100 g
Ultra silica gel, 5 / 40% ethyl acetate in hexanes) to afford the title
compound (1.73 g, 6.68 mmol, 60% yield, 20:1 linear/branched) as a
yellow oil. 1H NMR (400 MHz, CDCl3; branched isomer indicated by
formula: [
a
]
¼ (aobs*100)/(l*c), where c ¼ (g of substrate/100 mL of
D
solvent) and l ¼ 1 dm. X-ray structures were collected on a Bruker
X8 Kappa DUO four-circle diffractometer with a Bruker APEX2 CCD
at the MIT Department of Chemistry X-Ray Diffraction Facility.
4.1. (2E,5E)-6-bromo-3-methylhepta-2,5-dien-1-ol (9)
To a solution of Grignard reagent 6 (73.5 mL, 0.85 M in THF,
62.5 mmol) was added THF (4.5 mL). After cooling to ꢀ50 ꢁC, cop-
per(I) bromide (897 mg, 6.25 mmol) was added. The reaction
mixture was allowed to stir under argon at ꢀ50 ꢁC for 30 min before
adding a solution of allylic bromide 7 (5.35 g, 25 mmol) in THF
(52 mL) dropwise via cannula. The reaction mixture was then
transferred to a bath at ꢀ30 ꢁC. After stirring at this temperature for
16 h, the reaction mixture was quenched with aqueous ammonium
chloride (saturated, 150 mL) at ꢀ30 ꢁC. After warming to room
temperature, the aqueous layer was extracted with diethyl ether
(4 ꢃ 200 mL). The combined organic extracts were washed with
brine, dried over magnesium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by Biotage col-
umn chromatography (340 g Ultra silica gel, 5 / 40% ethyl acetate
in hexanes) to afford the title compound (2.97 g, 14.5 mmol, 58%
yield, >20:1 linear/branched) as a yellow oil, with a minor un-
known impurity (not present after the next step). 1H NMR
*)
d
5.85 (ddt, J ¼ 7.8, 6.4, 1.4 Hz, 1H), 5.77e5.69 (m, 2H*), 5.49 (td,
J ¼ 6.3, 1.3 Hz, 1H*), 5.40 (ddt, J ¼ 7.0, 5.6, 1.4 Hz, 1H), 5.18 (ddt,
J ¼ 7.4, 6.0, 1.4 Hz, 1H), 4.15 (d, J ¼ 6.9 Hz, 2H, 2H*), 2.73e2.70 (m,
2H, 2H*), 2.70e2.67 (m, 2H, 2H*), 2.23 (d, J ¼ 1.2 Hz, 3H, 3H*), 1.65
(s, 3H, 3H*), 1.61 (s, 3H, 3H*). 13C NMR (101 MHz, CDCl3)
d 138.98,
134.54, 130.16, 123.57, 122.93, 120.40, 59.56, 39.62, 38.00, 23.32,
16.64, 16.32. FT-IR (ATR, cmꢀ1): 3440, 2977, 2917, 1718, 1670, 1428,
1379, 1232, 1165, 1092, 1061, 996, 917, 860. HRMS (ESI, m/z):
calculated for C12H19BrNaO ([MþNa]þ): 281.0517, found: 281.0519.
4.4. (2E,5E,8E)-9-bromo-1-(methoxymethoxy)-3,6-dimethyldeca-
2,5,8-triene (4)
To a solution of allylic alcohol 11 (518 mg, 2.00 mmol) in
dichloromethane (8 mL) at 0 ꢁC, N,N-diisopropylethylamine
(0.941 mL, 698 mg, 5.40 mmol) was added, followed by dropwise
addition of chloromethyl methyl ether (0.304 mL, 322 mg,
4.00 mmol). After stirring at 0 ꢁC for 5 min, the reaction mixture
was allowed to stir at room temperature for 3 h. The reaction
mixture was then cooled to 0 ꢁC before adding additional N,N-dii-
sopropylethylamine (0.453 mL, 336 mg, 2.60 mmol) and chlor-
omethyl methyl ether (0.152 mL, 161 mg, 2.00 mmol). The reaction
mixture was then allowed to stir at room temperature for an
additional 3 h before diluting with dichloromethane (50 mL). The
organic layer was washed with aqueous hydrochloric acid (1 M,
2 ꢃ 25 mL) and aqueous sodium bicarbonate (saturated, 25 mL),
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by Biotage column chromatog-
raphy (50 g Ultra silica gel, 2 / 20% ethyl acetate in hexanes) to
afford the title compound (500 mg, 1.65 mmol, 82% yield) as a
yellow oil. The product was stored over solid potassium carbonate
(400 MHz, CDCl3; impurity indicated by *)
d
5.86 (ddt, J ¼ 8.9, 7.5,
1.2 Hz, 1H), 5.65e5.61 (m*), 5.43 (ddt, J ¼ 6.9, 5.5, 1.4 Hz, 1H),
4.24e4.21 (m*), 4.15 (d, J ¼ 6.9 Hz, 2H), 2.70 (d, J ¼ 7.9 Hz, 2H), 2.23
(d, J ¼ 1.2 Hz, 3H), 1.67 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 136.95,
129.37, 124.69, 120.91, 59.40, 39.31, 23.31, 16.59. FT-IR (ATR, cmꢀ1):
3319, 2982, 2918, 1670, 1648, 1427, 1380, 1236, 1194, 1094, 1052,
995, 910, 842, 776. HRMS (ESI, m/z): calculated for C8H13BrNaO
([MþNa]þ): 227.0047, found: 227.0039.
4.2. (2E,5E)-1,6-dibromo-3-methylhepta-2,5-diene (10)
To a solution of allylic alcohol 9 (2.46 g, 12.0 mmol) in diethyl
ether (12 mL) at 0 ꢁC, phosphorus tribromide (0.417 mL, 1.20 g,
4.44 mmol) was added dropwise. After stirring at 0 ꢁC for 10 min,
the reaction mixture was partially concentrated under reduced
pressure with ice/water in the rotovap bath (to approximately 25%
volume). The solution was then filtered through a plug of silica gel,
eluting with 10% diethyl ether in pentanes (approximately 3e4
column volumes). The filtrate was concentrated under reduced
pressure (with ice/water in the rotovap bath) to afford the title
compound (3.01 g, 11.2 mmol, 93% yield, 20:1 linear/branched) as a
yellow oil. 1H NMR (400 MHz, CDCl3; branched isomer indicated by
at ꢀ20 ꢁC to limit decomposition. 1H NMR (400 MHz, CDCl3)
d 5.86
(tq, J ¼ 7.8, 1.4 Hz, 1H), 5.35 (tq, J ¼ 6.9, 1.4 Hz, 1H), 5.20 (tq, J ¼ 7.2,
1.3 Hz, 1H), 4.64 (s, 2H), 4.08 (d, J ¼ 6.9 Hz, 1H), 3.38 (s, 3H),
2.75e2.68 (m, 4H), 2.23 (d, J ¼ 0.7 Hz, 3H), 1.66 (s, 3H), 1.61 (s, 3H).
13C NMR (126 MHz, CDCl3)
d 140.14, 134.47, 130.18, 122.97, 120.42,
*)
d
6.15 (dd, J ¼ 17.2,10.6,1H*), 5.94 (tq, J ¼ 7.6,1.4 Hz,1H*), 5.84 (tq,
120.38, 95.74, 63.84, 55.34, 39.64, 38.02, 23.31, 16.75, 16.30. FT-IR
(ATR, cmꢀ1): 2927, 2886, 1772, 1673, 1651, 1449, 1380, 1268, 1213,
1148, 1100, 1036, 943, 918, 868. HRMS (ESI, m/z): calculated for
J ¼ 7.8, 1.4 Hz, 1H), 5.56 (tdt, J ¼ 8.4, 2.7, 1.4 Hz, 1H), 5.21 (d,
J ¼ 17.2 Hz, 1H*), 5.07 (d, J ¼ 10.6 Hz, 1H*), 4.00 (d, J ¼ 8.4 Hz, 2H,
2H*), 2.75 (d, J ¼ 7.9 Hz, 2H, 2H*), 2.23 (dt, J ¼ 1.5, 0.9 Hz, 3H, 3H*),
C
14H23BrNaO2 ([MþNa]þ): 325.0779, found: 325.0771.
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
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6
M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
4.5. tert-butyldimethyl(((2R,4aR,7R,8aS)-6-methylene-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)silane (13)
dimethylsilane (9.90 g, 20.2 mmol) in THF at 0 ꢁC, potassium tert-
butoxide (4.53 g, 40.4 mmol) was added. After stirring at 0 ꢁC for
30 min, the reaction mixture was quenched with water (100 mL),
and the aqueous layer was extracted with ether (3 ꢃ 150 mL). The
combined organic extracts were washed with brine, dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by Biotage automated chroma-
tography (100 g Ultra silica gel, 0 / 15% diethyl ether in hexanes
with 2% triethylamine) to afford the title compound (7.30 g,
20.1 mmol, 99% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3)
To a solution of olefin 12 (11.3 g, 30.0 mmol) in dichloro-
methane/methanol (300 mL, 5:1 dichloromethane/methanol)
at ꢀ78 ꢁC, ozone was bubbled for approximately 1 h (until the so-
lution acquired a persistent blue color). The reaction mixture was
then purged with nitrogen for 2 h (until the solution turned
colorless). At ꢀ78 ꢁC, sodium borohydride (5.67 g, 150 mmol) was
added, and the reaction mixture was removed from the cooling
bath. After stirring overnight at room temperature, the reaction
mixture was quenched with aqueous ammonium chloride (satu-
rated, 150 mL). The aqueous layer was extracted with diethyl ether
(3 ꢃ 150 mL). The combined organic layers were washed with
brine, dried over magnesium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by Biotage
automated chromatography (100 g Ultra silica gel, 5 / 40% ethyl
acetate in hexanes) to afford ((2R,4aR,6S,7R,8aS)-7-((tert-butyldi-
methylsilyl)oxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-
yl)methanol (10.3 g, 27.1 mmol, 90% yield) as a colorless oil. 1H NMR
d
7.53e7.44 (m, 2H), 7.41e7.31 (m, 3H), 5.54 (s, 1H), 4.70 (dd, J ¼ 1.8,
0.7 Hz, 1H), 4.66 (dd, J ¼ 1.8, 0.8 Hz, 1H), 4.39 (dd, J ¼ 10.4, 4.9 Hz,
1H), 4.24 (ddt, J ¼ 10.8, 5.5, 1.8 Hz, 1H), 3.75 (dd, J ¼ 10.4, 10.4 Hz,
1H), 3.75e3.67 (m, 1H), 3.55 (ddd, J ¼ 10.2, 9.1, 4.9 Hz, 1H), 2.43
(ddd, J ¼ 11.4, 4.9, 4.9 Hz, 1H), 1.82 (dd, J ¼ 11.4, 11.3 Hz, 1H), 0.93 (s,
9H), 0.12 (s, 3H), 0.12 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 161.24,
137.36, 129.29, 128.50, 126.31, 101.90, 93.62, 76.13, 74.03, 69.37,
67.10, 39.17, 25.89, 18.31, ꢀ4.74, ꢀ4.87. FT-IR (ATR, cmꢀ1): 2956,
2931, 2887, 2858, 1661, 1364, 1321, 1288, 1252, 1216, 1135, 1094,
1027, 963, 856, 837, 777, 697. HRMS (DART, m/z): calculated for
20
(400 MHz, CDCl3)
d
7.55e7.44 (m, 2H), 7.42e7.31 (m, 3H), 5.52 (s,
C
20H31O4Si ([MþH]þ): 363.1992, found: 363.1976. [
a
]
¼ þ17.3
D
1H), 4.33 (dd, J ¼ 10.4, 4.8 Hz, 1H), 3.87 (ddd, J ¼ 11.5, 6.3, 2.8 Hz,
1H), 3.81e3.61 (m, 3H), 3.52 (ddd, J ¼ 12.0, 8.9, 4.1 Hz, 1H), 3.43
(ddd, J ¼ 9.3, 9.0, 4.8 Hz, 1H), 3.35 (ddd, J ¼ 9.3, 5.3, 2.8 Hz, 1H), 2.42
(ddd, J ¼ 11.7, 4.5, 4.5 Hz, 1H), 1.75 (dd, J ¼ 11.5, 11.4 Hz, 1H), 0.88 (s,
(c ¼ 1.04, CHCl3).
4.6. ethyl (E)-4-((2R,4aR,6S,7R,8aS)-7-((tert-butyldimethylsilyl)
oxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)-3-
methylbut-2-enoate (15)
9H), 0.09 (s, 6H). 13C NMR (126 MHz, CDCl3)
d 137.47, 129.28, 128.52,
126.31, 101.90, 82.56, 76.61, 73.11, 69.44, 66.65, 62.51, 38.71, 25.81,
18.03, ꢀ4.07, ꢀ4.81. FT-IR (ATR, cmꢀ1): 2935, 2930, 2859, 1457,
1364, 1253, 1091, 1031, 858, 837, 776, 698. HRMS (DART, m/z):
A flask with exocyclic olefin 13 (1.09 g, 3.00 mmol) was evacu-
ated under high vacuum for 1 h to remove air. After backfilling with
argon, a solution of 9-borabicyclo[3.3.1]nonane dimer (1.83 g,
7.50 mmol) in THF (23 mL) was added via cannula. The reaction
mixture was allowed to stir at room temperature for 3 h before
charging with an aqueous solution of sodium bicarbonate (1.01 g,
12.0 mmol in 12 mL water, degassed by sparging with argon for
15 min). After stirring at room temperature for an additional
20 min, the flask was quickly opened before adding dichloro[1,10-
bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane
adduct (245 mg, 0.300 mmol). A solution of vinyl triflate 14 (1.57 g,
6.00 mmol) in DMF (45 mL, degassed by sparging with argon for
30 min) was then added dropwise via cannula. The reaction
mixture was allowed to stir at room temperature for 20 h with
vigorous stirring. It was then diluted with water (100 mL), and the
aqueous layer was extracted with ether (3 ꢃ 100 mL). The com-
bined organic layers were washed with aqueous lithium chloride
(5% w/w, 100 mL) and brine (100 mL), dried over magnesium sul-
fate, filtered, and concentrated under reduced pressure. The
resulting residue was dissolved in THF (20 mL) and water (20 mL)
before adding sodium perborate tetrahydrate (4.62 g, 30 mmol).
After stirring vigorously for 2 h at room temperature, the reaction
mixture was diluted with water (50 mL). The aqueous layer was
extracted with diethyl ether (3 ꢃ 100 mL). The combined organic
extracts were dried over magnesium sulfate, filtered, and concen-
trated under reduced pressure. The residue was purified by Biotage
automated chromatography (100 g Ultra silica gel, 2 / 20% ethyl
acetate in hexanes) to afford the title compound (1.23 g, 2.58 mmol,
calculated for C20H33O5Si ([M ꢀ H]þ): 381.2097, found: 381.2089.
20
[
a]
¼ ꢀ55.0 (c ¼ 1.05, CHCl3).
D
To a solution of ((2R,4aR,6S,7R,8aS)-7-((tert-butyldimethylsilyl)
oxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)methanol
(3.39 g, 8.90 mmol) in THF (45 mL) at room temperature, triphe-
nylphosphine (2.80 g, 10.7 mmol) and imidazole (1.45 g, 21.4 mmol)
were added. After cooling to ꢀ40 ꢁC, iodine (2.71 mmol, 10.7 mmol)
was added. The reaction mixture was then removed from the
cooling bath and allowed to warm to room temperature. After
stirring at this temperature for 1.5 h, additional triphenylphosphine
(0.467 g, 1.78 mmol) and iodine (0.452 g, 1.78 mmol) were added at
room temperature. After stirring at room temperature for an
additional 30 min, the reaction mixture was quenched with
aqueous sodium thiosulfate (saturated, 150 mL). The aqueous layer
was extracted with diethyl ether (3 ꢃ 100 mL). The combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
Biotage automated chromatography (50 g HP silica gel, 1 /15%
diethyl ether in hexanes) to afford tert-butyl(((2R,4aR,6R,7R,8aS)-6-
(iodomethyl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)
oxy)dimethylsilane (4.19 g, 8.54 mmol, 96% yield) as a colorless oil
that solidified upon storage at 0 ꢁC. 1H NMR (500 MHz, CDCl3)
d
7.51e7.45 (m, 2H), 7.42e7.31 (m, 3H), 5.53 (s, 1H), 4.34 (dd,
J ¼ 10.5, 4.9 Hz, 1H), 3.73 (dd, J ¼ 10.3, 10.3 Hz, 1H), 3.63 (ddd,
J ¼ 10.7, 8.5, 4.8 Hz, 1H), 3.56 (ddd, J ¼ 11.7, 9.0, 4.1 Hz, 1H),
3.53e3.43 (m, 2H), 3.37 (dd, J ¼ 10.6, 5.0 Hz, 1H), 2.96 (ddd, J ¼ 8.1,
4.9, 2.8 Hz, 1H), 2.42 (ddd, J ¼ 11.6, 4.4, 4.4 Hz, 1H), 1.77 (dd, J ¼ 11.4,
11.4 Hz, 1H), 0.88 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H). 13C NMR
86% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d 7.51e7.45
(101 MHz, CDCl3)
d
137.48, 129.28, 128.51, 126.31, 101.90, 80.26,
(m, 2H), 7.41e7.32 (m, 3H), 5.72 (q, J ¼ 1.2 Hz, 1H), 5.50 (s, 1H), 4.28
(dd, J ¼ 10.5, 4.9 Hz, 1H), 4.16 (q, J ¼ 7.1 Hz, 2H), 3.63 (dd, J ¼ 10.3,
10.3 Hz, 1H), 3.57e3.42 (m, 2H), 3.39 (ddd, J ¼ 9.4, 9.3, 2.1 Hz, 1H),
3.33 (ddd, J ¼ 10.1, 8.9, 4.9 Hz, 1H), 2.69 (ddd, J ¼ 14.3, 1.7, 1.7 Hz,
1H), 2.41 (ddd, J ¼ 11.7, 4.4, 4.4 Hz, 1H), 2.20 (d, J ¼ 1.3 Hz, 3H), 2.10
(dd, J ¼ 14.3, 9.6 Hz, 1H), 1.72 (ddd, J ¼ 11.7, 11.7, 10.4 Hz, 1H), 1.28 (t,
J ¼ 7.1 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.09 (s, 3H). 13C NMR
76.47, 73.21, 70.47, 69.38, 38.44, 25.86, 17.98, 8.07, ꢀ3.85, ꢀ4.33. FT-
IR (ATR, cmꢀ1): 2953, 2930, 2857, 1457, 1362, 1253, 1090, 1004, 859,
854, 776, 750, 697, 670. HRMS (DART, m/z): calculated for
20
C
20H32IO4Si ([MþH]þ): 491.1115, found: 491.1116. [
a
]
¼ ꢀ50.5
D
(c ¼ 1.04, CHCl3).
To a solution of tert-butyl(((2R,4aR,6R,7R,8aS)-6-(iodomethyl)-
2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)
(101 MHz, CDCl3)
d 166.83, 156.89, 137.57, 129.25, 128.50, 126.33,
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
synthesis, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.039

M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
7
117.75, 101.90, 81.21, 76.63, 73.23, 70.59, 69.52, 59.68, 43.13, 39.04,
25.87, 19.29, 18.06, 14.49, ꢀ3.78, ꢀ4.62. FT-IR (ATR, cmꢀ1): 2953,
2932, 2859, 1715, 1651, 1456, 1386, 1366, 1253, 1217, 1140, 1088,
1030, 1006, 964, 862, 836, 776, 750, 698. HRMS (DART, m/z):
phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)methyl)-3-
methyloxiran-2-yl)methanol (3.16 g, 7.00 mmol, 91% yield, 10:1 dr)
as a white solid. 1H NMR (400 MHz, CDCl3; minor diastereomer
indicated by * where observed)
d 7.50e7.46 (m, 2H), 7.40e7.31 (m,
calculated for C26H41O6Si ([MþH]þ): 477.2672, found: 477.2689.
3H), 4.30 (dd, J ¼ 10.5, 4.9 Hz, 1H), 4.25 (dd, J ¼ 10.5, 4.9 Hz, 1H*),
3.89 (ddd, J ¼ 11.9, 7.5, 4.3 Hz, 1H), 3.76e3.63 (m, 2H), 3.85e3.79
(m, 1H*), 3.52 (ddd, J ¼ 11.7, 9.0, 4.2 Hz, 1H), 3.44 (ddd, J ¼ 10.6, 8.9,
4.7 Hz, 1H), 3.40e3.28 (m, 2H), 3.01 (dd, J ¼ 6.7, 4.3 Hz, 1H), 2.40
(ddd, J ¼ 11.7, 4.4, 4.4 Hz, 1H), 2.37e2.30 (m, 1H*), 2.08 (dd, J ¼ 14.7,
1.7 Hz, 1H), 1.76e1.55 (m, 3H), 1.36 (s, 3H), 0.88 (s, 9H), 0.08 (s, 3H),
20
[
a]
¼ ꢀ39.9 (c ¼ 1.09, CHCl3).
D
4.7. (2R,4aR,6S,7R,8aS)-6-(((2R,3R)-3-(hydroxymethyl)-2-
methyloxiran-2-yl)methyl)-2-phenylhexahydropyrano[3,2-d][1,3]
dioxin-7-ol (8)
0.07 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 137.54, 129.27, 128.51,
To a solution of ester 15 (4.38 g, 9.19 mmol) in dichloromethane
(46 mL) at ꢀ78 ꢁC, diisobutylaluminum hydride (23.9 mL, 1 M in
dichloromethane, 23.9 mmol) was added dropwise. After stirring
at ꢀ78 ꢁC for 50 min, the reaction mixture was quenched by the
dropwise addition of methanol (1 mL) before removing from the
cooling bath and diluting with ether (150 mL). At room tempera-
ture, the mixture was then poured into aqueous Rochelle's salt
(saturated,150 mL) and stirred vigorously for 3 h. The aqueous layer
was then extracted with diethyl ether (3 ꢃ 150 mL). The combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
Biotage automated chromatography (100 g Ultra silica gel, 8 / 66%
ethyl acetate in hexanes) to afford (E)-4-((2R,4aR,6S,7R,8aS)-7-
((tert-butyldimethylsilyl)oxy)-2-phenylhexahydropyrano[3,2-d]
[1,3]dioxin-6-yl)-3-methylbut-2-en-1-ol (3.38 g, 7.78 mol, 85%
126.33, 101.92, 80.22, 76.55, 73.14, 70.37, 69.53, 61.96, 61.51, 60.21,
40.23, 39.03, 25.88, 18.04, 18.04, ꢀ3.83, ꢀ4.59. FT-IR (ATR, cmꢀ1):
3400, 2030, 2858, 1456, 1388, 1363, 1252, 1089, 1029, 1007, 861, 837,
775, 750, 698, 670. HRMS (DART, m/z): calculated for C24H39O6Si
20
([MþH]þ): 451.2516, found: 451.2530. [
a
]
¼ ꢀ49.7 (c ¼ 1.04,
D
CHCl3).
To a solution of ((2R,3R)-3-(((2R,4aR,6S,7R,8aS)-7-((tert-butyl-
dimethylsilyl)oxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-
yl)methyl)-3-methyloxiran-2-yl)methanol (1.70 g, 3.77 mmol) in
THF (5 mL) at room temperature, tetra-n-butylammonium fluoride
(7.54 mL, 1 M in THF, 7.54 mmol) was added. After stirring for 1 h,
the reaction mixture was partially concentrated under reduced
pressure to approximately 25% volume. The mixture was then
loaded directly onto a column for purification by Biotage auto-
mated chromatography (50 g Ultra silica gel, 20 / 50/100% ethyl
acetate in hexanes with 2% triethylamine, then 0 / 10% methanol
in ethyl acetate) to afford the title compound (1.27 g, 3.77 mmol,
quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3)
yield) as a white solid. 1H NMR (400 MHz, CDCl3)
d 7.51e7.45 (m,
2H), 7.40e7.32 (m, 3H), 5.50 (s, 1H), 5.48 (ddd, J ¼ 7.0, 7.0, 1.0 Hz,
1H), 4.27 (dd, J ¼ 10.5, 4.9 Hz, 1H), 4.18 (d, J ¼ 6.9 Hz, 2H), 3.65 (dd,
J ¼ 10.3, 10.3 Hz, 1H), 3.57e3.40 (m, 2H), 3.39e3.26 (m, 2H), 2.60 (d,
J ¼ 14.4 Hz, 1H), 2.40 (ddd, J ¼ 11.7, 4.4, 4.4 Hz, 1H), 1.99 (dd, J ¼ 14.5,
9.8 Hz, 1H), 1.67e1.77 (m, 4H), 1.31 (br s, 1H), 0.89 (s, 9H), 0.09 (s,
d
7.51e7.46 (m, 2H), 7.40e7.33 (m, 3H), 5.53 (s, 1H), 4.31 (dd,
J ¼ 10.5, 4.9 Hz, 1H), 3.85 (ddd, J ¼ 11.6, 6.7, 4.8 Hz, 1H), 3.61e3.79
(m, 3H), 3.56 (ddd, J ¼ 11.6, 9.0, 4.2 Hz, 1H), 3.40e3.31 (m, 2H), 3.07
(dd, J ¼ 6.4, 4.8 Hz, 1H), 2.50 (ddd, J ¼ 11.6, 4.4, 4.4 Hz, 1H), 2.44 (d,
J ¼ 5.4 Hz, 1H), 2.14 (dd, J ¼ 15.0, 3.5 Hz, 1H), 1.87 (dd, J ¼ 15.1,
6.8 Hz, 1H), 1.75e1.65 (m, 2H), 1.40 (s, 3H). 13C NMR (101 MHz,
6H). 13C NMR (101 MHz, CDCl3)
d 137.58, 136.99, 129.20, 128.46,
126.31, 125.58, 101.83, 81.69, 76.71, 73.18, 70.62, 69.57, 59.48, 41.74,
39.08, 25.87, 18.05, 16.89, ꢀ3.81, ꢀ4.62. FT-IR (ATR, cmꢀ1): 3387,
2929, 2858, 1669, 1457, 1387, 1362, 1252, 1184, 1089, 1006, 862, 836,
CDCl3)
d 137.49, 129.27, 128.51, 126.32, 101.87, 80.06, 73.50, 69.48,
775, 750, 698, 670. HRMS (DART, m/z): calculated for C24H39O5Si
69.21, 62.54, 61.24, 60.05, 40.46, 38.05, 17.94 (one ethereal carbon
likely under solvent peak). FT-IR (ATR, cmꢀ1): 3387, 2934, 2871,
1445, 1387, 1286, 1185, 1096, 1068, 1018, 917, 808, 753, 699. HRMS
20
([M þ NH4]þ): 452.2832, found: 452.2837. [
a
]
¼ ꢀ47.4 (c ¼ 1.00,
D
CHCl3).
In a round-bottom flask, 4 Å powdered molecular sieves (2 g)
were activated by heating under reduced pressure. After cooling to
room temperature, the flask was charged with dichloromethane
(DART, m/z): calculated for C18H25O6 ([MþH]þ): 337.1651, found:
20
337.1657. [
a
]
¼ ꢀ17.6 (c ¼ 1.00, CHCl3).
D
(50 mL) and
D
-(-)-diethyl tartrate (198
m
L, 238 mg, 1.16 mmol) un-
4.8. (2R,4aR,5aS,7R,8S,9aR,10aS)-7-methoxy-8-(methoxymethyl)-
7-methyl-2-phenyloctahydro-4H-pyrano[20,30:5,6]pyrano[3,2-d]
[1,3]dioxine (16)
der argon. The mixture was then cooled to ꢀ20 ꢁC before adding
titanium isopropoxide (274 mL, 263 mg, 0.925 mmol) and, drop-
wise, tert-butylhydroperoxide (2.80 mL, 5.5 M in decane,
15.4 mmol). After stirring at this temperature for 20 min, a solution
To a solution of epoxy alcohol 8 (1.27 g, 3.77 mmol) in THF
(60 mL) at ꢀ78 ꢁC under argon, a solution of potassium bis(-
trimethylsilyl)amide (1.88 g, 9.43 mmol) in THF (15 mL) was added
dropwise via cannula. After stirring at ꢀ78 ꢁC for 5 min, the reac-
tion mixture was then transferred to a bath at 0 ꢁC. After stirring at
0 ꢁC until starting material was consumed by TLC (5 h), the flask
was charged with sodium hydride (754 mg, 60% w/w in mineral oil,
18.9 mmol), followed by methyl iodide (2.35 mL, 5.35 g, 37.7 mmol)
dropwise. The reaction mixture was then removed from the cooling
bath and was allowed to stir at room temperature overnight. The
mixture was then cooled to 0 ꢁC before quenching with aqueous
ammonium chloride (saturated, 100 mL). The aqueous layer was
extracted with diethyl ether (3 ꢃ 125 mL). The combined organic
extracts were dried over magnesium sulfate, filtered, and concen-
trated under reduced pressure. The residue was purified by Biotage
automated chromatography (100 g Ultra silica gel, 7 / 60% ethyl
acetate in hexanes) to afford the title compound (1.20 g, 97% w/w
with ethyl acetate, 3.17 mmol, 84% yield, 17:1 endo/exo) as a white
of
(E)-4-((2R,4aR,6S,7R,8aS)-7-((tert-butyldimethylsilyl)oxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)-3-methylbut-2-
en-1-ol (3.35 g, 7.71 mmol) in dichloromethane (27 mL) was added
dropwise. The reaction mixture was then allowed to stir at ꢀ20 ꢁC
overnight under argon before transferring to a bath at 0 ꢁC. The
mixture was then added slowly to a solution of iron(II) sulfate
heptahydrate (2.59 g) and tartaric acid (771 mg) in water (26.9 mL)
at 0 ꢁC. After stirring at room temperature for 15 min, the aqueous
layer was extracted with diethyl ether (4 ꢃ 50 mL). To the combined
organic extracts, a solution of sodium hydroxide in brine (25 mL e
made by dissolving 1.25 g sodium chloride and 7.49 g sodium hy-
droxide in 22.5 mL water) was added. This suspension was allowed
to stir vigorously at room temperature for 1 h before separating the
layers. The organic layer was dried over magnesium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified
by Biotage automated chromatography (100 g Ultra silica gel,
10 / 80% ethyl acetate in hexanes) to afford ((2R,3R)-3-
(((2R,4aR,6S,7R,8aS)-7-((tert-butyldimethylsilyl)oxy)-2-
foam. 1H NMR (400 MHz, CDCl3)
d 7.52e7.46 (m, 2H), 7.41e7.31 (m,
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
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8
M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
3H), 5.53 (s, 1H), 4.30 (dd, J ¼ 10.4, 4.8 Hz, 1H), 3.69 (dd, J ¼ 10.3,
10.3 Hz, 1H), 3.64 (dd, J ¼ 10.3, 1.6 Hz, 1H), 3.58 (ddd, J ¼ 11.5, 9.1,
4.3 Hz, 1H), 3.53 (dd, J ¼ 8.3, 1.5 Hz, 1H), 3.45e3.33 (m, 5H), 3.25 (s,
3H), 3.24e3.14 (m, 2H), 2.55 (ddd, J ¼ 11.7, 3.9, 3.9 Hz, 1H), 2.25 (dd,
J ¼ 11.3, 3.8 Hz, 1H), 1.75 (dd, J ¼ 11.2, 11.2 Hz, 1H), 1.59 (dd, J ¼ 11.2,
1H), 1.86 (dd, J ¼ 6.2, 6.2 Hz, 1H), 1.60e1.50 (m, 2H), 1.16 (s, 3H), 0.86
(s, 9H), 0.06 (s, 6H). 13C NMR (101 MHz, CDCl3)
82.56, 82.35, 76.81,
d
75.93, 74.06, 71.52, 67.00, 62.80, 59.44, 49.10, 40.35, 39.11, 25.81,
18.26,18.01, ꢀ4.11, ꢀ4.85. FT-IR (ATR, cmꢀ1): 3510, 2931, 2859,1461,
1375, 1252, 1087, 1055, 956, 871, 835, 776, 754. HRMS (ESI, m/z):
11.2 Hz, 1H), 1.19 (s, 3H). 13C NMR (101 MHz, CDCl3)
d
137.45, 129.25,
calculated for C19H38KO6Si ([MþK]þ): 429.2075, found: 429.2064.
20
128.47, 126.34, 102.00, 83.00, 77.41, 74.06, 73.85, 71.43, 69.33, 59.42,
49.11, 40.31, 35.02, 18.29 (two ethereal carbons likely under solvent
peaks). FT-IR (ATR, cmꢀ1): 2977, 2938, 2876, 1456, 1378, 1335, 1314,
1295, 1177, 1092, 1015, 959, 929, 878, 751, 700. HRMS (DART, m/z):
[a
]
¼ þ2.11 (c ¼ 1.01, CHCl3).
D
To
a solution of ((2R,3S,4aR,6S,7R,8aS)-3-((tert-butyldime-
thylsilyl)oxy)-7-methoxy-6-(methoxymethyl)-7-
methyloctahydropyrano[3,2-b]pyran-2-yl)methanol
(293 mg,
calculated for C20H29O6 ([MþH]þ): 365.1964, found: 365.1968.
0.75 mmol), DMSO (533
mL, 586 mg, 7.5 mmol), and triethylamine
20
[
a]
¼ ꢀ50.6 (c ¼ 1.00, CHCl3).
(732
m
L, 531 mg, 5.25 mmol) in dichloromethane (3 mL) at 0 ꢁC
D
under argon, sulfur trioxide pyridine complex (477 mg, 3 mmol)
was added. The reaction mixture was then removed from the
cooling bath and allowed to stir at room temperature for 2.5 h
before diluting with dichloromethane (25 mL). The organic layer
was washed with water (15 mL) and brine (15 mL) before drying
over magnesium sulfate, filtering, and concentrating under reduced
pressure. The residue was purified by Biotage automated chroma-
tography (25 g Ultra silica gel, 8 / 60% ethyl acetate in hexanes
with 2% triethylamine) to afford the title compound (241 mg,
0.621 mmol, 83% yield) as a slightly brown oil. This compound was
used immediately in the next step to limit decomposition. 1H NMR
4.9. (2S,3S,4aR,6S,7R,8aS)-3-((tert-butyldimethylsilyl)oxy)-7-
methoxy-6-(methoxymethyl)-7-methyloctahydropyrano[3,2-b]
pyran-2-carbaldehyde (5)
To a solution of bis-tetrahydropyran 16 (2.18 g, 5.98 mmol) in
dichloromethane/methanol (24 mL, 1:1) at room temperature, p-
toluenesulfonic acid monohydrate (455 mg, 2.39 mmol) was added.
After stirring at room temperature for 3 h, the reaction mixture was
quenched with triethylamine (approximately 5 mL) and concen-
trated under reduced pressure. The residue was purified by Biotage
automated chromatography (100 g Ultra silica gel, 50 / 100% ethyl
acetate in hexanes, then 0 / 10% methanol in ethyl acetate) to
(400 MHz, CDCl3)
d
9.73 (d, J ¼ 0.9 Hz, 1H), 3.84 (ddd, J ¼ 10.3, 10.1,
4.7 Hz, 1H), 3.76 (dd, J ¼ 9.6, 1.0 Hz, 1H), 3.63 (dd, J ¼ 10.2, 1.6 Hz,
1H), 3.52 (dd, J ¼ 8.4, 1.7 Hz, 1H), 3.39 (s, 3H), 3.39e3.33 (m, 1H),
3.24 (s, 3H), 3.14e3.05 (m, 2H), 2.54 (ddd, J ¼ 11.7, 4.0, 4.0 Hz, 1H),
2.30 (dd, J ¼ 11.4, 3.7 Hz, 1H), 1.71e1.60 (m, 2H), 1.16 (s, 3H), 0.87 (s,
afford
(2R,3S,4aR,6S,7R,8aS)-2-(hydroxymethyl)-7-methoxy-6-
(methoxymethyl)-7-methyloctahydropyrano[3,2-b]pyran-3-ol
(1.31 g, 4.74 mmol, 79% yield) as a white solid. 1H NMR (400 MHz,
CDCl3)
d
3.87 (ddd, J ¼ 11.5, 5.8, 4.1 Hz, 1H), 3.78 (ddd, J ¼ 11.5, 6.4,
9H), 0.07 (s, 3H), 0.04 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 198.41,
5.1 Hz, 1H), 3.70 (dddd, J ¼ 11.2, 9.7, 5.0, 5.0 Hz, 1H), 3.64 (dd,
J ¼ 10.3, 1.6 Hz, 1H), 3.52e3.47 (m, 1H), 3.40e3.33 (m, 4H),
3.29e3.22 (m, 4H), 3.12e3.03 (m, 2H), 2.53 (ddd, J ¼ 11.4, 4.0,
4.0 Hz, 1H), 2.24 (dd, J ¼ 11.4, 3.9 Hz, 1H), 2.07e2.03 (m, 1H), 1.97
(dd, J ¼ 6.1, 6.1 Hz, 1H), 1.61e1.49 (m, 2H), 1.17 (s, 3H). 13C NMR
85.20, 82.61, 75.86, 75.83, 74.00, 71.38, 67.49, 59.46, 49.16, 40.08,
39.66, 25.74, 18.23, 18.00, ꢀ4.06, ꢀ4.88. FT-IR (ATR, cmꢀ1): 2932,
2859, 1464, 1375, 1253, 1093, 1007, 957, 867, 838, 778. HRMS (ESI,
m/z): calculated for C19H36NaO6Si ([MþNa]þ): 411.2179, found:
20
411.2152. [
a
]
¼ þ2.1 (c ¼ 0.27, CHCl3).
D
(101 MHz, CDCl3)
d 82.62, 81.46, 76.75, 76.03, 74.05, 71.46, 67.20,
63.37, 59.41, 49.11, 40.31, 38.54, 18.30. FT-IR (ATR, cmꢀ1): 3412,
2941, 2873, 1457, 1376, 1120, 1087, 1035, 955, 751. HRMS (DART, m/
4.10. (S,2E,5E,8E)-1-((2R,3S,4aR,6S,7R,8aS)-3-((tert-
butyldimethylsilyl)oxy)-7-methoxy-6-(methoxymethyl)-7-
methyloctahydropyrano[3,2-b]pyran-2-yl)-10-(methoxymethoxy)-
2,5,8-trimethyldeca-2,5,8-trien-1-ol (20)
z): calculated for C13H25O6 ([MþH]þ): 277.1651, found: 277.1655.
20
[
a]
¼ ꢀ39.4 (c ¼ 1.07, CHCl3).
D
To a solution of (2R,3S,4aR,6S,7R,8aS)-2-(hydroxymethyl)-7-
methoxy-6-(methoxymethyl)-7-methyloctahydropyrano[3,2-b]py-
ran-3-ol (1.24 g, 4.49 mmol) in DMF (45 mL), imidazole (1.22 g,
17.9 mmol) and t-butyldimethylsilyl chloride (2.03 g, 13.5 mmol)
were added. After stirring at 50 ꢁC for 6 h, the reaction mixture was
allowed to cool to room temperature before diluting with ether
(100 mL). The organic layer was washed with aqueous hydrochloric
acid (1 M, 100 mL), aqueous sodium bicarbonate (saturated,
100 mL), and brine (100 mL). The organic layer was then dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure. Without purification, this crude material was then dis-
solved in dichloromethane/methanol (56 mL, 1:1) and cooled to
0 ꢁC. ( )-Camphorsulfonic acid was added, and the reaction
mixture was allowed to stir at 0 ꢁC for 1.5 h. At this point, TLC
indicated consumption of the bis-TBS-protected diol, and the
mixture was quenched with triethylamine and concentrated under
reduced pressure. The residue was purified by Biotage automated
chromatography (50 g Ultra silica gel, 10 / 80% ethyl acetate in
hexanes) to afford ((2R,3S,4aR,6S,7R,8aS)-3-((tert-butyldime-
thylsilyl)oxy)-7-methoxy-6-(methoxymethyl)-7-
To a solution of MOM ether 4 (371 mg, 1.22 mmol) in diethyl
ether (1.53 mL) at ꢀ78 ꢁC under argon, tert-butyllithium (2.84 mL,
0.95 M in pentanes) was added dropwise. After the addition was
complete, additional diethyl ether (1.5 mL) was added to aid in
stirring. After 30 min at ꢀ78 ꢁC, a solution of zinc bromide (1.55 mL,
0.87 M in diethyl ether) was added dropwise via syringe. The re-
action mixture was then transferred to a 0 ꢁC bath. After stirring at
this temperature for 1 h, a solution of aldehyde 5 (238 mg,
0.612 mmol) in toluene (6.1 mL) was added dropwise via cannula.
The reaction mixture was then allowed to stir overnight as the
cooling bath expired. The mixture was then quenched with
aqueous ammonium chloride (saturated, 25 mL). The aqueous layer
was extracted with ether (3 ꢃ 40 mL). The combined organic layers
were washed with brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
Biotage automated chromatography (25 g Ultra silica gel, 6 / 50%
ethyl acetate in hexanes) to afford the title compound (294 mg,
0.480 mmol, 78% yield, >20:1 dr) as a colorless oil. 1H NMR
(500 MHz, CDCl3)
d
5.44 (tdd, J ¼ 7.4, 1.4, 1.4 Hz, 1H), 5.35 (tdd,
methyloctahydropyrano[3,2-b]pyran-2-yl)methanol (1.55 g, 97% w/
w with ethyl acetate, 3.83 mmol, 85% yield over two steps) as a
J ¼ 7.0, 1.4, 1.3 Hz, 1H), 5.20 (tdd, J ¼ 7.0, 2.6, 1.1 Hz, 1H), 4.63 (s, 2H),
4.20 (d, J ¼ 9.7 Hz, 1H), 4.07 (d, J ¼ 6.9 Hz, 2H), 3.83 (ddd, J ¼ 10.8,
9.0, 4.9 Hz, 1H), 3.62 (dd, J ¼ 10.1, 1.6 Hz,1H), 3.50 (dd, J ¼ 8.5, 1.5 Hz,
1H), 3.38 (s, 3H), 3.37 (s, 3H), 3.33e3.38 (m, 2H), 3.23 (s, 3H), 3.17
(dd, J ¼ 9.0, 1.1 Hz, 1H), 3.05e3.01 (m, 2H), 2.78e2.74 (m, 2H), 2.72
(d, J ¼ 7.5 Hz, 2H), 2.48 (ddd, J ¼ 11.4, 4.1, 4.1 Hz, 1H), 2.18 (d,
colorless oil. 1H NMR (400 MHz, CDCl3)
d
3.84 (ddd, J ¼ 11.5, 6.4,
2.9 Hz, 1H), 3.66e3.57 (m, 3H), 3.50 (dd, J ¼ 8.5, 1.5 Hz, 1H), 3.39 (s,
3H), 3.40e3.33 (m, 1H), 3.24 (s, 3H), 3.26e3.21 (m, 1H), 3.12e3.01
(m, 2H), 2.45 (ddd, J ¼ 11.4, 4.2, 4.2 Hz, 1H), 2.24 (dd, J ¼ 11.5, 4.0 Hz,
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
synthesis, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.039

M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
9
J ¼ 9.8 Hz, 1H), 2.12 (dd, J ¼ 11.5, 3.6 Hz, 1H), 1.66 (d, J ¼ 1.3 Hz, 3H),
1.65 (d, J ¼ 1.2 Hz, 3H), 1.61 (d, J ¼ 1.3 Hz, 3H), 1.14 (s, 3H), 0.87 (s,
(100 mg) in a nitrogen-filled glovebox. After removing it from the
glovebox, the flask was charged with dichloromethane (1.63 mL)
9H), 0.10 (s, 3H), 0.08 (s, 3H). 13C NMR (126 MHz, CDCl3)
d
140.48,
and
L
-(þ)-diethyl tartrate (4.2
mL, 5.0 mg, 0.0245 mmol) under
136.85, 136.19, 122.86, 121.69, 120.19, 95.71, 82.76, 82.42, 76.69,
75.93, 74.06, 72.60, 71.50, 66.40, 63.88, 59.45, 55.34, 49.10, 40.28,
39.20, 38.07, 37.88, 25.88, 18.33, 18.05, 16.76, 16.42,
13.65, ꢀ4.01, ꢀ4.82. FT-IR (ATR, cmꢀ1): 2932, 2882, 1459, 1376,
1252,1088,1040, 872, 836, 776, 736. HRMS (ESI, m/z): calculated for
argon. The mixture was then cooled to ꢀ20 ꢁC before adding tita-
nium isopropoxide (5.8 mL, 5.6 mg, 0.0196 mmol). After stirring at
this temperature for 20 min, tert-butylhydroperoxide (59.3 mL,
5.5 M in decane, 0.326 mmol) was added dropwise. The reaction
mixture was then allowed to stir at ꢀ20 ꢁC overnight under argon
before transferring to a bath at 0 ꢁC. The mixture was then added
slowly to a solution of iron(II) sulfate heptahydrate (55 mg) and
tartaric acid (16 mg) in water (0.57 mL) at 0 ꢁC. After stirring at
room temperature for 15 min, the aqueous layer was extracted with
diethyl ether (4 ꢃ 5 mL). To the combined organic extracts, a solu-
tion of sodium hydroxide in brine (1.6 mL e made by dissolving
80 mg sodium chloride and 480 mg sodium hydroxide in 1.44 mL
water) was added. This suspension was allowed to stir vigorously at
room temperature for 1 h before separating the layers. The organic
layer was dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by Biotage
automated chromatography (10 g Ultra silica gel, 10 / 80% ethyl
acetate in hexanes) to afford (S)-((2R,3S,4aR,6S,7R,8aS)-3-((tert-
butyldimethylsilyl)oxy)-7-methoxy-6-(methoxymethyl)-7-
C
33H60NaO8Si
([MþNa]þ):
635.3955,
found:
635.3940.
20
[
a
]
¼ ꢀ1.22 (c ¼ 1.00, CHCl3).
D
4.11. (R,2E,5E,8E)-1-((2R,3S,4aR,6S,7R,8aS)-3-((tert-
butyldimethylsilyl)oxy)-7-methoxy-6-(methoxymethyl)-7-
methyloctahydropyrano[3,2-b]pyran-2-yl)-10-(methoxymethoxy)-
2,5,8-trimethyldeca-2,5,8-trien-1-ol (21)
To a solution of allylic alcohol 20 (147 mg, 0.240 mmol) in
dichloromethane (2.4 mL) at room temperature, sodium bicar-
bonate (101 mg, 1.20 mmol) was added, followed by DesseMartin
periodinane (203 mg, 0.480 mmol). After stirring for 1.5 h at room
temperature, the reaction mixture was quenched with a 1:1
mixture of saturated aqueous sodium bicarbonate and saturated
aqueous sodium thiosulfate (10 mL total). The biphasic mixture was
stirred vigorously at room temperature for 30 min before extraction
with dichloromethane (3 ꢃ 10 mL). The combined organic layers
were washed with aqueous sodium bicarbonate (saturated) and
brine, dried over sodium sulfate, filtered, and concentrated under
reduced pressure. Without purification, a suspension of this crude
material and cerium trichloride heptahydrate (894 mg, 2.40 mmol)
in methanol (4.8 mL) was cooled to ꢀ40 ꢁC before adding sodium
borohydride (45.4 mg, 1.20 mmol). After stirring at this tempera-
ture for 20 min, the reaction mixture was removed from the cooling
bath and allowed to warm to room temperature before quenching
with aqueous ammonium chloride (saturated, 25 mL). The aqueous
layer was extracted with ethyl acetate (3 ꢃ 40 mL). The combined
organic extracts were washed with brine, dried over sodium sul-
fate, filtered, and concentrated under reduced pressure. The residue
was purified by Biotage automated chromatography (25 g Ultra
silica gel, 7 / 55% ethyl acetate in hexanes) to afford the title
compound (112 mg, 0.183 mmol, 76% yield over two steps, >10:1
methyloctahydropyrano[3,2-b]pyran-2-yl)((2S,3S)-3-((2E,5E)-7-
(methoxymethoxy)-2,5-dimethylhepta-2,5-dien-1-yl)-2-
methyloxiran-2-yl)methanol (94.1 mg, 0.150 mmol, 92% yield,
>20:1 dr) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d 5.41e5.29
(m, 2H), 4.62 (s, 2H), 4.07 (d, J ¼ 7.0 Hz, 2H), 3.82 (ddd, J ¼ 10.8, 8.6,
4.5 Hz, 1H), 3.62 (dd, J ¼ 10.1, 1.5 Hz, 1H), 3.49 (dd, J ¼ 8.5, 1.5 Hz,
1H), 3.38 (s, 3H), 3.37 (s, 3H), 3.37e3.29 (m, 3H), 3.22 (s, 3H),
3.13e2.98 (m, 2H), 2.90 (dd, J ¼ 7.1, 4.8 Hz, 1H), 2.77e2.72 (m, 2H),
2.48 (dt, J ¼ 11.7, 4.2 Hz, 1H), 2.35 (dd, J ¼ 15.0, 4.9 Hz, 1H), 2.27 (dd,
J ¼ 11.5, 4.1 Hz, 1H), 2.21 (dd, J ¼ 14.9, 7.2 Hz, 1H), 1.70 (d, J ¼ 1.3 Hz,
3H), 1.67 (s, 3H), 1.65e1.53 (m, 3H), 1.34 (s, 3H), 1.16 (s, 3H), 0.87 (s,
9H), 0.12 (s, 3H), 0.11 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 140.23,
133.64, 123.67, 120.41, 95.70, 82.65, 82.20, 78.13, 76.45, 76.41, 74.01,
71.72, 71.47, 63.83, 60.42, 60.32, 59.46, 55.34, 49.16, 40.28, 39.53,
38.47, 38.09, 25.87, 18.24, 18.02, 16.74, 16.69, 12.89, ꢀ3.54, ꢀ4.72.
FT-IR (ATR, cmꢀ1): 2931, 2881, 2858, 1461, 1375, 1249, 1090, 1040,
956, 920, 870, 836, 776. HRMS (ESI, m/z): calculated for
C
33H60NaO9Si
([MþNa]þ):
651.3904,
found:
651.3900.
dr) as a colorless oil. 1H NMR (500 MHz, CDCl3)
d
5.41 (td, J ¼ 7.4,
[a
]
¼ ꢀ13.4 (c ¼ 1.03, CHCl3).
20
D
1.6 Hz, 1H), 5.35 (ddt, J ¼ 6.9, 5.5, 1.4 Hz, 1H), 5.20 (tdd, J ¼ 7.4, 1.4,
1.4 Hz, 1H), 4.63 (s, 2H), 4.14 (dd, J ¼ 6.4, 3.5 Hz, 1H), 4.07 (d,
J ¼ 7.0 Hz, 2H), 3.68 (ddd, J ¼ 10.8, 8.9, 4.6 Hz, 1H), 3.62 (dd, J ¼ 10.2,
1.5 Hz, 1H), 3.48 (dd, J ¼ 8.7, 1.5 Hz, 1H), 3.38 (s, 3H), 3.37 (s, 3H),
3.37e3.30 (m, 2H), 3.26 (dd, J ¼ 8.9, 6.3 Hz, 1H), 3.22 (s, 3H),
3.04e2.94 (m, 2H), 2.78e2.67 (m, 4H), 2.46 (dt, J ¼ 11.7, 4.2 Hz, 1H),
2.16 (dd, J ¼ 11.4, 4.1 Hz, 1H), 1.70e1.53 (m, 10H), 1.47 (t, J ¼ 11.3 Hz,
1H), 1.14 (s, 3H), 0.88 (s, 9H), 0.10 (s, 6H). 13C NMR (126 MHz, CDCl3)
To a mixture of (S)-((2R,3S,4aR,6S,7R,8aS)-3-((tert-butyldime-
thylsilyl)oxy)-7-methoxy-6-(methoxymethyl)-7-
methyloctahydropyrano[3,2-b]pyran-2-yl)((2S,3S)-3-((2E,5E)-7-
(methoxymethoxy)-2,5-dimethylhepta-2,5-dien-1-yl)-2-
methyloxiran-2-yl)methanol (117 mg, 0.186 mmol) in dimethoxy-
methane/acetonitrile (2:1, 16.8 mL) was added a 0.05 M solution of
sodium tetraborate decahydrate in 4 ꢃ 10ꢀ4 M aqueous Na2EDTA
(11.0 mL), tetra-n-butylammonium hydrogen sulfate (18.9 mg,
0.0558 mmol), and ketone 22 (96.1 mg, 0.372 mmol). This mixture
was cooled to 0 ꢁC with vigorous stirring. Dropwise via syringe
pump, a solution of Oxone® (915 mg, 1.49 mmol) in 4 ꢃ 10ꢀ4 M
aqueous Na2EDTA (9.3 mL) and a 0.89 M aqueous solution of po-
tassium carbonate (9.3 mL) were added simultaneously over
30 min. After the addition was complete, the reaction mixture was
allowed to stir at 0 ꢁC for 2.5 h. The mixture was then diluted with
water (50 mL), and the aqueous layer was extracted with ethyl
acetate (4 ꢃ 50 mL). The combined organic extracts were washed
with brine, dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by Biotage
automated chromatography (25 g Ultra silica gel, 15 /100% ethyl
acetate in hexanes with 2% triethylamine) to afford the title com-
pound (106 mg, 99% w/w with ethyl acetate, 0.159 mmol, 85% yield,
5:1 dr, major diastereomer/all minor diastereomers) as a colorless
d
140.46, 135.95, 135.56, 127.53, 121.95, 120.20, 95.70, 82.59, 82.51,
79.38, 76.70, 76.24, 73.99, 71.49, 63.86, 59.45, 55.33, 49.09, 40.23,
39.46, 38.07, 38.04, 25.91, 18.24, 18.03, 16.78, 16.29, 14.35,
12.06, ꢀ3.27, ꢀ4.70. FT-IR (ATR, cmꢀ1): 2932, 2883, 2858, 1462,
1374, 1250, 1089, 1038, 862, 835, 775. HRMS (ESI, m/z): calculated
for
C
33H60NaO8Si ([MþNa]þ): 635.3955, found: 635.3933.
20
[
a]
¼ ꢀ26.5 (c ¼ 0.833, CHCl3).
D
4.12. (S)-((2R,3S,4aR,6S,7R,8aS)-3-((tert-butyldimethylsilyl)oxy)-7-
methoxy-6-(methoxymethyl)-7-methyloctahydropyrano[3,2-b]
pyran-2-yl)((2S,3S)-3-(((2S,3S)-3-(((2S,3S)-3-((methoxymethoxy)
methyl)-2-methyloxiran-2-yl)methyl)-2-methyloxiran-2-yl)
methyl)-2-methyloxiran-2-yl)methanol (23)
An oven-dried flask with allylic alcohol 21 (100 mg, 0.163 mmol)
was charged with activated, powdered 4 Å molecular sieves
oil. 1H NMR (500 MHz, CDCl3)
d 4.73e4.63 (m, 2H), 3.89e3.77 (m,
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
synthesis, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.039

10
M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
1H), 3.74 (dd, J ¼ 11.4, 5.0 Hz, 1H), 3.67e3.59 (m, 2H), 3.49 (d,
J ¼ 8.5 Hz, 1H), 3.44e3.41 (m, 1H), 3.38 (s, 6H), 3.37e3.28 (m, 3H),
3.23 (s, 3H), 3.14e3.00 (m, 3H), 2.95 (dd, J ¼ 7.6, 4.5 Hz,1H), 2.48 (dt,
J ¼ 11.8, 4.3 Hz, 1H), 2.27 (dd, J ¼ 11.4, 4.2 Hz, 1H), 1.94e1.82 (m, 2H),
1.75e1.66 (m, 2H), 1.65e1.54 (m, 3H), 1.39 (s, 3H), 1.35 (s, 3H), 1.31
(s, 3H), 1.16 (s, 3H), 0.87 (s, 9H), 0.11 (s, 6H). 13C NMR (126 MHz,
2% triethylamine, then 0 / 10% methanol in ethyl acetate) to afford
the title compound (39.0 mg, 0.0612 mmol, 83% yield) as a colorless
oil. This compound was stored frozen in benzene at ꢀ20 ꢁC to avoid
decomposition. 1H NMR (500 MHz, CDCl3)
d 7.38e7.29 (m, 5H), 4.72
(d, J ¼ 11.3 Hz, 1H), 4.69e4.63 (m, 2H), 4.52 (d, J ¼ 11.3 Hz, 1H),
3.80e3.74 (m, 1H), 3.73 (dd, J ¼ 11.3, 4.8 Hz, 1H), 3.66e3.61 (m, 2H),
3.51e3.48 (m, 2H), 3.42e3.30 (m, 9H), 3.23 (s, 3H), 3.11e2.94 (m,
5H), 2.49 (ddd, J ¼ 11.7, 4.4, 4.4 Hz,1H), 2.26 (dd, J ¼ 11.5, 4.4 Hz,1H),
1.82e1.78 (m, 2H), 1.74e1.71 (m, 1H), 1.62e1.47 (m, 3H), 1.39 (s, 3H),
1.35 (s, 3H), 1.35 (s, 3H), 1.15 (s, 3H). 13C NMR (125 MHz, CDCl3)
CDCl3)
d 96.73, 82.64, 82.05, 78.27, 76.49, 76.37, 71.85, 71.45, 66.23,
61.30, 60.14, 59.76, 59.45, 59.20, 59.12, 57.84, 55.52, 49.17, 40.26,
39.48, 37.93, 37.44, 25.84, 18.26, 18.00, 17.31, 17.13,
12.73, ꢀ3.54, ꢀ4.77 (one ethereal carbon likely under solvent peak).
FT-IR (ATR, cmꢀ1): 2931, 2886, 2859, 1460, 1387, 1252, 1090, 1039,
955, 916, 862, 836, 777, 729. HRMS (ESI, m/z): calculated for
d
146.45, 137.25, 128.81, 128.38, 128.16, 109.90, 96.74, 84.61, 82.56,
80.98, 76.50, 76.24, 74.09, 73.36, 71.45, 68.61, 66.17, 61.30, 60.27,
59.44, 59.42, 59.14, 58.99, 58.44, 55.53, 49.14, 40.26, 37.66, 18.27,
17.21, 17.18, 13.84. FT-IR (ATR, cmꢀ1): 2923, 2854, 1456, 1377, 1208,
C
33H60NaO11Si
([MþNa]þ):
683.3803,
found:
683.3811.
20
[
a
]
¼ ꢀ17.0 (c ¼ 1.08, CHCl3).
D
1086, 1040, 955, 920, 868, 752, 699. HRMS (ESI, m/z): calculated for
20
4.13. (((2R,3S,4aR,6S,7R,8aS)-2-((S)-(benzyloxy)((2R,3S)-3-
(((2S,3S)-3-(((2S,3S)-3-((methoxymethoxy)methyl)-2-
methyloxiran-2-yl)methyl)-2-methyloxiran-2-yl)methyl)-2-
C
34H52NaO11 ([MþNa]þ): 659.3407, found: 659.3405. [
a
]
¼ ꢀ60.
D
(c ¼ 0.12, CHCl3).
methyloxiran-2-yl)methyl)-7-methoxy-6-(methoxymethyl)-7-
methyloctahydropyrano[3,2-b]pyran-3-yl)oxy)(tert-butyl)
dimethylsilane (24)
4.15. Procedure for cyclization with KHMDS
To a solution of alcohol 3 (1.0 mg, 0.00157 mmol) in THF (125 mL)
at ꢀ78 ꢁC under argon, a solution of potassium bis(trimethylsilyl)
To a solution of triepoxide 23 (105 mg, 0.159 mmol, 5:1 dr) in
benzyl bromide (1.08 mL) at room temperature, tetra-n-buty-
lammonium iodide (5.9 mg, 0.0159 mmol) was added. After stirring
at room temperature for 5 min, silver(I) oxide (368 mg, 1.59 mmol)
was added. The reaction mixture was allowed to stir at room
temperature for 4.5 h before filtering through a short plug of Celite,
eluting with diethyl ether. The filtrate was concentrated under
reduced pressure, and the residue was purified by Biotage auto-
mated chromatography (10 g Ultra silica gel,10 / 80% ethyl acetate
in hexanes) to afford the title compound (98.0 mg, 99% w/w with
ethyl acetate, 0.129 mmol, 81% yield, 5:1 dr, major/all other di-
astereomers) as a colorless oil. 1H NMR (500 MHz, CDCl3, undesired
amide (3.1 mg, 0.0157 mmol) in THF (30 mL) was added dropwise
via syringe. After stirring at ꢀ78 ꢁC for 5 min, the reaction mixture
was transferred to an ice/water bath. After stirring at 0 ꢁC for 8 h,
the reaction mixture was allowed to stir overnight as the cooling
bath expired. The mixture was then quenched with aqueous
ammonium chloride (saturated). The aqueous layer was extracted
with ethyl acetate (4ꢃ). The combined organic extracts were
washed with brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was dissolved in
benzene-d6 for analysis by 1H NMR spectroscopy. A 3:1 ratio of 25/
26 was observed.
diastereomer indicated by * where visible)
d
7.41e7.27 (m, 5H),
4.15.1. (2R,3R,4S,4aS,5aS,7R,8S,9aR,10aS)-4-(benzyloxy)-7-
methoxy-2-(((2S,3S)-3-(((2S,3S)-3-((methoxymethoxy)methyl)-2-
methyloxiran-2-yl)methyl)-2-methyloxiran-2-yl)methyl)-8-
(methoxymethyl)-3,7-dimethyldecahydro-2H-dipyrano[3,2-b:20,30-
e]pyran-3-ol (25)
4.71e4.64 (m, 2H), 4.61 (d, J ¼ 12.5 Hz, 1H), 4.54 (d, J ¼ 12.5 Hz, 1H),
3.91 (td, J ¼ 10.2, 4.9 Hz, 1H), 3.74 (dd, J ¼ 11.5, 4.9 Hz, 1H),
3.67e3.59 (m, 2H), 3.55e3.45 (m, 2H), 3.38 (s, 3H), 3.38 (s, 3H),
3.37e3.33 (m, 1H), 3.28e3.24 (m, 1H), 3.23 (s, 3H), 3.10e2.97 (m,
3H), 2.93 (dd, J ¼ 7.2, 4.9 Hz, 1H), 2.61 (dd, J ¼ 8.4, 3.1 Hz, 1H), 2.43
(ddd, J ¼ 11.6, 4.2, 4.2 Hz, 1H), 2.37 (dd, J ¼ 11.3, 3.9 Hz, 1H), 1.83 (dd,
J ¼ 14.5, 4.9 Hz, 1H), 1.77e1.69 (m, 2H), 1.60e1.40 (m, 4H), 1.39 (s,
3H), 1.38 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H), 0.85 (s, 9H*), 0.75 (s, 9H),
0.09 (s, 3H*), 0.07 (s, 3H*), 0.02 (s, 3H), ꢀ0.08 (s, 3H). 13C NMR
1H NMR (500 MHz, C6D6)
d 7.26e7.23 (m, 2H), 7.15e7.04 (m, 3H),
4.96 (d, J ¼ 11.6 Hz, 1H), 4.51 (s, 2H), 4.48 (d, J ¼ 11.6 Hz, 1H), 3.79 (d,
J ¼ 10.2 Hz, 1H), 3.71 (dd, J ¼ 10.7, 4.3 Hz, 1H), 3.69e3.59 (m, 4H),
3.49 (dd, J ¼ 11.4, 5.4 Hz, 1H), 3.35 (dd, J ¼ 10.3, 8.0 Hz, 1H), 3.21 (d,
J ¼ 0.7 Hz, 3H), 3.20 (d, J ¼ 0.9 Hz, 3H), 3.20e3.18 (m, 1H), 3.15 (dd,
J ¼ 10.1, 2.6 Hz, 1H), 3.03 (dd, J ¼ 5.5, 5.5 Hz, 1H), 2.94 (d, J ¼ 0.6 Hz,
3H), 2.91e2.79 (m, 3H), 2.59 (ddd, J ¼ 11.0, 4.0, 4.0 Hz, 1H), 2.14 (d,
J ¼ 14.7 Hz, 1H), 2.10 (dd, J ¼ 11.3, 3.9 Hz, 1H), 1.88 (dd, J ¼ 14.9,
9.7 Hz, 1H), 1.77 (dd, J ¼ 14.3, 5.6 Hz, 1H), 1.65 (dd, J ¼ 14.4, 6.9 Hz,
1H),1.56 (dd, J ¼ 11.3,11.2 Hz,1H),1.47 (dd, J ¼ 11.2,11.2 Hz,1H),1.25
(s, 3H), 1.20 (s, 3H), 1.13 (s, 3H), 1.01 (s, 3H). 13C NMR (126 MHz,
(126 MHz, CDCl3)
d 138.21, 128.72, 128.61, 128.09, 127.99, 96.75,
85.96, 82.48, 79.23, 76.62, 76.26, 74.10, 71.76, 71.56, 67.17, 66.21,
61.29, 60.05, 59.89, 59.41, 59.22, 59.10, 55.52, 49.10, 40.32, 39.83,
37.86, 25.87, 18.13, 17.92, 17.20, 17.03, 14.36, ꢀ3.97, ꢀ4.92. FT-IR
(ATR, cmꢀ1): 2930, 2884, 2858, 1456, 1375, 1329, 1250, 1088, 1043,
917, 870, 836, 776, 731, 698. HRMS (ESI, m/z): calculated for
C
40H66NaO11Si
([MþNa]þ):
773.4272,
found:
773.4257.
C6D6) d 138.90,128.78, 96.74, 83.50, 82.58, 80.29, 77.32, 77.21, 76.76,
20
[
a
]
¼ ꢀ25.5 (c ¼ 0.523, CHCl3).
75.08, 74.09, 71.86, 71.39, 70.56, 66.49, 60.90, 59.11, 58.94, 58.69,
58.69, 55.07, 48.64, 40.95, 37.78, 36.37, 35.75, 19.33, 19.27, 18.18,
17.30 (two aromatic carbons likely under solvent peaks). FT-IR
(ATR, cmꢀ1): 2924, 2854, 1458, 1377, 1333, 1211, 1101, 1039, 936,
D
4.14. (2S,3S,4aR,6S,7R,8aS)-2-((S)-(benzyloxy)((2R,3S)-3-(((2S,3S)-
3-(((2S,3S)-3-((methoxymethoxy)methyl)-2-methyloxiran-2-yl)
methyl)-2-methyloxiran-2-yl)methyl)-2-methyloxiran-2-yl)
methyl)-7-methoxy-6-(methoxymethyl)-7-methyloctahydropyrano
[3,2-b]pyran-3-ol (3)
920, 741, 698. HRMS (ESI, m/z): calculated for
C
34H52NaO11
20
([MþNa]þ): 659.3407, found: 659.3402. [
a]
¼ ꢀ10. (c ¼ 0.090,
D
CHCl3).
To a solution of benzyl ether 24 (55.7 mg, 0.0742 mmol) in THF
4.15.2. (2R,3R,4S,4aS,5aS,7R,8S,9aR,10aS)-4-(benzyloxy)-2-((S)-2-
hydroxy-2-((2R,5S)-5-((methoxymethoxy)methyl)-4-methyl-2,5-
dihydrofuran-2-yl)propyl)-7-methoxy-8-(methoxymethyl)-3,7-
dimethyldecahydro-2H-dipyrano[3,2-b:20,30-e]pyran-3-ol (26)
(750
(222
m
L) at room temperature, tetra-n-butylammonium fluoride
mL, 1 M in THF, 0.222 mmol) was added. After stirring at room
temperature for 2 h, the reaction mixture was then loaded directly
onto a column for purification by Biotage automated chromatog-
raphy (10 g Ultra silica gel, 20 / 100% ethyl acetate in hexanes with
1H NMR (500 MHz, C6D6)
d
7.30e7.22 (m, 3H), 7.18e7.05 (m, 2H),
5.78 (d, J ¼ 1.8 Hz, 1H), 4.98e4.94 (m, 2H), 4.73 (d, J ¼ 2.5 Hz, 1H),
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
synthesis, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.039

M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
11
4.55e4.50 (m, 2H), 4.45 (d, J ¼ 11.4 Hz,1H), 4.03 (dd, J ¼ 10.2, 2.5 Hz,
1H), 3.84e3.78 (m, 2H), 3.66e3.56 (m, 4H), 3.54 (dd, J ¼ 10.6,
4.3 Hz, 1H), 3.35 (dd, J ¼ 10.4, 7.9 Hz, 1H), 3.25 (s, 3H), 3.24e3.17 (m,
1H), 3.17 (s, 3H), 3.07 (dd, J ¼ 9.7, 2.3 Hz, 1H), 2.99e2.94 (m, 1H),
2.94 (s, 3H), 2.79 (ddd, J ¼ 11.6, 9.1, 4.3 Hz, 1H), 2.71 (ddd, J ¼ 11.3,
9.0, 3.9 Hz, 1H), 2.43 (dd, J ¼ 14.7, 2.4 Hz, 1H), 2.14 (ddd, J ¼ 11.0, 4.2,
4.2 Hz, 1H), 2.08 (dd, J ¼ 11.2, 4.1 Hz, 1H), 1.87 (dd, J ¼ 14.8, 10.3 Hz,
1H), 1.55 (s, 3H), 1.49e1.43 (m, 1H), 1.37 (m, 1H), 1.34 (s, 3H), 1.14 (s,
NSF Grants CHE-0946721 and CHE-0234877, respectively. NMR
spectroscopy was carried out on instruments purchased with the
assistance of NSF Grants CHE-9808061 and CHE-8915028.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.01.039.
3H), 1.00 (s, 3H). 13C NMR (125 MHz, C6D6)
d 138.89, 137.81, 128.81,
128.59, 128.35, 123.92, 96.91, 93.44, 87.99, 83.76, 82.82, 79.88,
78.04, 77.29, 77.08, 75.31, 74.95, 74.09, 71.80, 71.59, 70.79, 69.37,
59.06, 54.97, 48.63, 40.96, 37.30, 35.48, 21.74, 19.41, 18.12, 12.60. FT-
IR (ATR, cmꢀ1): 2924, 2855, 1731, 1671, 1456, 1377, 1334, 1209, 1085,
References
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1030, 955, 921, 741, 699. HRMS (ESI, m/z): calculated for
20
C
34H52NaO11 ([MþNa]þ): 659.3407, found: 659.3407. [
a]
¼ þ28
D
(c ¼ 0.14, CHCl3).
4.16. Procedure for cyclizations with NaHMDS and LiHMDS
To a solution of alcohol 3 (1.0 mg, 0.00157 mmol) in THF (130 mL)
at ꢀ78 ꢁC in a microwave vial under argon (with a rubber septum),
a solution of the appropriate base (0.0157 mmol) in THF (25 mL) was
added dropwise via syringe. After stirring at ꢀ78 ꢁC for 5 min, the
reaction mixture was removed from the cooling bath and was
allowed to warm to room temperature before replacing the septum
with a crimped cap (under positive pressure of argon). The reaction
mixture was then allowed to stir at 80 ꢁC for 13 h. After cooling to
room temperature, the reaction mixture was quenched with
aqueous ammonium chloride (saturated). The aqueous layer was
extracted with ethyl acetate (4ꢃ). The combined organic extracts
were washed with brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was dissolved in
benzene-d6 for analysis by 1H NMR spectroscopy. For NaHMDS, a
2:1 ratio of 25/26 was observed. For LiHMDS, a 9:1 ratio of 27/26
was observed.
7. Wan S, Gunaydin H, Houk KN, Floreancig PE.
7915e7923.
8. Armbrust KW, Beaver MG, Jamison TF. J Am Chem Soc. 2015;137:6941e6946.
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(b) Morten CJ, Jamison TF. Tetrahedron. 2009;65:6648e6655.
12. For the allylation of a trisubstituted electrophile with three alkyl substituents,
see: Placzek AT, Hougland JL, Gibbs RA Org Lett. 2012;14:4038e4041.
13. Wang G, Yin N, Negishi E-i. Chem Eur J. 2011;17:4118e4130.
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16. Buchanan GS, Cole KP, Li G, Tang Y, You L-F, Hsung RP. Tetrahedron. 2011;67:
10105e10118.
4.16.1. Tetrahydrofuran-tetrahydropyran pentad (27)
1H NMR (500 MHz, C6D6)
d 7.60e7.52 (m, 2H), 7.27e7.23 (m,
2H), 7.15e7.11 (m, 1H), 5.00 (d, J ¼ 11.8 Hz, 1H), 4.92 (d, J ¼ 11.8 Hz,
1H), 4.37 (s, 1H), 4.18 (dd, J ¼ 12.8, 4.4 Hz, 1H), 4.07 (dd, J ¼ 10.4,
2.2 Hz, 1H), 3.98e3.92 (m, 2H), 3.84 (d, J ¼ 2.8 Hz, 1H), 3.79 (dd,
J ¼ 10.3, 1.4 Hz, 1H), 3.69e3.60 (m, 2H), 3.46 (dd, J ¼ 10.4, 8.5 Hz,
1H), 3.38 (dd, J ¼ 10.3, 7.9 Hz, 1H), 3.27 (dd, J ¼ 9.8, 2.8 Hz, 1H), 3.18
(s, 3H), 3.06 (s, 3H), 3.01e2.95 (m, 2H), 2.94 (s, 3H), 2.91e2.82 (m,
1H), 2.55 (ddd, J ¼ 10.8, 3.8, 3.8 Hz, 1H), 2.33e2.25 (m, 2H), 2.14 (dd,
J ¼ 11.4, 3.5 Hz, 1H), 2.00 (dd, J ¼ 11.2, 6.2 Hz, 1H), 1.83 (dd, J ¼ 12.8,
10.6 Hz, 1H), 1.68e1.57 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H), 1.20 (s, 3H),
17. Accessed in ten steps from 2-deoxy-
D-ribose. See: Sasaki M, Tsukano C,
Tachibana K Org Lett. 2002;4:1747e1750.
18. Babinski D, Soltani O, Frantz DE. Org Lett. 2008;10:2901e2904.
19. Attempts to conduct the coupling reaction between the analogous alkyl halide
and vinyl boronate were unsuccessful.
20. Sasaki M, Fuwa H. Nat Prod Rep. 2008;25:401e426.
21. Pfenninger A. Synthesis. 1986:89e116.
22. Parker RE, Isaacs NS. Chem Rev. 1959;59:737e799.
23. (a) Nicolaou KC, Claremon DA, Barnette WE.
J Am Chem Soc. 1980;102:
6611e6612;
1.05 (s, 3H). 13C NMR (126 MHz, C6D6)
d 140.13, 128.38, 127.52,
(b) Sasaki M, Inoue M, Tachibana K. J Org Chem. 1994;59:715;
(c) Matsukura H, Morimoto M, Koshino H, Nakata T. Tetrahedron Lett. 1997;38:
5545e5548;
(d) Sasaki M, Inoue M, Takamatsu K, Tachibana K. J Org Chem. 1999;64:
9399e9415;
97.45, 83.49, 82.74, 81.63, 80.03, 79.93, 79.33, 77.95, 77.64, 77.60,
75.26, 74.63, 74.13, 74.02, 73.31, 71.90, 70.75, 58.89, 55.09, 48.66,
40.84, 40.56, 38.15, 36.15, 23.79, 21.42, 18.35, 16.33 (one aromatic
carbon likely under a solvent peak). FT-IR (ATR, cmꢀ1): 2925, 2855,
1456, 1377, 1096, 1083, 1027, 974, 736. HRMS (ESI, m/z): calculated
(e) Yadav JS, Raju A, Ravindar K, Reddy BVS. Tetrahedron Lett. 2013;54:
3227e3229.
24. The cascades described in ref. 6 utilize a weak base (Cs2CO3) and have not been
demonstrated with methyl-substituted epoxides.
for
C
34H52NaO11 ([MþNa]þ): 659.3407, found: 659.3398.
20
[
a]
¼ ꢀ1.1 (c ¼ 0.18, CHCl3).
25. Alternative bases such as Cs2CO3 in methanol, NaH in THF, and KOt-Bu in THF
provided inferior endo/exo ratios and/or intractable reaction mixtures.
Although we did not attempt this reaction under aqueous conditions, cycli-
zation of a similar epoxy alcohol in water proceeds with 5:1 endo/exo selec-
tivity. See ref. 11a.
D
Acknowledgments
26. Identical regioselectivity was observed when the same conditions were used
for the cyclization of an analog of 8 in which the primary alcohol was protected
as a methyl ether.
27. Hanson RM. Org React. 2002;60:1e47.
28. Fuwa H, Sasaki M, Tachibana K. Tetrahedron. 2001;57:3019e3033.
29. Shi Y. Acc Chem Res. 2004;37:488e496.
30. These conditions were necessary to avoid intramolecular silyl transfer. See:
Brummond KM, Hong S J Org Chem. 2005;70:907e916.
31. Crystallographic data (excluding structure factors) for the structures in this
We thank the NIGMS for financial support (GM72566 and a
fellowship to M.H.K. F32GM108181). We thank Dr. Adam Brown for
preliminary allylation studies and Drs. Satapanawat Sittihan, Eliz-
abeth Kelley, Tamara Halkina, and Evan Styduhar for helpful dis-
cussions (all MIT). We also thank Dr. Peter Müller (MIT) for X-ray
crystallography and Li Li (MIT) for obtaining mass spectra, which
were conducted on instruments purchased with the assistance of
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
synthesis, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.039

12
M.H. Katcher, T.F. Jamison / Tetrahedron xxx (2018) 1e12
paper have been deposited with the Cambridge Cambridge Crystallographic
34. (a) Byers JA, Jamison TF. J Am Chem Soc. 2009;131:6383e6385;
(b) Byers JA, Jamison TF. Proc Natl Acad Sci Unit States Am. 2013;110:
16724e16729.
35. When heated under aqueous conditions (H2O, 60 ºC, 7 d), 3 produced 25 and
other unidentified products.
Data Centre as CCDC 1478185. Copies of the Data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
þ44-(0)1223e336033 or e-mail: deposit@ccdc.cam.ac.uk).
32. See Supplementary Data.
33. The coupling constants for one of these protons were 11.2 and 6.2 Hz. For the
equatorial proton on the methylene carbon of ring G of 27, the coupling con-
stants were 11.4 and 3.5 Hz.
36. Fulmer GR, Miller AJM, Sherden NH, et al. Organometallics. 2010;29:
2176e2179.
Please cite this article in press as: Katcher MH, Jamison TF, Studies toward brevisulcenal F via convergent strategies for marine ladder polyether
synthesis, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.039