A new tactic for tocopherol synthesis using intramolecular benzyne trapping by an alcohol

Article abstract of DOI:10.3987/COM-15-S(T)52

A formal total synthesis of (S)-α-Tocopherol, the major component of natural Vitamin E has been achieved using intramolecular benzyne trapping as a key step to form the chroman ring. The synthesis also features an efficient new method for benzotriazole N-Amination using an oxaziridine; chiral, nonracemic intermediates are generated using asymmetric dihydroxylation.

Full text of DOI:10.3987/COM-15-S(T)52

HETEROCYCLES, Vol. 93, No. 2, 2016
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HETEROCYCLES, Vol. 93, No. 2, 2016, pp. 647 - 672. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 4th September, 2015, Accepted, 28th October, 2015, Published online, 14th November, 2015
DOI: 10.3987/COM-15-S(T)52
A NEW TACTIC FOR TOCOPHEROL SYNTHESIS USING
INTRAMOLECULAR BENZYNE TRAPPING BY AN ALCOHOL
David W. Knight* and Qing Xu
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff,
CF10 3AT, UK. e-mail: knightdw@cf.ac.uk
Abstract – A formal total synthesis of (S)-α-tocopherol, the major component
of natural Vitamin E has been achieved using intramolecular benzyne trapping
as a key step to form the chroman ring. The synthesis also features an efficient
new method for benzotriazole N-amination using an oxaziridine; chiral, non-
racemic intermediates are generated using asymmetric dihydroxylation.
This paper is dedicated to Professor Lutz Tietze on his 75th birthday, with all
best wishes.
INTRODUCTION
α-Tocopherol 1 is the major component of naturally occurring Vitamin E, the remaining components
of which generally consist of less methylated analogues and examples containing alkenes in their side
chains.1
HO
O
1
Figure 1. α-Tocopherol, the major component of the natural Vitamin E mixture
The acetate derived from tocopherol is manufactured on a multi-ton scale by coupling
trimethylhydroquinone and isophytol followed by acetylation and is used primarily as an anti-oxidant
in a very wide variety of foods, pharmaceuticals, cosmetics, indeed almost any product which can
suffer from the deleterious effects of oxidation upon prolonged storage.2 More recent investigations

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have revealed that tocopherol is distinguished by its ability to inhibit oxytosis, 5-lipoxygenase and
phospholipase A2 along with various kinases as well as being capable of activating protein
phosphatase 2A and of gene regulation.3 It has been strongly suggested that vitamin E should be
studied much more seriously, in view of these discoveries.3c The anti-oxidant activity usually involves
generation of a phenoxide radical followed by quinone formation and concomitant opening of the
chroman ring.
Such anti-oxidant activity is not confined to tocopherol in this area: the analogous, commercially
available acid, trolox 2, also obtained from trimethylhydroquinone but together with methacrylic acid
and formaldehyde, displays similar anti-oxidant properties and is differentiated from the very
lipophilic vitamin E components by reason of its highly polar carboxylic acid group.4 Contrasting
applications as a preservative as well as a precursor to the tocopherols mark this compound out as an
important member of this series, especially at it can be readily resolved.
HO
O
CO2H
2
Figure 2. Trolox, a non-natural but powerful anti-oxidant
Synthetic activity in this area has employed many of the known methods for the asymmetric formation
of C-O bonds. Once achieved, many earlier syntheses utilised the ‘Cohen’ approach outlined in
Scheme 1.5 Thus, a phenol or hydroquinone 3 carrying a suitably functionalised side chain, either
protected or unprotected as shown, is oxidized to the corresponding quinone level and cyclised by mild
acid treatment to the acetal 4, subsequent reduction of which then leads to the target chroman-2-
methanol 5. There are many versions of this strategy, in which the order of events may be altered or an
intermediate related to acetal 4 not isolated. Clearly, there are then many possibilities for the
elaboration of a suitable side chain.6
OH
HO
O
HO
OH
OH
(OH)
O
O
O
3
4
5
Scheme 1. The 'Cohen' approach

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649
Unsurprisingly, the Sharpless epoxidation7 and AD-mix methods8 have both been employed in the
asymmetric synthesis of tocopherol. More modern approaches have usually focussed instead on
formation of the chroman C-O bond from similar chiral, non-racemic precursors, often by
intramolecular attack of the phenol group onto an activated intermediate derived from diols 3 or by a
similar attack but onto an allylic alcohol or related structure, activated by a chiral catalyst, which is
often palladium-based9,10 but can also be a gold11 or ruthenium species.12 Various enzymatic
resolutions and related methods have also proven useful in preparing enantiomerically enriched
samples of the tocopherols,13 which have also been obtained using a biomimetic approach.14
RESULTS AND DISCUSSIONS
The setting for our work in this area was the discovery that lateral deprotonation of the 1-
aminobenzotriazole derivative 6 provides a quantitative conversion into the dianion 7, which could
then be reacted with a range of electrophiles to give generally excellent yields of a range of
analogues.15 In the light of the classic work by Rees’ group,16 this then provided an approach to 3-
substituted benzynes, following N-deprotection and amine oxidation. One particular finding was that
such benzynes could be effectively trapped in an intramolecular fashion by a pendant hydroxyl group
(cf. 8) to give iodo-chromans 9, as well as other bicyclic derivatives (Scheme 2).17
I
N
N
N
N
N
N
NIS
N
N
N
2.Li
O
R
NHBoc
N
NH2
OBut
R
O
OH
6
7
8
9
Scheme 2. Lateral metallation - benzyne trapping by an alcohol as an appropach to chromans
In general, alcohols have not been used in this way previously,18 probably because benzyne generation
was achieved from a halobenzene or a 1,2-dihalobenzene using halogen-metal exchange, which
inevitably meant that the hydroxyl group would be deprotonated; it seems that such alkoxides, being
‘hard’ nucleophiles, are incompatible with the much softer benzynes. In the final oxidation step of the
present method (Scheme 2), the alcohol is not ionized: the original Rees methods used either lead(IV)
acetate or N-bromosuccinimide for this purpose; we found that N-iodosuccinimide (NIS) gave
enhanced yields.17 Of course, a potential bonus of this methodology is the incorporation of the iodine
atom, which lends itself to additional homologation by a plethora of coupling and other reactions.

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Hence, this method, overall, could be regarded a having some generality for the synthesis of 1,2,3,4-
tetrasubstituted benzenes.
We wished to demonstrate that it was possible to apply this methodology to the synthesis of the
tocopherol precursor alcohol 10, with the particular aim of demonstrating that such a benzyne-based
approach could be successfully used to synthesise a more highly substituted target. In the light of the
foregoing results, the structure of alcohol 10 leads back to two, seemingly readily available, starting
materials. (Scheme 3). Trapping of the key benzyne 12 was expected to be regiospecific in favour of
chroman formation17 and also result in incorporation of a halogen atom (X = Br or I) into the chroman
11, which should allow addition of the final methyl group. The key benzyne 12 could then be
generated from 1-aminobenzotriazole 13, or its regioisomer, itself a product of a Sonogashira coupling
between the fully-substituted benzene 14 and the alkyne-diol 15, followed by a double hydrogenation
of both the nitro and alkyne functions and triazole formation. We chose not to use our dianion
methodology (Scheme 2), as trapping of such an intermediate (cf. dianion 7) with saturated alkyl
halides or epoxides was not generally very efficient and it was also likely to be a synthetic challenge to
form a single regioisomer of a suitably substituted aminobenzotriazole.15 In addition, other model
reactions suggested that there would be a lack of regioselectivity in metallations of more highly
substituted N-Boc-aminobenzotriazoles. The need for and the nature of the protecting groups in the
alkyne diols 15 and subsequent derivatives were also far from clear.
OH
MeO
MeO
MeO
OH
1
OH
OH
O
O
X
10
11
12
OR
OR
OR
MeO
I
MeO
RO
NH2
N
N
NO2
14
N
H2N
15
13
Scheme 3. Retrosynthetic analysis for a possible benzyne-based appropach to chroman-2-methanol 10
Synthesis of the fully-substituted benzene 18 began with an efficient nitration19 of commercial 2,6-
dimethylanisole, given that the temperature was always kept below 70 oC (see Experimental), followed
by reduction of the resulting 4-nitro derivative 16a to the corresponding aniline 16b using transfer
hydrogenation20 and acetylation to give acetanilide 16c in excellent overall yields (Scheme 4).

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651
Subsequent iodination using N-iodosuccinimide in acetic acid21 worked well and the sequence was
completed by a slow but efficient nitration of the resulting iodide 17 to install all the required
functionality. Any variation in the order of this sequence gave (much) lower returns, as expected.
MeO
MeO
MeO
I
MeO
I
a-c
d
e
R
NHAc
NHAc
NO2
16a R = NO2
16b R = NH2
16c R= NHAc
17
18
Scheme 4. Reagents and conditions: a) 70% HNO3, HOAc, 0-65 oC (61%); b) 10% Pd-C, cyclohexene, EtOH, 80 oC,
~14 h (91%); c) AcCl, Et3N, THF, 0-20 oC,14 h (89%); d) NIS, HOAc, reflux, 1.5 h (70%); e) 70% HNO3, HOAc, 65 oC,
5 h (76%).
The second component, the alkyne-diol 20a was obtained from enyne 19, readily obtained by acid-
catalysed dehydration of the acetylene-acetone adduct,22 by asymmetric dihydroxylation using AD-
mix β.22 While we were unable to achieve useful separations of the diol enantiomers using a variety of
GC and HPLC methods, the derived benzoate 20b proved readily separable by GC; unhappily, the
enantiomeric enrichment was below 10% (Scheme 5). This is perhaps not too surprising, as terminal
alkenes are often not good substrates for this reaction and an alkyne group is hardly a sterically
dominant substituent. However, having secured a supply of the diol 20a, we chose to continue with
this essentially racemic material, to hopefully establish suitable conditions to enable completion of the
projected synthesis.
OR
a, b
OH
19
20a R = H [< 10% ee]
20b R = Bz
Scheme 5. Reagents and conditions: a) AD-mix-β, MeSO2NH2,
t BuOH-H2O (1:1), rt, 24 h (67%); b) BzCl, Et3N, CH2Cl2, rt 14 h (71%).
The first of these steps was Sonogashira coupling between the iodo-anisole 18 and the alkyne-diol 20a.
This proved to be quite slow and required relatively large amounts of the catalysts to achieve even this
rate of reaction, despite the activating effect of the nitro group, which we chose to retain for this very
reason, and, to a lesser extent, the N-acetyl group. Happily, after a 24 h reflux in THF, a 77% isolated
yield of the desired coupled product 21 was obtained (Scheme 6). Similarly, some experimentation

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HETEROCYCLES, Vol. 93, No. 2, 2016
was required to establish optimised conditions for the simultaneous reduction of both the nitro and
alkyne groups: eventually, it was found that prolonged exposure to Pearlman’s catalyst (20%
palladium hydroxide on carbon) at ambient temperature secured an essentially quantitative yield of the
desired aniline 22. Under more vigorous conditions, especially when a reduction was heated, we also
noticed the formation of a by-product, which remained unidentified at this stage.
OH
OH
OH
OH
OH
OH
MeO
MeO
MeO
18
+
a
b
c,d
R
NHAc
NHAc
20a
N
N
NO2
NH2
N
21
22
23a R = Ac
23b R = H
Scheme 6. Reagents and conditions: a) Pd(Ph3P)4 (20 mol%), Et3N, 18 (1 eq.), 20a (2 eq.),
THF, CuI (20 mol%), reflux, 24 h (77%); b) 20% Pd(OH)2-C, MeOH, H2 (1 atm.), 48 h, rt, (99%);
c) MeOH, rt, aq NaNO2 (3 eq.), 5M HCl, 0 oC, 0.5 h (73%); d) K2CO3, aq MeOH, rt, 4 h (99%) .
The same unidentified by-product was again evident in initial attempts to form the triazole ring by
diazotization of aniline 22; eventually, its formation was much reduced by using three equivalents of
sodium nitrite to carry out the diazotization-cyclisation step, which then delivered >70% yields of the
benzotriazole 23a from which the acetyl group was readily removed by mild, base-catalysed
hydrolysis to give the free benzotriazole 23b. The excellent yield was only realised when a non-
aqueous work-up was used, due to the water solubility of this polar product. Unexpectedly, its NMR
spectra, when obtained for a solution in CD3OD, showed the presence of essentially a single tautomer,
whereas in CDCl3, two forms were observed, in a 2:1 ratio. Possibly, the tautomer shown, 23b, may be
favoured by hydrogen bonding between the new amino group and the pendant hydroxyls. A small
amount of the by-product was also isolated during this stage: a small sample showed that it did not
13
contain a carbonyl group (IR), but did have a C resonance for a quaternary carbon at ~ 155 ppm,
1
together with five methyl singlets in its H NMR spectrum, but in slightly differing positions than
related derivatives 21-23a (Scheme 6). MS data (APCI) indicated its formation by loss of water: a
probable molecular ion at m/z 293 (M + H) contrasted with that for the N-acetyl benzotriazole 23a at
m/z 311 (M + H).
We deduced that this was the benzimidazole 24, formed by intramolecular cyclization of the N-acetyl
benzotriazole 23a, either when more vigorous hydrogenation conditions were used or when
diazotization was relatively slow, allowing such an (acid-catalysed) cyclisation to compete with

HETEROCYCLES, Vol. 93, No. 2, 2016
653
benzotriazole formation (Figure 3). Hence, relatively mild conditions or excess reagents were essential
to secure high yields from these two steps [b) and c), Scheme 6].
OH
MeO
OH
NH
N
24
Figure 3. The benzimidazole by-product .
The next step was electrophilic N-amination.23 In previous work,15 we had optimised the original
Campbell and Rees method,24 which used hydroxylamine-O-sulfonic acid as the source of an
electrophilic amino group. However, the relatively delicate nature of benzotriazole 23b meant that the
method failed in this case. Fortunately, a mild alternative was the series of N-alkoxycarbonyl-
oxaziridines, which can deliver an alkoxycarbonylamino group to a free amine function, thereby
forming an N-N bond.25,26 A range of such derivatives have been assessed, all of which carry electron-
withdrawing groups; one of the best appeared to be the chloral derivative 25.27 We were delighted to
find that simply stirring this compound with the benzotriazole 23b in dichloromethane at ambient
temperature delivered an essentially quantitative yield of the desired aminated product 26 (Scheme 7).
CCl3
OH
OH
O N
Boc
MeO
MeO
OH
MeO
OH
c
e
b
25
(±)-10
23b
OR
d
a
NHBoc
NH2
O
N
N
N
N
N
N
I
27
26
28a R = H
28b R = Ac
Scheme 7. a) CH2Cl2, rt, 18 h (94%); b) 20% TFA, CH2Cl2, rt, 0.75 h; c) K2CO3, CH2Cl2, filter, add NIS (2.5 eq.)
rt, 1 h (63% 28a; two steps); d) AcCl, pyridine, DMAP (cat.), rt, 14 h (75%); e) 28a, Me4Sn, (dba)3Pd2.CHCl3,
o
Ph3P, CuI, Et2NH, NMP, 100 C, 24 h (59%).
Rather than risk difficulties with the isolation of the doubtless polar free amine 27, we chose to
deprotect using trifluoroacetic acid and, after basification, treat the residue directly with N-
iodosuccinimide. We were delighted to then isolate the desired iodo-chroman 28a, in 63% yield for the
two steps, which was converted into the corresponding acetate 28b, simply to more clearly observe the
AB-system due to the new CH2OR group, which overlapped with the methoxyl resonance in the initial

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HETEROCYCLES, Vol. 93, No. 2, 2016
product 28a (Scheme 7). A modified Stille methylation, with the addition of copper(I) iodide,28 was
then used to complete the sequence, giving a 59% yield of the target chroman, (±)-10.
A final problem was therefore to find a method suitable for obtaining the alkyne-diol 20a, or a related
protected form, in optically enriched form. We thought to add considerable bulk to the alkyne group in
diol 19 in the form of a large silicon group. However, exposure of such a derivative 29 to AD-mix-β
once again failed to give significant chiral induction: HPLC analysis of the derived acetate 30b
showed a ee of only 12.7% (Scheme 8). Hydrolytic kinetic resolution29 of the derived epoxy-alkyne 31
also failed to give significant chiral induction.
19
a
OH
OR
O
d
b,c
TBDPS
TBDPS
TBDPS
30a R = H
30b R = Ac
29
31
Scheme 8. a) BuLi, THF, ice bath, t-BuPh2SiCl, 2 h (86%); b) AD-mix-β (Scheme 5), 70%;
c) Ac2O, pyridine, rt, 18 h (90%); d) m-CPBA, CH2Cl2, rt, 2 h (95%).
We therefore turned to the known if chemically more distant chiral, non-racemic diol 33.30 This time,
AD-mix-α was used to obtain the required diol 33 with chemical and optical yields both of 91%, in
agreement with the initial report of its synthesis (Scheme 9). Protection as the corresponding dioxolane
34 and selective Dibal-H reduction then proceeded smoothly to give the aldehyde 35, which was
converted into the alkyne 36 by addition of a trichloromethyl group to the aldehyde, acetylation,
elimination of HCl using zinc and further HCl elimination from the resulting dichloroalkene using
butyl lithium.31 The method was readily scalable and routinely gave overall yields of around 60%.
Alternatives based on Wittig chemistry (Seyferth-Gilbert or Ohira-Bestmann methods) were either low
yielding or unsuccessful.
O
O
O
O
a)
b)
c)
d)
MeO
MeO
MeO
N
N
OH
N
O
O
O
OH
O
O
O
32
33
34
35
36
Scheme 9. a) AD-mix-α (ref. 30), (91%) (91% ee); b) 2,2-dimethoxypropane, p-TSA, toluene, reflux, 2 h (87%);
c) Dibal-H, THF, ice bath, 1 h (100%); d) i) Cl3CCO2Na, Cl3CCO2H, DMF, ice bath, 4 h, no cooling, then ice
bath, add Ac2O, rt, 1 h, add HOAc then Zn, 60 oC, 1 h (57%), ii) BuLi, THF -30 oC - rt, 1 h (99%).

HETEROCYCLES, Vol. 93, No. 2, 2016
655
Sadly, attempts to use the dioxolane alkyne 36 in the Sonogashira coupling with iodo-anisole 18 (see
Scheme 6) were only partly successful as, unexpectedly, around half the product was simply the
deiodinated arene. Attempts to hydrolyse the dioxolane group were also not viable in our hands, using
Brønsted or Lewis acid-based methods, due to the extreme sensitivity of the diol 20a to dehydration.
Basic deprotection conditions were therefore required and so silyl protection was next investigated.
Silylation of the dihydroxyamide 33 was slow but uneventful while Dibal-H reduction of the resulting
bis-silyl derivative 37 was insufficiently selective, giving the expected aldehyde 38 along with the
corresponding alcohol and desilylation at the tertiary site (Scheme 10). By contrast, low temperature
reduction using ethereal LiAlH4 was completely selective and gave an 88% isolated yield, lowered no
doubt by the high volatility of the aldehyde 38. Corey-Fuchs homologation32 then delivered the alkyne
40 by way of the dibromoalkene 39 and thence the (S)-alkyne-diol 20a.
Br
Br
O
OTBS
OTBS
O
OTBS
OTBS
OTBS
OTBS
OTBS
a)
b)
c)
d)
e)
MeO
(S)-20a
33
N
OTBS
39
37
38
40
Scheme 10. a) t-BuMe2SiCl, imidazole, DMF, 35 oC, 18 h (94%); b) LiAlH4, Et2O, -78 oC, 40 min., aq. NaOH work-
up (88%); c) Ph3P, CBr4, CH2Cl2, rt, 4 h (74%); d) BuLi, THF, - 30 oC, rt 1 h (59%); e) TBAF, THF, rt 2 h (82%).
Using the same method as above (Scheme 6), the (S)-alkyne-diol 20a was successfully coupled to the
iodo-anisole 18 to give the expected (S)-(+)-alkynyl anisole 21 (Figure 4). We were also able to
hydrolyse the acetyl group in iodo-anisole 18 to give the corresponding aniline 14; this too coupled
well with the (S)-alkyne-diol 20a leading to the homologated aniline (S)-(+)-41, thereby completing a
formal asymmetric synthesis of tocopherol 1.
OH
OH
OH
OH
MeO
MeO
I
MeO
18
+
(S)-20a
NHAc
NH2
NH2
NO2
(S)-(+)-21
Figure 4. Chiral, non-racemic derivatives.
NO2
NO2
14
(S)-(+)-41
In any synthetic scheme that encounters problems; simply altering the order of steps can often obviate
these. As a small caveat to the foregoing synthesis, we have shown that this might be possible in this

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HETEROCYCLES, Vol. 93, No. 2, 2016
case, by first incorporating an alkene into a suitable benzotriazole and then carrying out the
asymmetric dihydroxylation step (Scheme 11).
R
OH
OH
R
a)
b)
c)
7
R
NHBoc
NHBoc
O
N
N
N
N
H
N
N
OH
I
42a R = Me
42b R = Ph
43a R = Me
43b R = Ph
44a R = Me
44b R = Ph
Scheme 11. a) crotyl chloride (43a) or cinnamyl bromide (43b), ref. 15, (97% and 78%); b) Scheme 5,
AD-mix-β, 65% and 82%; c) As Scheme 7, steps b and c, (68% and 57%).
Thus, alkylation of the dianion 7 (Scheme 2)15 derived from 1-aminobenzotriazole, by both (E)-crotyl
and (E)-cinnamyl halides gave excellent yields of the unsaturated homologues 42a,b. Asymmetric
dihydroxylation then worked well with both substrates to give the diols 43a,b, the optical purities of
which were 76% and 82% respectively according to hplc analysis (see 30b in Experimental). Both
then underwent sequential deprotection and regiospecific cyclisation, as described above, to provide
reasonable but unoptimised yields of the iodochromans 44a,b. Hence, this alternative approach may
have some potential in this and related areas for the elaboration of a wide variety of substituted
chromans.
We have thus reached our goal of synthesising a tocopherol precursor using intramolecular benzyne
trapping by an alcohol group. Clearly, the approach overall is quite lengthy but does demonstrate the
viability of this key step and could probably be shortened in a number of ways. Additionally, the use
of the oxaziridine 25 should be of considerable use in this and related areas in future, when N-
amination is required. The final feature of note in this synthesis is the incorporation of an iodine atom
at a late stage, which suggests that this chemistry could be useful for the synthesis of radio-labelled
products, for example using iodine 131, which has a half-life of around eight days.
EXPERIMENTAL
Infrared spectra were recorded using a Perkin Elmer 1600 series FTIR instrument as thin films or KBr
1
disks. H NMR spectra were all recorded for dilute solutions in deuteriochloroform, unless otherwise
13
stated, using a Bruker AM 400 MHz instrument with chloroform as internal reference (δ = 7.27). C
NMR spectra were all recorded in deuteriochloroform using a Bruker AM 400 MHz instrument,
operating at 100 MHz with chloroform as internal reference (δ = 77.30). Low resolution mass spectra

HETEROCYCLES, Vol. 93, No. 2, 2016
657
were obtained using a Fisons VG Platform II instrument and high resolution spectra were measured by
the EPSRC Service, Swansea University. All extracts were dried over dried magnesium sulfate.
Column chromatography was performed using Silica 60A, particle size 35-70 micron, from Fisher
Scientific.
2,6-Dimethyl-4-nitroanisole (16a): To an ice-cold, stirred solution of 2,6-dimethylanisole 15 (40.00 g,
294 mmol) in glacial acetic acid (60 mL) was added dropwise 70% nitric acid (60 mL). After the
o
addition was complete and gas evolution began to subside, the solution was slowly heated to 65 C
resulting in the formation of a pale yellow solution. [CAUTION: It is essential to keep the reaction
o
temperature below 70 C at all times as, above this, the mixture on occasions detonated with
extreme violence; protection by a blast screen in recommended in any event]. The solution was
then allowed to cool to ambient temperature and diluted with water (300 mL). Nitrogen was bubbled
through the resulting deep brown solution for ca. 0.5 h to remove most of the nitrogen oxides present.
The resulting yellow precipitate was separated by vacuum filtration and washed with copious water
o
then crystallised from ethanol to give the nitroanisole 16a (32.6 g, 61%), mp 91.5-93.5 C (lit.18 mp
89-91 oC); 1H NMR δ 2.28 (s, 6H, 2 x Me), 3.71 (s, 3H, OMe), 7.83 (s, 2H, ArH); 13C NMR δ 16.8 (2
x Me), 60.3 (OMe), 124.6 (2 x ArCH), 132.7 (2 x ArC), 143.8 (ArC), 162.8 (ArC); m/z (APCI) 152
(M-29, 100%).
4-Amino-2,6-dimethylanisole (16b): To a suspension of 10% Pd-C (0.65 g) in ethanol (130 mL) at rt
was added portionwise the foregoing nitroanisole 16a (10.00 g, 55 mmol) followed by cyclohexene
(32 mL, 330 mmol). The mixture was then heated under reflux for 14 h, cooled to rt and filtered
through celite. The filter cake was washed with ethanol and the combined filtrates evaporated to leave
the sensitive aniline 16b (7.56 g, 91%) as a brown solid which was sufficiently pure for further use
o
o
and which showed mp 62-63 C (lit.33 mp 60-61 C), IR (KBr) 3772, 3612, 3397, 1605, 1487, 1340,
1219, 1150, 1016 cm-1; 1H NMR δ 2.24 (s, 6H, 2 x Me), 3.47-3.51 (br s, 2H, NH2), 3.69 (s, 3H, OMe),
13
6.39 (2, 2H, 2 x ArH); C NMR δ 16.5 (2 x Me), 60.4 (OMe), 115.7 (2 x ArCH), 131.9 (2 x ArC),
142.5 (ArC), 150.0 (ArC); m/z (APCI) 152 (M + 1, 100%).
4-Acetamido-2,6-dimethylanisole (16c): A stirred solution of the foregoing aniline 16b (7.60 g, 50
mmol) in dry THF (100 mL) containing triethylamine (7.4 mL, 53.2 mmol) was cooled in an ice-bath
before the addition of acetyl chloride (4.0 mL, 54.1 mmol). The resulting solution was stirred
overnight without further cooling then quenched by the sequential addition of saturated aqueous
ammonium chloride (47 mL) and 2M hydrochloric acid (47 mL). The resulting mixture was extracted
with ether (3 x 75 mL) and the combined extracts washed with water (75 mL) and brine (75 mL) then
dried and evaporated. Crystallisation of the residue from ethanol left the acetamide 16c (8.60 g, 89%);
mp 136-137 oC [lit.34 mp 136-138 oC]; IR (KBr) 3315, 1659, 1612, 1558, 1462, 1221, 1038, 1010 cm-1;

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1H NMR δ 2.10 (s, 3H, Ac), 2.22 (s, 6H, 2 x Me), 3.64 (s, 3H, OMe), 6.94 (br s, 1H, NH), 7.08 (s, 2H,
2 x ArH); 13C NMR δ 16.5 (2 x Me), 24.8 (MeCO), 60.2 (OMe), 121.1 (2 x ArCH), 131.7 (2 x ArC),
133.8 (ArC), 153.9 (ArC), 168.9 (C=O); m/z (APCI) 194 (M+, 100%).
4-Acetamido-2,6-dimethyl-5-iodoanisole (17): A suspension of the foregoing acetamide 16c (7.4 g,
38.1 mmol) and N-iodosuccinimide (12.9 g, 57.2 mmol) in glacial acetic acid (120 mL) was heated to
reflux for 1.5 h. The resulting purple solution was cooled to rt and neutralised with 2M aqueous
sodium hydroxide to give a suspension which was vacuum filtered. The solid was washed with water
then crystallised from ethyl acetate to give the iodo-anisole 17 (8.5 g, 70%); mp 189-191 oC; IR (KBr)
3272, 1651, 1527, 1461, 1377, 1228, 1160, 1006 cm-1; 1H NMR δ 2.08 (s, 3H, Ac), 2.12 (s, 3H, Me),
13
2.28 (s, 3H, Me), 3.52 (s, 3H, OMe), 7.15-7.25 (br s, 1H, NH), 7.61 (s, 1H, 3-H); C NMR δ 16.4
(Me), 22.9 (Me), 24.8 (Me), 60.4 (OMe), 96.4 (C-I), 123.0 (3-CH), 131.7 (ArC), 134.4 (ArC), 135.1
(ArC), 153.9 (ArC), 168.5 (C=O); m/z (APCI) 320 (M+ + H, 100%). Anal. Calcd for C11H14INO2: C,
41.38; H, 4.42; N, 4.39. Found: C, 41.60; H, 4.35; N, 4.36.
4-Acetamido-2,6-dimethyl-5-iodo-3-nitroanisole (18): The foregoing iodo-anisole 17 (1.00 g, 3.1
mmol) was stirred in glacial acetic acid (10 mL) at rt as 70% nitric acid (2.0 mL) was added dropwise.
The resulting solution was then stirred at 65 oC for 5 h, cooled to rt, diluted with water (18 mL) and the
resulting precipitate collected by filtration and crystallised from aqueous ethanol to give the nitro-
o
iodide 18 (0.85 g, 76%); mp 226-227 C; IR (KBr) 3617, 3212, 1667, 1519, 1455, 1376, 1272, 1221,
1
1039, 989 cm-1; H NMR δ 2.17 (s, 3H, Ac), 2.22 (s, 3H, Me), 2.49 (s, 3H, Me), 3.72 (s, 3H, OMe),
7.06-7.17 (br s, 1H, NH); 13C NMR δ 12.2 (Me), 23.7 (Me), 23.9 (Me), 61.0 (OMe), 106.3 (CI), 125.2
(ArC), 126.3 (ArC), 127.3 (ArC), 139.9 (ArC), 156.2 (ArC), 169.3 (C=O); m/z (APCI) 365 (M+ + H,
100%). Anal. Calcd for C11H13IN2O4: C, 36.28; H, 3.60; N, 7.69. Found: C, 36.43; H, 3.81; N, 7.56.
2-Methyl-1-buten-3-yne (19): 2-Methylbut-3-yn-2-ol (50 g) and p-toluenesulfonic acid (50 g) were
o
stirred together and heated to 90 C under a distillation apparatus. After 3 h, the distillate was
redistilled (bath temp. 50 oC) to give the enyne 19 (11.4 g, 29%); bp 34 oC; IR (film) 3300, 3100, 1614,
1
1455, 1374, 1266, 1214, 1171, 1013, 961, 904 cm-1; H NMR δ 1.71 (s, 3H, Me), 2.71 (s, 1H, 4-H),
5.11 (app. s, 1H, 1-Ha), 5.21 (app. s, 1H, 1-Hb).21
3,4-Dihydroxy-3-methyl-1-butyne (20a): AD-mix-β (63.70 g) was added to a stirred mixture of t-
butanol (225 mL) and water (225 mL) followed by methanesulfonamide (4.30 g). Once the mixture
became clear, the foregoing enyne 19 (3.00 g, 45.5 mmol) was added and the resulting mixture stirred
at rt for 24 h. Sodium sulfite (68 g) was then added and stirring continued for 1 h. The mixture was
then extracted with dichloromethane (4 x 100 mL) and the combined extracts washed with 2M
aqueous potassium hydroxide (2 x 50 mL) then dried and evaporated. Column chromatography over
silica gel eluted with ether-hexanes (2:1) then separated the diol 20a (3.1 g, 67%) as a pale yellow oil.

HETEROCYCLES, Vol. 93, No. 2, 2016
659
IR (film) 3430, 2113, 1622, 1511, 1376, 1244, 1060, 953, 891 cm-1; 1H NMR δ 1.37 (s, 3H, Me), 2.39
13
(s, 1H, 1-H), 3.44 (d, J = 7.6 Hz, 1H, 4-Ha), 3.60 (d, J = 7.6 Hz, 1H, 4-Hb); C NMR δ 25.6 (Me),
68.6 (3-C), 70.7 (4-CH2), 72.6 (1-CH), 86.3 (2-C); m/z (APCI) 100 (M+, 100%).
(±)-2-Hydroxy-2-methyl-3-butyn-1-yl benzoate (20b): Benzoyl chloride (26 µL, 0.22 mmol) was
added to a stirred solution of the diol 20a (20 mg, 0.2 mmol) in dry dichloromethane containing
triethylamine (30 µL, 0.22 mmol). After stirring overnight at rt, the solution was diluted with
dichloromethane (5 mL) and washed with water (3 mL), 1M hydrochloric acid (2 mL) and brine then
dried and evaporated. Short-column chromatography (SiO2; petrol-ether 4:1) separated the benzoate
20b (29 mg, 71%) as a colourless oil; IR (film) 3456, 3284, 2360, 1722, 1452, 1371, 1274, 1116, 710;
1H NMR δ 1.53 (s, 3H, 2-Me), 2.43 (s, 1H, 4-H), 2.92 (br s, 1H, OH), 4.23 (d, J = 11.1 Hz, 1H, 1-Ha),
4.36 (d, J = 11.1 Hz, 1H, 1-Hb), 7.36 (t, J = 7.6 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 8.00 (dd, J = 7.6, 1.0
13
Hz, 2H); C NMR δ 26.4 (Me), 67.3 (CH2), 71.6 (2-C), 73.1 (4-CH), 85.1 (3-C), 128.9 (2 x ArCH),
130.0 (ArC), 130.2 ArCH), 133.7 (2 x ArCH), 166.8 (C=O); m/z (APCI) 205 (M+H, 100%).
o
o
o
GC analysis using a chiral CDX-β column at 150 C (detector: 300 C; injection: 250 C]; column
head pressure: 20 psi, Rt ~ 14.2 min. showed < 10% ee against a racemic sample.
Sonogashira coupling; General Procedure:35 The aryl iodide (3.5 mmol) was stirred in degassed
THF (40 mL) then triethylamine (14 mL) and tetrakis(triphenylphosphine)palladium(0) (0.80 g, 0.7
mmol) was added followed by the 1-alkyne (7.0 mmol). The resulting solution was degassed again by
passage of dry nitrogen for 40 minutes before copper(I) iodide (133 mg, 0.7 mmol) was added and the
mixture stirred at reflux for 24 h then cooled to rt and the bulk of the THF evaporated. The residue was
diluted with water (35 mL) and extracted with dichloromethane (3 x 50 mL). The combined extracts
were dried and evaporated and the product(s) separated by column chromatography over silica gel,
typically using 5% MeOH-CHCl3 as elutant.
(±)-4-Acetamido-2,6-dimethyl-5-[3’,4’-dihydroxy-3’-methylbut-1’-yn-1’-yl]-3-nitroanisole (21):
Following the general Sonogashira procedure, the nitro-iodide 18 (1.30 g, 3.5 mmol) was coupled with
the diol 20a (0.70 g, 7.0 mmol) using (Ph3P)4Pd (0.80 g, 0.7 mmol) to give the alkyne-diol 21 (1.00 g,
o
86%) as a pale yellow, amorphous solid, mp 178-182 C (MeOH); IR 3822, 3580, 3280, 1667, 1504
1
cm-1; H NMR δ 1.46 (s, 3H, 3’-Me), 2.13 (s, 3H, Ac), 2.23 (s, 3H, ArMe), 2.36 (s, 3H, ArMe), 3.04
13
(br s, 2H, 2 x OH), 3.43-3.50 (m, 2H, 4’-CH2), 3.65 (S, 3H, OMe), 7.54 (BR S, 1H, NH); C NMR
(CD3OD) δ 12.1 (Me), 15.5 (Me), 23.0 (Me), 26.6 (Me), 61.4 (OMe), 70.2 (CH2), 71.4 (C), 78.7 (C),
103.9 (1’-C), 124.3 (ArC), 126.2 (ArC), 127.7 (ArC), 128.3 (ArC), 138.6 (ArC), 157.8 (ArC), 173.4
(C=O); m/z (APCI) 319 (M+-OH, 100%). HR-MS (FAB). Calcd for C16H21N2O6 (M+H): 337.1396.
Found: m/z 337.1400.

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HETEROCYCLES, Vol. 93, No. 2, 2016
(±)-4-Acetamido-3-amino-2,6-dimethyl-5-[3’,4’-dihydroxy-3’-methylbut-1’-yl]anisole (22): The
alkyne-diol 21 (0.22 g, 0.66 mmol) was added to a suspension of 20% palladium hydroxide on carbon
(Pearlman’s catalyst) (44 mg) in methanol (40 mL) and the mixture stirred under an atmosphere of
hydrogen for 48 h then filtered through celite. The solid was washed with warm methanol and the
combined filtrates evaporated to leave the aniline 22 (0.202 g, 99%) as a pale yellow gum; IR (film)
3418, 1641, 1461, 1121 cm-1; 1H NMR δ 1.09 (s, 3H, 3’-Me), 1.42 (t, J ca. 8.6 Hz, 2’-CH2), 1.68-1.73
(m, 2H, NH2), 1.95 (s, 3H, Me), 2.04 (s, 3H, Me), 2.08 (s, 3H, Me), 2.45 (t, J ca. 8.6 Hz, 1’-CH2), 2.79
(br s, §1H, OH), 2.93 (br s, 1H, OH), 3.30-3.36 (m, 2H, 4-CH2), 3.49 s, 3H, OMe), 7.89 (s, 1H,
13
NHCO); C NMR (CD3OD) δ 11.0 (Me), 12.3 (Me), 23.2 (Me), 24.1 (Me), 24.7 (CH2), 39.5 (CH2),
60.9 (OMe), 70.6 (CH2OH), 74.1 (3’-C), 115.6 (ArC), 119.3 (ArC), 119.8 (ArC), 139.0 (ArC), 142.8
(ArC), 158.0 (ArC), 174.0 (C=O); m/z (APCI) 311 (M++H, 100%). HR-MS (FAB). Calcd for
C16H27N2O4 (M+H): 311.1965. Found: m/z 311.1963.
(±)-1-Acetyl-7-(3’,4’-dihydroxy-3’-methylbutan-1’-yl)-4,6-dimethyl-5-methoxybenzotriazole
(23a): To a solution of the foregoing aniline 22 (0.34 g, 1.1 mmol) in methanol (3 mL) at rt was added
a solution of sodium nitrite (0.22 g, 3.3 mmol) in water (0.6 mL). The resulting solution was added
o
slowly to a stirred solution of 10M hydrochloric acid (1.0 mL) in water (1.2 mL) maintained at 0 C.
Stirring at this temperature was continued for 0.5 h then water (12 mL) was added and the mixture
extracted with dichloromethane (3 x 20 mL). The combined extracts were dried and evaporated to
o
leave the N-acetyl-benzotriazole 23a (0.266 g, 73%) as a colourless solid, mp 99-102 C (CHCl3-
1
petrol); IR (KBr) 3270, 1745, 1459, 1366, 1309, 1266, 1130, 1094 cm-1; H NMR δ 1.24 (s, 3H, 3’-
Me), 1.72 (t, J = 8.8 Hz, 2H, 2’-CH2), 2.38 (s, 3H, Ac), 2.49-2.54 (br res., 2H, 2 x OH), 2.66 (s, 3H,
ArMe), 2.96 (s, 3H, ArMe), 2.99-3.15 (m, 2H, 1’-CH2), 3.41 (dd, J = 11.3, 5.9 Hz, 1H, 4’-Ha), 3.54
(dd, J = 11.3, 5.9 Hz, 1H, 4’-Hb), 3.70 (s, 3H, OMe); 13C NMR δ 9.6 (Me), 12.0 (Me), 22.1 (Me), 24.3
(Me), 24.9 (2’-CH2), 37.3 (1’-CH2), 59.5 (OMe), 68.2 (4’-CH2), 71.8 (3’-C), 118.9 (ArC), 123.4 (ArC),
126.8 (ArC), 133.6 (ArC), 145.4 (ArC), 154.4 (ArC), 169.9 (C=O); m/z (APCI) 322 (M++H, 100%).
HR-MS (FAB). Calcd for C16H24N3O4 (M+H): 322.1761. Found: m/z 322.1763.
(±)-7-(3’,4’-Dihydroxy-3’-methylbut-1’-yl)-4,6-dimethyl-5-methoxybenzotriazole
(23b):
Potassium carbonate (0.14 g, 1.00 mmol) and water (0.5 mL) were added to a stirred solution of the
foregoing N-acetyl-benzotriazole 23a (0.10 g, 0.32 mmol) in methanol (2 mL) at rt and the hydrolysis
followed by tlc. Upon completion (ca. 4 h), the bulk of the methanol was evaporated and the residue
taken up into dichloromethane (20 mL), which was then dried, filtered and evaporated. The solid
residue was washed with methanol and the combined filtrates evaporated to leave the benzotriazole
o
23b (0.09 g, 99%) as a colourless solid, mp 250-252 C (MeOH); IR (KBr) 3376, 1621, 1434, 1140,
1071, 998, 880 cm-1; 1H NMR (CD3OD) δ 1.17 (s, 3H, 3’-Me), 1.64-1.73 (m, 2H, 2’-CH2), 2.23 (s, 3H,

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661
Ac), 2.45 (s, 3H, ArMe), 2.97-3.03 (m, 2H, 1’-CH2), 3.36 (d, J = 11.3 Hz, 1H, 4’-Ha), 3.41 (d, J = 11.3
13
Hz, 1H, 4’-Hb), 3.62 (s, 3H, OMe); C NMR (CD3OD) δ 11.8 (Me), 12.6 (Me), 24.4 (Me), 24.6 (2’-
CH2), 39.6 (1’-CH2), 61.3 (OMe), 70.3 (4’-CH2), 74.4 (3’-C), 115.3 (ArC), 124.6 (ArC), 127.8 (ArC),
142.7 (ArC), 145.0 (ArC), 153.9 (ArC); m/z (APCI) 280 (M++H, 100%). HR-MS (FAB). Calcd for
C14H22N3O3 (M+H): 280.1656. Found: m/z 280.1652.
(±)-1-(tert-Butylcarbonylamino)-7-(3’,4’-dihydroxy-3’-methylbut-1’-yl)-4,6-dimethyl-5-
methoxybenzotriazole (26): To a stirred solution of the foregoing benzotriazole 23b (0.28 g, 1 mmol)
in dry dichloromethane (8 mL) at rt was added the N-Boc-oxaziridine 25 (0.53 g, 2.0 mmol)27 and the
resulting solution stirred overnight. The solvent was then evaporated and the residue separated by
column chromatography (5% MeOH-CHCl3) to give the N-Boc-amino-benzotriazole 26 (0.40 g, 94%)
1
as a yellow oil; IR (film) 3274, 1739, 1452, 1362, 1248, 1158, 1110, 1050, 906, 834, 732 cm-1; H
NMR δ 1.23 (s, 3H, 3’-Me), 1.32-1.75 (br s, 9H, Boc), 1.78 (t, J = 8.6 Hz, 2H, 2’-CH2), 2.30 (s, 3H,
ArMe), 2.56 (s, 3H, ArMe), 2.99-3.02 (m, 2H, 1’-CH2), 3.54 (d, J = 11.3 Hz, 1H, 4’-Ha), 3.65 (d, J =
13
11.3 Hz, 1H, 4’-Hb), 3.69 (s, 3H, OMe); C NMR δ 7.9 (Me), 10.9 (Me), 21.9 (Me), 24.9 (2’-CH2),
27.1 (3 x Me), 37.1 (1’-CH2), 59.5 (4’-CH2), 59.6 (OMe), 72.1 (3’-C), 82.4 (CMe3),109.0 (ArC), 124.9
(ArC), 126.0 (ArC), 129.5 (ArC), 139.4 (ArC), 152.7 (ArC), 156.7 (C=O); m/z (APCI) 395 (M++H,
100%). HR-MS (FAB). Calcd for C19H31N4O5 (M+H): 395.2289. Found: m/z 395.2295.
(±)-8-Iodo-6-methoxy-2,5,7-trimethylchroman-2-methanol (28a): The N-Boc-amino-benzotriazole
26 (0.22 g, 0.56 mmol) was dissolved in a stirred solution of trifluoroacetic acid (1.1 mL) in
dichloromethane (5 mL) at rt. The deprotection was followed by tlc and when complete (ca. 0.75 h),
the volatiles were evaporated, finally under high vacuum. The residue was then dissolved in
dichloromethane (5 mL) and stirred with anhydrous potassium carbonate (1.0 g) for 0.25 h and filtered.
The solid was washed with warm dichloromethane and the combined filtrates concentrated to a
volume of ca. 5 mL and protected from light before N-iodosuccinimide (0.38 g, 1.7 mmol) was added
in one portion. The resulting purple solution was stirred at rt for a further 1 h then diluted with
dichloromethane (15 mL) and the solution washed with saturated aqueous sodium thiosulfate (5 mL)
and then dried and evaporated. Silica gel column chromatography (petrol-EtOAc, 2:1) separated the
iodochroman 28a (0.129 g, 63%) as a yellow semi-solid; IR (film) 3390, 1450, 1390, 1219, 1058, 882
cm-1; 1H NMR δ 1.21 (s, 3H, 2-Me), 1.67 (ddd, J = 13.6, 6.0, 4.8, 3-Ha), 1.80-1.90 (m, 1H, 3-Hb), 2.08
13
(s, 3H, ArMe), 2.35 (s, 3H, ArMe), 2.56-2.60 (m, 2H, 4-CH2), 3.57 (m, 5H, CH2OH and OMe); C
NMR δ 11.0 (2-Me), 19.2 (ArMe), 19.4 (3-CH2), 20.9 (ArMe), 26.9 (4-CH2), 59.5 (OMe), 68.2
(CH2OH), 77.2 (2-C), 90.0 (C-I), 117.8 (ArC), 128.4 (ArC), 132.3 (ArC), 146.8 (ArC), 149.1 (ArC);
m/z (APCI) 345 (M+-OH, 100%). HR-MS (NH4-CI). Calcd for C14H23INO3 (M+NH4): 380.0717.
Found: m/z 380.0714.

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(±)-2-Acetoxymethyl-8-iodo-6-methoxy-2,5,7-trimethylchroman (28b): Iodochroman 28a (30 mg,
0.08 mmol) was stirred in dry pyridine (1.5 mL) containing acetyl chloride (0.02 mL, 0.24 mmol) and
4-dimethylaminopyridine (2 mg) overnight at rt. The solution was then diluted with dichloromethane
(5 mL) and washed with water (2 x 2 mL), saturated aqueous copper sulphate (2 mL) and saturated
aqueous potassium carbonate (2 mL) then dried and evaporated. Silica gel column chromatography
(ether-hexane 1:3) separated the acetoxy-chroman 28b (23 mg, 75%) as a yellow oil; IR (film) 1744,
1
1450, 1390, 1260, 1057, 800 cm-1; H NMR δ 1.28 (s, 3H, 2-Me), 1.72-1.88 (m, 2H, 3-CH2), 2.05 (s,
3H, ArMe), 2.06 (s, 3H, ArMe), 2.34 (s, 3H, Ac), 2.53 (app. t, J = 6.9 Hz, 2H, 4-CH2), 3.56 (s, 3H,
13
OMe), 4.02 (d, J = 11.3 Hz, 1H, 1’-Ha), 4.09 (d, J = 11.3 Hz, 1H, 1’-Hb); C NMR δ 11.0 (2-Me),
19.4 (ArMe), 20.0 (ArMe), 20.1 (3-CH2), 20.9 (MeCO), 28.7 (4-CH2), 59.5 (OMe), 67.2 (CH2OH),
74.3 (2-C), 89.1 (C-I), 117.2 (ArC), 128.3 (ArC), 133.0 (ArC), 147.1 (ArC), 149.0 (ArC), 169.9
(C=O); m/z (APCI) 277 (M+-I, 100%). HR-MS (EI). Calcd for C16H21IO4 (M+): 404.0485. Found: m/z
404.0483.
(±)-6-Methoxy-2,5,7,8-tetramethylchroman-2-methanol (10): To a solution of the iodochroman 28a
(0.153 g, 0.75 mmol) in 1-methyl-2-pyrrolidinone (NMP; 3 mL) at rt was added triphenylphosphine
(40 mg), tris-(dibenzylideneacetone)dipalladium(0).CHCl3 (50 mg) and copper(I) iodide (15 mg). The
stirred mixture was then degassed for 0.5 h before the addition of diethylamine (0.5 mL) and
o
tetramethyltin (0.75 g, 4.5 mmol) in NMP (1 mL) and then heated at 100 C for 24 h. The cooled
suspension was then diluted with 10% aqueous sodium sulfite (40 mL) and extracted with ether (3 x 25
mL). The combined extracts were washed with 10% aqueous potassium fluoride (15 mL) then dried
and evaporated. Column chromatography (SiO2; petrol-EtOAc 2:1) of the residue separated the
chroman-methanol (±)-10 (0.111 g, 59%) as a thick, colourless oil, which slowly solidified, mp 49-52
oC; IR 3310, 1450, 1233, 1040 cm-1; 1H NMR δ 1.23 (s, 3H, 2-Me), 1.74 (ddd, J = 13.6, 6.1, 4.8, 3-Ha),
1.80-1.90 (m, 1H, 3-Hb), 2.08 (s, 3H, ArMe), 2.16 (s, 3H, ArMe), 2.30 (s, 3H, ArMe), 2.56-2.67 (m,
13
2H, 4-CH2), 3.54 (2 x d (partly obscured), JAB = 11.1 Hz, CH2OH), 3.56 (s, 3H, OMe); C NMR δ
11.2 (Me), 11.4 (Me), 12.4 (Me), 19.9 (Me), 20.3 (Me), 27.4 (4-CH2), 60.0 (OMe), 68.8 (CH2OH),
75.2 (2-C), 117.3 (ArC), 122.4 (ArC), 125.1 (ArC), 128.0 (C), 146.9 (ArC), 149.3 (ArC); m/z (APCI)
251 (M++ H, 100%). HR-MS (FAB). Calcd for C15H22O3 (M+): 250.1569. Found: m/z 250.1567. The
spectroscopic data were identical to those recorded previously for a while solid, no mp quoted.2d
4-(tert-Butyldiphenylsilyl)-2-hydroxy-2-methylbut-3-yn-1-yl
acetate
(30b):
i)
4-(tert-
Butyldiphenylsilyl)-2-methyl-1-buten-3-yne (29): Butyl lithium (24 mL of a 2.5M solution in hexanes,
60 mmol) was added dropwise to a stirred solution of 2-methyl-1-buten-3-yne 19 (4.00 g, 60 mmol) in
dry THF (45 mL), cooled in an ice bath. After 0.25 h, t-butylchlorodiphenylsilane (14.0 g, 60 mmol)
was added dropwise and stirring continued for 2 h before the bulk of the THF was evaporated. The

HETEROCYCLES, Vol. 93, No. 2, 2016
663
residue was partitioned between ether (10 mL) and water (10 mL) and the separated aqueous layer
extracted with ether (3 x 10 mL). The combined ether solutions were dried, filtered through a pad of
silica gel and evaporated to leave the silane 29 (17.7 g, 86%) as a light yellow oil of sufficient purity
for use in the next step, which showed IR (film) 3428, 2154, 1682, 1589 cm-1; 1H NMR δ 0.99 (s, 9H,
t-Bu), 1.92 (s, 2H, 2-Me), 5.27 (d, J = 1.7 Hz, 1-Ha), 5.41 (d, J = 1.7 Hz, 1-Hb), 7.27-7.33 (m, 6H),
13
7.63-7.67 (m, 4H); C NMR δ 19.1 (CMe3), 25.4 (2-Me), 26.6 (3 x Me), 88.5 (4-C), 109.0 (3-C),
123.3 (1-CH2), 127.8, 129.7, 134.8, 135.2 (2-C), 135.6 (2 x ArC); m/z (APCI) 305 (M+H), 100%). ii)
4-(tert-Butyldiphenylsilyl)-2-methylbut-3-yne-1,2-diol (30a): Using exactly the same method as for the
dihydroxylation of enyne 19, reaction of the foregoing silylated enyne (0.58 g, 1.7 mmol) with AD-
mix-β (2.40 g) gave the silyl diol 30a (0.44 g, 70%); IR (film) 3426, 2359, 1635, 1428, 1110, 908, 700
cm-1; 1H NMR δ 1.01 (s, 9H), 1.51 (s, 3H, 2-Me), 3.56 (d, J = 11.0 Hz, 1-Ha), 3.70 (d, J = 11.0 Hz, 1-
Hb), 7.29-7.35 (m, 6H), 7.68 (d, J = 7.1 Hz, 4H); 13C NMR δ 18.5 (CMe3), 24.1 (2-Me), 27.0 (3 x Me),
58.9 (2-C), 70.7 (CH2), 84.1 (4-C), 111.6 (3-C), 127.8 (ArCH), 129.7 (ArCH), 132.9 (ArC), 135.5
(ArCH). iii) 4-(tert-Butyldiphenylsilyl)-2-hydroxy-2-methylbut-3-yn-1-yl acetate (30b): Acetic
anhydride (2 drops) was added to a solution of the silyl diol 30a (20 mg) in pyridine (0.5 mL) and the
resulting solution stirred at rt for 18 h and then diluted with water (1 mL) and extracted with ether (3 x
3 mL). The combined extracts were dried and evaporated and the residue separated by column
chromatography (EtOAc-petrol 4:1) to give the acetate 30b (19 mg, 90%) as a colourless oil, ee =
12.7%; IR 3438, 2173, 1745, 1650, 1471, 1372, 1237, 1110, 1048, 968, 921 cm-1; 1H NMR δ 1.00 (s,
9H), 1.55 (s, 3H, 2-Me), 2.06 (s, 3H, MeCO), 2.54 (br s, 1H, OH), 4.02 (d, J = 11.1 Hz, 1-Ha), 4.28 (d,
13
J = 11.1 Hz, 1-Hb), 7.29-7.37 (m, 6H), 7.69 (d, J = 6.4 Hz, 4H); C NMR δ 18.5 (CMe3), 25.3 (3 x
Me), 26.0 (2-Me), 27.0 (MeCO), 67.2 (2-C), 71.1 (CH2), 84.2 (4-C), 110.6 (3-C), 127.8 (ArCH), 129.7
(ArCH), 132.8 (ArC), 135.5 (ArCH).
Chiral hplc analysis using an 5µ OD column at 0.8 mL min-1 flow of 0.7% IPA in hexanes, detector set
at 254 nm, gave a retention time of ~ 25 min.
2-(tert-Butyldiphenylsilyl)ethyn-1-yl-2-methyloxirane (31): To a well-stirred solution of the silyl
butenyne 29 (0.60 g, 1.73 mmol) in dichloromethane (9 mL) was added m-chloroperoxybenzoic acid
(0.60 g, 3.46 mmol). The resulting suspension was stirred for 2 h at rt before saturated aqueous sodium
bicarbonate (10 mL) was added and the mixture extracted with ether (3 x 15 mL). The combined
extracts were dried and evaporated and the residue separated by column chromatography (ether-hexane
9:1) to give the oxirane 31 (0.59 g, 95%) as a yellow oil; IR (film) 3429, 2156, 1589, 1471, 1428, 1362,
1
1193, 1111, 1009, 907, 820 cm-1; H NMR δ 0.99 (s, 9H), 1.57 (s, 3H, 2-Me), 2.71 (d, J = 5.6 Hz, 3-
13
Ha), 3.03 (d, J= 5.6 Hz, 3-Hb), 7.26-7.35 (m, 6H), 7.62-7.69 (m, 4H); C NMR δ 19.0 (CMe3), 23.3

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HETEROCYCLES, Vol. 93, No. 2, 2016
(2-Me), 27.0 (3 x Me), 48.0 (2-C), 56.1 (CH2), 83.2 (4-C), 109.2 (3-C), 128.2 (ArCH), 130.5 (ArC),
132.9 (ArC), 135.2 (ArCH), 136.0 (ArCH); m/z (APCI) 321 (M+ + H, 100%).
(+)-(R)-2,3-Dihydroxy-2,N-dimethyl-N-methoxy propanamide (33): AD-mix-α directed
dihydroxylation of the Weinreb amide derivative 32 (6.10 g, 47.1 mmol) of methacrylic acid as
26
described previously30 gave the expected dihydroxyamide 33 (7.00 g, 91%), which showed [α]D = +
25
4.3 (c 2.0 g/100 mL MeOH) [lit.30 [a]D = + 4.7 (c 1.80 g/100 mL MeOH)] and otherwise identical
spectroscopic and analytical data.
(R)-N-Methoxy-N-methyl-2,2,4-trimethyl-1,3-dioxolane-4-carboxamide (34): A solution of the
dihydroxyamide 33 (3.25 g, 19.9 mmol), 2,2-dimethoxypropane (12.3 mL, 99.5 mmol) and p-
toluenesulfonic acid monohydrate (76 mg) in toluene (60 mL) was heated under reflux for 2 h then
cooled and evaporated. Silica gel column chromatography (EtOAc-petrol 1:1) separated the dioxolane
34 (3.60 g, 87%) as a colourless oil: IR 1658, 1456, 1372, 1247, 1211 cm-1; 1H NMR δ 1.16 (s, 3H, 5-
Me), 1.25 (s, 3H, 2-Me), 1.31 (s, 3H, 2-Me), 3.10 (br. s, 3H, NMe), 3.53 (s, 3H, OMe), 3.56 (d, J = 8.3
Hz, 4-Ha), 4.37 (d, J = 8.3 Hz, 4-Hb); 13C NMR δ 23.4 (5-Me), 26.1 (2-Me), 27.3 (2-Me), 60.7 ~(NMe),
61.1 (OMe), 73.0 (4-CH2), 77.7 (5-C), 110.7 (2-C), 171.7 (C=O); m/z (APCI) 204 (M+H, 100%).
(S)-4-Ethynyl-2,2,4-trimethyl-1,3-dioxolane (36): i) (R)-2,2,4-Trimethyl-1,3-dioxolane-4-carb-
oxaldehyde (35): Dibal-H (53.2 mL of a 1M solution in THF, 53.2 mmol) was added dropwise to a
stirred solution of the acetal 34 (3.60 g, 17.7 mmol) in THF cooled in an ice-water bath. After 1 h at
this temperature, the reaction mixture was poured into 5% hydrochloric acid in ethanol (50 mL) and
the resulting mixture partitioned between brine (20 mL) and ether (100 ml). The separated organic
solution was washed with water (15 mL) then dried and evaporated to leave the aldehyde 35 (2.80 g,
1
100%); IR (film) 3424, 1725, 1458, 1373 cm-1; H NMR δ 1.29 (s, 3H, Me), 1.39 (br s, 6H, 2 x Me),
13
3.66 (s, 2H, 4-CH2), 9.59 (s, 1H, CHO); C NMR δ 18.2 (Me), 25.4 (Me), 25.8 (Me), 69.8 (4-CH2),
76.3 (C), 83.6 (C), 201.4 (C=O); m/z (APCI) 145 (M + H, 100%), which was used immediately in the
next step. ii) (S)-4-(2,2-Dichloroethen-1-yl)-2,2,4-trimethyl-1,3-dioxolane: Sodium trichloroacetate
(4.70 g, 25.4 mmol) was added in portions to a stirred solution of the foregoing aldehyde 35 (2.27 g,
15.9 mmol) and trichloroacetic acid (4.20 g, 25.4 mmol) in DMF (12 mL); an ice-water bath was used
o
to maintain the temperature below 35 C during the addition. The mixture was then stirred without
o
further cooling for 4 h as CO2 was continually evolved before cooling to 5 C and the addition of
acetic anhydride (3.0 mL, 31.8 mmol), which caused increased CO2 evolution. After a further 1 h at rt,
the mixture was diluted with acetic acid (15 mL) and cooled in an ice-water bath. Zinc powder (2.10 g,
31.8 mmol) was then added in one portion and the mixture heated to 60 oC for 1 h. After cooling to rt,
water (10 mL) was added and the mixture extracted with hexanes (3 x 30 mL). The combined extracts
were washed with water (10 mL) and brine (10 mL) then dried and evaporated to leave the crude

HETEROCYCLES, Vol. 93, No. 2, 2016
665
dichloroalkene (1.89 g, 57%) as a pale yellow oil; IR (film) 1613, 1451, 1372, 1210, 1111, 991, 883,
810 cm-1; 1H NMR δ 1.30 (s, 3H, Me), 1.36 (s. 3H, Me), 1.42 (s, 3H, Me), 3.88 (d, J = 8.6 Hz, 4-Ha),
13
4.09 (d, J = 8.6 Hz, 4-Hb), 6.20 (s, 1H, :CH); C NMR δ 24.3 (Me), 26.0 (Me), 27.2 (Me), 73.9 (4-
CH2), 80.5 (C), 109.5 (C), 120.2 (:C), 136.0 (:CH). iii) (S)-4-Ethynyl-2,2,4-trimethyl-1,3-dioxolane
(36): To a stirred solution of the foregoing dichloroalkene (1.64 g, 7.8 mmol) in THF (10 mL)
o
maintained at -30 C was added dropwise butyl lithium (9.4 mL of a 2.5M solution in hexanes, 23.5
mmol). The resulting solution was stirred for 1 h without further cooling then quenched by the addition
of saturated aqueous ammonium chloride (10 mL) and diluted with ether (30 mL). The separated
aqueous phase was extracted with ether (3 x 30 mL) and the combined organic solutions washed with
water (10 mL) and brine (10 mL) then dried, filtered through a pad of silica gel and the filtrate and
washings evaporated to leave the alkyne 36 (1.10 g, 99%) as a pale yellow oil; IR (film) 3430, 2140,
1
1460, 1369, 1270, 1200 cm-1; H NMR δ 1.28 (s, 3H, 5-Me), 1.39 (s, 3H, Me), 1.43 (s, 3H, 2-Me),
2.35 (s, 1H, 2’-H), 3.65 (d, J = 8.2 Hz, 4-Ha), 4.05 (d, J = 8.2 Hz, 4-Hb); m/z (APCI) 141 (M + H,
100%).
(+)-(R)-2,3-Di-(tert-butyldimethylsilyloxy)-2,N-dimethyl-N-methoxy propanamide (37): t-
Butyldimethylsilyl chloride (23.0 g, 152 mmol) was added to a stirred solution of the dihydroxyamide
33 (10.30 g, 63.3 mmol) and imidazole (21.50 g, 316.5 mmol) in dry DMF (40 mL), which was then
o
stirred at 35 C for 18 h before being cooled to rt, diluted with water (10 mL) and extracted with
dichloromethane (3 x 50 mL). The combined extracts were washed with water (20 mL) and brine (20
mL) and then dried and evaporated. Silica gel column chromatography (EtOAc-petrol 95:5) then
26
separated the bis-silyl ether 37 (23.2 g, 94%) as a colourless oil; [α]D = + 3.2 (c 2.0 g/100 mL
CHCl3); IR (film) 1670, 1472, 1387, 1361, 1251, 1214, 1033, 778, 723 cm-1; 1H NMR δ 0.00 (s, 3H),
0.01 (s, 3H), 0.08 (s, 3H), 0.11 (s, 3H), 0.83 (s, 9H), 0.84 (s, 9H),
(R)-2,3-Di-(tert-butyldimethylsilyloxy)-2-methylpropanal (38): Lithium aluminium hydride (80 mL
of a 1M solution in ether, 77.7 mmol) was added dropwise to a stirred solution of the bis-silyl ether 37
o
(10.1 g, 25.9 mmol) in ether (260 mL) maintained at – 78 C. Stirring was continued at this
temperature for 40 mins. and then an aqueous solution of 2M sodium hydroxide (40 mL) was slowly
added. After warming to rt, the resulting mixture was separated and the aqueous layer extracted with
ether (3 x 100 mL). The combined organic solutions were dried and carefully evaporated to leave the
aldehyde 38 (7.50 g, 88%) as a pale yellow oil, which was sufficiently pure for the next step and which
1
showed: IR (film) 2858, 1740, 1472, 1388, 1362, 1255, 1156, 1108 cm-1; H NMR δ -0.08 (s, 3H,
MeSi), -0.06 (s, 3H, MeSi), 0.01 (s, 3H, MeSi), 0.02 (s, 3H, MeSi), 0.80 (s, 9H), 0.82 (s, 9H), 1.12 (s,
3H, 3-Me), 3.51-3.55 (m, 2H), 9.51 (s, 1H, CHO); 13C NMR δ -5.8 (MeSi), -5.7 (MeSi), -3.6 (MeSi), -

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HETEROCYCLES, Vol. 93, No. 2, 2016
3.2 (MeSi), 15.2 (2-Me), 18.1 (CSi), 18.2 (CSi), 25.7 (6 x Me), 68.4 (3-CH2), 80.7 (2-C), 204.6
(CHO); m/z (APCI) 333 (M + H, 100%).
(+)-(S)-1,1-Dibromo-3,4-di-(tert-butyldimethylsilyloxy)-3-methylbut-1-ene
(39):
Triphenyl-
phosphine (44.0 g, 167.7 mmol) was added to a stirred solution of carbon tetrabromide (27.8 g, 83.3
mmol) in dichloromethane (200 mL) followed by the foregoing aldehyde 38 (13.9 g, 41.9 mmol). The
resulting solution was stirred at rt for 4 h then washed with water (30 mL), the solvent evaporated and
the residue separated by silica gel column chromatography (pentane-ether 9:1) to give the
dibromoalkene 39 (15.2 g, 74%) as a colourless oil; [α]D25 = + 2.7 (c 1.9 g/100 mL CHCl3); IR (film)
1607, 1472, 1388, 1361, 1255, 1108, 1036, 938, 836 cm-1; 1H NMR δ -0.01 (s, 3H, MeSi), 0.00 (s, 3H,
MeSi), 0.04 (s, 3H, MeSi), 0.05 (s, 3H, MeSi), 0.81 (s, 9H), 0.84 (s, 9H), 1.38 (s, 3H, 3-Me), 3.42 (d, J
= 9.1 Hz, 4-Ha), 3.52 (d, J = 9.1 Hz, 4-Hb), 6.64 (s, 1H, 2-H); 13C NMR δ -5.6 (MeSi), -3.0 (MeSi), -
2.3 (MeSi), -2.2 (MeSi), 18.2 (CSi), 18.3 (CSi), 22.6 (3-Me), 25.8 (3 x Me), 25.9 (3 x Me), 69.7 (4-
CH2), 87.3 (3-C), 143.5 (2-CH), 204.5 (1-C); m/z (APCI) 279 (M – TBS, Me and Br +H).
(+)-(S)-3,4-Di-(tert-butyldimethylsilyloxy)-3-methylbut-1-yne (40): To a stirred solution of the
dibromoalkene 39 (5.25 g, 10.8 mmol) in THF (175 mL) maintained at -30 oC was slowly added butyl
lithium (13 mL of a 2.5M solution in hexanes, 32.5 mmol) and the resulting solution stirred without
additional cooling for 1 h then treated with saturated aqueous ammonium chloride (10 mL) and ether
(50 mL). The separated aqueous layer was extracted with ether (3 x 50 mL) and the combined organic
solutions washed with water (20 mL) and brine (20 mL) then dried and evaporated. Silica gel column
26
chromatography then separated the alkyne 40 (2.60 g, 59%) as a colourless oil; [α]D = + 3.5 (c 1.0
g/100 mL CHCl3); IR (film) 3311, 1472, 1389, 1361, 1254, 1190, 1119, 1032, 939, 836, 777 cm-1; 1H
NMR δ 0.00 (s, 3H, MeSi), 0.01 (s, 3H, MeSi), 0.10 (s, 3H, MeSi), 0.11 (s, 3H, MeSi), 0.80 (s, 9H),
0.84 (s, 9H), 1.36 (s, 3H, 3-Me), 2.32 (s, 1H, 1-H), 3.35 (d, J = 9.5 Hz, 4-Ha), 3.47 (d, J = 9.5 Hz, 4-
13
Hb); C NMR δ -5.3 (MeSi), -5.2 (MeSi), -3.0 (MeSi), -2.9 (MeSi), 18.0 (CSi), 18.3 (CSi), 25.7 (3 x
Me), 25.9 (3 x Me), 27.4 (3-Me), 69.9 (2-C), 71.6 (4-CH2), 72.3 (1-CH), 87.2 (2-C); m/z (APCI) 329
(M + H, 100%). HR-MS (APCI). Calcd for C17H37O2Si2 (M+): 329.2332. Found: m/z 329.2337.
(-)-(S)-3,4-Dihydroxy-3-methyl-1-butyne ((S)-(-)-20a): Tetrabutylammonium fluoride (7.6 mL of a
1M solution in THF) was added dropwise to a stirred solution of the foregoing alkyne 40 (1.00 g, 3.0
mmol) at rt. After 2 h, the solvent was evaporated and the residue separated by silica gel column
26
chromatography (petrol-EtOAc 95:5) to give the (S)-diol 20a (0.25 g, 82%) as a pale yellow oil, [α]D
= -0.7 (c 20.0 g/100 mL CHCl3); all other spectroscopic and analytic data were identical to the
racemate (±)-20a described above.
(+)-(S)-4-Acetamido-2,6-dimethyl-5-[3’,4’-dihydroxy-3’-methylbut-1’-yn-1’-yl]-3-nitroanisole
(21): Following the general Sonogashira procedure, the nitro-iodide 18 (0.364 g, 1.0 mmol) was

HETEROCYCLES, Vol. 93, No. 2, 2016
667
coupled with the (S)-diol 20a (0.20 g, 2.0 mmol) using (Ph3P)4Pd (0.578 g, 0.5 mmol), copper(I)
iodide (0.095 g) and triethylamine (3.6 mL, 26 mmol) to give the (S)-(+)-alkyne-diol 21 (0.26 g, 77%)
o
26
as a pale yellow solid, mp 173-174.5 C (MeOH); [α]D = +3.5 (c 1.9 g/100 mL MeOH); all other
spectroscopic and analytic data were identical to the racemate (±)-21 described above.
4-Amino-2,6-dimethyl-5-iodo-3-nitroanisole (14): The nitro-iodide 18 (0.32 g, 0.88 mmol) was
dissolved in methanol (5 mL) before concentrated sulfuric acid (0.18 mL) was added. The resulting
solution was heated to reflux for 16 h, then cooled and poured onto ice (~20 g) and the mixture
basified using potassium carbonate. The product was extracted into dichloromethane (3 x 10 mL) and
the combined extracts dried and evaporated. Silica gel column chromatography then separated the
o
nitroanisole 14 (0.18 g, 64%) as a bright yellow solid, mp 214-215 C; IR (KBr) 3375, 1602, 1455,
1
1259, 1047, 799, 650 cm-1; H NMR δ 2.24 (s, 3H), 2.40 (s, 3H), 3.58 (s, 3H, OMe), 5.25 (br s, 2H,
NH2); m/z (EI) 322 (M, 100%). Anal. Calcd for C9H11IN2O3: C, 33.56; H, 3.44; N, 8.70. Found: C,
33.78; H, 3.51; N, 8.55.
(+)-(S)-4-Amino-2,6-dimethyl-5-[3’,4’-dihydroxy-3’-methylbut-1’-yn-1’-yl]-3-nitroanisole (41):
By the general Sonogashira procedure, coupling between the nitroanisole 14 (0.18 g, 0.55 mmol) and
the (S)-(+)-diol 21 (0.11 g, 1.1 mmol) using (Ph3P)4Pd (0.324 g, 0.28 mmol), copper(I) iodide (0.053
g) and triethylamine (2.0 mL, 14.3 mmol) in THF (6 mL) gave the unprotected (S)-alkyne-diol 41
o
25
(0.127 g, 79%) as a yellow solid, mp 163-164 C; [α]D = +6.8 (c 1.7 g/100 mL MeOH); IR 3377,
2221, 1603, 1509, 1452, 1376, 1330, 1260, 1198, 1153, 1116, 1054, 998, 912, 873, 767, 733 cm-1; 1H
NMR δ 1.50 (s, 3H, 3’-Me), 2.26 (s, 3H, ArMe), 2.28 (s, 3H, ArMe), 3.05 (br res, 2H, 2 x OH), 3.55 (s,
3H, OMe), 3.56 (d, J = 11.0 Hz, 4’-Ha), 3.69 (d, J = 11.0 Hz, 4’-Hb), 5.62 (br res, 2H, NH2); 13C NMR
δ 13.9 (Me), 15.8 (Me), 25.9 (Me), 60.9 (OMe), 69.7 (CH2), 71.2 (C), 78.5 (C), 102.5 (C), 108.8 (C),
128.9 (C), 134.8 (C), 140.2 (C), 141.0 (C), 148.1 (C); m/z (APCI 277 (M – OH, 100%). HR-MS
(APCI). Calcd for C14H17N2O4 (M+ - OH): 277.1188. Found: m/z 277.1197.
(E)-1-(tert-Butyloxycarbonylamino)-7-(3’-penten-1’-yl)benzotriazole (42a): Following the
previously reported procedure for metalation and homologation,15 treatment of the dianion 7 derived
from 1-(tert-butyloxycarbonylamino)-7-methylbenzotriazole 6 (0.30 g, 1.2 mmol) using BuLi-
TMEDA with crotyl chloride (0.13 mL, 1.32 mmol) gave the (E)-pentene 42a (0.35 g, 97%) as a thick
1
yellow oil; IR (film) 3166, 1750, 1606, 1455, 1394, 1370, 1252, 1160, 1050, 966, 910, 749 cm-1; H
NMR δ 1.30-1.53 (br res, 9H, t-Bu), 1.54-1.58 (m, 3H, 5’-Me), 2.24-2.38 (m, 2H, 2’-CH2), 2.94 (t, J =
8.3 Hz, 1’-CH2), 5.39-5.41 (m, 2H, 3’- and 4’-H), 7.20-7.23 (m, 2H), 7.75-7.79 (m, 1H), 8.59 (br s, 1H,
NH); 13C NMR δ 11.9 (5’-Me), 27.0 (3 x Me), 29.3 (CH2), 32.7 (CH2), 82.7 (C), 117.0 (ArCH), 123.7
(ArCH), 124.3 (:CH), 125.2 (:CH), 127.9 (ArCH), 129.8 (7-C), 143.7 (C-N), 152.5 (C-N), 157.2

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HETEROCYCLES, Vol. 93, No. 2, 2016
(C=O); m/z (APCI) 302 (M+, 100%). HR-MS (FAB). Calcd for C16H23N4O2 (M+ + H): 303.1816.
Found: m/z 303.1816.
(3’R, 4’R)-1-(tert-Butyloxycarbonylamino)-7-(3’,4’-dihydroxypent-1’-yl)benzotriazole (43a):
Following the procedure detailed above for the preparation of diol 20a, reaction of the foregoing
pentene 42a (0.273 g, 0.9 mmol) with AD-mix-β (1.26 g) at rt for 42 h gave the diol 43a (0.196 g,
65%) as a thick, pale yellow oil; IR (film) 3252, 1749, 1508, 1456, 1370, 1254, 1159, 912, 733 cm-1;
1H NMR (rotameric) δ 1.08 (d, J = 6.3 Hz, 3H, 5’-Me), 1.22-1.52 (br s, 9H, 3 x Me), 1.71-1.80 (m,
2H), 2.75 (br s, 1H, OH), 3.00-3.13 (m, 2H), 3.13 (br s, 1H, OH), 3.35-3.48 (m, 1H, 3’-H), 3.56 (qd, J
= 6.3, 6.0 Hz, 1H, 4’-H), 7.22-7.25 (m, 2H), 7.81-7.85 (m, 1H), 9.16 (br s, 1H, NH); 13C NMR δ 18.5
(5’-Me), 26.9 (3 x Me), 33.8 (2’-CH2), 42.2 (1’-CH2), 69.4 (CH), 73.8 (CH), 82.4 (C), 117.0 (CH),
123.6 (CH), 124.2 (7-C), 127.8 (CH), 129.8 (C-N), 143.7 (C-N), 152.9 (C=O); m/z (APCI) 336 (M+,
100%). HR-MS (FAB). Calcd for C16H25N4O4 (M+ + H): 337.1868. Found: m/z 337.1868. [ee: ~ 76%]
(-)-(1’R, 2R)-2-(1-Hydroxyethyl)-8-iodochroman (44a): Using the same procedure for benzyne
generation and trapping that gave the iodochroman 28a, treatment of the foregoing diol 43a (0.074 g,
0.22 mmol) with trifluoroacetic acid (0.44 mL) and N-iodosuccinimide (0.124 g, 0.55 mmol) gave the
29
iodochroman 44a (0.046 g, 68%) as a thick, yellow oil; [α]D = - 7.4 (c 6.25 g/100 mL CHCl3); IR
1
(film) 3367, 1454, 1261 cm-1; H NMR δ 1.26 (d, J = 6.0 Hz, 3H, ‘-Me), 1.45-1.61 (br res, 1H, OH),
1.67-1.78 (m, 1H, 3-Ha), 1.93-1.98 (m, 1H, 3-Hb), 2.67 (ddd, J = 16.3, 5.4, 2.7 Hz, 1H, 4-Ha), 2.77
(ddd, J = 16.3, 12.1, 5.9 Hz, 1H, 4-Hb), 3.78-3.84 (m, 2H, 2- and 1’-H), 6.56 (t, J = 7.7 Hz, 1H, 6-H),
7.02 (d, J = 7.7 Hz, 1H, 7-H), 7.49 (d, J = 7.7 Hz, 1H, 5-H); 13C NMR δ 18.5 (Me), 23.9 (CH2), 24.8
(CH2), 70.0 (CH), 81.6 (CH), 85.8 (C-I), 122.2 (CH), 123.1 (4a-C), 130.3 (CH), 136.9 (CH), 142.9
(8a-C); m/z (APCI) 286 (M+-H2O, 100%). HR-MS (NH4-CI). Calcd for C11H17INO2 (M+ + NH4):
322.0298. Found: m/z 322.0296.
(E)-1-(tert-Butyloxycarbonylamino)-7-(4’-phenyl-3’-buten-1’-yl)benzotriazole (42b): Following
the previously reported procedure for metalation and homologation,15 treatment of the dianion 7
derived from 1-(tert-butyloxycarbonylamino)-7-methyl)benzotriazole 6 (0.918 g, 3.7 mmol) using
BuLi-TMEDA with cinnamyl bromide (0.87 g, 4.4 mmol) gave the (E)-butene 42b (1.05 g, 78%) as a
colourless oil; IR (film) 3458, 1745, 1494, 1453, 1368, 1253, 1157, 966, 750 cm-1; 1H NMR δ 1.35 (br
res, 9H, t-Bu), 2.41 (td, J = 7.1, 6.7 Hz, 2H, 2’-CH2), 3.00 (t, J = 7.1 Hz, 1’-CH2), 6.10 (dt, J = 15.9,
6.7 Hz, 1H, 3’-H), 6.28 (d, J = 15.9 Hz, 1H, 4’-H), 7.03-7.21 (m, 7H), 7.66-7.72 (br res, 1H, ArH),
13
9.32 (br s, 1H, NH); C NMR δ 28.1 (3 x Me), 30.1 (2’-CH2), 34.0 (1’-CH2), 83.6 (C), 118.1 (CH),
124.7 (ArC), 125.0 (CH), 126.0 (CH), 127.2 (CH), 128.5 (CH), 129.0 (CH), 137.4 (C), 144.7 (C-N),
153.9 (C-N), 154.1 (C=O); m/z (APCI) 365 (M+ + H, 100%). HR-MS (FAB). Calcd for C21H25N4O2
(M+ + H): 365.1972. Found: m/z 365,1972.

HETEROCYCLES, Vol. 93, No. 2, 2016
669
(3’R,
4’R)-1-(tert-Butyloxycarbonylamino)-7-(3’,4’-dihydroxy-4’-phenylbutan-1’-yl)benzotri-
azole (43b): Following the procedure detailed above for the preparation of diol 20a, reaction of the
foregoing butene 42b (0.737 g, 2.0 mmol) with AD-mix-β (2.80 g) at rt for 40 h gave the diol 43b
(0.65 g, 82%) as a thick, pale yellow oil; IR (film) 3498, 1735, 1453, 1368, 1253, 1157 cm-1; 1H NMR
(rotameric) δ 1.22-1.35 (br s, 9H, 3 x Me), 1.46-1.51 (br s, 1H, OH), 1.54-1.63 (br s, 1H, OH), 2.80-
2.86 (m, 2’-Ha), 2.96-3.01 (m, 1H, 2’-Hb), 3.53-3.57 (m, 1H, 3’-H), 3.80-3.86 (m, 2H, 1’-CH2), 4.30 (d,
J = 6.6 Hz, 1H, 4’-H), 6.95 (d, J = 7.0 Hz, ArH), 7.05-7.19 (m, 6H), 7.60 (d, J = 7.0 Hz, 1H, ArH),
13
9.70 (br s, 1H, NH); C NMR δ 25.7 (2’-CH2), 27.1 (3 x Me), 33.4 (1’-CH2), 74.5 (CH), 77.2 (CH),
82.6 (C), 116.9 (CH), 124.8 (CH), 126.0 (C), 126.7 (CH), 127.2 (CH), 127.8 (CH), 128.5 (CH), 130.8
(C), 142.0 (C-N), 144.4 (C-N), 154.7 (C=O); m/z (APCI) 399 (M+ + H, 100%). HR-MS (FAB). Calcd
for C21H27N4O4 (M+ + H): 399.2027. Found: m/z 399.2025. [ee: ~ 82%].
(-)-(1’R, 2R)-2-(1-Hydroxy-1-phenylmethyl)-8-iodochroman (44b): Using the same procedure for
benzyne generation and trapping that gave the iodochroman 28a, treatment of the foregoing diol 43b
(0.628 g, 1.60 mmol) with trifluoroacetic acid (6.3 mL) and N-iodosuccinimide (0.90 g, 4.0 mmol)
26
gave the iodochroman 44b (0.334 g, 57%) as a thick, yellow oil; [α]D = -19.7 (c 3.00 g/100 mL
CHCl3); IR (film) 3564, 1562, 1494; 1448, 1237, 1194, 1093, 1045, 905, 887, 761, 701 cm-1; 1H NMR
δ 1.53-1.70 (m, 2H, 3-CH2), 2.60-2.65 (m, 2H, 4-CH2), 3.12 (br s, 1H, OH), 4.01 (ddd, J = 10.5, 7.8,
2.7 Hz, 1H, 2-H), 4.65 (d, J = 7.8 Hz, 1H, 1’-H), 6.54 (t, J = 7.6 Hz, 1H, ArH), 6.91 (d, J = 7.6 Hz, 1H,
ArH), 7.24-7.39 (m, 5H), 7.49 (d, J = 7.6 Hz, 1H, ArH); 13C NMR δ 23.5 (3-CH2), 24.7 (4-CH2), 77.5
(2-CH), 81.4 (1’-CH), 85.8 (C-I), 122.4 (CH), 123.2 (4a-C), 127.4 (CH), 128.5 (CH), 128.6 (CH),
129.7 (CH), 137.0 (CH), 139.0 (C), 152.4 (C); m/z (APCI) 366 (M+, 100%). HR-MS (NH4-CI). Calcd
for C16H19INO2 (M+ + NH4): 384.0455. Found: m/z 384.0458.
ACKNOWLEDGEMENTS
We are grateful to the British Council for an ORS award, which partly funded this project.
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