Studies on the synthesis of reidispongiolide A: Stereoselective synthesis of the C(22)-C(36) fragment

Article abstract of DOI:10.1016/j.tet.2011.10.029

A highly stereoselective synthesis of the C(22)-C(36) fragment 2 of reidispongiolide A is described. This synthesis features the highly stereoselective mismatched double asymmetric crotylboration reaction of the aldehyde derived from 5 and the new chiral

Full text of DOI:10.1016/j.tet.2011.10.029

Tetrahedron 67 (2011) 10274e10280
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Studies on the synthesis of reidispongiolide A: stereoselective synthesis
of the C(22)eC(36) fragment
*
Maben Ying, William R. Roush
Department of Chemistry, The Scripps Research Institute, Florida, 130 Scripps Way, Jupiter, FL 33458, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2011
Received in revised form 7 October 2011
Accepted 10 October 2011
Available online 18 October 2011
A highly stereoselective synthesis of the C(22)eC(36) fragment 2 of reidispongiolide A is described. This
synthesis features the highly stereoselective mismatched double asymmetric crotylboration reaction of
the aldehyde derived from 5 and the new chiral reagent (S)-(E)-7 that provides 12 with >15:1 dr.
Subsequent coupling of the derived vinyl iodide 3 with aldehyde 16 provided allylic alcohol 17, that was
elaborated by three steps into the targeted reidispongiolide fragment 2.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Studies on the synthesis of
reidispongiolide A
Mismatched double asymmetric
crotylboration
Stereoselective synthesis of the anti,anti
stereotriad
1. Introduction
The reidispongiolides and sphinxolides are structurally related,
biologically active families of marine natural products isolated from
the New Caledonian sponges Reidispongia coerulea and Neosiphonia
superstes.1e4 According to previous research, these compounds in-
hibit actin filament assembly assembling and induce F-actin de-
polymerization.5 These compounds also have the ability to
circumvent multi-drug resistance mediated by P-glycoprotein in
cell-based assays.5 Reidispongiolide A, the most active member of
reidispongiolide family, exhibits potent cytotoxicity against various
human cancer cell lines (IC50 0.01e0.16 m
g/mL).3
Fig. 1. Structures of selected members of the reidispongiolideesphinxolide natural
The relative configuration of the C(7), C(10e15), C(24e28), and
C(32e33) subunits of sphinxolide B were first assigned by J-based
NMR methods.6 The relative and absolute stereochemistry of the
C(17e22)7, C(22e35),8 and C(5e16)9 subunits of reidispongiolide A
were assigned via asymmetric synthesis. The absolute configura-
tion of this family of natural products was determined from the
actin-bound X-ray crystal structure of reidispongiolide A (Fig. 1).10
The structure complexity and biological properties of reidis-
pongiolide A have stimulated interest in its synthesis. The total
synthesis of reidispongiolide A was reported by Paterson and
co-workers in 2007.11,9,12 More recently, Suenaga and co-workers
products.
reported the synthesis of the C(11e22) and C(23e35) fragments of
1.13 Because recent research suggests that the C(24)eC(36) side
chain plays a very important role in the binding of the reisipongio-
lides to the actin target,14,15 we have focused our current efforts on
this segment of the natural product.
We report here a highly stereoselective synthesis of the reidis-
pongiolide A C(22)eC(36) subunit 2 that proceeds along the general
outline of the retrosynthetic analysis that is presented in Scheme 1.
The synthetic target 2 possesses seven stereocenters, including the
C(26)eC(28) antieanti stereotriad that represents a historically
difficult challenge for synthesis via asymmetric aldol or crotylme-
talation reactions,16 as this bond construction is stereochemically
* Corresponding author. Tel.: þ1 561 228 2450; fax: þ1 561 228 3052; e-mail
address: roush@scripps.edu (W.R. Roush).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.029

M. Ying, W.R. Roush / Tetrahedron 67 (2011) 10274e10280
10275
mismatched. However, synthesis of the anti, anti stereotriad with
exceptional stereochemical control is now possible by virtue of the
remarkable enantioselectivity of the new -stannyl crotylborane 7,
a
that is, accessible via enantioselective hydroboration of racemic
allene 8 with diisopinocampheylborane [(Ipc)2BH].17,18 Thus, by
application of this new crotylboration technology we anticipated
that vinyl iodide intermediate 3 could be assembled via
a-stan-
nylcrotylboration of the aldehyde deriving from 5 with the chiral
reagent (S)-(E)-7. Similarly, we anticipated that vinyl iodide frag-
ment 4 would be accessible via
hyde deriving from 6 with the
a
-stannylallylboration of the alde-
a
-stannylallylborane (R)-9, that is,
readily accessible via the hydroboration of allenylstannane 10 with
[(lIpc)2BH].19
Scheme 2. Synthesis of vinyl iodide 3.
Alcohol 6 also served as the starting material for synthesis of
vinyl iodide fragment 4 (Scheme 4). The aldehyde generated by
Swern oxidation of 6 was added to a ꢀ78 ꢁC solution the
a-stan-
nylallylborane reagent (R)-9, generated by the hydroboration of
allenylstannane 10 with (lIpc)2BH as previously described,19 to
give 14 in 67% yield and with >50:1 dr. The (R)-stereochemistry of
the hydroxyl group of 14 was assigned by using the Mosher ester
method. Treatment of 14 with I2 followed by alcohol O-methyla-
tion gave vinyl iodide 4 in 80% yield. Deprotection of PMB ether of
4 gave the primary alcohol 15 in 76% yield, which was then oxi-
dized under DesseMartin oxidation26 conditions to give aldehyde
16. Aldehyde 16 is not stable for long-term storage and was usually
freshly prepared before immediately before use in subsequent
chemistry (Scheme 3).
Scheme 1. Retrosynthetic analysis of 2.
2. Results and discussion
The synthesis of fragment 3 (Scheme 2) starts from the primary
alcohol 6, which is prepared in two steps from commercially
available precuresors.20 Alcohol 6 was oxidized to the corre-
sponding aldehyde using a Swern procedure21 and then the alde-
hyde was treated with the diisopropyl (R,R)-tartrate (E)-
crotylboronate reagent22 to give the known homoallylic alcohol 11
in 88% yield with 14:1 diastereoselectivity.23 Protection of the hy-
droxyl group of 11 as a TBS ether followed by PMB ether depro-
tection with DDQ24 provided primary alcohol 5 in 69% yield over
the two steps. Alcohol 5 was then oxidized to the corresponding
aldehyde and then added to a solution of a-stannylcrotylborane (S)-
(E)-7 that was generated, as previously described, via the hydro-
boration of racemic allene 8 with (dIpc)2BH.17 This reaction pro-
ceeded overnight at ambient temperature and provided the
vinylstannane product 12, with the requisite antieanti stereo-
chemistry at C(26e28), in 66% yield with >15:1 dr. The stereo-
chemistry of 12 was assigned by analogy to related mismatched
double asymmetric reactions described elsewhere.18 Treatment of
12 with I2 in Et2O effected tineiodine exchange and afforded vinyl
iodide 13 in 73% yield. O-Methylation of the hindered hydroxyl
group of 13 proved challenging. Attempted use of NaH and MeI for
this step caused partial migration of the TBS unit between two
hydroxyl groups, while use of Me3OBF4 and Proton SpongeÒ led to
partial deprotection of TBS ether. Fortunately, use of MeOTf and 2,6-
di-tert-butylpyridine resulted in a very clean reaction that provided
3 in 85% yield.25
Scheme 3. Synthesis of vinyl iodide 4 and elaboration to aldehyde 16.
Treatment of vinyl iodide 3 with t-BuLi at ꢀ78 ꢁC generated the
corresponding the vinyllithium intermediate which was then
treated with aldehyde 16, also at ꢀ78 ꢁC. This reaction gave alcohol
17 in 50% yield as a ca. 2:1 mixture of diastereomers (Scheme 4).
This mixture was of no consequence, as both alcohols smoothly
were oxidized in the next step upon treatment with the
DesseMartin periodinane reagent. The resulting enone was then

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M. Ying, W.R. Roush / Tetrahedron 67 (2011) 10274e10280
chiral reagent (S)-(E)-7 that provides 12 with >15:1 dr. Subsequent
coupling of the derived vinyl iodide 3 with aldehyde 16 provided
allylic alcohol 17, that was elaborated by three steps into the tar-
geted reidispongiolide fragment 2. This work sets the stage for
further studies on the chemistry and biology of reidispongiolide A,
that will be reported in due course.
4. Experimental
4.1. General experimental details
All reaction solvents were purified before use. Tetrahydrofuran,
dichloromethane, diethyl ether, and toluene were purified by
passing through a solvent column composed of activated A-1 alu-
mina. Unless indicated otherwise, all reactions were conducted
undeꢁr an atmosphere of argon using flame-dried or oven-dried
ꢀ
(170 C) glassware. 4 A molecular sieves were activated under
Scheme 4. Initial studies on the coupling of vinyl iodide 3 and aldehyde 16.
high vacuum with at 180 ꢁC for 12 h and re-activated through
flame-drying immediately prior to use.
treated with Stryker’s copper hydride reagent27 to give ketone 18 in
60% yield from 17. It was anticipated that 18 would be a suitable
substrate for introduction of the N-methylformamide unit, by ap-
plication of Porco’s procedure.28e31 While this proved to be the
case, a small amount of epimerization occurred at C(32) in the
conversion of 18 to 2 owing to the basicity of these reaction con-
ditions. Unfortunately, the epimerization at C(32) could not be
avoided, and the best result that we obtained was a 13:1 mixture of
2 and its (C32)-epimer.
Fortunately, this epimerization process could be avoided by in-
troducing the N-methyl formamide unit prior to oxidation of the
C(31)-alcohols (Scheme 5). Thus, the N-methyl formamide was
introduced at the stage of alcohol 17 to give 19 in 72% yield.30,31
Subsequent oxidation of 19 with the DesseMartin periodinane re-
agent, followed by reduction of the enone using Stryker’s copper
hydride reagent afforded 2 in 50% over the final two steps. The 1H
NMR spectrum of 2 showed no evidence of epimerization of the
C32 stereocenter.
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on commercial instruments at 400 or 500 MHz. Carbon-13
nuclear magnetic resonance (13C NMR) spectra were recorded at
100 MHz. The proton signal for residual non-deuterated solvent (
for CHCl3) was used as an internal reference for 1H NMR spectra. For
13C NMR spectra, chemical shifts are reported relative to the
77.16
resonance of CHCl3. Coupling constants are reported in Hz. Infrared
(IR) spectra were recorded as films on an FTIR instrument. Mass
spectra were recorded on a commercial spectrometer. Optical rota-
tions were measured at 25 ꢁC on a polarimeter using a 10-cm, 1-mL
quartz cell.
d7.26
d
4.2. Experimental procedures
4.2.1. (2S,3S,4S)-1-((4-Methoxybenzyl)oxy)-2,4-dimethylhex-5-en-
3-ol (11). A solution of the oxalyl chloride (1 mL, 11.4 mmol) in dry
CH2Cl2 (20 mL) was added DMSO (1.86 mL, 26 mmol) dropwise at
ꢀ78 ꢁC. This mixture was stirred for 15 min, then a solution of al-
cohol 6 (2.10 g, 10 mmol) in CH2Cl2 (10 mL) was added dropwise.
The reaction mixture was stirred at ꢀ78 ꢁC for 30 min. Diisopro-
pylethylamine (9.2 mL, 52.8 mmol) was then added and the mix-
ture was allowed to warm to room temperature. The mixture was
diluted with Et2O (100 mL). The organic phase was separated and
washed with 1 N HCl, sat aqueous NaHCO3 solution and brine, and
then dried over MgSO4. Filtration and concentration of this solution
under reduced pressure provided the aldehyde as colorless oil,
which was used immediately in the next step without further
purification.
A 1.0 M solution of diisopropyl (R,R)-tartrate (E)-crotylboronate
ꢀ
in toluene (20 mL, 20 mmol) was added to a slurry of powdered 4 A
molecular sieves (0.4 g) in toluene (10 mL) at ambient temperature.
The mixture was stirred for 20 min, then was cooled to ꢀ78 ꢁC and
a solution of the aldehyde in toluene (10 mL) was added dropwise.
After being stirred for 8 h at ꢀ78 ꢁC, the reaction mixture was
quenched by 1 M NaOH (40 mL). The resulting two-phase mixture
was stirred vigorously for 30 min, and extracted with Et2O
(3ꢂ50 mL). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated. Purification of the crude
product by column chromatography (4:1 hexanes/EtOAc) provided
the known alcohol 11 (2.32 g, 88% for two steps) as colorless oil.23
Scheme 5. Completion of the synthesis of 2.
3. Conclusion
4.2.2. (2S,3S,4S)-3-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylhex-5-
en-1-ol (5). A solution of the alcohol 11 (1.79 g, 6.8 mmol) and 2,6-
lutidine (1.6 mL, 13.6 mmol) in CH2Cl2 (60 mL) at ꢀ78 ꢁC was
treated with TBSOTf (1.85 mL, 10.2 mmol). The reaction mixture
was stirred for 1 h and warmed to 0 ꢁC over 30 min. The reaction
was quenched by addition of saturated aqueous NaHCO3 (30 mL).
In summary, we have developed a highly stereoselective syn-
thesis of C(22)eC(36) fragment 2 of reidispongiolide A that features
the highly stereoselective mismatched double asymmetric cro-
tylboration reaction of the aldehyde derived from 5 and the new

M. Ying, W.R. Roush / Tetrahedron 67 (2011) 10274e10280
10277
The resulting mixture was extracted with CH2Cl2 (3ꢂ30 mL). The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated. Purification of the crude product by
column chromatography (9:1 hexanes/EtOAc) provided the known
TBS ether (2.29 g, 89%) as a colorless oil.23
(381 mg,1.5 mmol) at room temperature. After being stirred for 1 h,
the reaction was diluted with saturated aqueous Na2S2O3. The or-
ganic layer was separated and the aqueous layer was extracted with
Et2O (3ꢂ20 mL). The combined organic layers were treated with
KF/Celite (700 mg per mmol of 12). This solution was stirred vig-
orously for at least 2 h and then filtered through Celite. Purification
of the crude product by column chromatography (9:1 hexanes/
Et2O) provided the vinyl iodide 13 (406 mg, 73%) as a colorless oil:
To a 0 ꢁC stirred CH2Cl2 solution (40 mL) of the above TBS ether
(2.29 g, 6.06 mmol) was added a small amount of pH 7 buffer (5%
relative to CH2Cl2) followed by DDQ (1.66 g, 7.3 mmol). The
resulting mixture was stirred at 0 ꢁC for 30 min, then was allowed
to warm to room temperature and stirred for another 30 min. The
mixture was then diluted with saturated aqueous NaHCO3 (50 mL)
and was extracted with CH2Cl2 (3ꢂ50 mL). The combined organic
layers were treated with NaBH4 (500 mg, 12.5 mmol) and then
washed with saturated aqueous NaHCO3, and brine. The extracts
were dried over MgSO4, filtered, and concentrated. Purification of
the crude product by column chromatography (4:1 hexanes/EtOAc)
provided the known alcohol 5 (1.23 g, 78%) as a colorless oil.32
[a
]
ꢀ17.6 (c 0.98, CHCl3); 1H NMR (400 MHz, CDCl3)
d 6.63 (dd,
D
J¼14.6, 9.4 Hz, 1H), 6.07e5.97 (m, 2H), 5.09e4.98 (m, 2H), 4.01 (s,
1H), 3.70 (t, J¼3.5 Hz, 1H), 3.67 (dt, J¼10.3, 2.0 Hz, 1H), 2.56e2.47
(m, 1H), 2.33e2.24 (m, 1H), 1.85e1.75 (m, 1H), 1.10 (d, J¼7.0 Hz, 3H),
1.05 (d, J¼7.0 Hz, 3H), 0.93 (s, 9H), 0.79 (d, J¼7.1 Hz, 3H), 0.13 (s, 3H),
0.08 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 147.8, 141.2, 114.7, 81.4,
76.4, 74.7, 43.9, 41.2, 40.3, 26.1, 20.3, 18.3, 17.7, 13.7, ꢀ3.9, ꢀ4.5. IR
(neat) 3480, 2959, 2930, 1640, 1602, 1463, 1254 cmꢀ1; HRMS m/z
for C18H35O2SiIH [MþH]þ calcd 439.1529 found 439.1525.
4.2.3. (3S,4S,5S,6S,7S,E)-6-((tert-Butyldimethylsilyl)oxy)-3,5,7-
trimethyl-1-(tributylstannyl)nona-1,8-dien-4-ol (12). To a solution
of oxalyl chloride (0.19 mL, 2.32 mmol) in dry CH2Cl2 (10 mL) was
added DMSO (0.36 mL, 5.1 mmol) dropwise at ꢀ78 ꢁC. This mixture
was stirred for 15 min, then a solution of alcohol 5 (500 mg,
1.93 mmol) in CH2Cl2 (3 mL) was added dropwise and the reaction
left at ꢀ78 ꢁC for 30 min. Diisopropylethylamine (1.77 mL,
10.2 mmol) was then added and the mixture was allowed to warm
to room temperature. Et2O (50 mL) was added to dilute the mix-
ture. The organic layer was separated and washed with 1 N HCl,
saturated aqueous NaHCO3 and brine, and then dried over MgSO4.
After being filtered, this solution was concentrated under vacuum
to give the aldehyde as colorless oil, which was used immediately in
the next step without further purification.
4.2.5. tert-Butyl(((3S,4S,5S,6S,7S,E)-9-iodo-6-methoxy-3,5,7-
trimethylnona-1,8-dien-4-yl)oxy)dimethylsilane (3). To a stirred so-
lution of freshly distilled MeOTf (0.52 mL, 4.7 mmol) in 2,6-di-tert-
butylpyridine (2.06 mL, 9 mmol) was added alcohol 13 (110 mg,
0.25 mmol) in CHCl3 (6 mL). The reaction mixture was then heated
to reflux for 15 h. The reaction mixture was then cooled to room
temperature and NH4OH (2 mL, aqueous) was added. The resulting
mixture was stirred for 2 h at room temperature and then was
poured into 30 mL of water. Once the organic layer separated, the
aqueous layer was extracted with CH2Cl2 (3ꢂ10 mL) and the com-
bined organic layers were washed with 1 N HCl, brine, dried over
MgSO4, and concentrated. Purification of the crude product by
column chromatography (silica gel, 100:1 hexanes/EtOAc) provided
the vinyl iodide 3 (96 mg, 81%) as a colorless oil: [
a
]
D ꢀ6.8 (c 1.04,
Generation of
a
-stannylcrotylborane (S)-(E)-7 was performed as
CHCl3); 1H NMR (400 MHz, CDCl3)
d
6.58 (dd, J¼14.6, 8.6 Hz, 1H),
follows.17 Finely powdered (dIpc)2BH (1.05, 3.86 mmol) was
weighed into a round bottom flask containing a stir bar in a glove
box. Et2O (10 mL) was added to the flask and the mixture was
cooled to 0 ꢁC. Racemic allenylstannane 8 (1.33 g, 3.86 mmol) was
added dropwise. This mixture was stirred for 5 h at 0 ꢁC, during
which time the solid (dIpc)2BH dissolved to leave a colorless solu-
tion of the reagent, (S)-(E)-7.
6.00 (dd, J¼14.6, 0.9 Hz, 1H), 5.88e5.78 (m, 1H), 5.05e4.98 (m, 2H),
3.82 (dd, J¼4.5, 2.4 Hz, 1H), 3.44 (s, 3H), 2.90 (dd, J¼8.6, 2.8 Hz, 1H),
2.51e2.41 (m, 1H), 2.34e2.23 (m, 1H), 1.74e1.65 (m, 1H), 1.10 (d,
J¼7.0 Hz, 3H), 1.01 (d, J¼7.0 Hz, 3H), 0.91 (s, 9H), 0.77 (d, J¼7.0 Hz,
3H), 0.08 (s, 3H), 0.08 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 148.3,
141.5, 114.5, 87.2, 74.9, 74.8, 60.8, 44.8, 42.9, 39.3, 26.3, 18.7, 18.2,
16.7, 11.9, ꢀ3.4, ꢀ3.5. IR (neat) 2959, 2929, 1640, 1602, 1462, 1252,
1093 cmꢀ1; HRMS m/z for C19H37O2SiIH [MþH]þ calcd 453.1686
found 453.1693.
A solution of the aldehyde (theoretically 1.93 mmol) in 3 mL of
Et2O was added at 0 ꢁC dropwise to the freshly prepared solution of
(S)-(E)-7. The mixture was allowed to warm to room temperature
and stirred overnight at room temperature. The reaction mixture
was then cooled to 0 ꢁC, then saturated aqueous NaHCO3 (6 mL) was
added followed by slow addition of 30% H2O2 (3 mL). This mixture
was stirred vigorously for 4 h at room temperature. After separation,
the aqueous layer was extracted with Et2O (3ꢂ20 mL). The com-
bined organic layers were dried over MgSO4 filtered and concen-
trated. Purification of the crude product by column chromatography
(silica gel neutralized with 1% Et3N in hexanes; 50:1 hexanes/Et2O)
providing alcohol 8 (766 mg, 66% yield over two steps) as a colorless
4.2.6. (2S,3R,E)-1-((4-Methoxybenzyl)oxy)-2-methyl-6-(tributyl-
stannyl)hex-5-en-3-ol (14). To a ꢀ78 ꢁC solution of oxalyl chloride
(0.25 mL, 2.85 mmol) in dry CH2Cl2 (10 mL) was added DMSO
(0.47 mL, 6.5 mmol) dropwise. The mixture was stirred for 15 min,
then a solution of alcohol 6 (525 mg, 2.5 mmol) in CH2Cl2 (3 mL)
was added dropwise. The reaction mixture was left at ꢀ78 ꢁC for
30 min. Diisopropylethylamine (2.3 mL, 13.2 mmol) was then
added and the mixture was allowed to warm to room temperature.
Et2O (50 mL) was added and the organic layer was washed with 1 N
HCl, saturated aqueous NaHCO3 and brine and dried over MgSO4.
The solution was filtered and then concentration under vacuum to
provide the crude aldehyde as colorless oil, which was used im-
mediately in the next step without further purification.
oil: [
a
]
D ꢀ5.2 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3)
d 6.06e5.97
(m, 2H), 5.91 (d, J¼19.2 Hz, 1H), 5.01 (m, 2H), 3.75 (dd, J¼4.1, 2.9 Hz,
1H), 3.62 (dt, J¼10.0, 2.6 Hz, 1H), 3.33 (s, 1H), 2.52e2.44 (m, 1H),
2.33e2.25 (m, 1H), 1.77 (ddd, J¼10.0, 7.1, 2.8 Hz, 1H), 1.53e1.42 (m,
6H), 1.36e1.24 (m, 6H), 1.09 (d, J¼7.0 Hz, 3H), 1.03 (d, J¼7.0 Hz, 3H),
0.94e0.83 (m, 25H), 0.80 (d, J¼7.0 Hz, 3H), 0.10 (s, 3H), 0.07 (s, 3H);
Generation of
a-stannylallylborane (R)-9 was performed fol-
lowing the literature procedure.19 Finely powdered (lIpc)2BH
(950 mg, 3.5 mmol) was weighed into a round bottom flask con-
taining a stir bar in a glove box. Toluene (10 mL) was added to the
flask and the mixture was cooled to ꢀ40 ꢁC. Allenylstannane 10
(1.65 g, 5 mmol) was added dropwise. This mixture was allowed to
warm to ꢀ20 ꢁC over 5 h, during which time the solid (lIpc)2BH
dissolved to leave a colorless solution of the reagent (R)-9.
13C NMR (101 MHz, CDCl3)
d 149.7,141.7,128.8,114.5, 80.2, 76.5, 44.9,
41.4, 41.0, 29.3, 27.4, 26.2,19.6,18.3,18.1,13.9,12.9, 9.6, ꢀ3.9, ꢀ4.3. IR
(neat) 3503, 2957, 2927, 1641, 1596, 1464, 1252 cmꢀ1; HRMS m/z for
C30H62O2SiSnH [MþH]þ calcd 603.3619, found 603.3645.
4.2.4. (3S,4S,5S,6S,7S,E)-6-((tert-Butyldimethylsilyl)oxy)-1-iodo-
3,5,7-trimethylnona-1,8-dien-4-ol (13). To
a
solution of vinyl-
A ꢀ78 ꢁC solution of the aldehyde (theoretically 2.5 mmol) in
3 mL toluene was added dropwise to the freshly prepared solution
stannane 12 (766 mg, 1.27 mmol) in Et2O (20 mL) was added iodine

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M. Ying, W.R. Roush / Tetrahedron 67 (2011) 10274e10280
of
a
-stannylallylborane (R)-9 in toluene. The mixture was stirred
1H), 2.44 (dddd, J¼15.1, 6.5, 4.8, 1.5 Hz, 1H), 2.30e2.21 (m, 1H),
1.89e1.80 (m, 1H), 0.91e0.86 (m, 3H). 13C NMR (101 MHz, CDCl3)
overnight at ꢀ78 ꢁC. The reaction was then allowed to warm to 0 ꢁC.
To this mixture was added saturated aqueous NaHCO3 (6 mL) fol-
lowed by slow addition of 30% H2O2 (3 mL). This mixture was
stirred vigorously for 4 h at room temperature. After separation of
the two phases, the aqueous layer was extracted with Et2O
(3ꢂ20 mL). The combined organic layers were dried over MgSO4
and concentrated. Purification of the crude product by column
chromatography (silica gel neutralized with 1% Et3N in hexanes;
85:15 hexanes/Et2O) provided alcohol 14 (900 mg, 67% yield over
d
141.9, 85.1, 77.0, 66.9, 57.8, 38.0, 36.9, 13.9. IR (neat) 3405, 2928,
1606, 1083 cmꢀ1; HRMS m/z for C8H15O2IH [MþH]þ calcd 271.0195
found 271.0204.
4.2.9. (1E,4R,5S,7E,9S,10S,11S,12S,13S)-12-((tert-Butyldimethylsilyl)
oxy)-1-iodo-4,10-dimethoxy-5,9,11,13-tetramethylpentadeca-1,7,14-
trien-6-ol (17). To a solution of DesseMartin periodinane (154 mg,
0.35 mmol) in CH2Cl2 (5 mL) was added alcohol 15 (81 mg,
0.3 mmol) in CH2Cl2 (3 mL). Once the reaction was complete (TLC
monitoring), Et2O (10 mL), saturated aqueous NaHCO3 (5 mL), and
Na2S2O3 (1 mL) were added. The organic layer was separated and
aqueous layer was extracted with Et2O (3ꢂ10 mL). The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated. The crude aldehyde 16 was used immediately with-
out purification in the next step.
two steps) as a colorless oil: [
(400 MHz, CDCl3)
6.10e5.96 (m, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.63e3.56 (m, 1H), 3.55
(dd, J¼9.2, 4.7 Hz, 1H), 3.47 (dd, J¼9.2, 6.7 Hz, 1H), 3.08 (d, J¼3.5 Hz,
1H), 2.48e2.40 (m, 1H), 2.30e2.21 (m, 1H), 1.92e1.81 (m, 1H),
1.53e1.44 (m, 6H), 1.33e1.26 (m, 6H), 0.92e0.85 (m, 18H). 13C NMR
a
]
þ2.2 (c 1.15, CHCl3); 1H NMR
D
d
7.27e7.23 (m, 2H), 6.91e6.84 (m, 2H),
(101 MHz, CDCl3)
d 151.4, 145.7, 131.6, 130.3, 129.4, 114.0, 74.8, 74.4,
73.2, 55.4, 43.8, 38.0, 29.3, 27.4, 14.0, 13.9, 9.6. IR (neat) 3479, 2924,
1613, 1512, 1247 cmꢀ1; HRMS m/z for C27H48O3SnH [MþH]þ calcd
541.2704 found 541.2711.
t-BuLi (0.4 mmol, 0.25 mL, 1.6 M in pentane) was added drop-
wise to a ꢀ78 ꢁC solution of vinyl iodide 3 (91 mg, 0.2 mmol) in THF
(2 mL). The mixture was stirred for 30 min, then a solution of al-
dehyde 16 (prepared from 0.3 mmol of alcohol 15) in THF (1 mL)
was added dropwise. The mixture was stirred at ꢀ78 ꢁC for addi-
tional 1.5 h, then the reaction mixture was allowed to warm to 0 ꢁC.
Saturated aqueous NH4Cl solution was then added to terminate the
reaction. The organic layer was separated and aqueous layer was
extracted with Et2O (3ꢂ10 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated. Purification of the
crude product by column chromatography (9:1 hexanes/EtOAc)
provided the alcohol 17 (58 mg, 50%) as a colorless oil, as a mixture
of two isomers (2:1 ratio). This mixture was carried to next step
4.2.7. 1-((((2S,3R,E)-6-Iodo-3-methoxy-2-methylhex-5-en-1-yl)oxy)
methyl)-4-methoxybenzene (4). To a solution of vinylstannane 14
(900 mg, 1.67 mmol) in Et2O (30 mL) was added iodine (460 mg,
1.8 mmol) at room temperature. The mixture was stirred for 1 h,
then saturated aqueous Na2S2O3 was added to reduce remaining
iodine. The organic phase was separated and the aqueous phase
was extracted with Et2O (3ꢂ30 mL). The combined organic layers
were treated with KF/Celite (700 mg per mmol of 14). This mixture
was stirred vigorously for at least 2 h and then filtered through
Celite. Purification of the crude product by column chromatography
(4:1 hexanes/EtOAc) provided the vinyl iodide product (618 mg,
1.64 mmol) as a colorless oil.
To a mixture of the above vinyl iodide (618 mg, 1.64 mmol) and
MeI (1.05 mL, 16.4 mmol) in DMF (10 mL) was added 60% NaH in
mineral oil (140 mg, 3.5 mmol). The reaction was stirred overnight
at room temperature. The mixture wasp poured into 50 mL water,
then the aqueous layer was separated and extracted with CH2Cl2
(3ꢂ30 mL). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated. Purification of the crude
product by column chromatography (4:1 hexanes/EtOAc) provided
the product 4 (524 mg, 80% yield over two steps) as a colorless oil:
without separation. 1H NMR (400 MHz, CDCl3)
d 6.63e6.48 (1H),
6.16e6.05 (1H), 5.90e5.59 (2H), 5.48e5.33 (1H), 5.03e4.92 (2H),
4.26 (1H), 3.86 (1H), 3.51e3.43 (3H), 3.39e3.33 (3H), 3.30e3.22
(1H), 2.91 (2H), 2.52e2.37 (2H), 2.33e2.17 (2H), 1.86e1.74 (1H),
1.74e1.64 (1H), 1.15e1.09 (3H), 1.01e0.96 (m, 3H), 0.90 (9H),
0.88e0.82 (m, 3H), 0.79e0.73 (m, 3H), 0.11e0.07 (m, 6H).
4.2.10. (4R,5R,9S,10S,11S,12S,13S,E)-12-((tert-Butyldimethylsilyl)
oxy)-1-iodo-4,10-dimethoxy-5,9,11,13-tetramethylpentadeca-1,14-
dien-6-one (18). To a solution of DesseMartin periodinane (44 mg,
0.1 mmol) in CH2Cl2 (1 mL) was added alcohol 17 (46 mg,
0.078 mmol) in CH2Cl2 (1 mL). Once the reaction was complete (TLC
monitoring), Et2O (5 mL), saturated aqueous NaHCO3 (2 mL), and
Na2S2O3 (0.5 mL) were added. The organic layer was separated and
the aqueous layer was extracted with Et2O (3ꢂ10 mL). The com-
bined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated to give crude product ketone (42 mg).
This crude product was used directly in the next step without
purification.
[
a
]
ꢀ28.6 (c 1.07, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.26e7.22
D
(m, 2H), 6.92e6.84 (m, 2H), 6.56 (dt, J¼14.6, 7.4 Hz, 1H), 6.04 (dt,
J¼14.4, 1.3 Hz, 1H), 4.42 (s, 2H), 3.81 (s, 3H), 3.38 (qd, J¼9.1, 5.8 Hz,
2H), 3.32 (s, 3H), 3.24e3.18 (m, 1H), 2.26 (dddd, J¼14.8, 7.1, 4.2,
1.4 Hz, 1H), 2.20e2.11 (m, 1H), 2.07e1.96 (m, 1H), 0.90 (d, J¼7.0 Hz,
3H). 13C NMR (101 MHz, CDCl3)
d 159.3, 143.2, 130.8, 129.3, 113.9,
81.3, 76.7, 72.9, 72.0, 57.8, 55.4, 36.7, 36.4, 13.1. IR (neat) 2904, 1612,
1512, 1244, 1086 cmꢀ1; HRMS m/z for C16H23O3INa [MþNa]þ calcd
413.0590 found 413.0592.
To a solution of Stryker’s copper hydride reagent ([PPh3CuH]6;
78 mg, 0.04 mmol) in 2 mL of degassed toluene was added the
above enone as a solution in toluene (1 mL, degassed) and 1 drop of
water via syringe. The mixture was stirred overnight at room
temperature, then was diluted with 20 mL of CH2Cl2. The combined
organic layers were washed with saturated aqueous NH4Cl solu-
tion, brine, dried over MgSO4, and concentrated. Purification of the
crude product by column chromatography (9:1 hexanes/EtOAc)
provided the ketone 18 (28 mg, 60% over two steps) as a colorless
4.2.8. (2S,3R,E)-6-Iodo-3-methoxy-2-methylhex-5-en-1-ol (15). To
a stirred 0 ꢁC solution of 4 (548 mg, 1.41 mmol) in CH2Cl2 (5 mL)
containing a small amount of pH 7 buffer (5% relative to CH2Cl2)
was added DDQ (522 g, 2.3 mmol). The mixture was stirred at 0 ꢁC
for 30 min, then was allowed to warm to room temperature and
stirred for another 30 min. Saturated aqueous NaHCO3 (20 mL)
was added, then the mixture was extracted with CH2Cl2
(3ꢂ20 mL). The combined organic layers were washed with satu-
rated aqueous NaHCO3, brine, dried over MgSO4, and concentrated.
Purification of the crude product by column chromatography
provided the primary alcohol 15 (290 mg, 76%) as a colorless oil:
oil: [
a]
ꢀ30.7 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d 6.56
D
(ddd, J¼14.7, 8.4, 6.5 Hz, 1H), 6.12 (dt, J¼14.5, 1.3 Hz, 1H), 5.92e5.79
(m, 1H), 5.06e4.96 (m, 2H), 3.84 (dd, J¼4.5, 2.1 Hz, 1H), 3.45e3.41
(m, 4H), 3.27 (s, 3H), 2.88 (dd, J¼8.3, 3.3 Hz, 1H), 2.76e2.67 (m, 1H),
2.55 (ddd, J¼17.5, 9.2, 5.3 Hz, 1H), 2.49e2.37 (m, 2H), 2.34e2.26 (m,
1H), 2.19e2.08 (m, 1H), 1.83e1.69 (m, 2H), 1.65 (ddd, J¼13.5, 6.8,
3.4 Hz, 1H), 1.44e1.33 (m, 1H), 1.01 (d, J¼7.0 Hz, 3H), 0.97 (d,
J¼6.9 Hz, 3H), 0.96 (d, J¼7.0 Hz, 3H), 0.91 (s, 9H), 0.81 (d, J¼7.0 Hz,
[
a
]
ꢀ41.4 (c 1.15, CHCl3); 1H NMR (400 MHz, CDCl3)
d 6.55 (ddd,
D
J¼14.7, 8.1, 6.8 Hz, 1H), 6.12 (dt, J¼14.4, 1.4 Hz, 1H), 3.67e3.54 (m,
2H), 3.39 (s, 3H), 3.19 (dt, J¼7.4, 4.9 Hz, 1H), 2.75 (dd, J¼7.0, 4.3 Hz,

M. Ying, W.R. Roush / Tetrahedron 67 (2011) 10274e10280
10279
3H), 0.09 (s, 2H), 0.08 (s, 3H). 13C NMR (101 MHz, CDCl3)
d
213.6,
periodinane (44 mg, 0.1 mmol) in CH2Cl2 (1 mL) was added alcohol
19 (37 mg, 0.07 mmol) in CH2Cl2 (1 mL). Once the reaction was
complete (TLC monitoring), Et2O (5 mL), saturated aqueous
NaHCO3 (2 mL), and Na2S2O3 (0.5 mL) were added. The organic
layer was separated and the aqueous layer was extracted with Et2O
(3ꢂ5 mL). The combined organic layers were washed with brine,
dried over MgSO4 and concentrated to give crude product ketone
(36 mg) that was used directly in the next step without purification.
To a solution of Stryker’s copper hydride reagent ([PPh3CuH]6;
69 mg, 0.035 mmol) in 2 mL of degassed toluene was added a so-
lution of the above ketone in toluene (1 mL, degassed) and 1 drop of
water via syringe. This mixture was stirred overnight at room
temperature, then was diluted with 20 mL of CH2Cl2. The organic
layer was washed with saturated aqueous NH4Cl solution, and
brine, then dried over MgSO4, filtered, and concentrated. Purifica-
tion of the crude product by column chromatography (1:1 hexanes/
EtOAc) provided product 2 (18 mg, 50% over two steps) as a color-
less oil. This material was showed no evidence of C(32) epimeri-
zation, but was a mixture of formamide rotamers. Otherwise, the
spectroscopic properties of this material were the same as de-
scribed above.
141.8, 141.7, 114.3, 88.8, 81.5, 77.1, 75.0, 60.9, 57.9, 49.1, 45.0, 41.6,
38.9, 36.4, 34.5, 26.3, 24.2, 18.7, 17.7, 16.7, 12.8, 12.3, ꢀ3.4, ꢀ3.5. IR
(neat) 2959, 2931, 1716, 1462, 1253, 1095 cmꢀ1; HRMS m/z for
C27H51O4SiIH [MþH]þ calcd 595.2680 found 595.2678.
4.2.11. N-((4R,5R,9S,10S,11S,12S,13S,E)-12-((tert-Butyldimethylsilyl)
oxy)-4,10-dimethoxy-5,9,11,13-tetramethyl-6-oxopentadeca-1,14-
dien-1-yl)-N-methylformamide (2). N-Methyl formamide (0.1 mL),
Cs2CO3 (26 mg, 0.08 mmol), CuTC (9 mg, 0.045 mmol), and 1,10-
phenanthroline (16 mg, 0.09 mmol) were placed in a flame-dried
10 mL Schlenk tube with a stir bar. Vinyl iodide 18 (27 mg,
0.045 mmol) in 1 mL of anhydrous DMA was added and the sys-
tem was degassed under vacuum until gas evolution ceased. The
mixture was heated to 45 ꢁC for 18 h. The reaction mixture was
then diluted with Et2O and pH 7 buffer. The organic layer was
separated and the aqueous layer was extracted with Et2O. The
combined organic layers was washed with brine, dried over
MgSO4, filtered, and concentrated. Purification of the crude
product by column chromatography (1:1 hexanes/EtOAc) provided
the product 2 (12 mg, 50%, 75% based on recovered starting ma-
terial) as a colorless oil. The product contains two amide rotamers
at room temperature, and was a 12:1 mixture of epimers at C(32):
Acknowledgements
[
a
]
ꢀ25.1 (c 0.75, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.28e8.06
D
(1H, 8.28 (s, 0.7H), 8.06 (s, 0.3H)), 7.18e6.51 (1H, 7.18 (d, J¼14.6 Hz,
0.3H), 6.51 (d, J¼14.0 Hz, 0.7H)), 5.94e5.76 (m, 1H), 5.17e4.95 (m,
3H), 3.84 (dd, J¼4.4, 2.0 Hz, 1H), 3.49e3.39 (m, 4H), 3.29e3.28 (3H,
3.29 (s, 2H), 3.28 (s, 1H)), 3.06e3.03 (3H, 3.06 (s, 1H), 3.03 (s, 2H)),
2.88 (dd, J¼8.3, 3.1 Hz, 1H), 2.78e2.67 (m, 1H), 2.60e2.39 (m, 3H),
2.35e2.25 (m, 1H), 2.22e2.08 (m, 1H), 1.83e1.70 (m, 2H),
1.70e1.62 (m, 1H), 1.37 (m, 1H), 0.98 (m, 9H), 0.91 (s, 9H), 0.81 (d,
J¼7.0 Hz, 3H), 0.08 (s, 3H), 0.08 (s, 3H). 13C NMR (101 MHz, CDCl3)
We thank the National Institutes of Health (GM038436) for
support of this research. We also thank Mr. Ming Chen for his
contributions to the early stages of this project, specifically his
pioneering studies of the mismatched double asymmetric cro-
tylboration reaction leading to 12.
References and notes
d
213.8, 162.3 (160.9), 141.8, 130.5 (126.5), 114.3, 105.7 (107.3), 88.8,
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82.5, 75.0, 60.9, 57.9 (57.7), 49.0 (49.2), 45.0, 41.5 (41.3), 38.9, 34.5,
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Methyl formamide (0.2 mL), Cs2CO3 (49 mg, 0.15 mmol), CuTC
(19 mg, 0.1 mmol), 1,10-phenanthroline (36 mg, 0.2 mmol) were
placed in a flame-dried 10 mL Schlenk tube with a stir bar. A solu-
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(3H), 3.00e2.81 (2H), 2.55e2.39 (2H), 2.33e2.17 (2H), 1.88e1.78
(1H), 1.73e1.65 (1H), 1.12 (3H), 1.02e0.95 (3H), 0.93e0.88 (9H),
0.88e0.81 (3H), 0.80e0.74 (3H), 0.10e0.04 (6H).
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dien-1-yl)-N-methylformamide (2). To a solution of DesseMartin

10280
M. Ying, W.R. Roush / Tetrahedron 67 (2011) 10274e10280
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