Gram scale synthesis of the C(1)-C(9) fragment of amphidinolide C

Article abstract of DOI:10.1016/j.tet.2013.07.026

An allylic cis-epoxide prepared by Sharpless asymmetric epoxidation was transformed in nine steps and 41% overall yield to the cyclization precursor 4 via a key one carbon homologation. Cobalt-catalyzed aerobic oxidative cyclization of 4 gave the trans-TH

Full text of DOI:10.1016/j.tet.2013.07.026

Tetrahedron 69 (2013) 8632e8644
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
Gram scale synthesis of the C(1)eC(9) fragment of amphidinolide C
*
Nicholas A. Morra, Brian L. Pagenkopf
The University of Western Ontario, Department of Chemistry, London, Ontario, N6A 5B7, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2013
Received in revised form 6 July 2013
Accepted 9 July 2013
Available online 16 July 2013
An allylic cis-epoxide prepared by Sharpless asymmetric epoxidation was transformed in nine steps and
41% overall yield to the cyclization precursor 4 via a key one carbon homologation. Cobalt-catalyzed
aerobic oxidative cyclization of 4 gave the trans-THF in 94% yield at gram scale. Subsequent manipula-
tions, including a StilleGennari olefination, Sharpless asymmetric dihydroxylation, CoreyeFuchs alky-
nylation, and Kazmaier hydrostannylation provided the fully functionalized C(1)eC(9) fragment 2
suitable for cross-coupling. The sequence is readily scalable and provides gram quantities of 2.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amphidinolide
Aerobic oxidation
Asymmetric dihydroxylation
Hydrostannylation
Natural products
1. Introduction
potent bioactivities of 5.8 and 4.6 ng/mL against murine
lymphoma and human epidermoid carcinoma cells, respectively.2
The amphidinolides are
a
structurally diverse family of
The synthesis of amphidinolide C has been approached by many
groups, resulting in the completion of several fragments, but no
total synthesis has been reported to date.3 The total synthesis of
amphidinolide F, which contains the same macrocyclic core but
a simpler side chain, has been reported by the groups of Carter
biologically active macrolides and linear polyketides isolated
from the symbiotic marine dinoflagellate Amphidinium sp. by
Kobayashi and co-workers.1 Amphidinolide C (1, Fig. 1) is one of
the most complex members featuring a 25-membered macro-
cycle, 2 trans-THF rings, and 12 stereocenters, and it displays
and Furstner.4 In particular, the C(1)eC(9) fragment has attracted
€
Fig. 1. Retrosynthesis of the C(1)eC(9) fragment.
considerable synthetic attention due to its significant stereo-
chemical complexity. It contains a methyl-substituted trans-
THF ring, an anti-diol, and an exocyclic olefin that is part of an
unusual diene system. An efficient and scalable synthesis of the
* Corresponding author. Tel.: þ1 519 661 2111; fax: þ1 519 661 3022; e-mail
address: bpagenko@uwo.ca (B.L. Pagenkopf).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.026

N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
8633
C(1)eC(9) fragment will be central for the total synthesis of
amphidinolide C.
The newly formed primary alcohol was protected as a silyl ether,
and the benzyl group was removed using reductive conditions to
expose alcohol 9 destined for one carbon homologation. Initially,
we had envisioned an umpolong nucleophilic homologation ap-
proach; thus the alcohol 9 was converted to the iodide 10. However,
the iodide failed to alkylate successfully using a variety of nucleo-
philes (2-Li-furan, NaCN, 2-Li-1,3-dithiane) and conditions (THF,
ether, HMPA), presumably due to steric hindrance around the pri-
mary iodide.
Given the failure of homologation via nucleophilic substitution,
attempts were made to lengthen the molecule by hydrolysis of
an enol ether prepared by a WittigeSchlosser olefination. Thus,
alcohol 9 was oxidized to the corresponding aldehyde under Par-
ikheDoering conditions, followed by reaction with the ylide pre-
pared in situ from 12 to form enol ether 13. Presumably, a simple
acid-mediated hydrolysis of the enol ether would lead to the ho-
mologated aldehyde 14, which could serve as a key intermediate
toward the C(1)eC(9) fragment. Unfortunately, despite a rigorous
screen of reagents and conditions (including mercury salts), suc-
cessful hydrolysis of the enol ether was not achieved. 1H NMR
analysis of the complex reaction mixtures suggested that cleavage
of the THF was a competitive decomposition pathway. To avoid the
problematic homologation with the THF intact, it was decided to
address the 1-carbon homologation prior to the formation of the
THF ring.
Our initial retrosynthetic disconnection of amphidinolide C in-
volved a macrolactonization and C(9)eC(10) Stille cross-coupling to
form the unique diene system (Fig. 1).5 This disconnection would
lead to a difunctionalized C(1)eC(9) intermediate (2) that would
allow for straightforward late stage fragment coupling. To access
the vinyl stannane, we envisioned functionalization of the THF al-
dehyde 3, which could be easily achieved via a cobalt-catalyzed
Mukaiyama oxidative cyclization of 4 employing our second gen-
eration catalyst, Co(nmp)2.6 We have previously reported the cy-
clization precursor, pentenol 4 that was made in four steps from
2,3-dihydrofuran.7 Alternatively, we considered oxidation of 5 fol-
lowed by a subsequent homologation. In this paper we describe an
alternative and more practical procedure to prepare 4 via the 1-
carbon homologation of 5 and the elaboration of 4 to 2.
2. Results and discussion
Our synthetic route began with a strategy to homologate sub-
sequent to the oxidative cyclization. The benzyl-protected epoxide
6, which was easily accessed in three steps from 2-butynol and
Sharpless epoxidation (Scheme 1), was converted to pentenol 7 by
opening with allyl magnesium bromide. The aerobic oxidative cy-
clization with Co(nmp)2 furnished THF alcohol 8 in quantitative
yield.6b It is worth noting that the yield was considerably lower
when employing the first generation catalysts, Co(modp)2 and
Co(piper)2.8
To this end, we began by opening the known Sharpless epoxide
15 (having been protected as the PMB ether) using allyl magnesium
bromide followed by conversion of the resulting alcohol into the
silyl ether (Scheme 2). Treatment of 16 with DDQ revealed the
Scheme 1. Failed homologation via nucleophilic substitution and enol ether hydrolysis.
Scheme 2. Successful homologation prior to THF ring formation.

8634
N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
primary alcohol, which was promptly oxidized to the correspond-
ing aldehyde (17) using IBX. This aldehyde was converted to the
enol ether using the previously optimized WittigeSchlosser con-
ditions, and, as anticipated, hydrolysis to the homologated alde-
hyde 18 proceeded smoothly using Hg(OAc)2 and Bu4NI.9
variable upon scale-up. The inconsistency rested in the cycli-
zation being complete within an hour (which we had not ob-
served before). After some optimization, a 94% yield of 26 on
multi-gram scale was obtained using 10% catalyst loading, and
a simple filtration as the only method of purification (entries
12 and 13).
To achieve the desired THF aldehyde intermediate envisioned
in our retrosynthesis (3), both 25 and 26 were oxidized to the
corresponding aldehydes (27 and 3) in good yield using the Par-
ikheDoering procedure, thus setting the stage for the final func-
tionalization of the C(1)eC(9) fragment (Scheme 3).
We had initially envisioned the use of Williams 1-alkoxyallene
(28) for a stereocontrolled allylation, which as reported was suc-
cessfully deployed with a variety of aldehydes including a TBS-
protected derivative of 3.10 Unfortunately, when we attempted to
apply the allylation reaction on 3, a 40:60 mixture diastereomers
was obtained along with significant destannylated product. The
initial report speculated that destannylation occurred via acid-
mediated protonolysis that could be avoided by ensuring basic
reaction conditions and work-up. In this regard, to simplify char-
acterization the reaction mixture was treated with a 1 N HCl/THF
solution for prolonged reaction times (1e4 h), but the tin moiety
persisted while the MOM group was removed, which suggests that
the destannylation mechanism is not due to a rapid proto-
destannylation.
Aldehyde 18 could be easily converted into the methyl ester
derivative 19, which is the oxidation state found in the natural
product, by Pinnick oxidation and methylation, followed by acidic
TBS removal to give pentenol 20. To converge with a previously
reported route,7 aldehyde 18 was reduced using DIBAL-H and the
corresponding alcohol was protected as the PMB ether (21).
Treatment of 21 with acidic methanol removed the TBS group in
95% yield, giving the known PMB protected pentenol 4.7 Compared
with our previously reported route,7 this process is longer (nine vs
four steps) and lower yielding (41% vs 52%). However, it benefits
from the use of inexpensive reagents, is easily scalable and suc-
cessfully provides the multi-gram quantities of 20 and 4 that were
required.
With a cost effective and scalable route to pentenols 20 and 4
secured, attention was given to the oxidative cyclization to form the
trans-THF ring 25 and 26 (Table 1). Initial cyclizations using the
methyl ester pentenol 20 and Co(modp)2 (23) were unsuccessful
(entry 1), and reactions using Co(nmp)2 resulted in complex re-
action mixtures (entry 2). Pre-activation of the catalyst (entry 3), as
well as lowering both the reaction temperature and catalyst loading
led to improved yields (entries 4e6), with the optimal conditions of
10% catalyst loading at 30 ꢀC resulting in an 88% yield of 25.
It was suggested that the E/Z ratio of 1-alkoxyallene 28 controls
the syn/anti selectivity of the alkylation;10 however it has been
Table 1
Oxidative cyclization of 20 and 4 using Co(modp)2 and Co(nmp)2
Entry
Starting material
Catalyst
Loading (mol %)
Temp (ꢀC)
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
20
20
20
20
20
20
4
4
4
4
4
Co(modp)2 (23)
Co(nmp)2 (24)
Co(nmp)2 (24)
Co(nmp)2 (24)
Co(nmp)2 (24)
Co(nmp)2 (24)
Co(modp)2 (23)
Co(nmp)2 (24)
Co(nmp)2 (24)
Co(nmp)2 (24)
Co(nmp)2 (24)
Co(nmp)2 (24)
Co(nmp)2 (24)
15
15
55
55
55
40
30
22
55
55
45
35
22
55
55
16
16
16
16
16
24
16
16
16
16
16
1
25
25
25
25
25
25
26
26
26
26
26
26
26
0
30
74
80
15b
12b
10b
10b
15
88
33 (90a)
0
15
15
10
55
81
9
10
11
12
13
15b
15b
15b
10b
67 (85a)
91
4
4
1
9274c
a
Yields based on recovered starting material.
Catalyst was pre-activated.
Reaction performed on a 15 mmol scale.
b
c
As shown previously, the first generation catalyst Co(modp)2
reported in the pioneering work of Mitchell that 1-alkoxyallene
(28) isomerizes under the BF3$OEt2 reaction conditions employed
by Williams.11 Moreover, it was found that using either pure trans-
28 or a 60:40 trans/cis mixture gave identical results (a 60:40
mixture of products) using a variety of aldehydes, including
hexanal.
(23) was incompatible with the PMB protecting group,6b and its
use gave a complex mixture of products (entry 7). The use of
pre-activated Co(nmp)2, lowering both the reaction tempera-
ture and catalyst loading improved the reaction yield (entries
8e11), but the yields were found to be uncharacteristically

N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
8635
Scheme 3. Three unsuccessful approaches to functionalize the THF aldehydes 3 and 27.
While work on the Williams allylation procedure was ongoing,
the allylation/hydroboration procedure using 30 reported by Roush
was explored as an alternative.12 Unfortunately, initial attempts at
reproducing the allylation conditions using 27 or 30 were un-
successful, resulting in complex reaction mixtures. Met with early
complications, this route was quickly abandoned, mostly due to the
product not containing the desired vinyl-stannane moiety required
for Stille cross-coupling.
subjected to either Sharpless asymmetric dihydroxylation (34) or
Shi epoxidation (35) conditions only starting material was
recovered in all cases.
Eneeyne 33 appeared to be an ideal substrate for accessing the
target 2 due to the potential conversion of the alkyne to the desired
stannyl-alkene. However, with the failure of 3 to undergo dihy-
droxylation or epoxidation a more activated cis olefin was explored.
Thus, cis a,b-unsaturated ester 36 was prepared with 14:1 cis/trans
A third attempt at functionalizing THF aldehyde 3 for coupling
started with a PetersoneYamamoto olefination using 32 to give 33
in a 70% yield as an 11:1 ratio of the desired cis to trans di-
astereomer.13 It was speculated that the diol could be installed by
either dihydroxylation or an epoxidation, ring opening, and in-
version sequence. Unfortunately, when the eneeyne 33 was
selectivity by treatment of aldehyde 3 with the StilleGennari
phosphonate (Scheme 4). The activated olefin was successfully
dihydroxylated via Sharpless asymmetric dihydroxylation to give
a diol as a 5:1 ratio of diastereomers, which was protected as the
acetonide. Note that 37 contains the entire carbon framework and
stereocenters of the C(1)eC(9) portion of amphidinolide C.
Scheme 4. Completion of the C(1)eC(9) fragment of amphidinolide C.

8636
N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
To fully functionalize 37 for fragment coupling, the ester was
with an International Clinical Centrifuge model CL at approximately
8000 rpm for 10 min (International Equipment Company, USA).
The 1H and 13C NMR spectra were obtained on 400 or 600 MHz
spectrometers. All spectra were obtained in deuterated chloroform
converted to the terminal alkyne (39) in a four-step procedure.
Reduction of the ester using DIBAL-H, followed by oxidation to al-
dehyde 38 in 85% yield over two steps, and CoreyeFuchs reaction
furnished alkyne 39 in 85% yield. The PMB protecting group was
cleaved with DDQ 39 to reveal alcohol 40 in 86% yield, which was
oxidized to the acid and quantitatively methylated to give methyl
ester 41. A related compound has been previously shown3c to un-
dergo regioselective Kazmaier14 hydro-stannylation with Coville’s
catalyst (42),15 and indeed we found that the procedure proceeded
smoothly to furnish the C(1)eC(9) fragment 2 in 77%.
and were referenced to residual chloroform at
d
7.25 ppm for 1H
spectra and the center peak of the triplet at
d
77.0 (t) for 13C spectra.
When peak multiplicities are given, the following abbreviations are
used: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of
doublet of doublets; t, triplet; q, quartet; m, multiplet; br, broad; a,
apparent. EI mass spectra were obtained on a Finnigan MAT 8200.
To ensure the correct stereochemistry at the C(7)eC(8) diol,
a small amount of acetonide 41 was converted to the known bis-
silylated species (44, Scheme 5). To that end, 41 was subjected to
PPTS to remove the acetonide, followed by treatment of diol 43
with 2 equiv of TBSCl to form 44 in 94% yield over two steps. The
spectral data of 44 matched the reported spectra exactly, con-
firming the structural assignment.3c
5. Experimental section
5.1. General
5.1.1. ((2S,3R)-3-Methyloxiran-2-yl)methanol (6a).
ꢀ
To a 500 mL round bottom flask containing 200 g of activated 4 A
molecular sieves was added CH2Cl2 (250 mL), and the flask was
placedina ꢁ20ꢀC coolingbath. (þ)-Diethyl tartrate(1.73 g, 8.4 mmol,
0.06 equiv) was added, followed by Ti(OiPr)4 (2.05 mL, 7 mmol,
0.05 equiv), and cis-butenol (10 g, 140 mmol, 1 equiv). After 1 h,
tBuOOH(5.33 M,52.5mL, 280mmol,2equiv)wasaddedportionwise
over 30 min. After 24 h the septumwas removed and dimethylsulfide
(20.7 mL, 280 mmol, 2 equiv) was added. The reaction mixture was
stirred open to atmosphere for another 24 h before being filtered
through a thin pad of packed Celite, and washed with CH2Cl2
(500 mL). Solvent was removed under reduced pressure and the
crude oil purified by flash chromatography (100% hexanes, 1 L, fol-
lowed by 70% EtOAc/Hex) to give pure epoxide (6a) (9.47 g,
107.8 mmol, 77% yield) as a yellow oil. Spectral data match literature
Scheme 5. Conversion of 41 to 44 for stereochemical confirmation.
3. Conclusions
In summary, we have reported an inexpensive and scalable
procedure to form pentenol 4 (nine steps, 41% yield) to comple-
ment our previously reported method (four steps, 52% yield).
This compound was elaborated into methyl ester derivative 25, and
the versatility of the second generation Co(nmp)2 has been dem-
onstrated in the cyclization of both substrates (4 and 20) in excel-
lent yield. The THF alcohol 26 was then elaborated to the
fully functionalized C(1)eC(9) fragment 2 using a StilleGennari
modified HWE reaction, Sharpless asymmetric dihydroxylation,
CoreyeFuchs alkynylation, and Kazmaier regioselective hydro-
values, [
a
]
20 ꢁ4.28(c1.0, CHCl3);literature[
a]
D
20 ꢁ4.26(c1.0, CHCl3).19
D
5.1.2. (2S,3R)-2-(Benzyloxymethyl)-3-methyloxirane (6).
ToasuspensionofNaH(24mg,10mmol,1.0equiv)inDMF(10mL)
at 0 ꢀC was added BnBr (1.71 g, 10 mmol, 1.0 equiv), followed by
epoxide (880 mg, 10 mmol, 1.0 equiv). The ice bath was removed
and after ca. 16 h the reaction mixture was poured into a half-satu-
rated solution NH4Cl (50 mL) in water ice (50 mL) and stirred for
5 min, after which the aqueous layer was extracted with EtOAc
(50 mLꢂ3). The combined organic layers were washed with brine,
dried over MgSO4, and filtered through a thin pad of packed Celite.
Solvent was removed under reduced pressure and the crude oil was
purified by flash chromatography (30% EtOAc/Hex) to yield the
benzyl ether (6) as a colorless oil (1.61 g, 9.07 mmol, 90.7%). Rf 0.15
stannylation. Further deployment of
2 for progress toward
amphidinolide C is underway and will be reported in due time.
4. General details
All reactions were run under an argon atmosphere unless oth-
erwise indicated. Reaction mixtures were stirred with a magnetic
stir bar. Flasks were oven dried and cooled in a desiccator or flame
dried under high vacuum (1 mmHg) prior to use unless water was
used in the reaction. Solvents and reagents were purified by stan-
dard methods.16 Dichloromethane, diethyl ether, and tetrahydro-
furan (THF) were purified by passing the solvents through activated
(10%EtOAc/Hex);1HNMR(400 MHz, CDCl3)
d7.36e7.27 (m, 5H), 4.63
(d, J¼11.7, 1H), 4.53 (d, J¼11.7 Hz, 1H), 3.70e3.66 (m, 1H), 3.58e3.54
(m, 1H), 3.19e3.15 (m, 1H), 3.12e3.07 (m, 1H), 1.26 (d, J¼5.7 Hz, 3H).
13C NMR (100 MHz, CDCl3)
d 137.9, 128.4, 127.8, 73.3, 68.1, 55.1,
ꢀ
alumina columns and further dried over 4 A molecular sieves. i-
51.8, 13.3. HRMS m/z 178.0999 (calcd for C11H14O2, 178.2270).
Propanol (99.5%, 0.2% H2O) was used as received from Caledon
Laboratory Chemicals. All other chemicals were of reagent quality
and used as obtained from commercial sources unless otherwise
noted. The progress of reactions was monitored by thin layer
chromatography (TLC) performed on F254 silica gel plates. The
plates were visualized by staining with ceric ammonium molyb-
date (CAM)17 or p-anisaldehyde. Column chromatography was
5.1.3. (2R,3R)-1-(Benzyloxy)-3-methylhex-5-en-2-ol (7).
ꢀ
performed with Silica Flash P60 60 A silica gel from Silicycle
To a freshly prepared solution of allyl magnesium bromide
(1.0 M in ether, 9 mL, 9 mmol, 1.5 equiv) was added to a flask
according to the Still method.18 Centrifugations were conducted

N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
8637
charged with CuI (112 mg, 0.58 mmol, 0.1 equiv) cooled to
ꢁ78 ꢀC. The cuperate was stirred for 30 min at ꢁ78 ꢀC before
epoxide 6 (1.04 g, 5.89 mmol, 1.0 equiv) was added neat. The
cooling bath was packed with dry ice and the reaction mixture
was allowed to warm to rt overnight (ca. 16 h). The reaction
mixture was carefully poured into a half-saturated solution NH4Cl
(20 mL) in water ice (40 mL) and stirred for 30 min, after which
time the aqueous layer was extracted with EtOAc (30 mLꢂ3). The
combined organic layers were washed with brine, dried over
MgSO4, and filtered through a thin pad of packed Celite. Solvent
was removed under reduced pressure and the crude oil was pu-
rified by flash chromatography (20% EtOAc/Hex) to yield the
major diastereomer 7 (827 mg, 3.76 mmol, 64%) as a yellow oil
and the minor diastereomer (194 mg, 0.88 mmol, 15%) as a yellow
oil. Rf 0.61 (40% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
overnight (ca. 16 h) before being poured into a half-saturated
solution of NH4Cl (200 mL), and the aqueous layer was extracted
with CH2Cl2 (3ꢂ200 mL) and the combined organic layers were
washed with brine (200 mL) and dried over MgSO4. Solvent was
removed under reduced pressure to give the TBS alcohol, which
was used without further purification. An empty 250 mL round
bottom flask equipped with a septa with a syringe in it, and
a needle attached to a tank of gaseous ammonia was cooled to
ꢁ78 ꢀC. The ammonia tank was opened to allow a slow but steady
stream of ammonia until approximately 50 mL had condensed in
the flask. To the flask containing the liquid ammonia was slowly
added THF (50 mL) and a large chunk of sodium. The reaction
mixture was stirred at ꢁ78 ꢀC for 40 min, by which time the
sodium dissolved and the solution turned blue. The TBS alcohol in
THF (20 mL) was added dropwise over 10 min, and the reaction
mixture was stirred for an additional 30 min. The cooling bath
was removed, the flask was allowed to warm to room tempera-
ture, and stirred for 30 min to allow evaporation of the ammonia.
The reaction mixture was then poured into a solution of half-
saturated NH4Cl (200 mL) and the aqueous layer was extracted
with EtOAc (3ꢂ100 mL). The combined organic layers are dried
over MgSO4, filtered through a pad of Celite and concentrated to
dryness under vacuum. The crude material was purified by col-
umn chromatography to give the product alcohol (9) as a yellow
oil (1.20 g, 4.62 mmol, 70% yield over two steps). Rf 0.42 (50%
d
7.38e7.26 (m, 5H), 5.84e5.73 (m, 1H), 5.05e4.98 (m, 1H), 4.55
(s, 2H), 3.63e3.56 (m, 2H), 3.40 (t, J¼9.0 Hz, 1H), 2.42 (s, 1H),
2.38e2.31 (m, 1H), 1.99e1.91 (m, 1H), 1.73e1.64 (m, 1H), 0.85 (d,
J¼7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 138.0, 137.0, 128.4,
127.8, 127.7, 116.2, 73.8, 72.5, 37.0, 35.8, 15.2. HRMS m/z 220.1459
(calcd for C14H20O2, 220.31).
5.1.4. ((2R,4R,5R)-5-(Benzyloxymethyl)-4-methyltetrahydrofuran-2-
yl)methanol (8).
EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
d 4.06e4.02 (m, 1H), 3.74
(dd, J¼11.3, 2.3 Hz, 1H), 3.62 (d, J¼4.7 Hz, 2H), 3.54e3.49 (m, 2H),
2.15e2.09 (m, 2H), 1.46e1.41 (m, 1H), 1.02 (d, J¼6.4 Hz, 3H), 0.89
(s, 9H), 0.05 (6H). 13C NMR (100 MHz, CDCl3)
d 85.9, 79.3, 66.0,
The cyclization precursor 7 (200 mg, 0.91 mmol, 1.0 equiv)
was added as a solution in 10 mL iPrOH to a flask charged with
Co(nmp)2 (24) (85 mg, 0.15 mmol, 0.15 equiv) under 1 atm of O2
(via balloon). At room temperature, tert-butyl hydrogen perox-
ide (5.33 M in isooctane, 0.2 mL, 1.0 mmol, 1.1 equiv) was added
in one portion, and the resulting solution was heated at 55 ꢀC
for 16 h. The flask was then cooled to room temperature, purged
with argon, and methyl iodide (0.62 mL, 1.0 mmol, 1.1 equiv)
was added to the reaction mixture at room temperature and
stirred for 24 h. The solution was concentrated under reduced
pressure (0.1 mmHg) to remove all traces of iPrOH, and the
residue was dissolved in water (10 mL) and CH2Cl2 (20 mL).
The heterogeneous mixture was separated and the aqueous
layer was extracted with CH2Cl2 (4ꢂ10 mL). The combined or-
ganic layers were washed with brine, dried (MgSO4), filtered
through a thin pad of silica on top of a thin pad of Celite and
concentrated under reduced pressure to yield 8 as a yellow oil
(145 mg, 0.61 mmol, 67%), which was used without further
purification. Rf 0.23 (70% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
62.9, 37.4, 34.8, 25.9, 18.4, 16.4, ꢁ5.3. HRMS m/z 261.1877 (calcd
for C13H28O2Si, 260.45).
5 . 1. 6 . t e r t - B u t y l ( ( ( 2 R , 4 R , 5 R ) - 5 - ( i o d o m e t h y l ) - 4 -
methyltetrahydrofuran-2-yl)methoxy) dimethylsilane (10).
To a flask charged with alcohol 9 (250 mg, 0.96 mmol,
1.0 equiv), triethylamine (0.3 mL, 1.92 mmol, 2.0 equiv), diluted
with CH2Cl2 (10 mL) and cooled to 0 ꢀC was added meth-
anesulfonyl chloride (0.081 mL, 1.05 mmol, 1.1 equiv) dropwise.
The reaction mixture was allowed to stir at rt for 30 min before
being poured into a half-saturated solution of ammonium chlo-
ride (10 mL) and diluted with CH2Cl2 (50 mL). The aqueous
layer was extracted with CH2Cl2 (3ꢂ50 mL) and the combined
organic layers were washed with brine, dried with MgSO4, and
filtered through a thin pad of Celite. Solvent was removed under
reduced pressure to afford the mesylate as a yellow oil (325 mg,
0.96 mmol, 100%), which was used without further purification.
To a flask charged with the mesylate (325 mg, 0.96 mmol,
1 equiv) in wet acetone (10 mL) equipped with a reflux condenser
was added NaI (720 mg, 4.8 mmol, 5.0 equiv). The reaction
mixture was heated to vigorous reflux and allowed to stir over-
night (ca. 16 h) before being cooled to 0 ꢀC and filtered through
a thin pad of silica over Celite. Solvent was removed under re-
duced pressure to afford a yellow oil, which was purified by
column chromatography (10% EtOAc/Hex) to afford 10 (287 mg,
0.78 mmol, 81%) as a yellow oil. Rf 0.47 (10% EtOAc/Hex); 1H NMR
d
7.35e7.25 (m, 5H), 4.58 (s, 2H), 4.13e4.05 (m, 1H), 3.70e3.65
(m, 2H), 3.56 (dd, J¼7.3, 3.0 Hz, 1H), 23.52e3.46 (m, 2H),
2.10e2.03 (m, 2H), 1.46e1.40 (m, 1H), 1.03 (d, J¼7.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3)
d 138.2, 128.3, 127.6, 127.6, 84.7, 79.2,
73.4, 71.7, 64.8, 36.5, 36.3, 16.8. HRMS m/z 236.1411 (calcd for
C14H20O3, 236.31).
5.1.5. ((2R,3R,5R)-5-((tert-Butyldimethylsilyloxy)methyl)-3-
methyltetrahydrofuran-2-yl)methanol (9).
(400 MHz, CDCl3)
d 4.12e4.08 (m, 1H), 3.66e3.62 (m, 2H), 3.39
(dd, J¼11.3, 2.3 Hz, 1H), 3.34 (dt, J¼10.3, 2.5 Hz, 1H), 3.22 (dd,
J¼6.4, 4.5 Hz, 1H), 2.20e2.16 (m, 1H), 2.06e2.00 (m, 1H),
1.61e1.55 (m, 1H), 1.05 (d, J¼7.0 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H).
To a solution of alcohol (8) (1.56 mg, 6.6 mmol, 1 equiv) in
CH2Cl2 (100 mL) was added imidazole (830 mg, 12.3 mmol,
2 equiv), followed by TBSCl (994 mg, 6.6 mmol, 1 equiv) and
DMAP (5 mg, catalytic). The reaction mixture was stirred
13C NMR (100 MHz, CDCl3)
d 84.0, 79.0, 65.7, 40.4, 37.3, 26.0, 18.4,
17.0, 10.1, ꢁ5.2.

8638
N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
5.1.7. (2R,3R,5R)-5-((tert-Butyldimethylsilyloxy)methyl)-3-
methyltetrahydrofuran-2-carbaldehyde (10a).
analysis. The reaction mixture was poured into a solution of
saturated NH4Cl (200 mL) in water ice (500 mL) and stirred for
10 min, after which the aqueous layer was extracted with EtOAc
(300 mLꢂ3). The combined organic layers were washed with brine,
dried over MgSO4, and filtered through a thin pad of packed Celite.
Solvent was removed under reduced pressure and the crude oil was
purified by flash chromatography (20% EtOAc/Hex) to yield 15
(15.6 g, 74.8 mmol, 86%) as a yellow oil. Rf 0.40 (30% EtOAc/Hex); 1H
A 50 mL round bottom flask containing oxalyl chloride (0.20 mL,
2.4 mmol, 1.2 equiv) in 15 mL of CH2Cl2 was cooled to ꢁ78 ꢀC and
DMSO (0.34 mL, 4.8 mmol, 2.4 equiv) in 5 mL CH2Cl2 was added
slowly portion wise over 20 min. After stirring for 45 min, alcohol
10 (285 mg, 1.09 mmol, 1 equiv) was added in 5 mL CH2Cl2 over
5 min slowly dropwise. After stirring for 1.5 h at ꢁ78 ꢀC, triethyl-
amine (1 mL, 10 mmol, 5 equiv) was added portion wise over 5 min.
After stirring for 15 min the dry ice/acetone bath was replaced with
a water ice/ice bath and the reaction mixture was allowed to warm
to 0 ꢀC, and stirred for 15 min. The reaction mixture was poured
into 10% HCl (50 mL), extracted with CH2Cl2 (3ꢂ50 mL), and the
combined organic layers were washed with saturated sodium bi-
carbonate (50 mL), brine (50 mL), and dried over MgSO4. Excess
solvent was removed under reduced pressure, giving 10a (282 mg,
1.09 mmol, 99% yield), which was used without further purification.
NMR (CDCl3, 600 MHz):
d
7.27 (d, J¼8.7 Hz, 2H), 6.87 (d, J¼8.7 Hz,
2H), 4.51 (ABd, J¼11.7 Hz, 2H), 3.79 (s, 3H), 3.63 (dd, J¼10.5, 4.7 Hz,
1H), 3.53 (dd, J¼11.3, 6.4 Hz, 1H), 3.14 (dt, J¼6.2, 4.2 Hz, 1H), 3.08
(pent, J¼5.1 Hz, 1H), 1.25 (d, J¼5.9 Hz, 3H). 13C NMR (150 MHz,
CDCl3)
d 159.2, 129.9, 129.4, 113.9, 72.9, 67.7, 55.2, 55.0, 51.7, 13.3.
HRMS m/z 208.1099 (calcd for C12H16O3, 208.1099).
5.1.10. (2R,3R)-1-(4-Methoxybenzyloxy)-3-methylhex-5-en-2-ol
(15a).
Rf 0.69 (50% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
d 9.62 (s, 1H),
To a freshly prepared solution of allyl magnesium bromide
(1.0 M in ether, 90 mL, 90 mmol, 1.5 equiv) was added to a flask
charged with CuI (1.12 g, 5.88 mmol, 0.1 equiv) cooled to ꢁ78 ꢀC.
The cuperate was stirred for 30 min at ꢁ78 ꢀC before epoxide 15
(12.26 g, 58.9 mmol, 1 equiv) was added neat. The cooling bath was
packed with dry ice and the reaction mixture was allowed to warm
to rt overnight (ca. 16 h). The reaction mixture was carefully poured
into a half-saturated solution NH4Cl (200 mL) in water ice (400 mL)
and stirred for 30 min, after which the aqueous layer was extracted
with EtOAc (300 mLꢂ3). The combined organic layers were washed
with brine, dried over MgSO4, and filtered through a thin pad of
packed Celite. Solvent was removed under reduced pressure and
the crude oil was purified by flash chromatography (20% EtOAc/
Hex) to yield the major diastereomer 15a (12.06 g, 48.2 mmol, 85%)
as a yellow oil and the minor diastereomer (1.34 g, 5.36 mmol, 9%)
as a yellow oil. Rf 0.28 (20% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
4.18 (td, J¼9.9, 4.1 Hz, 1H), 3.75 (dd, J¼9.3, 2.9 Hz, 1H), 3.72 (dd,
J¼11.3, 4.1 Hz, 1H), 3.65 (dd, J¼11.3, 4.1 Hz, 1H), 2.31e2.24 (m, 1H),
2.18e2.14 (m, 1H), 1.57e1.52 (m, 1H) 1.14 (d, J¼7.0 Hz, 3H), 0.89 (s,
9H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3)
d 202.4, 138.0, 88.9,
81.3, 65.3, 36.9, 36.5, 25.9, 16.3, ꢁ5.4.
5.1.8. tert-Butyl(((2R,4R,5R)-5-((E)-2-methoxyvinyl)-4-
methyltetrahydrofuran-2-yl)methoxy)dimethylsilane (13).
To a solution of tBuOK (134 mg, 1.2 mmol, 1.3 equiv) in THF
(3 mL) was added Ph3PCH2OMeCl (479 mg, 1.4 mmol, 1.5 equiv) in
one portion, and the red solution was stirred at rt for 1 h. To the red
solution was added crude aldehyde (10a) (235 mg, 0.9 mmol,
1 equiv) in a minimal amount of THF (ca. 2 mL). After 1 h the crude
reaction mixture was poured into a rapidly stirring solution of half-
saturated NH4Cl (30 mL), and the aqueous layer was extracted with
CH2Cl2 (3ꢂ20 mL) and the combined organic layers were washed
with brine, dried over MgSO4 and filtered through a thin pad of
packed Celite/silica. Solvent was removed under reduced pressure
to give the crude enol ether (13) (192 mg, 0.67 mmol, 75%) used in
the next reaction without further purification. Rf 0.28 (10% EtOAc/
d
7.25 (d, J¼9.0 Hz, 2H), 6.88 (d, J¼9.0 Hz, 2H), 5.77 (dddd, J¼16.9,
10.2, 7.8, 6.4 Hz, 1H), 5.03e4.99 (m, 2H), 4.48 (d, J¼1.6 Hz, 2H), 3.79
(s, 3H), 3.56e3.53 (m, 1H), 3.39e3.35 (m, 1H), 2.42 (br s, 1H),
2.37e2.31 (m, 1H), 1.98e1.89 (m, 1H), 1.73e1.63 (m, 1H), 0.85 (d,
J¼6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 159.2, 137.0, 130.0, 129.2,
116.0,113.7, 73.6, 72.9, 72.1, 55.1, 36.9, 35.7, 15.1. HRMS m/z 250.1572
(calcd for C15H22O3, 250.1569).
5.1.11. tert-Butyl((2R,3R)-1-(4-methoxybenzyloxy)-3-methylhex-5-
en-2-yloxy)dimethylsilane (16).
Hex); 1H NMR (CDCl3, 400 MHz):
d
6.52 (d, J¼12.9 Hz, 0.5H), 6.06 (d,
J¼5.5 Hz, 0.5H), 4.69 (dd, J¼12.7, 8.8 Hz, 0.5H), 4.40e4.33 (m, 1.5H),
4.10e4.04 (m, 1H), 3.73e3.56 (m, 6H), 2.20e2.13 (m, 1H), 1.89e1.83
(m, 1H), 1.55e1.43 (m, 2H), 1.00 (d, J¼7.0 Hz, 1.5H), 0.98 (d, J¼7.0 Hz,
1.5H), 0.91 (s, 9H), 0.06 (s, 6H). HRMS m/z 286.1973 (calcd for
C15H30O3Si, 286.48).
To a solution of alcohol (15a) (10.7 g, 42.6 mmol,1 equiv) in DMF
(300 mL) was added imidazole (5.8 g, 85.2 mmol, 2 equiv), followed
by TBSCl (6.6 g, 42.6 mmol, 1 equiv) and DMAP (50 mg, catalytic).
The reaction mixture was stirred overnight (ca. 16 h) before being
poured into a half-saturated solution of NH4Cl, and the aqueous
layer was extracted with CH2Cl2 (5ꢂ200 mL) and the combined
organic layers were washed with brine and dried over MgSO4.
Solvent was removed under reduced pressure to give the TBS al-
cohol, which was purified by flash chromatography (5% EtOAc/Hex)
to give the pure alcohol (16) as a yellow oil (15.3 g, 42.2 mmol, 99%
5.1.9. (2S,3R)-2-((4-Methoxybenzyloxy)methyl)-3-methyloxirane
(15).
To a solution of NaH (2.3 g, 95.7 mmol, 1.1 equiv) in DMF
(200 mL) cooled to 0 ꢀC was added 4-methoxybenzyl bromide
(20.3 g, 101 mmol, 1.16 equiv), followed by dropwise addition of
epoxide 6a (7.7 g, 87 mmol, 1 equiv). The reaction mixture was
warmed to rt and after 30 min it was judged to be complete by TLC
yield). Rf 0.53 (10% EtOAc/Hex); 1H NMR (600 MHz, CDCl3)
d 7.25 (d,
J¼8.8 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 5.80e5.75 (m, 1H), 5.01e4.97
(m, 2H), 4.44 (q, J¼9.4 Hz, 2H), 3.80 (s, 3H), 3.71 (q, J¼4.8 Hz, 1H),
3.46 (dd, J¼9.7, 5.0 Hz, 1H), 3.37 (dd, J¼9.7, 6.2 Hz, 1H), 2.25e2.21

N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
8639
(m, 1H), 1.87e1.82 (m, 1H), 1.79e1.72 (m, 1H), 0.89 (s, 3H), 0.89 (s,
9H), 0.06 (s, 6H). 13C NMR (150 MHz, CDCl3)
159.0, 138.0, 130.5,
129.2, 115.5, 113.6, 75.1, 72.9, 72.5, 55.2, 36.5, 36.0, 25.9, 18.2, 15.9,
1 equiv) in a minimal amount of THF (ca. 20 mL). After 16 h the
crude reaction mixture was poured into a rapidly stirring solution
of half-saturated NH4Cl (300 mL), and the aqueous layer was
extracted with CH2Cl2 (3ꢂ200 mL) and the combined organic layers
were washed with brine, dried over MgSO4, and filtered through
a thin pad of packed Celite/silica. Solvent was removed under re-
duced pressure to give the crude enol ether (17a), which was
contaminated with some Wittig byproducts, and the crude mixture
was used in the next reaction without further purification.
d
ꢁ4.2, ꢁ4.9. HRMS m/z 363.2341 (calcd for C21H36O3Si, 364.2434).
20
[
a]
þ4.11 (c 1.0, CHCl3).
D
5.1.12. (2R,3R)-2-(tert-Butyldimethylsilyloxy)-3-methylhex-5-en-1-
ol (16a).
5.1.15. (3S,4R)-3-(tert-Butyldimethylsilyloxy)-4-methylhept-6-enal
(18).
PMB alcohol (16) (6.89 g, 18.9 mmol, 1 equiv) was dissolved in
CH2Cl2 (140 mL), water (35 mL), and saturated sodium bicarbonate
(10 mL). DDQ (8.58 g, 37.8 mmol, 2 equiv) was added in one portion
and the reaction mixture was rigorously stirred for 1.5 h at which
point the reaction was judged to be complete by TLC analysis. The
reaction mixture was poured into a rapidly stirring solution of half-
saturated sodium bicarbonate (100 mL) and half-saturated sodium
thiosulfate (200 mL), and the aqueous layer was extracted with
CH2Cl2 (5ꢂ200 mL) and the combined organic layers were washed
with brine and dried over MgSO4. Solvent was removed under re-
duced pressure to give the crude alcohol, which was purified by
flash chromatography (10% EtOAc/Hex) to give the pure alcohol 16a
as a yellow oil (4.24 g, 17.4 mmol, 92% yield). Rf 0.51 (20% EtOAc/
The crude mixture of enol ether (17a) and Wittig byproducts
was dissolved in wet THF (300 mL) and water (30 mL), and
Hg(OAc)2 (7.84 g, 24.6 mmol, 1.5 equiv) was added in one portion.
The solution was stirred at rt for 1.5 h at which point disappearance
of the enol ether was confirmed by TLC analysis. Tetrabuty-
lammonium iodide (18.1 g, 49.2 mmol, 3 equiv) was added in one
portion, and the reaction mixture was stirred for 1 h at rt before
being poured into a rapidly stirring solution of half-saturated KI
(100 mL) and half-saturated sodium thiosulfate (200 mL), and the
aqueous layer was extracted with CH2Cl2 (4ꢂ200 mL) and the
combined organic layers were washed with brine dried over MgSO4
and filtered through a thin pad of packed Celite. Solvent was re-
moved under reduced pressure to give the crude aldehyde, which
was purified by flash chromatography (20% EtOAc/Hex) to give the
pure aldehyde 18 (2.60 g, 10.2 mmol, 62% yield over two steps). Rf
Hex); 1H NMR (600 MHz, CDCl3)
d
5.74 (ddd, J¼17.0,10.1, 7.0 Hz,1H),
5.03e4.98 (m, 2H), 3.59e3.55 (m, 3H), 2.25e2.21 (m, 1H) 1.84e1.77
(m, 3H), 0.90 (s, 9H), 0.87 (s, J¼7.0 Hz, 3H), 0.06 (s, 6H). 13C NMR
(150 MHz, CDCl3) d 137.3, 115.9, 76.2, 63.5, 37.2, 36.3, 25.8, 18.1, 14.9,
ꢁ4.4, ꢁ4.5. HRMS m/z 245.1942 (calcd for C13H28O2Si, 244.1859).
20
[
a]
ꢁ4.36 (c 1.0, CHCl3).
D
0.50 (10% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
d 9.79 (s, 1H),
5.78e5.71 (m, 1H), 5.02e5.00 (m, 2H), 4.14 (dt, J¼8.2, 4.1 Hz, 1H),
2.54e2.49 (m, 1H), 2.42e2.26 (m, 1H), 2.11e2.07 (m, 1H), 1.85
(dt, J¼14.3, 7.5 Hz, 1H), 1.74 (dt, J¼12.9, 6.4 Hz, 1H), 0.88 (d,
J¼7.0 Hz, 3H), 0.86 (s, 9H), 0.04 (d, J¼17.5 Hz, 6H). 13C NMR
5.1.13. (2R,3R)-2-(tert-Butyldimethylsilyloxy)-3-methylhex-5-enal
(17).
(100 MHz, CDCl3)
d 202.5, 136.8, 116.2, 71.0, 46.5, 39.1, 37.4, 25.7,
18.0, 14.0, ꢁ4.5, ꢁ4.6.
5.1.16. (3S,4R)-3-(tert-Butyldimethylsilyloxy)-4-methylhept-6-en-1-
ol (18a).
Alcohol 16a (4.02 g, 16.4 mmol, 1 equiv) was dissolved in wet
EtOAc (120 mL), and IBX (9.2 g, 32.9 mmol, 2 equiv) was added. The
suspension was stirred at 80 ꢀC for 5 h, at which point the reaction
was judged complete by TLC analysis. The flask was removed from
the heat and allowed to cool to rt before the solution was filtered
through a thin pad of silica over a pad of packed Celite, and the filter
cake was washed with 400 mL EtOAc. Solvent was removed under
reduced pressure to give the pure aldehyde 17 (3.97 g, 16.3 mmol,
99% yield), which was used in the next step without further puri-
To a round bottom flask cooled to 0 ꢀC and charged with DIBAL-
H (1.0 M, 82 mL, 82 mmol, 2.0 equiv) in CH2Cl2 (200 mL) was added
aldehyde (18) (10.5 g, 41 mmol, 1 equiv) portion wise over 10 min.
The reaction mixture was stirred at rt until completion by TLC
analysis (ca. 0.5 h). The reaction mixture was poured into half-
saturated solution of NH4Cl (200 mL) and a solution of Rochelle’s
salt (25 g in 100 mL water), and CH2Cl2 was added. The solution was
stirred vigorously until it became homogenous (ca. 16 h), after
which the aqueous layer was extracted with CH2Cl2 (3ꢂ100 mL)
and the combined organic layers were washed with brine and dried
with MgSO4. Solvent was removed under reduced pressure to af-
ford the crude product, which was purified by flash chromatogra-
phy (10% EtOAc/Hex) to give alcohol (18a) as a yellow oil (9.85 g,
38.1 mmol, 93% yield). Rf 0.46 (20% EtOAc/Hex); 1H NMR (600 MHz,
fication. Rf 0.72 (20% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
d 9.61
(d, J¼2.0 Hz, 1H), 5.69 (ddd, J¼17.0, 10.0, 7.2 Hz, 1H), 5.05e4.99 (m,
2H), 3.79 (dd, J¼4.3, 2.0 Hz, 1H), 2.26e2.20 (m, 1H) 2.05e1.89 (m,
2H), 0.95 (s, 9H), 0.92 (d, J¼6.6 Hz, 3H), 0.06 (s, 6H). 13C NMR
(100 MHz, CDCl3)
d 205.0, 136.9, 116.8, 81.2, 37.3, 35.8, 25.7, 18.2,
16.1, ꢁ4.5, ꢁ4.6.
5.1.14. tert-Butyl((3R,4R,E)-1-methoxy-4-methylhepta-1,6-dien-3-
yloxy)dimethylsilane (17a).
CDCl3)
d
5.74 (ddt, J¼17.3, 10.0, 7.1 Hz, 1H), 5.01e4.97 (m, 2H),
3.79e3.71 (m, 3H), 2.21 (br t, J¼4.9 Hz, 1H), 2.13e2.06 (m, 1H),
1.85e1.75 (m,1H),1.74e1.68 (m,1H),1.68e1.61 (m, 2H), 0.88 (s, 9H),
0.85 (d, J¼6.6 Hz, 3H), 0.06 (d, J¼3.9 Hz, 6H). 13C NMR (150 MHz,
To a solution of tBuOK (3.90 g, 34.8 mmol, 2.0 equiv) in THF
(200 mL) was added Ph3PCH2OMeCl (13.1 g, 38.3 mmol, 2.2 equiv)
in one portion, and the red solution was stirred at rt for 1 h. To the
red solution was added crude aldehyde (17) (3.97 g, 16.4 mmol,
CDCl3)
d
137.3, 115.8, 74.4, 60.7, 38.4, 37.8, 33.3, 25.8, 18.0,13.8, ꢁ4.4,
ꢁ4.6. HRMS m/z 259.2085 (calcd for C14H30O2Si, 258.2015).

8640
N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
5.1.17. (3S,4R)-Methyl 3-(tert-butyldimethylsilyloxy)-4-methylhept-
6-enoate (19).
J¼8.6 Hz, 2H), 6.86 (d, J¼8.6 Hz, 2H), 5.75 (ddt, J¼17.0, 10.0, 7.2 Hz,
1H), 5.01e4.95 (m, 2H), 4.40 (ABd, J¼11.7 Hz, 2H), 3.80 (s, 3H), 3.72
(dt, J¼8.1, 4.0 Hz, 1H), 3.50 (sex, J¼7.4 Hz, 2H), 2.13e2.07 (m, 1H),
1.85e1.78 (m, 1H), 1.71e1.63 (m, 2H), 0.86 (s, 9H), 0.83 (d, J¼6.6 Hz,
3H), 0.00 (d, J¼3.9 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 159.1, 137.7,
130.7, 129.2, 115.5, 113.7, 72.5, 72.4, 67.3, 55.2, 38.7, 37.3, 32.1, 25.9,
18.1, 14.1, ꢁ4.4, ꢁ4.6. HRMS m/z 377.2524 (calcd for C22H38O3Si,
378.2590).
To the crude aldehyde 18 (100 mg, 0.4 mmol, 1.0 equiv) and 2-
methyl-2-butene (0.17 mL, 1.6 mmol, 4 equiv) in tBuOH (3 mL)
and pH 7 buffer (0.67 M, 2 mL) was added NaClO2 (113 mg, 1 mmol,
2.5 equiv) in water (1 mL). The reaction mixture was monitored by
TLC until completion (ca. 30 min) at which point it was poured into
a half-saturated solution of sodium sulfate (30 mL) and acidified
with HCl (2 M solution, 3 mL). The aqueous layer was extracted
with CH2Cl2 (5ꢂ20 mL) and the combined organic layers were
washed with brine and dried over MgSO4. Solvent was removed
under reduced pressure, and the crude oil was dissolved in MeOH
(10 mL) and CH2Cl2 (10 mL) and a stir bar was added. To the solution
was added TMSediazomethane (1.0 M solution) dropwise until the
yellow color persists (ca. 0.1 mL). The reaction mixture was stirred
an additional 5 min before excess acetic acid (1 mL) was added in
one portion and the color dissipates. Volatiles were removed under
reduced pressure and the oil was purified by flash chromatography
(20% EtOAc/Hex) to give pure methyl ester 19 (81 mg, 0.297 mmol,
5.1.20. (3S,4R)-1-(4-Methoxybenzyloxy)-4-methylhept-6-en-3-ol
(4).
To a solution of freshly prepared imidate (9.0 g, 31.9 mmol,
1.5 equiv) in toluene (150 mL) was added alcohol (18a) (5.50 g,
21.3 mmol, 1 equiv) followed by Yb(OTf)3 (20 mg, catalytic). The
reaction mixture was stirred at rt until completion by TLC analysis
(ca. 0.5 h). Solvent was removed under reduced pressure to afford
the crude product, which was purified by flash chromatography (2%
EtOAc/Hex) to yield (4) as a yellow oil (7.89 g, 20.8 mmol, 98%
yield). Rf 0.71 (20% EtOAc/Hex); 1H NMR (600 MHz, CDCl3)
d 7.24 (d,
J¼8.7 Hz, 2H), 6.86 (d, J¼8.7 Hz, 2H), 5.79 (ddt, J¼17.3, 10.0, 7.1 Hz,
1H), 5.04e4.97 (m, 2H), 4.45 (m, 2H), 4.45 (s, 2H), 3.79 (s, 3H), 3.71
(dt, J¼9.5, 4.9 Hz, 1H), 3.61 (q, J¼6.4 Hz, 2H), 3.00 (d, J¼2.3 Hz, 1H),
2.30e2.26 (m, 1H), 1.90 (dt, J¼13.9, 8.3 Hz, 1H), 1.73e1.70 (m, 2H),
1.64e1.59 (m, 1H), 0.86 (d, J¼6.4 Hz, 3H). 13C NMR (150 MHz, CDCl3)
74%). 1H NMR (400 MHz, CDCl3)
d
5.76 (ddt, J¼16.9, 10.0, 7.0 Hz, 1H),
5.01 (d, J¼7.0 Hz,1H), 4.97 (s,1H), 4.12 (dt, J¼8.0, 4.2 Hz,1H), 3.64 (s,
3H), 2.42e2.21 (m, 2H), 2.11e2.05 (m, 1H), 1.85e1.77 (m, 1H),
1.75e1.66 (m, 1H), 0.87 (t, J¼7.0 Hz, 3H), 0.86 (s, 9H), 0.03 (d,
J¼17.2 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 173.5, 136.7, 116.0, 71.2,
d
159.3, 137.6, 130.0, 129.3, 115.8, 113.8, 75.2, 73.0, 69.4, 55.3, 38.6,
51.5, 37.9, 36.6, 14.8.
36.9, 32.8, 15.1. HRMS m/z 264.1725 (calcd for C16H24O3, 264.1725).
[
a
]
20 þ1.73 (c 1.0, CHCl3). The ee was determined to be 85% by (R)-
D
5.1.18. (3S,4R)-Methyl 3-hydroxy-4-methylhept-6-enoate (20).
Mosher’s analysis.
5 .1. 21. M e t h yl 2 - ( ( 2 S , 3 R , 5 R ) - 5 - ( h y d r o x y m e t h yl ) - 3 -
methyltetrahydrofuran-2-yl)acetate (25).
To a solution of methyl ester (19) (836.4 mg, 2.92 mmol, 1 equiv)
in MeOH (20 mL) was added 10-CSA (677 mg, 2.92 mmol, 1 equiv).
The reaction mixture was stirred at rt until completion by TLC
analysis (ca. 1 h). The reaction mixture was poured into half-satu-
rated solution of sodium bicarbonate (50 mL) and diluted with
EtOAc (50 mL), the aqueous layer was extracted with EtOAc
(4ꢂ30 mL) and the combined organic layers were washed with
brine and dried with MgSO4. Solvent was removed under reduced
pressure to afford 20 as a yellow oil, which was used without fur-
ther purification (481 mg, 2.80 mmol, 96% yield). Rf 0.25 (40%
EtOAc/Hex); Rf¼0.44 (40% EA/Hex); 1H NMR (400 MHz, CDCl3)
The pre-activated Co(nmp)2 (24) (prepared above, 0.1 mmol,
0.1 equiv) was diluted with 10 mL iPrOH, and alcohol (20)
was added (172 mg, 1.0 mmol, 1 equiv). The reaction mixture was
heated to 30 ꢀC under an oxygen atmosphere for 16 h. Solvent
was removed under reduced pressure, followed by high vacuum
(0.1 mmHg) to remove all traces of iPrOH. The crude mixture was
diluted with EtOAc (10 mL) and filtered through a thin pad of silica
(<1 cm) over packed Celite to remove the catalyst. The pad was
washed with EtOAc (100 mL) and the filtrate was concentrated
under reduced pressure to give THF alcohol (25) (177 mg,
0.94 mmol, 94%) as a yellow oil, which was used without further
d
5.81e5.75 (m, 1H), 5.07e4.99 (m, 1H), 3.88e3.82 (m, 1H), 3.71 (s,
3H), 2.91 (d, J¼3.5 Hz, 1H), 2.54e2.51 (m, 1H), 2.44e2.39 (m, 1H),
2.32e2.26 (m, 1H), 1.97e1.92 (m, 1H), 1.70e1.65 (m, 1H), 0.88 (d,
J¼7.0, 3H).
purification. 1H NMR (600 MHz, CDCl3)
d 4.12e4.08 (m, 1H), 3.85
(td, J¼8.5, 4.1 Hz, 1H), 3.69 (s, 3H), 3.65 (dd, J¼11.7, 2.9 Hz, 1H), 3.48
(dd, J¼11.7, 5.9 Hz, 1H), 2.56e2.53 (m, 1H), 2.49e2.45 (m, 1H), 2.08
(dd, J¼12.4, 6.4 Hz, 1H), 2.02e1.95 (m, 2H), 1.43 (ddd, J¼12.1, 10.7,
5.1.19. tert-Butyl((3S,4R)-1-(4-methoxybenzyloxy)-4-methylhept-6-
en-3-yloxy)dimethylsilane (21).
9.4 Hz,1H),1.03 (d, J¼7.0 Hz, 3H). 13C NMR (150 MHz, CDCl3)
d 171.9,
81.6, 78.8, 64.8, 51.7, 39.9, 39.1, 36.2, 16.2. HRMS m/z 189.1119 (calcd
for C9H16O4, 188.2).
To a solution of freshly prepared PMB-imidate (9.0 g, 31.9 mmol,
1.5 equiv) in toluene (150 mL) was added alcohol 18a (5.50 g,
21.3 mmol, 1 equiv) followed by Yb(OTf)3 (20 mg, catalytic). The
reaction mixture was stirred at rt until completion by TLC analysis
(ca. 0.5 h). Solvent was removed under reduced pressure to afford
the crude product, which was purified by flash chromatography (2%
EtOAc/Hex) to yield 21 as a yellow oil (7.89 g, 20.8 mmol, 98% yield).
5.1.22. ((2R,4R,5S)-5-(2-(4-Methoxybenzyloxy)ethyl)-4-
methyltetrahydrofuran-2-yl)methanol (26).
Procedure to pre-activate Co(nmp)2: To a flask charged with
Co(nmp)2 (24) (452 mg, 0.8 mmol, 0.1 equiv) and iPrOH (100 mL)
Rf 0.71 (20% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
d 7.24 (d,

N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
8641
€
was added tBuOOH (5.33 M, 0.2 mL, 1.08 mmol, 0.14 equiv). The
reaction mixture was heated to 55 ꢀC under an oxygen atmosphere
for 1 h, and solvent was removed under reduced pressure. The
activated Co(nmp)2 was dried under high vacuum (0.1 mmHg) for
5 min to ensure that any remaining peroxide was removed.
Hunig’s base (430 mg, 3.34 mmol, 7 equiv). The reaction mixture
was allowed to stir for 10 min before SO3$Pyr (227 mg, 1.43 mmol,
3 equiv) was added portion wise over 5 min. The reaction was
monitored by TLC until completion (ca. 2 h) before being slowly
poured into a half-saturated solution of sodium bicarbonate
(10 mL), and diluted with CH2Cl2 (10 mL). The aqueous layer was
extracted with CH2Cl2 (3ꢂ20 mL) and the combined organic layers
were washed with brine, and dried with MgSO4. Solvent was re-
moved under reduced pressure, and the crude residue was dis-
solved in EtOAc (10 mL) and water (30 mL). The aqueous layer
was extracted with EtOAc (3ꢂ20 mL) and the combined organic
layers were washed with brine, and dried with MgSO4. Solvent
was removed under reduced pressure, to afford 27 as a yellow oil
(42 g, 0.226 mmol, 47% yield), which was used without further
purification. The second extraction using EtOAc removes oxidation
byproducts from the reaction mixture without using column
chromatography, which was shown to decompose the aldehyde. 1H
Cyclization: The pre-activated Co(nmp)2 (24) (prepared above,
0.8 mmol, 0.1 equiv) was diluted with 100 mL iPrOH, and alcohol (4)
was added (2.06 g, 7.8 mmol, 1 equiv). The reaction mixture was
heated to 55 ꢀC under an oxygen atmosphere for exactly 1 h, and
allowed to cool to rt. Solvent was removed under reduced pressure,
followed by high vacuum (0.1 mmHg) to remove all traces of iPrOH.
The crude mixture was diluted with EtOAc (40 mL) and filtered
through a thin pad of silica (<1 cm) over packed Celite to remove
the catalyst. The pad was washed with EtOAc (400 mL) and the
filtrate was concentrated under reduced pressure to give THF al-
cohol (26) (2.05 g, 7.34 mmol, 94%) as a yellow oil, which was used
without further purification. The product rapidly decomposes, and
the decomposition product characteristically results in broad peaks
at 3.65 and 3.45 ppm. The presence of the decomposition product
leads to the loss of fine splitting and peaks are reported as multi-
NMR (600 MHz, CDCl3)
d
9.65 (d, J¼1.7 Hz, 1H), 4.29 (td, J¼8.2,
2.3 Hz, 1H), 3.94 (td, J¼8.2, 4.1 Hz, 1H), 3.69 (s, 3H), 2.59e2.56 (m,
1H), 2.53e2.49 (m, 1H), 2.34 (dt, J¼12.4, 7.5 Hz, 1H), 2.05e1.97 (m,
1H), 1.59 (dt, J¼12.3, 9.1 Hz, 1H), 1.02 (d, J¼6.4 Hz, 3H). 13C NMR
plets. 1H NMR (600 MHz, CDCl3)
d
7.25 (d, J¼8.6 Hz, 2H), 6.87 (d,
J¼8.6 Hz, 2H), 4.43 (d, J¼2.0 Hz, 2H), 4.06 (ddt, J¼9.4, 6.2, 3.1 Hz,
1H), 3.79 (s, 3H), 3.62e3.48 (m, 4H), 2.09e2.03 (m, 1H), 1.94e1.85
(m, 2H), 1.73e1.65 (m, 1H), 1.37e1.29 (m, 1H), 1.01 (d, J¼6.6 Hz, 3H).
(150 MHz, CDCl3) d 202.6, 171.4, 83.1, 81.9, 51.8, 39.0, 38.7, 35.8, 16.1.
HRMS m/z 187.0974 (calcd for C13H28O2Si, 186.2).
13C NMR (150 MHz, CDCl3)
d
159.1, 130.6, 129.2, 113.7, 82.4, 78.3,
5.1.25. ((Z)-4-((2R,4R,5S)-5-(2-(4-Methoxybenzyloxy)ethyl)-4-
72.6, 67.4, 65.2, 55.3, 40.1, 36.6, 34.3, 16.4. HRMS m/z 280.1667
methyltetrahydrofuran-2-yl)but-3-en-1-ynyl)trimethylsilane (33).
(calcd for C16H24O4, 280.1675).
5.1.23. (2R,4R,5S)-5-(2-(4-Methoxybenzyloxy)ethyl)-4-
methyltetrahydrofuran-2-carbaldehyde (3).
To a 50 mL round bottomed flask charged with tert-butyldi-
methyl(3-(trimethylsilyl)prop-2-ynyl)silane (240 mg, 1.06 mmol,
2.0 equiv) in THF (5 mL) cooled to ꢁ78 ꢀC was added nBuLi (2.28 M,
0.47 mL, 1.06 mmol, 2.0 equiv). The reaction mixture was warmed
to ꢁ20 ꢀC and stirred for 1 h before being re-cooled to ꢁ78 ꢀC
before Ti(OiPr)4 (301 mg, 1.06 mmol, 2.0 equiv) was added. The
reaction mixture was stirred for 10 min before aldehyde (27)
(120 mg, 0.53 mmol, 1.0 equiv) was added. The reaction mixture
was stirred at ꢁ78 ꢀC for 1 h, warmed to ꢁ20 ꢀC, and monitored by
TLC until complete (1 h). The reaction mixture was then poured into
a solution of half-saturated NH4Cl (100 mL) and the aqueous layer
was extracted with EtOAc (3ꢂ500 mL). The combined organic
layers are dried over MgSO4, filtered through a pad of Celite, and
concentrated to dryness under vacuum. The crude material was
purified by column chromatography to give the product eneeyne
(33) as a yellow oil as a 14:1 cis/trans mixture (128 mg, 0.34 mmol,
65% yield). Rf 0.48 (20% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
A flask charged with freshly prepared alcohol 26 (2.24 g,
8 mmol, 1 equiv), and DMSO (3.12 g, 40 mmol, 5 equiv) in CH2Cl2
ꢀ
€
(120 mL) was cooled to 0 C and Hunig’s base (9.6 mL, 56 mmol,
7 equiv) was added. The reaction mixture was stirred for 5 min
before sulfurtrioxideepyridine complex (3.82 g, 24 mmol, 3 equiv)
was added in one portion. The reaction mixture was stirred at 0 ꢀC
for 2 h before being poured into half-saturated solution of sodium
bicarbonate (150 mL) and diluted with CH2Cl2 (100 mL), the
aqueous layer was extracted with CH2Cl2 (3ꢂ50 mL) and the
combined organic layers were washed with brine, and dried with
MgSO4. Solvent was removed under reduced pressure to afford the
crude product, which was purified by flash chromatography (40%
EtOAc/Hex) to yield aldehyde 3 (2.0 g, 7.4 mmol, 90% yield) as
a yellow oil. Rf 0.62 (70% EtOAc/Hex); 1H NMR (600 MHz, CDCl3)
d
9.63 (s, 1H), 7.25 (d, J¼8.6 Hz, 2H), 6.87 (d, J¼8.6 Hz, 2H), 4.44 (s,
d
7.25 (d, J¼8.7 Hz, 2H), 6.86 (d, J¼8.7 Hz, 2H), 5.96 (dd, J¼11.4,
2H), 4.26e4.23 (m, 1H), 3.79 (s, 3H), 3.63e3.56 (m, 3H), 2.33 (dt,
J¼12.9, 7.6 Hz, 1H), 1.95e1.89 (m, 2H), 1.73 (dt, J¼14.3, 5.9 Hz, 1H),
1.58e1.53 (m, 1H), 1.00 (d, J¼7.0 Hz, 3H). 13C NMR (150 MHz, CDCl3)
8.0 Hz, 1H), 5.51 (d, J¼10.9 Hz, 1H), 4.94e4.88 (m, 1H), 4.44 (s, 2H),
3.79 (s, 3H), 3.65e3.55 (m, 3H), 2.34 (dt, J¼12.4, 6.5 Hz, 1H),
1.94e1.85 (m, 2H), 1.72e1.69 (m, 1H), 1.32e1.25 (m, 2H), 1.02 (d,
J¼6.6 Hz, 3H), 0.17 (s, 9H).
d
203.0, 159.1, 130.5, 129.2, 113.7, 84.2, 81.6, 72.7, 67.1, 55.2, 39.3,
36.0, 34.0, 16.2. HRMS m/z 278.1510 (calcd for C16H22O4, 278.1518).
5.1.26. (Z)-Methyl 3-((2R,4R,5S)-5-(2-(4-methoxybenzyloxy)ethyl)-
4-methyltetrahydrofuran-2-yl)acrylate.
5.1.24. Methyl 2-((2S,3R,5R)-5-formyl-3-methyltetrahydrofuran-2-
yl)acetate.
A 25 mL round bottom flask was charged with alcohol 25
(90 mg, 0.48 mmol, 1 equiv), diluted with CH2Cl2 (5 mL) and cooled
to 0 ꢀC. DMSO (186 mg, 2.39 mmol, 5 equiv) was added, followed by
To a solution of the StilleGennari phosphonate (5.10 g,
16.0 mmol, 1.5 equiv) in THF (60 mL) and 18-crown-6 ether (11.3 g,
42.8 mmol, 4.0 equiv) cooled to ꢁ78 ꢀC was added KHMDS (0.91 M,

8642
N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
17.6 mL, 16.0 mmol, 1.5 equiv) dropwise over 5 min. The reaction
mixture was stirred at ꢁ78 ꢀC for 20 min before a solution of al-
dehyde 3 (2.98 g, 10.7 mmol, 1.0 equiv) in THF (20 mL) was added
dropwise over 10 min. The reaction mixture was stirred at rt for 3 h
at ꢁ78 ꢀC, warmed to rt, and stirred for an additional 10 min before
being poured into a half-saturated solution NH4Cl (150 mL). The
aqueous layer was extracted with EtOAc (50 mLꢂ3), and the com-
bined organic layers were washed with brine, dried over MgSO4,
and filtered through a thin pad of packed Celite. Solvent was re-
moved under reduced pressure and the crude oil was purified by
flash chromatography (20% EtOAc/Hex) to yield 36 (2.79 g,
8.35 mmol, 78%) as a yellow oil. Rf 0.68 (50% EtOAc/Hex); 1H NMR
and the combined organic layers were washed with brine, dried
over MgSO4, and filtered through a thin pad of packed Celite. Sol-
vent was removed under reduced pressure and the crude oil was
purified by flash chromatography (50% EtOAc/Hex) to yield 37 as an
inseparable mixture of diastereomers (1.55 g, 3.80 mmol, 95%) as
a yellow oil. Rf 0.73 (75% EtOAc/Hex); 1H NMR (400 MHz, CDCl3,
major diastereomer)
d
7.25 (d, J¼8.8 Hz, 2H), 6.86 (d, J¼8.8 Hz, 2H),
4.55 (d, J¼7.0 Hz, 1H), 4.42 (ABd, J¼11.1 Hz, 2H), 4.26 (dd, J¼7.0,
4.7 Hz, 1H), 4.05 (ddd, J¼8.8, 6.7, 5.0 Hz, 1H), 3.79 (s, 3H), 3.68 (s,
3H), 3.60e3.48 (m, 3H), 2.17 (dt, J¼12.1, 7.1 Hz, 1H), 1.86e1.83 (m,
2H), 1.68e1.61 (m, 1H), 1.59 (s, 3H), 1.56 (d, J¼13.5 Hz, 1H),
1.52e1.46 (m, 1H), 1.41 (s, 1H), 1.38 (s, 3H) 1.01 (d, J¼6.4 Hz, 3H);
HRMS m/z 408.2152 (calcd for C22H32O7, 408.2148).
(400 MHz, CDCl3)
d
7.27 (d, J¼8.6 Hz, 2H), 6.86 (d, J¼8.6 Hz, 2H),
6.29 (dd, J¼11.5, 7.2 Hz, 1H), 5.73 (dd, J¼11.5, 1.5 Hz, 1H), 5.38 (ddd,
J¼13.8, 9.8, 1.5 Hz, 1H), 4.43 (s, 2H), 3.79 (s, 3H), 3.68 (s, 3H),
3.63e3.52 (m, 3H), 2.49 (dt, J¼12.7, 6.5 Hz, 1H), 1.98e1.85 (m, 2H),
1.76 (m, 2H), 1.31e1.23 (m, 1H), 1.00 (d, J¼6.2 Hz, 3H). 13C NMR
5.1.29. ((4R,5S)-5-((2R,4R,5S)-5-(2-(4-Methoxybenzyloxy)ethyl)-4-
methyltetrahydrofuran-2-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)
methanol.
(100 MHz, CDCl3) d 166.3, 159.1, 152.4, 130.7, 129.2, 118.2, 113.7, 82.9,
74.8, 72.6, 67.4, 55.2, 51.2, 41.2, 40.0, 34.3, 16.4. HRMS m/z 334.1773
(calcd for C19H26O5, 334.1780).
5.1.27. (2S,3R)-Methyl 2,3-dihydroxy-3-((2R,4R,5S)-5-(2-(4-
methoxybenzyloxy)ethyl)-4-methyltetrahydrofuran-2-yl)propanoate
(36a).
To a solution of DIBAL-H (1.0 M, 7.60 mL, 7.60 mmol, 2.0 equiv) in
CH2Cl2 (20 mL) cooled to 0 ꢀC was added the mixture of di-
astereomeric esters 37 (1.55 g, 3.80 mmol, 1 equiv) in CH2Cl2
(10 mL) portion wise over 10 min. The reaction mixture was stirred
at rt until completed by TLC analysis (ca. 3 h). The reaction mixture
was poured into half-saturated solution of NH4Cl (100 mL) and
a solution of Rochelle’s salt (10 g in 50 mL water), and CH2Cl2
(100 mL) was added. The solution was stirred vigorously until it
became homogenous (ca. 16 h), after which the aqueous layer was
extracted with CH2Cl2 (3ꢂ50 mL) and the combined organic layers
were washed with brine, and dried with MgSO4. Solvent was re-
moved under reduced pressure to afford the crude product, which
was purified by flash chromatography (50% EtOAc/Hex) to give al-
cohol 37a as a yellow oil (1.14 g, 3.01 mmol, 79% yield) and the
diastereomer (285 mg, 0.75 mmol, 19%). Rf 0.22 (50% EtOAc/Hex);
To a solution of alkene 36 (1.32 g, 4.0 mmol, 1 equiv) in tBuOH
(15 mL) and distilled water (15 mL) cooled to 0 ꢀC were added
AD-mix (5.6 g), K2OsO4 (140 mg, 0.12 mmol, 0.06 equiv), and
(DHQD)2PYR (104 mg, 0.06 mmol, 0.03 equiv). The reaction mixture
was stirred at 0 ꢀC and monitored by TLC analysis until complete
(ca. 3 days). Upon completion, the contents were poured into
a solution consisting of half-saturated NH4Cl (50 mL), half-satu-
rated sodium thiosulfate (50 mL), and water (50 mL). The reaction
mixture was stirred rigorously for 10 min, diluted with CH2Cl2
(100 mL), and the aqueous layer was extracted with CH2Cl2
(50 mLꢂ4), and the combined organic layers were washed with
brine, dried over MgSO4, and filtered through a thin pad of packed
Celite. Solvent was removed under reduced pressure and the crude
oil (36a) was used in the next reaction without further purification.
Rf 0.73 (75% EtOAc/Hex); 1H NMR (400 MHz, CDCl3, major di-
1H NMR (400 MHz, CDCl3)
d
7.25 (d, J¼8.2 Hz, 2H), 6.85 (d, J¼8.2 Hz,
2H), 4.42 (ABd, J¼11.1 Hz, 2H), 4.17e4.12 (m, 2H), 4.07e4.05 (dd,
J¼6.4, 3.5 Hz, 1H), 3.79 (s, 3H), 3.72e3.64 (m, 3H), 3.61e3.57 (m,
1H), 3.57e3.51 (m, 1H), 3.21 (dd, J¼8.8, 4.7 Hz, 1H), 2.15 (dt, J¼12.3,
6.7 Hz,1H),1.92e1.87 (m, 2H),1.71e1.63 (m, 2H),1.49 (s, 3H),1.36 (s,
3H), 1.02 (d, J¼7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 159.1, 130.6,
129.3, 113.7, 108.4, 83.5, 78.9, 77.5, 75.0, 72.7, 67.4, 61.5, 55.2, 39.6,
27.9, 34.0, 27.4, 25.6, 15.8. HRMS m/z 380.2198 (calcd for C21H32O6,
380.2199).
astereomer)
d
7.22 (d, J¼8.7 Hz, 2H), 6.85 (d, J¼8.7 Hz, 2H), 4.40 (s,
2H), 4.25 (dd, J¼8.2, 4.1 Hz, 1H), 4.01 (ddd, J¼9.7, 6.2, 2.9 Hz, 1H),
3.77 (s, 3H), 3.74 (s, 3H), 3.75e3.68 (m, 1H), 3.56e3.48 (m, 3H), 3.41
(d, J¼9.4 Hz, 1H), 2.70 (d, J¼7.6 Hz, 1H), 2.04 (dt, J¼12.4, 6.4 Hz, 1H),
1.89e1.82 (m, 2H), 1.65e1.57 (m, 2H), 1.00 (d, J¼6.4, 3H).
5.1.30. (4S,5S)-5-((2R,4R,5S)-5-(2-(4-Methoxybenzyloxy)ethyl)-4-
methyltetrahydrofuran-2-yl)-2,2-dimethyl-1,3-dioxolane-4-
carbaldehyde (38).
5.1.28. (4S,5S)-Methyl
5-((2R,4R,5S)-5-(2-(4-methoxybenzyloxy)
ethyl)-4-methyltetrahydrofuran-2-yl)-2,2-dimethyl-1,3-dioxolane-4-
carboxylate (37).
Alcohol 37a was oxidized to the corresponding aldehyde using
a procedure analogous to that used for 27, on a 5.93 mmol scale
resulting in aldehyde 38 (1.64 g, 5.93 mmol, 100%), which was used
without further purification. Rf 0.19 (20% EtOAc/Hex); 1H NMR
The crude diol 36a was dissolved in 2,2-dimethoxy propane
(50 mL), and p-toluene sulfonic acid (50 mg, catalytic) was added in
one portion. The reaction mixture was stirred at rt overnight (ca.
16 h) before being poured into a half-saturated solution NaHCO3
(100 mL). The aqueous layer was extracted with EtOAc (50 mLꢂ3),
(400 MHz, CDCl3)
d
9.59 (d, J¼2.3 Hz, 1H), 7.24 (d, J¼8.8 Hz, 2H),
6.85 (d, J¼8.8 Hz, 2H), 4.41 (s, 2H), 4.32 (dd, J¼4.1, 2.3 Hz, 2H), 4.05
(ddd, J¼9.0, 6.7, 2.9 Hz, 1H), 3.78 (s, 3H), 3.59 (td, J¼9.2, 2.6 Hz, 1H),
3.55 (ddd, J¼9.2, 7.2, 4.7 Hz,1H), 3.52e3.48 (m, 1H), 2.10 (dt, J¼12.0,

N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
8643
7.5 Hz,1H),1.87e1.80 (m, 2H),1.63e1.58 (m, 2H),1.55 (s, 3H),1.38 (s,
thiosulfate (300 mL), and the aqueous layer was extracted with
CH2Cl2 (5ꢂ300 mL) and the combined organic layers were washed
with brine and dried over MgSO4. Solvent was removed under re-
duced pressure to give the crude alcohol, which was purified by
flash chromatography (50% EtOAc/Hex) to give the pure alcohol 40
as a yellow oil (922 mg, 3.63 mmol, 86% yield). Rf 0.22 (50% EtOAc/
3H), 0.99 (d, J¼6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 201.6, 159.1,
130.7, 129.2, 113.7, 111.0, 83.3, 81.7, 81.2, 74.4, 72.7, 67.5, 55.2, 40.3,
36.5, 33.9, 26.9, 25.2, 15.8.
5.1.31. (4R,5S)-4-Ethynyl-5-((2R,4R,5S)-5-(2-(4-methoxybenzyloxy)
ethyl)-4-methyltetrahydrofuran-2-yl)-2,2-dimethyl-1,3-dioxolane
(39).
Hex); 1H NMR (400 MHz, CDCl3)
d
4.69 (dd, J¼5.8, 2.3 Hz, 1H), 4.26
(dt, J¼9.1, 6.9 Hz, 1H), 3.98 (dd, J¼7.6, 5.9 Hz, 1H), 3.82e3.75 (m,
2H), 3.63 (td, J¼8.6, 3.2 Hz, 1H), 2.79 (br s, 1H), 2.50 (d, J¼2.3 Hz,
1H), 2.31 (dt, J¼5.9, 5.9 Hz, 1H), 2.00e1.95 (m, 1H), 1.90e1.85 (m,
1H), 1.72e1.66 (m, 1H), 1.53 (s, 3H), 1.35 (s, 3H), 1.27e1.22 (m, 1H),
1.01 (d, J¼6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 111.1, 85.2, 80.8,
79.8, 77.7, 75.6, 66.7, 60.9, 39.4, 37.2, 35.3, 29.6, 27.5, 26.0, 16.0.
5.1.33. Methyl 2-((2S,3R,5R)-5-((4S,5R)-5-ethynyl-2,2-dimethyl-1,3-
dioxolan-4-yl)-3-methyltetrahydrofuran-2-yl)acetate (41).
A 250 mL flask was charged with triphenylphosphine (7.0 g,
26.6 mmol, 5.0 equiv) and CH2Cl2 (70 mL) and was cooled to 0 ꢀC.
The septum was temporarily removed to add carbon tetrabromide
(4.36 g, 13.3 mmol, 2.5 equiv) in one portion. The ice bath was re-
moved and the reaction mixture was stirred at room temperature
for 30 min, after which it was re-cooled to 0 ꢀC. The above crude
aldehyde 38 (2.01 g, 5.33 mmol, 1 equiv) was added in one portion
and the reaction mixture was stirred for 30 min, at which point it
was judged complete by TLC. Hexanes (250 mL) was added, and the
reaction mixture was allowed to warm to rt, at which point it was
filtered through Celite, and concentrated to dryness. To the crude
oil was added more hexanes (500 mL), filtered, and concentrated.
This procedure was repeated for a total of three filtrations at which
point the crude oil was purified by column chromatography (20%
EtOAc/Hex) to afford the dibromide as a yellow oil (2.56 g,
4.80 mmol, 90% yield). A 250 mL flask was charged with dibromide
(2.56 g, 4.80 mmol, 1 equiv), diluted with THF (150 mL), and cooled
to ꢁ78 ꢀC. nBuLi (2.50 M, 4.80 mL, 12.0 mmol, 2.5 equiv) was added
slowly dropwise over 15 min. The reaction mixture was stirred at
ꢁ78 ꢀC for 1 h at which point it was judged complete by TLC. The
reaction mixture was slowly poured into a half-saturated solution
of NH4Cl (150 mL), the aqueous layer was extracted with CH2Cl2
(3ꢂ150 mL), and the combined organic layers were washed with
brine, and dried with MgSO4. Solvent was removed under reduced
pressure, and the crude product was purified by column chroma-
tography (2% EtOAc/Hex) to afford alkyne 39 as a yellow oil (1.61 g,
4.32 mmol, 95% yield). Rf 0.57 (50% EtOAc/Hex); 1H NMR (400 MHz,
Alcohol 40 was oxidized to the corresponding aldehyde using
a procedure analogous to that used for 27, on a 4.29 mmol
scale resulting in the aldehyde (1.10 g, 4.29 mmol, 83%), which was
used without further purification. To the crude aldehyde (1.10 g,
4.29 mmol, 1.0 equiv) and 2-methyl-2-butene (1.20 g, 17.2 mmol,
4 equiv) in tBuOH (50 mL) and pH 7 buffer (0.67 M, 20 mL) was
added NaClO2 (1.21 g, 10.7 mmol, 2.5 equiv) in water (20 mL). The
reaction was monitored by TLC until completion (ca. 30 min) at
which point it was poured into a half-saturated solution of sodium
sulfate (75 mL) and acidified with HCl (2 M solution, 10 mL). The
aqueous layer was extracted with CH2Cl2 (5ꢂ75 mL) and the
combined organic layers were washed with brine and dried over
MgSO4. Solvent was removed under reduced pressure, and the
crude oil was dissolved in MeOH (50 mL) and CH2Cl2 (50 mL) and
a stir bar was added. To the solution was added TMSediazo-
methane (1.0 M solution) dropwise until the yellow color persists
(ca. 3 mL). The reaction mixture was stirred an additional 5 min
before excess acetic acid (5 mL) was added in one portion and the
color dissipates. Volatiles were removed under reduced pressure
and the oil was purified by flash chromatography (20% EtOAc/Hex)
to give methyl ester 41 (786 mg, 2.79 mmol, 65%). Rf 0.32 (50%
CDCl3)
d
7.25 (d, J¼8.6 Hz, 2H), 6.86 (d, J¼8.6 Hz, 2H), 4.66 (dd,
J¼5.5, 2.3 Hz, 1H), 4.42 (s, 2H), 4.23 (td, J¼8.8, 6.2 Hz, 1H), 3.97 (dd,
J¼8.4, 5.7 Hz, 1H), 3.79 (s, 3H), 3.67e3.55 (m, 3H), 2.47 (d, J¼1.9 Hz,
1H), 2.33 (dt, J¼12.4, 6.5 Hz, 1H), 2.02e1.93 (m, 1H), 1.89 (ddd,
J¼14.3, 7.2, 3.1 Hz, 1H), 1.84e1.77 (m, 1H), 1.57 (s, 3H), 1.38 (s, 3H),
1.24e1.13 (m, 2H), 1.02 (d, J¼6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
d
4.66 (dd, J¼5.6, 2.0 Hz,
1H), 4.26 (dd, J¼15.2, 8.8 Hz, 1H), 3.99 (dd, J¼8.2, 5.9 Hz, 1H), 3.93
(dt, J¼8.5, 6.0 Hz, 1H), 3.66 (s, 3H), 2.66 (dd, J¼15.5, 6.1 Hz, 1H), 2.51
(dd, J¼15.5, 6.1 Hz, 1H), 2.48 (d, J¼2.3 Hz, 1H), 2.36 (dt, J¼12.4,
6.4 Hz,1H), 2.10e2.04 (m,1H),1.55 (s, 3H),1.36 (s, 3H),1.25e1.19 (m,
1H), 1.02 (d, J¼7.0 Hz, 3H). The product was of insufficient purity to
obtain a 13C NMR and was used without further purification.
d
159.1, 130.7, 129.2, 113.7, 111.5, 83.1, 81.4, 80.1, 77.8, 75.4, 72.6, 67.3,
66.7, 55.2, 39.3, 37.7, 33.8, 29.7, 27.8, 26.3, 16.5.
5.1.32. 2-((2S,3R,5R)-5-((4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-
dioxolan-4-yl)-3-methyltetrahydrofuran-2-yl)ethanol (40).
5.1.34. Methyl 2-((2S,3R,5R)-5-((4S,5S)-2,2-dimethyl-5-(1-(tributyl-
stannyl)vinyl)-1,3-dioxolan-4-yl)-3-methyltetrahydrofuran-2-yl)ace-
tate (2).
The PMB ether (39) (1.58 g, 4.22 mmol, 1 equiv) was dissolved in
CH2Cl2 (150 mL), water (20 mL), and saturated sodium bicarbonate
(20 mL). DDQ (1.91 g, 8.44 mmol, 2 equiv) was added in one portion
and the reaction mixture was rigorously stirred for 1.5 h at which
point the reaction was judged to be complete by TLC analysis. The
reaction mixture was poured into a rapidly stirring solution of half-
saturated sodium bicarbonate (300 mL) and half-saturated sodium
To a flask containing BHT (5 mg, catalytic) and Mo(CO)3(NCtBu)3
(119 mg, 0.28 mmol, 0.1 equiv) was added alkyne 41 (786 mg,
2.79 mmol, 1.0 equiv) in THF (60 mL). To the solution was added
tributyltinhydride (2.44 g, 8.37 mmol, 3.0 equiv) and the reaction
mixture was heated to 55 ꢀC and monitored by TLC until complete

8644
N.A. Morra, B.L. Pagenkopf / Tetrahedron 69 (2013) 8632e8644
(24 h). Upon completion, the reaction mixture was loaded onto
a silica gel column buffered with 1% triethylamine and eluted with
3e5% EtOAc/hexanes to give 2 as a yellow oil (1.09 g, 1.89 mmol,
pure alcohol as a yellow oil (33.4 mg, 0.071 mmol, 97% yield).
Spectral data were identical to the reported literature.3c
68%). Rf 0.57 (20% EtOAc/Hex); 1H NMR (400 MHz, CDCl3)
d 5.90 (s,
Acknowledgements
2H), 5.41 (s, 1H), 4.82 (d, J¼5.4 Hz, 1H), 4.05 (t, J¼6.7 Hz, 1H),
3.92e3.88 (m, 1H), 3.67 (s, 3H), 2.62 (dd, J¼15.0, 6.2 Hz, 1H), 2.46
(dd, J¼14.7, 6.4 Hz, 1H), 2.10 (dt, J¼12.5, 6.4 Hz, 1H), 1.96e1.91 (m,
1H), 1.52e1.48 (m, 6H), 1.36e1.30 (m, 6H), 1.02 (d, J¼6.4 Hz, 3H),
0.97e0.93 (m, 3H), 0.90 (t, J¼7.0 Hz, 9H). 13C NMR (100 MHz, CDCl3)
We thank the Natural Sciences and Engineering Council
of Canada (NSERC) for financial support of this work. N.A.M.
acknowledges NSERC for a CGS-D scholarship. We thank Mr. Jona-
than Dube and Professor Paul Ragogna (UWO) for a generous
donation of 42.
d
171.5, 115.3, 111.5, 81.8, 81.7, 81.2, 81.1, 79.9, 78.0, 75.6, 75.5, 66.7,
66.6, 51.6, 51.5, 39.5, 38.9, 38.8, 38.8, 37.4, 27.6, 26.2, 26.2, 16.6.
Supplementary data
5.1.35. Methyl 2-((2S,3R,5R)-5-((1R,2R)-1,2-dihydroxybut-3-ynyl)-3-
methyltetrahydrofuran-2-yl)acetate.
1H, 13C NMR spectra of all new compounds. Supplementary data
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2013.07.026.
References and notes
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reaction was monitored by TLC until complete (ca. 6 h), at which
point it was diluted with water (30 mL) and EtOAc (30 mL). The
aqueous layer was extracted with EtOAc (3ꢂ20 mL) and the
combined organic layers were washed with brine, and dried
with MgSO4. Solvent was removed under reduced pressure, and
the crude product was purified by column chromatography
(50% EtOAc/Hex) to afford alcohol 43 as a yellow oil (17.7 mg,
0.073 mmol, 84.3% yield). Rf 0.73 (60% EtOAc/Hex); 1H NMR
3. (a) C(18)eC(34): Roy, S.; Spilling, C. D. Org. Lett. 2010, 12, 5326e5329; (b) C(1)e
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4.51e4.43 (m, 2H), 3.87 (td, J¼8.9, 3.7 Hz, 1H),
€
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J¼8.2 Hz, 1H), 2.59e2.52 (m, 2H), 2.48e2.42 (m, 1H), 2.12 (dt,
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d 171.5, 115.3, 111.5, 81.8,
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To a solution of alcohol 43 (17.7 mg, 0.073 mmol,1 equiv) in DMF
(2 mL) was added imidazole (25 mg, 0.365 mmol, 5.0 equiv), fol-
lowed by TBSCl (28.4 mg, 0.182 mmol, 2.5 equiv) and DMAP (5 mg,
catalytic). The reaction mixture was heated to 60 ꢀC allowed to stir
overnight (ca. 16 h) before being cooled to rt and poured into a half-
saturated solution of NH4Cl (20 mL), and the aqueous layer was
extracted with CH2Cl2 (3ꢂ30 mL) and the combined organic layers
were washed with brine and dried over MgSO4. Solvent was re-
moved under reduced pressure to give the TBS alcohol 44, which
was purified by column chromatography (5% EtOAc/Hex) to give the
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