The total synthesis of (-)-aplysin via a lithiation-borylation- propenylation sequence

Article abstract of DOI:10.1016/j.tet.2012.05.095

A concise, highly enantioselective synthesis of sesquiterpene natural products (-)-debromoaplysin and (-)-aplysin has been completed. The key steps included lithiation-borylation of a secondary benzylic carbamate to give a tertiary boronic ester followed by propenylation which installed the quaternary stereocenter with complete enantioselectivity. Subsequent RCM followed by deprotection and in situ cyclization led to debromoaplysin with good diastereoselectivity from which the target compound was prepared in just eight overall steps.

Full text of DOI:10.1016/j.tet.2012.05.095

Tetrahedron 68 (2012) 7598e7604
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The total synthesis of (ꢀ)-aplysin via a lithiationeborylationepropenylation
sequence
,
Catherine J. Fletcher a, Daniel J. Blair a, Katherine M.P. Wheelhouse b, Varinder K. Aggarwal a
*
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK
b GlaxoSmithKline UK LtD, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise, highly enantioselective synthesis of sesquiterpene natural products (ꢀ)-debromoaplysin and
(ꢀ)-aplysin has been completed. The key steps included lithiationeborylation of a secondary benzylic
carbamate to give a tertiary boronic ester followed by propenylation which installed the quaternary
stereocenter with complete enantioselectivity. Subsequent RCM followed by deprotection and in situ
cyclization led to debromoaplysin with good diastereoselectivity from which the target compound was
prepared in just eight overall steps.
Received 21 March 2012
Received in revised form 4 May 2012
Accepted 22 May 2012
Available online 28 May 2012
This paper is dedicated to Professor Manfred
Reetz, one of the most creative academics of
his generation and a pretty good tennis
player too, on the occasion of the Tetrahe-
dron Prize. Many congratulations
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Lithiationeborylation
Quaternary stereocenter
Aplysin
Total synthesis
Sesquiterpene
1. Introduction
of these, aplysin (1) has attracted the most attention with four
published enantioselective routes to date.12
Over the last 50 years, marine mollusc species aplysia and the
red algal species laurencia have provided a wealth of sesquiterpe-
noid natural products.1 These marine molluscs are known to feed
almost exclusively on the laurencia algae and sequester compounds
exhibiting antifeedant properties to protect themselves from pre-
dation.2 A number of these sesquiterpenes can be grouped together
due to structural similarities, such as aplysin (1) and debromoa-
plysin3 (2); laurinterol4 (3) and debromolaurinterol5 (4); filiformin6
(5) and debromofiliformin7 (6); 3,7-dihydroxy-dihydrolaurene8
(7); laurequinone9 (8); allolaurinterol6 (9); 7-hydroxylaurene7
(10); carabical10 (11) and laurol11 (12). All of these contain a cyclo-
pentane ring with a benzylic quaternary stereogenic centre and an
array of methyl substitutions with varying stereochemistry. The
aromatic ring in each case shows the same p-methyl, o-hydroxy
substitution relative to the quaternary centre (Fig. 1). There have
been numerous syntheses of aplysia and laurencia sesquiterpenes;
Ronald and co-workers in 198013 were the first to report a syn-
thesis of enantioenriched (ꢀ)-aplysin, but their synthesis used an
(isopinocamphenyloxy) methyl ether for simultaneous phenolic
hydroxyl protection and diastereomeric resolution, so did not
constitute an asymmetric synthesis.
The first enantioselective synthesis in 1992 by Takano12a used
a Fisher indolisation of a chiral cyclopentanone starting material to
introduce the quaternary stereocenter. Fukumoto’s synthesis in
199412b used a tandem Katsuki-Sharpless asymmetric epoxidation
of 2-aryl-2-cyclopropylidene ethanols and Yoshida’s synthesis in
201012c used an Eschenmoser/Claisen rearrangement of an enan-
tioenriched allylic alcohol to introduce the quaternary stereocenter.
Whilst these syntheses use some elegant methodology to in-
troduce the quaternary stereocenter, they are relatively long and
require a number of functional group interconversions. Srikrishna’s
synthesis in 200112d is the shortest to date, with only ten steps and
employing a Claisen rearrangement to introduce the quaternary
stereocenter. However, it suffers from low diastereoselectivity in
the key step (5:1:2 ratio of the required diastereomer, the minor
diastereomer and an unwanted side product).
* Corresponding author. Tel.: þ44 (0) 117 954 6315; fax: þ44 (0) 117 925 1295;
e-mail address: v.aggarwal@bristol.ac.uk (V.K. Aggarwal).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.095

C.J. Fletcher et al. / Tetrahedron 68 (2012) 7598e7604
7599
Fig. 1. Natural products derived from aplysia and laurencia.
All syntheses reported to date converge at intermediate 13,
completing the synthesis with a highly face-selective reduction
using Adam’s catalyst and finally bromination (Scheme 1).
Scheme 3. Retrosynthetic analysis of core structure 14.
Scheme 1. Previous completion of aplysin.
in three facile steps (Scheme 4). After protection of the phenol of 20-
hydroxy-40-methylacetophenone as the methyl ether, Noyori re-
duction16 with RuCl(p-cymene)[(R,R)-Ts-DPEN] (18) gave alcohol 19
in 97:3 er. Simple carbamoylation completed the carbamate syn-
thesis with the same high er. Furthermore, recrystallization from
pentane enabled enantioenrichment to >99:1 er without signifi-
cant loss of yield. Primary boronic ester 17b was prepared in one
step from bromomethylboronic acid pinacol ester and 2-
methylallyl Grignard in 91% yield.
Recently, we reported a method for the preparation of highly
enantioenriched tertiary boronic esters through
a
lith-
iationeborylation reaction of secondary aryl carbamates with
pinacol boronic esters.14 We then demonstrated the homologation
of these tertiary boronic esters to give quaternary stereocenters in
high yields and with complete stereoretention (Scheme 2).15 We
envisaged that our methodology could be applied to the synthesis
of aplysin, which contains a quaternary stereogenic centre, by
a concise route.
Scheme 2. Lithiationeborylationevinylation sequence for preparation of quaternary
stereocenters.
The key structural features of aplysin, including the quaternary
stereocenter, are common to a range of sesquiterpene natural
products. In our synthesis, we sought not only to devise a concise
and highly stereoselective synthesis of aplysin, but to devise a route
that would enable access to a host of natural products in just a few
transformations from elaboration of a common precursor. We de-
cided upon core structure 14 as the key common precursor and so
made it our initial target.
Scheme 4. Preparation of carbamate 16a and boronic ester 17b.
Retrosynthetic analysis of 14 took us back to tertiary boronic
ester 15ab via olefination and ring-closing metathesis (Scheme 3).
The boronic ester in turn could be derived from enantioenriched
carbamate 16a and boronic ester 17b via lithiationeborylation.
With carbamate 16a and boronic ester 17b in hand, we were
now ready to test the lithiationeborylation step. As had been found
previously with carbamates with an ortho-methoxy substituent,14b
use of TMEDA was essential to achieve clean lithiation. The first
attempt at the lithiationeborylation led to 15ab in 47% yield (Table
1, entry 1). Initially, the reason for the moderate yield was not clear
and so we investigated the steps in the reaction, individually.
Lithiation of carbamate 16a with sBuLi in Et2O at ꢀ78 ꢁC over
a range of times, followed by addition of deuterated methanol
2. Results and discussion
The synthesis of the core structure 14 began with the prepara-
tion of tertiary boronic ester 15ab. Carbamate 16a was synthesized

7600
C.J. Fletcher et al. / Tetrahedron 68 (2012) 7598e7604
Table 1
caution. Unsurprisingly, use of 2-propenyl magnesium bromide
Investigation into lithiationeborylation step
was ineffective in forming any boron-ate complex intermediate
(monitored by 11B NMR). Changing to the more reactive organo-
lithium afforded some product but incomplete conversion from the
starting boronic ester (2:1 SM:P observed by 1H NMR). Previously,
in formation of boron-ate complexes in hindered systems, it was
found that raising the temperature of the bath to ꢀ40 ꢁC was re-
quired to effect full ate complex formation.19 Pleasingly, we found
that upon reacting the organolithium with the tertiary boronic
ester for 1 h at ꢀ78 ꢁC followed by 1 h at ꢀ40 ꢁC, followed by ad-
dition of iodine in MeOH and warming to room temperature, bis
olefin 20 was isolated in quantitative yield and >99:1 er with
complete retention of stereochemistry from the boronic ester
starting material (Scheme 5).
Entry
Carbamate
1ꢁ Boronic ester
3ꢁ Boronic ester
Yield %
er
1
2
3
4
16a
16a
16a
16b
17b
17b
17a
17b
15ab
15ab
15aa
15bb
47
46a
76
>99:1
nd
nd
45
>99:1
a
Boronic ester (2 equiv) 17b used.
showed that full lithiation was achieved after 15 min (100% D
incorporation observed by 1H NMR). Monitoring of the reaction by
11B NMR showed that after 2 h at room temperature there was no
boron-ate complex remaining, indicating that this time was
sufficient for the 1,2-metallate rearrangement to occur. However,
significant quantities of carbamate starting material (w15e20%)
were recovered from the reaction despite using an excess of boronic
ester 17 [1.5 or 2 equiv (entries 1, 2)]. As the lithiation was shown to
be complete, this suggests some reversibility of the boron-ate
complex.
We decided to examine the effect on yield of the structure of the
boronic ester and carbamate groups independently. When using
carbamate 16a with a simple alkyl boronic ester, butyl boronic acid
pinacol ester 17a, the reaction proceeded smoothly to give tertiary
boronic ester 15aa in a considerably improved 76% yield (entry 3).
When using carbamate 16b, with no aromatic substituents and
alkenyl boronic ester 17b a similarly low yield of 15bb was obtained
to that obtained with carbamate 16a (entry 4). This indicated that
the low yield observed was due to the structure of the boronic ester.
We have previously observed that when alkenes are present in
the boron-ate complex, e.g., A (Fig. 2), 1,2-migration can be severely
retarded.17 This was attributed to co-ordination of lithium to the
double bond.18 Similar co-ordination, e.g., B (Fig. 2), may be re-
sponsible here for the lower yields observed. Despite the moderate
yield, the tertiary boronic ester 15ab was obtained in excellent er,
without any loss of stereochemical information from the carbamate
starting material, and the reaction was easily scaled up to 10 mmol
with equally good result.
Scheme 5. Propenylation of tertiary boronic ester 15ab.
The final step to form the key core intermediate 14 was ring
closing metathesis (RCM). However, steric hindrance also posed
a potential problem in this step due to the 1,1-disubstitution of both
olefins in 20, which would require formation of a tetrasubstituted
alkene adjacent to a quaternary centre. Tetrasubstituted olefins are
known to be difficult to form, although there are examples in the
literature using both molybdenum20 and ruthenium21 based cata-
lysts. Similarly, formation of olefins adjacent to quaternary ster-
eocenters has been shown to be difficult. For example, both Trost22
and Thomas23 have independently reported being unable to form
a disubstituted double bond with an adjacent quaternary stereo-
center in the attempted syntheses of the macrocycle bryostatin 1.
The RCM proposed in our strategy stands out as an especially dif-
ficult case as it would encounter both of these obstacles. Indeed,
only one example of a RCM with this scaffold existed in the liter-
ature,24 which utilized 1.3 mol % Grubbs II catalyst in refluxing
toluene for 12 h. Application of these conditions to 20, however
gave no reaction. Increasing the catalyst loading to 10 mol %
allowed partial conversion to the product, but neither extending
the reaction time nor adding the catalyst portionwise effected any
change. Alternative catalysts were therefore examined. Pleasingly,
it was found that 10 mol % of HoveydaeGrubbs II, in refluxing
toluene for 24 h was successful in forming the desired tetrasub-
stituted olefin 14, in quantitative yield (Scheme 6). With the core
structure in hand, our task fell to the elaboration to sesquiterpene
natural products.
Fig. 2. Possible co-ordination of lithium to double bonds in boron-ate complexes.
The next step was to convert the tertiary boronic ester into an
all-carbon quaternary stereocenter using the methodology pre-
viously developed within the Aggarwal group.15 Tertiary boronic
ester 15ab, however, is particularly hindered due to the o-methoxy
substituent and the olefination step represented a propenylation
(rather than the previously reported vinylation) with a hindered
organolithium, both of which had hitherto not been tested. With
these two points in mind the olefination was approached with
Scheme 6. Ring closing metathesis to give core structure 14.
We thought that deprotection of the methyl ether of 14 could
lead, under acidic conditions, to spontaneous cyclization upon
water work-up to give debromoaplysin 2. BBr3 is commonly used to
deprotect methyl ethers in this series of natural products,12a,25

C.J. Fletcher et al. / Tetrahedron 68 (2012) 7598e7604
7601
however with our substrate only decomposition products were
obtained. Use of TMS-I was more successful and led to a mixture of
products in a 7:2:1 ratio of debromoaplysin (2), C10-epi-debro-
moaplysin (21) and debromofiliformin (6), respectively (Table 2,
entry 1). We supposed that during the reaction the methyl ether
was cleaved to give the silyl ether and MeI, and subsequent cycli-
zation occurred upon aqueous work-up. Debromoaplysin (2) is the
result of protonation on the less hindered face and the C10-epimer
(21) on the more hindered face, which accounts for the preference
observed. Debromofiliformin is the result of a 6-endo-trig cycliza-
tion, rather than a 5-exo-trig again with protonation on the less
hindered face.
Scheme 7. Completion of (ꢀ)-aplysin.
Table 2
all respects to the natural product. This completed the total syn-
Optimization of deprotectionecyclization step
thesis of (ꢀ)-aplysin in just eight steps, and 12% overall yield.
3. Conclusion
A highly concise, novel route to (ꢀ)-debromoaplysin and
(ꢀ)-aplysin has been completed with excellent enantioselectivity
and good diastereoselectivity in the cyclization step. Complete
stereocontrol was observed in the lithiationeborylation and pro-
penylation steps leading to the all carbon quaternary stereocenter of
(ꢀ)-aplysin in >99% er. Application of this method towards the
synthesis of other aplysia and laurencia sesquiterpenes is underway.
Entry
Phenola
Temp, ꢁC
2b
21b
6b
4. Experimental
4.1. General
1
2
3
4
5
6
7
None
22
23
24
24
rt
rt
rt
rt
ꢀ40
ꢀ78
ꢀ78
70
50
60
65
80
80
80
20
10
5
10
40
35
30
5
5
All required fine chemicals were used directly without purifi-
cation unless mentioned. Compounds lacking experimental details
were prepared according to the literature as cited and are in
agreement with published spectra. All air- and water-sensitive re-
actions were carried out in flame-dried glassware under argon at-
mosphere using standard Schlenk manifold technique. 1H- and 13C-
Nuclear Magnetic Resonance (NMR) spectra were acquired at var-
ious field strengths as indicated, and were referenced to CHCl3 (7.27
and 77.0 ppm for 1H and 13C, respectively) or TMS (0.00 ppm for 1H
and 13C). 1H NMR coupling constants are reported in hertz and refer
to apparent multiplicities and not true coupling constants. Data are
reported as follows: chemical shift, multiplicity (s¼singlet, br
s¼broad singlet, d¼doublet, t¼triplet, q¼quartet, qi¼quintet,
sx¼sextet, sp¼septet, m¼multiplet, dd¼doublet of doublet, etc.)
and integration. 11B NMR spectra were recorded with complete
proton decoupling using BF3$Et2O (0.0 ppm) as an external stan-
dard. High resolution mass spectra were recorded using Electronic
Ionization (EI), Electron Spray Ionization (ESI) or Chemical Ioniza-
tion (CI). For CI, methane was used. Infrared spectra were obtained
using a Perkin Elmer Spectrum One FT-IR spectrometer, reporting
as ATR plates (solids) or films (oils) irradiating over the range
4000 cmꢀ1 and 600 cmꢀ1. Optical rotations were obtained on
a PerkineElmer 241 MC polarimeter. Analytical TLC: aluminium
15
15
15
24
5
5
24c
a
Phenol (2 equiv).
Ratio determined by NMR to nearest 5%.
Phenol and TMS-I premixed.
b
c
With this promising result we sought further improvements.
Lowering the temperature of reaction mixture to 0 ꢁC gave similar
results. We then considered the use of hindered phenols (Fig. 3) to
promote delivery of a proton to the less hindered face. With the use
of o-cresol (22) we saw a marked improvement in dr (entry 2),
which continued to improve as we moved to more hindered phe-
nols 23 (entry 3) and 24 (entry 4) supporting our theory. Un-
fortunately, this also resulted in a significant increase in the
formation of debromofiliformin 6. Lowering the temperature of the
reaction to ꢀ40 ꢁC and ꢀ78 ꢁC was successful in significantly re-
ducing the formation of debromofiliformin 6 at a slight cost in the
dr, but overall provided optimum conversion to the desired product
debromoaplysin 2.
backed plates pre-coated (0.25 mm) with Merck Silica Gel 60 F254
.
Compounds were visualized by exposure to UV-light or by dipping
the plates in a 5% solution of [MoO3]12[PO4H3] in EtOH followed by
heating. Flash column chromatography was performed using Merck
Silica Gel 60 (40e63 mm). All mixed solvent eluents are reported as
Fig. 3. Phenol additives used in the cyclization of 14.
v/v solutions. Melting points were determined with a Boetius hot
stage apparatus and were not corrected. Chiral HPLC separations
were done using an Agilent 1100 series normal phase high per-
formance liquid chromatography unit using HP Chemstation soft-
ware, on Chiralpak IA (250ꢂ4.6 mm) with Chiralpak IA Guard
Cartridge (10ꢂ4 mm), Chiralpak IB (250ꢂ4.6 mm) with Chiralpak IB
Guard Cartridge (10ꢂ4 mm) or Chiralpak IC (250ꢂ4.6 mm) with
We found these results to be reproducible on larger scales, and
after separation of both side products by flash column chroma-
tography we were able to obtain a 48% isolated yield of pure
(ꢀ)-debromoaplysin (Scheme 7). Bromination using bromine in
chloroform gave (ꢀ)-aplysin 1 in 81% yield, which was identical in

7602
C.J. Fletcher et al. / Tetrahedron 68 (2012) 7598e7604
Chiralpak IC Guard Cartridge (10ꢂ4 mm) columns and monitored
by DAD (Diode Array Detector). Solvents were purified by standard
6.69 (1H, s), 6.77 (1H, d, J¼7.8 Hz), 7.24 (1H, d, J¼7.8 Hz); dC
(100 MHz, CDCl3) 21.1 (br, 4ꢂ CH3); 21.5 (CH3), 21.9 (CH3), 45.7 (br,
2ꢂ CH), 55.3 (CH3), 67.8 (CH), 111.4 (CH), 121.0 (CH), 125.9 (C), 128.7
(CH), 138.1 (C), 155.1 (C), 155.8 (C); m/z (CI) 395 (5), 379 (10), 351 (5),
294 (20), 293 (35, Mþ), 292 (40), 249 (25), 234 (40), 149 (100), 102
(25%); HRMS (CI): Mþ, found 293.1997. C17H27NO3 requires 293.1991.
s
methods.26 TMEDA was distilled over CaH2. BuLi was purchased
from Acros. The molarity of organolithium solutions was de-
termined by titration using salicylaldehyde phenylhydrazone as
indicator.27
4.1.1. 20-Methoxy-40-methyl acetophenone 25. KOH (4.85 g,
86 mmol, 1.3 equiv) and dimethyl sulfate (8.21 mL, 86.6 mmol,
1.3 equiv) were added to a solution of 20-hydroxy 40-methyl-
acetophenone (9.26 mL, 66.6 mmol, 1 equiv) in anhydrous acetone
(140 mL) and stirred at room temperature for 16 h. The solvent was
removed in vacuo and the residue dissolved in EtOAc (400 mL) and
washed with water (400 mL) and brine (400 mL). The organic phase
was dried over MgSO4, filtered and concentrated in vacuo giving
the crude product as a colourless oil. This oil was purified by flash
column chromatography (15:85 EtOAc/petroleum ether) to give
methyl ether 25 (10.3 g, 95%) as white needles, mp 36e38 ꢁC from
hexane (lit.28 37e38 ꢁC); Rf (15% EtOAc/petroleum ether) 0.22; dH
(400 MHz, CDCl3) 2.39 (3H, s), 2.60 (3H, s), 3.90 (3H, s), 6.77 (1H, s),
6.81 (1H, d, J¼7.9 Hz), 7.68 (1H, d, J¼7.9 Hz); dC (100 MHz, CDCl3)
21.8 (CH3), 31.8 (CH3), 55.4 (CH3), 112.2 (CH), 121.3 (CH), 125.4 (C),
130.5 (CH), 144.8 (C), 159.1 (C), 199.1 (C). Data were consistent with
those previously reported.28
4.1.4. 4,4,5,5-Tetramethyl-2-(3-methylbut-3-enyl)-1,3,2-dioxaborolane
17b. 2-Methylallylmagnesium chloride (0.5 M in THF, 98 mL,
49 mmol, 1.1 equiv) was added dropwise to a solution of bromo-
methylboronic acid pinacol ester (9.78 g, 44.3 mmol, 1 equiv) in THF
(90 mL) at ꢀ78 ꢁC over 0.5 h. The reaction mixture was allowed to
warm to room temperature over night, after which the reaction was
quenched with water (150 mL). The organic layer was separated and
the aqueous layer washed with EtOAc (3ꢂ150 mL). The organic
phases were combined, dried over MgSO4 and concentrated in vacuo
affording boronic ester 17b as a colourless oil (8.1 g, 91%), which was
used without further purification; Rf (10% EtOAc/petroleum ether)
0.35; dH (400 MHz, CDCl3) 0.93 (2H, t, J¼7.9 Hz, CH2), 1.25 (12H, s,
CH3),1.72 (3H, s, CH3), 2.12 (2H, t, J¼7.9 Hz, CH2), 4.67 (2H, br s, CH2);
dC (100.6 MHz, CDCl3), 22.6 (CH3), 24.9 (4ꢂ CH3), 31.8 (CH2), 83.1 (2ꢂ
C), 108.5 (CH2), 147.9 (C); dB (128 MHz, CDCl3) 34.0. Data were con-
sistent with those previously reported.29
4.1.5. (R)-2-(2-(2-Methoxy-4-methylphenyl)-5-methylhex-5-en-2-
yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (þ)-15ab. sBuLi (1.16 M
in hexane; 11.2 mL, 13 mmol, 1.3 equiv) was added dropwise to
a solution of carbamate (ꢀ)-16a (2.94 g, 10 mmol, 1 equiv, >99:1
er) and TMEDA (2 mL, 15 mmol, 1.5 equiv) in Et2O (45 mL) at
ꢀ78 ꢁC. The reaction was stirred for 15 min after which boronic
ester 17b (2.94 g, 15 mmol, 1.5 equiv) was added dropwise at
ꢀ78 ꢁC. The solution was stirred at ꢀ78 ꢁC for 1 h, after which
MgBr2 (1.0 M in MeOH; 17 mL, 17 mmol, 1.7 equiv) was added
dropwise. The reaction mixture was allowed to warm to room
temperature over night. The reaction mixture was concentrated in
vacuo and the residue dissolved in Et2O (300 mL) to which water
(300 mL) was added and the organic phase separated. The aque-
ous phase was extracted with Et2O (2ꢂ300 mL), the organic
phases were combined, dried over MgSO4 and concentrated in
vacuo giving an oil, which was purified by column chromatogra-
phy (Gradient: 5:95 to 7:93 EtOAc/pentane) to give boronic ester
(þ)-15ab as white needles (1.61 g, 47%, >99:1 er); mp 63e65 ꢁC;
[found: C, 73.59; H, 9.93. C21H34O3B requires C, 73.26; H, 9.66%]; Rf
4.1.2. (R)-(þ)-1-(20-Methoxy-40-methylphenyl)ethanol (þ)-19. Formic
acid (11.64 mL, 290 mmol, 5.4 equiv) was added to triethylamine
(17.4 mL, 116 mmol, 2.1 equiv) at 0 ꢁC, and then warmed to room
temperature. 20-Hydroxy 40-methylacetophenone 25 (8.89 g,
54 mmol, 1 equiv) and (S)-RuCl[(1R,2R)-p-TsNCH (C6H5)NH2](h6
-
p-cymene) (344 mg, 0.54 mmol, 0.01 equiv) were added and the
mixture stirred for 96 h whilst bubbling N2 through the reaction
mixture via a needle. The reaction mixture was quenched with water
(250 mL), and the organic layer separated. The aqueous phase was
washed with EtOAc (3ꢂ250 mL), the organic phases were combined,
dried over MgSO4, filtered and concentrated to give the crude
product as a black oil. The oil was purified by flash column chro-
matography (1:9 EtOAc/petroleum ether) to give alcohol (þ)-19 as
a colourless oil (91%, 8.18 g, 97:3 er); [found: C, 72.16; H, 8.70.
C10H14O2 requires C, 72.26; H, 8.49%]; Rf (25% EtOAc/petroleum
ether) 0.33; ½a 2D0
ꢃ
þ20 (c 0.98, CHCl3); nmax (liquid film) 3383, 2969,
2927,1613,1256,1081,1038, 813 cmꢀ1
;
dH (400 MHz, CDCl3) 1.51 (3H,
d, J¼6.6 Hz); 2.36 (3H, s), 2.62 (1H, br d, J¼4.5 Hz), 3.86 (3H, s), 5.07
(1H, qd, J¼6.6, 4.5 Hz), 6.71 (1H, s), 6.78 (1H, d, J¼7.6 Hz), 7.22 (1H, d,
J¼7.6 Hz); dC (100 MHz, CDCl3) 21.5 (CH3), 22.8 (CH3), 55.2 (CH3), 66.4
(CH), 111.4 (CH), 121.3 (CH), 126.0 (C), 130.4 (CH), 138.3 (C), 156.5 (C);
m/z (CI) 177 (5),166 (15, Mþ),151 (40),149 (100),135 (20),123 (30%);
HRMS (CI): Mþ, found 166.0991. C10H14O2 requires 166.0994.
(5% EtOAc/petroleum ether) 0.17; ½a D20
ꢃ
þ38 (c 1, CHCl3); nmax (ATR
plate) 3031, 2974, 2933, 1611, 1577, 1503, 1146, 810 cmꢀ1
;
dH
(400 MHz, CDC13), 1.24 (6H, s), 1.25 (6H, s), 1.26 (3H, s), 1.68 (3H, s),
1.69e1.84 (2H, m), 1.90e2.02 (2H, m), 2.32 (3H, s), 3.79 (3H, s),
4.63 (2H, s), 6.64 (1H, s), 6.74 (1H, d, J¼7.8 Hz), 7.07 (1H, d,
J¼7.8 Hz); dC (100 MHz, CDCl3) 21.3 (CH3), 22.7 (CH3), 24.9 (2ꢂ
CH3), 24.9 (2ꢂ CH3), 32.9 (CH2), 34.7 (CH2), 54.7 (CH3), 82.7 (2ꢂ C),
109.0 (CH2), 110.9 (CH), 121.2 (CH), 126.2 (CH), 132.8 (C), 135.9 (C),
147.3 (C), 156.4 (C); dB (128 MHz; CDCl3) 34.1; m/z (CI) 345 (25,
MHþ), 329 (20), 245 (100%); HRMS (CI): MþH, found 345.2609.
C21H34O3B requires 345.2601.
4.1.3. (R)-1-(2-Methoxy-4-methylphenyl)ethyl diisopropyl-carbamate
(ꢀ)-16a. (R)-(þ)-1-(20-Methoxy-40-methylphenyl)ethanol
(þ)-19
(8.00 g, 48 mmol, 1 equiv) was added to a solution of N,N-diiso-
propylcarbamoyl chloride (9.48 g, 57.6 mmol, 1.2 equiv) and trie-
thylamine (8.08 mL, 57.6 mmol, 1.2 equiv) in dichloromethane
(100 mL), and heated to reflux for 48 h. The reaction mixture was
cooled to room temperature and water (250 mL) was added. The
organic phase was separated and the aqueous phase extracted with
dichloromethane (3ꢂ250 mL), the organic phases were combined,
dried (MgSO4), filtered and concentrated in vacuo to give the crude
product as a yellow oil. Purification by column chromatography (1:9
EtOAc/petroleum ether) gave carbamate (ꢀ)-16 as colourless cubes
(11.93 g, 81%, 97:3 er; >99:1 recryst from pentane 90%); mp
4.1.6. (R)-2-Methoxy-4-methyl-1-(2,3,6-trimethylhepta-1,6-dien-3-
yl)benzene (þ)-20. tBuLi (14.6 mL, 23.3 mmol, 8 equiv) was added
dropwise to a solution of 2-bromoprop-1-ene (1.02 mL, 11.6 mmol,
4 equiv) in THF (25 mL) at ꢀ78 ꢁC for 30 min. Boronic ester
(þ)-15ab (1.00 g, 2.91 mmol, 1 equiv >99:1 er) in THF (12 mL) was
added dropwise at ꢀ78 ꢁC and the reaction mixture stirred for 1 h,
then warmed to ꢀ40 ꢁC for a further hour. The mixture was cooled
to ꢀ78 ꢁC prior to dropwise addition of iodine (2.95 g, 11.6 mmol,
4 equiv) in MeOH (46 mL), which was stirred at ꢀ78 ꢁC for 0.5 h,
followed by warming to 0 ꢁC for a further 0.5 h. The reaction
mixture was warmed to room temperature and Na2S2O3 (100 mL,
52e53 ꢁC from pentane; Rf (10% EtOAc/petroleum ether) 0.23; ½a 2D0
ꢃ
ꢀ20 (c 1, CHCl3); nmax (ATR plate) 2969, 2933,1683, 1285,1065, 1045,
810 cmꢀ1
2.35 (3H, s), 3.82 (3H, s), 3.84e4.20 (2H, br m), 6.16 (1H, q, J¼6.5 Hz),
;
dH (400 MHz, CDCl3) 1.24 (12H, br s),1.50 (3H, d, J¼6.5 Hz),

C.J. Fletcher et al. / Tetrahedron 68 (2012) 7598e7604
7603
5% w/v aqueous) was added and the resultant biphasic mixture was
stirred for a 1 h. The organic phase was separated and the aqueous
phase washed with Et2O (3ꢂ125 mL). The combined organic phases
were dried over MgSO4 and solvent removed in vacuo and purified
by column chromatography (pentane) to give diene (þ)-20 as
a colourless oil (0.73 g, 98%, >99:1 er); [found: C, 83.48; H, 10.38.
C18H26O requires C, 83.67; H, 10.14%]; Rf (100% petroleum ether)
solution of (ꢀ)-2 (14 mg, 0.065 mmol, 1 equiv) in CHCl3 (5 mL) at
ꢁC. The reaction mixture was stirred at room temperature for
0
10 min, after which all solvent was removed to give a light brown
oil. The oil was filtered through a short plug of silica to give aplysin
(ꢀ)-1 (0.0156 g, 81%) as fine white needles; mp 84e85 ꢁC (lit.3
85e86 ꢁC); Rf (1:1 CH2Cl2/hexane) 0.6; ½a 2D2
ꢀ80 (c 1, CHCl3) lit.:
ꢃ
½
a 2D1
ꢃ
ꢀ84.2 (c 0.31, CHCl3);13
½
a 3D2
ꢃ
ꢀ83.5 (c 0.31, CHCl3);12a
½ ꢃ
a 2D5
0.19; ½a 2D0
ꢃ
þ41 (c 1, CHCl3); nmax (liquid film) 3072, 2968, 2925,
ꢀ83.2 (c 0.15, CHCl3);12b dH (500 MHz, CDCl3) 1.11 (3H, d, J¼6.9 Hz),
1.15 (1H, s), 1.29 (3H, s), 1.32 (3H, s), 1.57e1.67 (2H, m), 1.72e1.82
(1H, m), 1.87 (1H, s), 2.32 (3H, s), 6.60 (1H, s), 7.15 (1H, s); dC
(100 MHz, CDCl3) 13.1 (CH3), 19.9 (CH3), 23.2 (CH3), 23.4 (CH3), 31.2
(CH2), 42.5 (CH2), 46.0 (CH), 54.3 (C), 99.8 (C), 110.9 (CH), 114.0 (C),
126.5 (CH), 136.2 (C), 136.9 (C), 158.2 (C); HRMS (APCI): MþH, found
295.0691. C15H20OBr requires 295.0692.
1638, 1575, 1501, 805 cmꢀ1
;
dH (400 MHz CDCl3) 1.42 (3H, s, 8-CH3),
1.55 (3H, d, J¼1.0 Hz), 1.57e1.66 (1H, m), 1.71 (3H, s), 1.76e1.90 (2H,
m), 2.31e2.40 (1H, m), 2.34 (3H, s), 3.73 (3H, s), 4.67 (2H, d,
J¼1.0 Hz), 4.75 (1H, d, J¼1.0 Hz), 4.81 (1H, quin., J¼1.0 Hz) 6.66 (1H,
s), 6.73 (1H, d, J¼7.8 Hz), 7.12 (1H, d, J¼7.8 Hz); dC (100 MHz, CDCl3)
20.8 (CH3); 21.2 (CH3), 22.7 (CH3), 24.9 (CH3), 33.4 (CH2), 36.1 (CH2),
45.8 (C), 55.1 (CH3), 108.4 (CH2), 109.1 (CH2), 112.7 (CH), 120.7 (CH),
127.8 (CH), 132.3 (C), 137.0 (C), 147.2 (C), 152.6 (C), 158.2 (C); m/z (CI)
258 (5, Mþ), 149 (40), 137 (30), 61 (100%); HRMS (CI): MþH, found
259.2061. C18H26O requires 259.2062.
Acknowledgements
We thank EPSRC and the European Research Council (ERC) in the
context of the European Community’s Seventh Framework
Programme (FP7/2007e2013, ERC grant no. 246785) for
financial support. VKA thanks EPSRC for a Senior Research Fel-
lowship. C.J.F. thanks the EPSRC and GSK for funding. We thank
Inochem-Frontier Scientific for generous donation of boronic acids
and boronic esters.
4.1.7. (R)-2-Methoxy-4-methyl-1-(1,2,3-trimethylcyclopent-2-enyl)
benzene (ꢀ)-14. HoveydaeGrubbs second generation alkene me-
tathesis catalyst (0.144 g, 0.23 mmol) was added to a solution of
(þ)-20 (0.600 g, 2.3 mmol, >99:1 er) in toluene (23 mL) and was
heated to reflux for 24 h. The reaction mixture was filtered
through a plug of silica, which was washed with 5% EtOAc/pen-
tane. The filtrate was concentrated in vacuo giving the cyclo-
pentene ꢀ14 as an oil, which solidified on standing (0.525 g, 99%);
mp 37e39 ꢁC; [found: C, 83.85; H, 9.98. C16H22O requires C, 83.43;
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.095.
H, 9.63%]; Rf (2% EtOAc/petroleum ether) 0.31; ½a D20
ꢀ7 (c 1,
ꢃ
CHCl3); nmax (ATR plate) 2960, 2915, 2859, 2836, 1610, 1574, 1500,
1255, 809 cmꢀ1
; dH (400 MHz, CDCl3), 1.43 (3H, s), 1.50 (3H, d,
References and notes
J¼1.0 Hz), 1.69 (3H, d, J¼1.0 Hz), 1.70e1.76 (1H, m), 2.12e2.18 (2H,
m), 2.23 (1H, ddd, J¼12.4, 6.8, 5.0 Hz), 2.31 (3H, s), 3.77 (3H, s),
6.65 (1H, d, J¼7.8 Hz), 6.68 (1H, s), 6.89 (1H, d, J¼7.8 Hz); dC
(100 MHz, CDCl3) 11.1 (CH3), 14.4 (CH3), 21.2 (CH3), 25.3 (CH3),
35.9 (CH2), 38.5 (CH2), 53.9 (C), 55.2 (CH3), 112.6 (CH), 120.4 (CH),
127.7 (CH), 131.7 (C), 133.3 (C), 136.7 (C), 136.7 (C), 158.3 (C); m/z
(CI) 230 (30, Mþ), 215 (100%); HRMS (CI): Mþ, found 230.1677.
C16H22O requires 230.1671.
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4.1.8. (ꢀ)-Debromoaplysin (ꢀ)-2. Trimethylsilyl iodide (0.07 mL,
0.47 mmol, 1 equiv) was added dropwise to a solution of (ꢀ)-14
(0.100 g, 0.43 mmol, 1 equiv) and 2,6-ditert-butylphenol (179 mg,
0.87 mmol, 2 equiv) in CH2Cl2 (4 mL) at ꢀ78 ꢁC and stirred at this
temperature for 24 h before dropwise addition of aqueous am-
monia (10 mL 17.5% w/v NH3/H2O). The reaction mixture was
warmed to room temperature and the organic layer separated, the
aqueous layer was washed with dichloromethane (3ꢂ10 mL). The
organic phases were combined, dried (MgSO4) and concentrated to
give the crude product as a yellow oil. The crude oil as purified by
column chromatography (5% toluene/pentane), to give debromoa-
plysin (ꢀ)-2 as a colourless oil (0.045 g, 48%); Rf (5% toluene/pen-
tane) 0.25; ½a 2D0
ꢃ
ꢀ62 (c 1.27, CHCl3) lit.: ½a D21
ꢀ68 (c not quoted,
ꢃ
CHCl3);13
½
a 2D5
ꢃ
ꢀ53 (c 0.15, CHCl3);30
½
a 2D9
ꢃ
ꢀ66.5 (c 0.72, CHCl3);12a
½
a 2D5
ꢃ
ꢀ61.8 (c 0.16, CHCl3);12b nmax (liquid film) 2954, 2928, 2865,
1619, 1593, 1499, 1280, 1122, 1008, 948, 801 cmꢀ1
; dH (400 MHz,
CDCl3) 1.15e1.24 (1H, m), 1.15 (3H, d, J¼6.8 Hz), 1.32 (3H, s), 1.35
(3H, s), 1.56e1.67 (2H, m), 1.79 (1H, m), 1.88 (1H, dd, J¼11.2, 6.1 Hz),
2.31 (3H, s), 6.55 (1H, s), 6.67 (1H, d, J¼7.3 Hz), 6.94 (1H, d,
J¼7.3 Hz); dC (100 MHz, CDCl3) 13.1, 20.0, 23.5, 31.2, 42.6, 46.1, 54.0,
98.9, 109.3, 120.68, 122.6, 133.4, 137.8, 158.9; m/z (CI) 216 (20, Mþ),
201 (80%); HRMS (CI): Mþ, found 216.1515. C15H20O requires
216.1514.
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4.1.9. (ꢀ)-Aplysin (ꢀ)-1. Bromine (0.97 mL, 0.1
M in CHCl3,
0.097 mmol, 1.5 equiv) was added dropwise to a vigorously stirred

7604
C.J. Fletcher et al. / Tetrahedron 68 (2012) 7598e7604
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