Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach

Article abstract of DOI:10.3762/bjoc.11.197

Bestmann ylide [(triphenylphosphoranylidene)ketene] acts as a chemical linchpin that links nucleophilic entities, such as alcohols or amines, with carbonyl moieties to produce unsaturated esters and amides, respectively. In this work, the formation of α,β

Full text of DOI:10.3762/bjoc.11.197

Preparation of conjugated dienoates with Bestmann ylide:
Towards the synthesis of zampanolide and dactylolide using a
facile linchpin approach
Jingjing Wang, Samuel Z. Y. Ting and Joanne E. Harvey*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1815–1822.
Centre for Biodiscovery, School of Chemical and Physical Sciences,
Victoria University of Wellington, PO Box 600, Wellington 6140, New
Zealand
doi:10.3762/bjoc.11.197
Received: 22 July 2015
Accepted: 07 September 2015
Published: 05 October 2015
Email:
Joanne E. Harvey* - joanne.harvey@vuw.ac.nz
Associate Editor: D. Y.-K. Chen
* Corresponding author
© 2015 Wang et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Bestmann ylide; dactylolide; dienoate;
(triphenylphosphoranylidene)ketene; zampanolide
Abstract
Bestmann ylide [(triphenylphosphoranylidene)ketene] acts as a chemical linchpin that links nucleophilic entities, such as alcohols
or amines, with carbonyl moieties to produce unsaturated esters and amides, respectively. In this work, the formation of α,β,γ,δ-
unsaturated esters (dienoates) is achieved through the coupling of Bestmann ylide, an alcohol and an α,β-unsaturated aldehyde.
Primary and secondary alcohols, including allylic alcohols, are suitable substrates; the newly formed alkene has an E-geometry.
Strategically, this represents a highly efficient route to unsaturated polyketide derivatives. A linchpin approach to the synthesis of a
major fragment of the natural products zampanolide and dactylolide is investigated using Bestmann ylide to link the C16–C20
alcohol with the C3–C8 aldehyde fragment.
Introduction
(Triphenylphosphoranylidene)ketene, Ph3P=C=C=O (1), was isolable Wittig reagents that can be used in subsequent transfor-
first reported in 1966 [1,2]. It initially attracted attention due to mations [4,5,9-11]. Furthermore, if the α-phosphoranylidene
its unique structure, namely the 145.5° angle of the C=C=P ester or amide is formed in the presence of an aldehyde, ketone
moiety and the unusually short C=C bond (1.210 Å). Its utility or ester, an additional in situ Wittig reaction can occur [12-18].
was subsequently explored, with pioneering work by Bestmann In this way, amides, esters and thioesters can be obtained
and co-workers [3-5] lending the name Bestmann ylide to this through three-component couplings [14,16]. Intramolecular
versatile and readily obtained reagent [6-8]. Studies revealed couplings with a Bestmann ylide linchpin have enabled direct
that the ylide readily reacts with alcohols and amines to form lactone and lactam synthesis [12-15], including the preparation
α-phosphoranylidene esters or amides, providing diverse of macrolactones [16-18]. An extension of this methodology to
1815

Beilstein J. Org. Chem. 2015, 11, 1815–1822.
γ-hydroxyenone substrates allows the preparation of α-alkyli- with metathesis to form the alkene at C8–C9. In our synthesis,
dene-γ-butyrolactones through tandem acylation and Michael the doubly unsaturated ester moiety will be formed through an
addition, followed by a Wittig reaction [19,20].
efficient linchpin reaction between the C16–C20 fragment
(alcohol 7) [42-45], the C3–C8 fragment (α,β-unsaturated alde-
Although the utility of the Bestmann ylide in the synthesis of hyde 8) and Bestmann ylide (1, Scheme 1). We plan to then
acyclic α,β-unsaturated esters and dienamides has already been attach the C9–C15 aldehyde fragment 6 by asymmetric alkyny-
reported [11,13,16], its application to the synthesis of α,β,γ,δ- lation, and form the pyran using an oxa-Michael addition, in a
unsaturated esters (i.e., dienoates) remains uncharted. In this manner reminiscent of that employed by Uenishi and
paper, a three-component reaction between α,β-unsaturated co-workers [34]. Finally, macrocyclisation will be achieved
aldehydes, alcohols and the Bestmann ylide is described. The through the well-established strategy of ring-closing metathesis
scope of this esterification–Wittig reaction sequence in the syn- at C8–C9.
thesis of α,β,γ,δ-unsaturated esters is studied, and the method is
applied in an approach towards the structurally related marine
natural products, zampanolide (2) and dactylolide (3, Figure 1),
wherein the Bestmann ylide represents a C1–C2 linchpin that
connects two segments of the macrocylic ring.
Figure 1: Structures of (−)-zampanolide (2) and (+)-dactylolide (3).
Scheme 1: Retrosynthesis of zampanolide involving a Bestmann ylide
linchpin strategy.
(−)-Zampanolide (2, Figure 1) was first isolated from the
marine sponge Fasciospongia rimosa found at Cape Zampa,
Results and Discussion
Japan [21], and subsequently from a Tongan sponge
Evaluation of the three-component reaction
Cacospongia mycofijiensis [22]. It was found to exhibit potent
for the synthesis of α,β,γ,δ-unsaturated
anticancer activities, with IC50 values in the nM scale against a
number of cell lines [22,23]. The structurally related compound, esters
(+)-dactylolide, was discovered in the marine sponge Dacty- The study of the reactions between Bestmann ylide, alcohols
lospongia [24] and has significantly lower cytotoxicity. The and α,β-unsaturated aldehydes began with the investigation of
absolute configuration of the natural material is not firmly the coupling between linchpin 1 [46], E-hex-2-en-1-ol (9a) and
established due to discrepancies in optical rotation values E-cinnamaldehyde (10a) (Table 1, entry 1). Typically, Best-
between natural and synthetic samples [25].
mann ylide reactions are performed at elevated temperature in a
high boiling and/or ether solvent, such as toluene, 1,4-dioxane
Zampanolide and dactylolide have engendered world-wide or THF [11,14-17,19,20]. To investigate the necessity for high
interest from the synthetic community, culminating in a number temperature, the primary reaction in this study was initiated at
of total syntheses [26-41]. Zampanolide is invariably prepared room temperature (19 °C) in toluene and then progressively
by appending the amide side-chain 4 to the aldehyde moiety of warmed to reflux (110 °C) while monitoring the progress by
dactylolide, so the synthesis of zampanolide requires the prior TLC. It was noted that the Bestmann ylide reagent was insol-
generation of dactylolide. Although fragment syntheses vary, uble up to 80 °C and no reaction was observed until the reac-
the late-stage fragment assembly of the dactylolide macrocycle tion mixture was heated at reflux. Under these conditions,
has centred mostly around construction of the C1–C5 dienoate incomplete consumption of the starting materials was seen after
by Wittig-type olefination reactions followed by ester hydro- 18 h and the poor conversion was attributed to the instability of
lysis and esterification with the C19 hydroxy group, combined Bestmann ylide over long periods at elevated temperatures and
1816

Beilstein J. Org. Chem. 2015, 11, 1815–1822.
in the presence of any adventitious nucleophilic source. al steric encumbrance and stereogenic centres, provided a good
Nonetheless, the product 11a was obtained in a modest yield yield of the product 11e [47] in THF, despite incomplete
(Table 1, entry 1). In response to these observations, the reac- conversion (Table 1, entry 7). Full conversion but a poor
tion was attempted in THF, a solvent in which Bestmann ylide isolated yield of the product was achieved in toluene after reac-
readily dissolved at room temperature. This provided better tion for 23 hours (Table 1, entry 8). Decreasing the reaction
conversion, although the isolated yield was only marginally im- time provided better results (Table 1, entry 9), indicating that
proved (Table 1, entry 2). Gratifyingly, the reaction of oct-2-en- the product may decompose upon prolonged periods at elevated
1-ol (9b) with cinnamaldehyde (10a) was efficient and high temperature. The Bestmann ylide coupling of menthol (9e) and
yielding (Table 1, entry 3). Use of a Z-allylic alcohol 9c, like- octa-2,4-dienal (10b) delivered the trienoate product 11f in
wise produced excellent amounts of the product dienoate good yields at both 0.1 and 0.3 mmol scale (Table 1, entries 10
(Table 1, entry 4), although a longer reaction time was required and 11). Taken together, these results indicate that both prima-
to achieve this. The Z-geometry of the allylic alcohol was ry and secondary alcohol substrates react effectively with conju-
retained, as expected. After this, the secondary allylic alcohol gated unsaturated aldehydes and the Bestmann ylide linchpin in
9d was investigated and a reasonable yield of the product was either THF or toluene, although prolonged reflux in toluene
obtained when the reaction was carried out in THF (Table 1, may cause degradation of the products. Small quantities (<10%)
entry 5). A comparative reaction in toluene was also performed of isomeric products, presumed to be the corresponding 2Z,4E-
and found to deliver a better yield of the product (Table 1, entry dienes of 11a, 11b and 11c, were observed in the reaction
6). The saturated secondary alcohol menthol (9e), with addition- mixtures derived from the primary alcohols. Only barely trace
Table 1: Coupling reactions of alcohols 9 and aldehydes 10 with Bestmann ylide (1)a.
Entry
Alcohol
Aldehyde
Conditionsb
Product
Yieldc
toluene, rt to 110 °C,
18 hd
1
2
3
53% (60%)
55% (94%)
93% (100%)
9a
9a
11a
11a
10a
10ae
THF, 66 °C, 2 hf
THF, 66 °C, 1.5 h
10a
10a
9b
9c
11b
11c
4
THF, 66 °C, 6 hg
91% (100%)
5
6
10a
10a
THF, 66 °C, 4.5 h
61% (100%)
71% (94%)
9d
9d
11d
11d
toluene, 110 °C, 5.5 h
1817

Beilstein J. Org. Chem. 2015, 11, 1815–1822.
Table 1: Coupling reactions of alcohols 9 and aldehydes 10 with Bestmann ylide (1)a. (continued)
7
10a
THF, 66 °C, 22 h
77% (85%)
9e
9e
9e
11e
8
9
10a
10a
toluene, 110 °C, 23 h
toluene, 110 °C, 9.5 hg
11e
11e
29% (100%)
53% (100%)
10
11
12
13
14
15
9e
9e
toluene, 110 °C, 3 h
toluene, 110 °C, 4.5 hg
THF, 66 °C, 3.5 h
67% (90%)
10b
10b
11f
11f
66% (100%)
<36% (43%)h
<49% (73%)h
42% (69%)
10a
10a
10a
10a
7a
7a
11g
11g
toluene, 110 °C, 2 h
THF, 66 °C, 8 h
7b
7b
11h
11h
toluene, 110 °C, 4 hg
70% (100%)
aUnless otherwise stated, reactions were performed on a 0.1 mmol scale using approximately 1:1:1 ratio of alcohol/Bestmann ylide/aldehyde.
bSolvent, temperature, reaction time. cIsolated yield. Conversion (given in brackets) was calculated based on relative integrations of peaks assigned
to the limiting reagent (aldehyde) and product in 1H NMR spectra of the crude reaction mixture after work-up. dReaction was carried out on 0.8 mmol
scale. e0.57 equiv of aldehyde 10a were used. fReaction was carried out on 0.2 mmol scale. gReaction was carried out on 0.3 mmol scale. hProduct
11g was contaminated with the regioisomer resulting from silyl migration and esterification of the primary hydroxy group (3:2 ratio 11g:isomeric C20
ester).
amounts of Z-alkenes were ever observed with secondary alco- dienoate product in modest yields. Unfortunately, it was found
hols. As the minor isomers were not able to be isolated, their that the product was not isolable in pure form but was contami-
identities are unconfirmed.
nated with further isomeric material. Careful analysis of the
product mixtures led to the realisation that silyl migration from
After these promising results, the homopropargylic secondary the primary to the secondary hydroxy group was occurring in
alcohol 7a [42], representing the C16–C20 fragment of the reaction, leading to the C20-linked ester isomer in addition
zampanolide, was subjected to Bestmann ylide linchpin reac- to the desired C19 ester 11g. In contrast, reactions of the PMB-
tions with cinnamaldehyde (10a) in THF and toluene (Table 1, protected variant 7b [43-45] with cinnamaldehyde afforded the
entries 12 and 13). In an attempt to avoid degradation, the reac- product 11h in pure form and reasonable-to-good yields in THF
tions were terminated prior to full conversion, leading to the and toluene (Table 1, entries 14 and 15, respectively).
1818

Beilstein J. Org. Chem. 2015, 11, 1815–1822.
Preparation of the C3–C8 fragment of
dactylolide/zampanolide
products 5b and 5c, respectively. While the reaction of 7b with
aldehyde 8 in THF took 11 h to go to completion (62% isolated
The aldehyde 8, representing the C3–C8 fragment of zampano- yield of 5b), the equivalent reaction in toluene required only 5 h
lide, was synthesised from acrolein (12) (Scheme 2). Firstly, (68% yield). Alcohol 7c was used to assess the compatibility of
Barbier reaction of acrolein with propargyl bromide followed an unprotected, terminal alkyne in this linchpin reaction with a
by silyl protection of the resulting alcohol afforded enyne 13. view to future synthetic ease [50]. Pleasingly, the reaction of
Treatment of the lithium alkynylide derived from 13 with aldehyde 8 with alcohol 7c in toluene provided the desired
methyl chloroformate produced the methyl ester 14 [48]. product 5c in a comparable yield (66%) after 5 h. In these reac-
Cuprate-mediated conjugate addition of a methyl nucleophile to tions, only the desired E,Z-diene isomer was observed.
the ynoate 14 provided the Z-enoate 15. Our attempts to directly
reduce the ester 15 to the aldehyde 8 were unsuccessful due to Conclusion
competitive over-reduction to the corresponding alcohol. There- In summary, an efficient three-component reaction between
fore, a two-step reduction–oxidation process was undertaken to (triphenylphosphoranylidene)ketene (Bestmann ylide, 1), an
afford the aldehyde 8 in a good yield.
alcohol and an unsaturated aldehyde delivers α,β,γ,δ-unsatu-
rated esters. This methodology enabled the facile synthesis of
E,Z-dienoate products 5b and 5c, which represent two-thirds of
the dactylolide/zampanolide macrocycle, suitably function-
alised for transformation to the natural products. This highly
efficient method for connecting the C3–C8 and C16–C20 frag-
ments through a C1–C2 linchpin in a single step contrasts with
other routes that require multiple-step sequences including
Wittig-type reaction, ester hydrolysis and coupling to the C19
alcohol. Elaboration of these compounds into the targets –
dactylolide, zampanolide and analogues thereof – is currently
under development in our lab.
Experimental
General procedure for Bestmann ylide linchpin reaction: To
a mixture of alcohol (1 equiv, 0.1–0.3 M) and Bestmann ylide
(1 equiv) in solvent (toluene or tetrahydrofuran) heated at
reflux, a solution of aldehyde (1 equiv, 1.0 M) was added. The
reaction was heated at reflux until full consumption of starting
material aldehyde was observed by TLC. After cooling to rt, the
Scheme 2: Synthesis of aldehyde 8.
Three-component coupling of dactylolide/
zampanolide fragments with Bestmann ylide
With aldehyde 8 in hand, a reaction with Bestmann ylide (1) reaction was concentrated and purified by silica column chro-
was performed in toluene using the TBDPS-protected alcohol matography.
7a. The α,β,γ,δ-unsaturated ester 5a was formed as a mixture of
diastereomers (Scheme 3), as expected, but was again contami- (2′E,2E,4E)-Hex-2′-enyl 5-phenylpenta-2,4-dienoate (11a).
nated with the regioisomer resulting from silyl migration (2:1 Rf = 0.23 (20:1 pet. ether:Et2O); 1H NMR (500 MHz, CDCl3) δ
ratio 5a:isomeric C20 ester). Employing the PMB-protected 7.48–7.43 (complex m, 3H), 7.36 (app. t, J = 7.6 Hz, 2H), 7.30
C19 alcohols 7b [43-45] and 7c [43-45,49] led to the desired (t, J = 6.9 Hz, 1H), 6.93–6.82 (complex m, 2H), 6.01 (d, J =
Scheme 3: Bestmann ylide linchpin coupling of the C16–C20 and C3–C8 fragments of zampanolide/dactylolide.
1819

Beilstein J. Org. Chem. 2015, 11, 1815–1822.
15.6 Hz, 1H), 5.81 (dt, J = 15.4, 6.6 Hz, 1H), 5.62 (dt, J = 15.4, 6.07 (d, J = 11.5 Hz, 1H), 5.80 (obs. ddd, J = 16.8, 10.6, 5.7 Hz,
6.2 Hz, 1H), 4.63 (d, J = 6.6 Hz, 2H), 2.14 (app. q, J = 7.1 Hz, 1H), 5.80 (obs. d, J = 15.2 Hz, 1H), 5.23–5.11 (obs. m, 1H),
2H), 1.43 (app. sext, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); 5.18 (obs. d, J = 17.2 Hz, 1H), 5.05 (d, J = 10.3 Hz, 1H), 4.53
13C NMR (125 MHz, CDCl3) δ 166.8, 144.7, 140.4, 136.3, (d, J = 11.5 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.25 (app. q, J =
136.0, 129.0, 128.8, 127.2, 126.2, 124.0, 121.2, 65.2, 34.3, 22.0, 6.2 Hz, 1H), 3.80 (s, 3H), 3.67 (app. d, J = 4.9 Hz, 2H),
13.6; IR (neat) cm−1: 2958 (m), 2929 (m), 1706 (s), 1625 (s), 2.69–2.54 (complex m, 3H), 2.36 (ddd, J = 13.0, 6.5, 5.5 Hz,
1449 (m), 1236 (s), 1172 (s), 997 (m), 689 (m); HRMS (ESI) 1H), 1.92 (s, 3H), 0.87 (s, 9H), 0.13 (s, 9H), 0.01 (s, 6H);
m/z: [M + H]+ calcd for C17H21O2, 257.1536 found, 257.1529, 13C NMR (500 MHz, CDCl3) δ 166.71, 166.69, 159.2, 146.58,
(Δ = 2.7 ppm).
146.56, 141.70, 141.67, 140.9, 130.1, 129.3, 126.09, 129.07,
118.89, 118.87, 114.2, 113.8, 102.0, 86.92, 86.90, 73.00, 72.99,
(1′R,2′S,5′R,2E,4E,6E)-2′-Isopropyl-5′-methylcyclohex-1′-yl 72.86, 72.82, 70.48, 70.47, 69.45, 69.41, 55.2, 41.7, 25.83,
deca-2,4,6-trienoate (11f). Rf = 0.14 (40:1 pet. ether:Et2O); 25.82, 25.64, 25.62, 22.32, 22.29, 18.1, 0.00, −0.01, −4.54,
1H NMR (500 MHz, CDCl3) δ 7.28 (dd, J = 15.4, 11.2 Hz, 1H), −4.88; IR (neat) cm−1: 2956 (s), 2857 (m), 2180 (w), 1714 (s),
6.53 (dd, J = 14.9, 10.7 Hz, 1H), 6.21 (dd, J = 14.9, 11.2 Hz, 1636 (m), 1513 (m), 1249 (s), 1033 (m), 837 (s), 775 (m), 760
1H), 6.13 (dd, J = 15.1, 10.7 Hz, 1H), 5.92 (dt, J = 14.9, 7.2 Hz, (m); HRMS (ESI) m/z: [M + H]+ calcd for C32H51O5Si2,
1H), 5.83 (d, J = 15.4 Hz, 1H), 4.75 (app. td, J = 10.9, 4.4 Hz, 571.3270; found, 571.3276, (Δ = 1.1 ppm).
1H), 2.12 (app. q, J = 7.3 Hz, 2H), 2.02 (br d, J = 12.2 Hz, 1H),
1.88 (septd, J = 6.8, 2.3 Hz, 1H), 1.71–1.65 (complex m, 2H), (2E,4Z)-1′-(para-Methoxybenzyloxy)pent-4′-yn-2′-yl 7-(tert-
1.50 (partially obs. m, 1H), 1.44 (m, 2H), 1.40 (partially obs. m, butyldimethylsilyloxy)-5-methylnona-2,4,8-trienoate (5c).
1H), 1.07 (app. qd, J = 12.9, 2.9 Hz, 1H), 0.99 (app. q, J = Rf = 0.32 (80% CH2Cl2 in n-hexane); 1H NMR (500 MHz,
11.5 Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H), 0.90 (d, J = 6.1 Hz, 3H), CDCl3) δ 7.58 (dd, J = 14.9, 11.7 Hz, 1H), 7.26 (d, J = 8.6 Hz,
0.89 (d, J = 6.8 Hz, 3H), 0.87 (partially obs. m, 1H), 0.76 (d, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.07 (d, J = 11.5 Hz, 1H), 5.80
J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.8, 144.6, (obs. ddd, J = 17.1, 10.5, 5.9 Hz, 1H), 5.80 (obs. d, J = 14.9 Hz,
141.0, 140.2, 130.0, 127.8, 120.5, 73.9, 47.2, 41.0, 35.0, 34.3, 1H), 5.23–5.14 (obs. m, 1H), 5.18 (obs. d, J = 16.9 Hz, 1H),
31.4, 26.3, 23.6, 22.2, 22.0, 20.7, 16.4, 13.7; IR (neat) cm−1: 5.05 (d, J = 10.3 Hz, 1H), 4.53 (d, J = 11.5 Hz, 1H), 4.48 (d, J =
2955 (s), 2930 (s), 2869 (s), 1694 (s), 1615 (s), 1456 (m), 1342 11.5 Hz, 1H), 4.25 (app. q, J = 5.6 Hz, 1H), 3.80 (s, 3H),
(m), 1133 (s), 1007 (s); HRMS (ESI) m/z: [M + H]+ calcd for 3.71–3.62 (m, 2H), 2.65 (ddd, J = 16.9, 6.6, 2.7 Hz, 1H), 2.58
C20H33O2, 305.2475; found, 305.2486, (Δ = 3.6 ppm). [α]D22 = (ddd, J = 16.9, 5.4, 2.5 Hz, 1H), 2.61–2.54 (obs. m, 1H), 2.36
−26 (c 0.42, CH2Cl2).
(app. dt, J = 13.1, 4.9 Hz, 1H), 1.97 (m, 1H), 1.92 (s, 3H), 0.86
(s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (500 MHz,
(2E,4E)-[1′-(para-Methoxybenzyloxy)-5′-trimethylsilyl]pent- CDCl3) δ 166.7, 159.2, 146.81, 146.78, 141.92, 141.89, 140.95,
4′-yn-2′-yl 5-phenylpenta-2,4-dienoate (11h). Rf = 0.28 (80% 140.93, 130.1, 129.31, 129.30, 126.07, 126.05, 118.71, 118.68,
CH2Cl2 in n-hexane); 1H NMR (500 MHz, CDCl3) δ 7.51–7.44 114.2, 113.8, 79.6, 73.0, 72.81, 72.77, 70.33, 70.30, 70.18,
(complex m, 3H), 7.37 (app. t, J = 7.1 Hz, 2H), 7.33 (m, 1H), 70.13, 69.3, 55.2, 41.8, 25.8, 25.66, 25.65, 20.97, 20.95, 18.1,
7.28 (br d, J = 8.8 Hz, 2H), 6.95–6.84 (complex m, 4H), 6.02 −4.54, −4.88; IR (neat) cm−1: 3308 (w), 2930 (m), 2857 (s),
(d, J = 15.4 Hz, 1H), 5.20 (app. dt, J = 10.5, 5.7 Hz, 1H), 4.55 2214 (w), 1712 (s), 1635 (m), 1612 (m), 1514 (s), 1248 (s),
(d, J = 11.5 Hz, 1H), 4.50 (d, J = 11.7 Hz, 1H), 3.80 (s, 3H), 1033 (m), 836 (s), 776 (s); HRMS (ESI) m/z: [M + H]+ calcd
3.72–3.67 (m, 2H), 2.68 (dd, J = 17.1, 7.1 Hz, 1H), 2.63 (dd, for C29H43O5Si, 499.2874; found, 499.2868, (Δ = 1.2 ppm).
J = 16.9, 5.9 Hz, 1H), 0.14 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 166.2, 159.2, 145.2, 140.7, 136.0, 130.1, 129.3,
Supporting Information
129.1, 128.8, 127.2, 126.2, 121.0, 113.8, 101.9, 87.1, 73.0, 70.7,
69.4, 55.2, 22.3, 0.00; IR (neat) cm−1: 3028 (w), 2957 (m),
Supporting Information File 1
2901 (m), 2178 (m), 1709 (s), 1625 (s), 1512 (m), 1245 (s),
1128 (s), 840 (s), 757 (s); HRMS (ESI) m/z: [M + H]+ calcd for
C27H33O4Si, 449.2143; found, 449.2146, (Δ = 0.67 ppm).
Full experimental methods; spectroscopic data and NMR
spectra of all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-197-S1.pdf]
(2E,4Z)-1′-(para-Methoxybenzyloxy)-5′-(trimethylsilyl-
oxy)pent-4′-yn-2′-yl 7-(tert-butyldimethylsilyloxy)-5-methyl-
nona-2,4,8-trienoate (5b). Rf = 0.30 (80% CH2Cl2 in
n-hexane); 1H NMR (500 MHz, CDCl3) δ 7.57 (dd, J = 14.9,
11.8 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H),
Acknowledgements
The authors gratefully acknowledge financial support from
Genesis Oncology Trust and the Health Research Council of
1820

Beilstein J. Org. Chem. 2015, 11, 1815–1822.
23.Field, J. J.; Pera, B.; Calvo, E.; Canales, A.; Zurwerra, D.; Trigili, C.;
Rodriguez-Salarichs, J.; Matesanz, R.; Kanakkanthara, A.;
Wakefield, S. J.; Singh, A. J.; Jiménez-Barbero, J.; Northcote, P.;
Miller, J. H.; López, J. A.; Hamel, E.; Barasoain, I.; Altmann, K.-H.;
Díaz, J. F. Chem. Biol. 2012, 19, 686–698.
New Zealand, and helpful discussions with Paul Teesdale-
Spittle, Rob Keyzers, Peter Northcote, Mark Bartlett and
Kalpani Somarathne (VUW). Sophie Geyrhofer prepared and
generously supplied IBX. Ian Vorster, Teresa Gen (VUW) and
Yinrong Lu (Callaghan Innovation) are thanked for technical
support.
doi:10.1016/j.chembiol.2012.05.008
24.Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.;
Gomez-Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775–778.
doi:10.1002/1099-0690(200102)2001:4<775::AID-EJOC775>3.0.CO;2-
Z
References
1. Daly, J. J.; Wheatley, P. J. J. Chem. Soc. A 1966, 1703–1706.
25.Chen, Q.-H.; Kingston, D. G. I. Nat. Prod. Rep. 2014, 31, 1202–1226.
doi:10.1039/C4NP00024B
doi:10.1039/j19660001703
2. Matthews, C. N.; Birum, G. H. Tetrahedron Lett. 1966, 7, 5707–5710.
doi:10.1016/S0040-4039(01)84182-4
26.Smith, A. B., III; Safanov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2001,
123, 12426–12427. doi:10.1021/ja012220y
3. Bestmann, H. J.; Sandmeier, D. Chem. Ber. 1980, 113, 274–277.
doi:10.1002/cber.19801130129
27.Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002,
124, 11102–11113. doi:10.1021/ja020635t
4. Bestmann, H. J.; Schobert, R. Synthesis 1989, 419–423.
doi:10.1055/s-1989-27271
28.Hoye, T. R.; Hu, M. J. Am. Chem. Soc. 2003, 125, 9576–9577.
doi:10.1021/ja035579q
5. Bestmann, H. J.; Kellermann, W. Synthesis 1994, 1257–1261.
doi:10.1055/s-1994-25676
29.Sanchez, C. C.; Keck, G. E. Org. Lett. 2005, 7, 3053–3056.
doi:10.1021/ol051040g
6. Bartlett, M. Synlett 2013, 24, 773–774. doi:10.1055/s-0032-1318264
7. Bestmann, H. J. Angew. Chem., Int. Ed. Engl. 1977, 16, 349–364.
doi:10.1002/anie.197703491
30.Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005,
44, 3485–3488. doi:10.1002/anie.200500564
31.Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321–2324.
doi:10.1021/ol0504897
8. Schobert, R. Org. Synth. 2005, 82, 140–146.
doi:10.1002/0471264229.os082.22
32.Ding, F.; Jennings, M. P. J. Org. Chem. 2008, 73, 5965–5976.
doi:10.1021/jo8009853
9. Boeckman, R. K., Jr.; Song, X.; Pero, J. E. J. Org. Chem. 2006, 71,
8969–8972. doi:10.1021/jo061732y
33.Louis, I.; Hungerford, N. L.; Humphries, E. J.; McLeod, M. D. Org. Lett.
2006, 8, 1117–1120. doi:10.1021/ol053092b
10.Schlenk, A.; Diestel, R.; Sasse, F.; Schobert, R. Chem. – Eur. J. 2010,
16, 2599–2604. doi:10.1002/chem.200902544
34.Uenishi, J.; Iwamoto, T.; Tanaka, J. Org. Lett. 2009, 11, 3262–3265.
doi:10.1021/ol901167g
11.Pachali, S.; Hofmann, C.; Rapp, G.; Schobert, R.; Baro, A.; Frey, W.;
Laschat, S. Eur. J. Org. Chem. 2009, 2828–2835.
doi:10.1002/ejoc.200900176
35.Zurwerra, D.; Gertsch, J.; Altmann, K.-H. Org. Lett. 2010, 12,
2302–2305. doi:10.1021/ol100665m
12.Jung, M. E.; Yoo, D. Org. Lett. 2011, 13, 2698–2701.
doi:10.1021/ol200796r
36.Zurwerra, D.; Glaus, F.; Betschart, L.; Schuster, J.; Gertsch, J.;
Ganci, W.; Altmann, K.-H. Chem. – Eur. J. 2012, 18, 16868–16883.
doi:10.1002/chem.201202553
13.Westman, J.; Orrling, K. Comb. Chem. High Throughput Screening
2002, 5, 571–574. doi:10.2174/1386207023330066
14.Fedoseyenko, D.; Raghuraman, A.; Ko, E.; Burgess, K.
Org. Biomol. Chem. 2012, 10, 921–924. doi:10.1039/C2OB06692K
15.Raghuraman, A.; Ko, E.; Perez, L. M.; Ioerger, T. R.; Burgess, K.
J. Am. Chem. Soc. 2011, 133, 12350–12353. doi:10.1021/ja2033734
16.Schobert, R.; Siegfried, S.; Gordon, G. J.
37.Yun, S. Y.; Hansen, E. C.; Volchkov, I.; Cho, E. J.; Lo, W. Y.; Lee, D.
Angew. Chem., Int. Ed. 2010, 49, 4261–4263.
doi:10.1002/anie.201001681
38.Ghosh, A. K.; Cheng, X. Org. Lett. 2011, 13, 4108–4111.
doi:10.1021/ol201626h
39.Ghosh, A. K.; Cheng, X.; Bai, R.; Hamel, E. Eur. J. Org. Chem. 2012,
4130–4139. doi:10.1002/ejoc.201200286
J. Chem. Soc., Perkin Trans. 1 2001, 2393–2397.
doi:10.1039/b105745f
40.Lee, K.; Kim, H.; Hong, J. Angew. Chem., Int. Ed. 2012, 51,
5735–5738. doi:10.1002/anie.201201653
17.Risi, R. M.; Burke, S. D. Org. Lett. 2012, 14, 1180–1182.
doi:10.1021/ol2034299
41.Larsen, E. M.; Wilson, M. R.; Zajicek, J.; Taylor, R. E. Org. Lett. 2013,
15, 5246–5249. doi:10.1021/ol402462h
18.Bestmann, H. J.; Kellermann, W.; Pecher, B. Synthesis 1993, 149–152.
doi:10.1055/s-1993-25820
And references cited therein.
19.Kitson, R. R. A.; McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett.
2011, 52, 561–564. doi:10.1016/j.tetlet.2010.11.143
20.Kitson, R. R. A.; Taylor, R. J. K.; Wood, J. L. Org. Lett. 2009, 11,
5338–5341. doi:10.1021/ol902191d
42.Kuntiyong, P.; Lee, T. H.; Kranemann, C. L.; White, J. D.
Org. Biomol. Chem. 2012, 10, 7884–7899. doi:10.1039/c2ob25766a
43.Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006,
128, 6745–6754. doi:10.1021/ja060812g
21.Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535–5538.
doi:10.1016/0040-4039(96)01149-5
44.Kiyotsuka, Y.; Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2002, 43,
2725–2729. doi:10.1016/S0040-4039(02)00403-3
45.Kiyotsuka, Y.; Kobayashi, Y. J. Org. Chem. 2009, 74, 7489–7495.
doi:10.1021/jo901728b
22.Field, J. J.; Singh, A. J.; Kanakkanthara, A.; Halafihi, T.;
Northcote, P. T.; Miller, J. H. J. Med. Chem. 2009, 52, 7328–7332.
doi:10.1021/jm901249g
1821

Beilstein J. Org. Chem. 2015, 11, 1815–1822.
46.Bestmann ylide [1, (triphenylphosphoranylidene)ketene] is
commercially available from Sigma–Aldrich as a stable crystalline solid
or can be generated by the method of reference [8]. It is essential to
thoroughly dry the crystals to remove residual nucleophilic solvent,
such as methanol, that would partake, upon dissolution, in reaction with
the ylide to afford a methyl ester side-product.
47.Larson, G. L.; Quiroz, F.; Suárez, J. Synth. Commun. 1983, 13,
833–844. doi:10.1080/00397918308063719
48.Direct formylation of the alkyne 13 was attempted using n-butyllithium
and N,N-dimethylformamide but afforded the ynal in only 28% yield.
Discouraged by the small quantity of material available from this
transformation, it was decided to prepare the enal 8 by a longer but
better-established route via the corresponding ester 14.
49.Maguire, R. J.; Munt, S. P.; Thomas, E. J.
J. Chem. Soc., Perkin Trans. 1 1998, 2853–2864.
doi:10.1039/a803422b
50.The ester products 5 slowly decompose to methyl dienoate byproducts
in the presence of methanol. As the most common acetylenic TMS
deprotection methods involve the use of methanol, it is deemed
beneficial to carry out the alkyne desilylation prior to formation of the
dienoate by the Bestmann ylide linchpin reaction.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.11.197
1822