Synthesis of highly substituted pyranonaphthalene spiroketals related to the griseusins using a Hauser-Kraus annulation strategy

Article abstract of DOI:10.1016/j.tet.2013.12.066

The synthesis of an advanced pyranonaphthalene spiroketal as an intermediate for the total synthesis of griseusin B is described. A one-pot Hauser-Kraus annulation-methylation via reaction of a highly-substituted enone with a cyanophthalide was employed to construct the naphthalene framework. Other key steps include Sharpless asymmetric dihydroxylation of a (Z)-alkene and an HF-pyridine mediated double TBS deprotection-spirocyclisation.

Full text of DOI:10.1016/j.tet.2013.12.066

Accepted Manuscript
Synthesis of Highly Substituted Pyranonaphthalene Spiroketals Related to the
Griseusins using a Hauser-Kraus Annulation Strategy
Briar Naysmith, Daniel Furkert, Margaret Brimble
PII:
S0040-4020(13)01934-0
10.1016/j.tet.2013.12.066
TET 25150
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 October 2013
Revised Date: 18 December 2013
Accepted Date: 24 December 2013
Please cite this article as: Naysmith B, Furkert D, Brimble M, Synthesis of Highly Substituted
Pyranonaphthalene Spiroketals Related to the Griseusins using a Hauser-Kraus Annulation Strategy,
Tetrahedron (2014), doi: 10.1016/j.tet.2013.12.066.
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ACCEPTED MANUSCRIPT
Synthesis of Highly Substituted Pyranonaphthalene Spiroketals Related to the Griseusins
using a Hauser-Kraus Annulation Strategy
Briar Naysmith, Daniel Furkert and Margaret Brimble*
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New
Zealand
Abstract
The synthesis of an advanced pyranonaphthalene spiroketal as an intermediate for the total
synthesis of griseusin B is described. A one-pot Hauser-Kraus annulation-methylation via reaction of
a highly-substituted enone with a cyanophthalide was employed to construct the naphthalene
framework. Other key steps include Sharpless asymmetric dihydroxylation of a (Z)-alkene and an HF-
pyridine mediated double TBS deprotection-spirocyclisation.
1. Introduction
The pyranonaphthoquinones are a large family of over one hundred natural products, mostly
isolated from bacteria and fungi. Many pyranonaphthoquinones have been found to exhibit a variety
of antibacterial, antifungal and anticancer properties.1,2 The griseusins (Figure 1) are a subgroup of the
pyranonaphthoquinone family that contain a 6,6-spiroketal ring fused to a juglone moiety. The first
griseusins were isolated from the fermentation broth of a Streptomyces griseus K-63 bacterium found
in a soil sample from Peru.3 Griseusin A 1 contains a C9-C10 fused γ-lactone ring whereas in
griseusin B 2 the lactone is ring-opened to the carboxylic acid. Since the discovery of griseusin A 1
and B 2 in 1976, fifteen more griseusin natural products have been isolated (3-17, Figure 1),4-11 some
as recently as 2012. Some of these compounds occur naturally as both enantiomers and differ in
oxidation state, acetylation and stereochemistry around the spiroketal ring. The griseusins display
variable substitution at C9 of the dihydropyran ring or the C2a-C8a quinone double bond. 3ʹ-O-α-D-
forosaminyl-(+)-griseusin A 8 contains a sugar moiety at C-3ʹ4 while yoropyrazone 14 possesses an
amide side chain and an additional 2-pyridazone ring.10

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Figure 1. Griseusin natural products.
The griseusins demonstrate interesting biological activity including antibacterial and anticancer
properties.3,4 Pyranonaphthoquinones in general have long been proposed to act as bioreductive
alkylating agents12 and have recently been shown to exhibit selective inhibitory activity against
serine/threonine AKT,13 both of which may contribute to their activity against cancer cells. Due to
their biological activity and interesting structures, the griseusins constitute attractive synthetic targets.
Despite this, there is only one total synthesis of (+)-griseusin A and B to date, achieved by Yoshii et
al. in 1983.14
We have recently reported the enantioselective synthesis of a griseusin B model spiroketal 21
using a Hauser-Kraus (HK) annulation strategy to construct the tetracyclic griseusin B framework 20
(Scheme 1).15 Remarkably, enone 19 underwent a one-pot annulation-methylation-double
deprotection-spirocyclisation sequence with cyanophthalide 18 to give a single isomer of the
spiroketal framework of griseusin B 20. Spiroketal 20 was elaborated to model griseusin B 21 by side-
chain manipulation and AgO facilitated oxidative demethylation.15

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Scheme 1. Synthesis of model griseusin B 21.15
2. Results and Discussion
It was envisioned that the griseusin B model strategy could be extended to the synthesis of the
natural products 4ʹ-deacetyl griseusin B 4 and griseusin B 2 from naphthalene 22 that is assembled via
an HK annulation between phthalide 18 and highly substituted enone 23 (Scheme 2). Horner-
Wadsworth-Emmons (HWE) reaction of highly oxygenated phosphonate 25 with aldehyde 24, which
was used our previous griseusin B model synthesis,15 would furnish enone 23. Phosphonate 25 should
be accessible by opening of lactone 26 with the anion derived from dimethyl methylphosphonate.16
Lactone 26 would be obtained by dihydroxylation of unsaturated lactone 27 that in turn is formed via
partial reduction, deprotection and lactonisation of previously synthesised alkyne 28.15
Scheme 2. Retrosynthetic analysis of griseusin B 2 and 4ʹ-deacetyl griseusin B 4.
Our synthetic endeavours began with efforts towards diol 30 (Scheme 3) that is required for the
preparation of phosphonate 25. Alkyne 28, synthesised according to the previous model synthesis,15
was partially hydrogenated over Lindlar catalyst in EtOAc. Initial efforts gave a complex mixture of
the (Z)- and (E)-alkenes as well as the fully saturated product, however the addition of quinoline
afforded a 93% yield of the desired (Z)-alkene 29 after 1.5 hours. Deprotection of the silyl ether using
TBAF followed by CSA-mediated lactonisation furnished unsaturated lactone 27. Dihydroxylation of
lactone 27 using NMO and osmium tetroxide resulted in complete consumption of the starting
material, however the desired lactone diol 30 could not be isolated.

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Reagents and conditions: (i) Lindlar catalyst (20 wt%), quinoline (1 v/v%), H2, EtOAc, 93%; (ii) TBAF (1
M), THF; (iii) CSA, CH2Cl2, 39% (2 steps).
Scheme 3. Initial route to lactone diol 30.
In order to address this problem, Sharpless asymmetric dihydroxylation of (Z)-alkene 29, the
precursor to lactone 27, was investigated. Dihydroxylation of alkene 29 with NMO and osmium
tetroxide gave a 1.2:1 ratio of the undesired (S,S)-diol 31b to the desired (R,R)-diol 31a, revealing a
slight bias of this system towards the (S,S)-diol 31b (Table 1, entry 1). Sharpless asymmetric
dihydroxylation using the (DHQ)2PHAL ligand with standard Sharpless conditions17 was not
complete after 7 days and proceeded with no selectivity (entry 2). Increasing the reaction temperature
and the concentration of ligand and osmium tetroxide gave an 84% yield of a 2.5:1 ratio of
inseparable diols 31a:31b in favour of the (R,R)-diol 31a after 3 days (entry 3). Decreasing the
temperature did not increase the diastereoselectivity, only yielding a 2.3:1 diastereomeric ratio of
31a:31b (entry 4). Dihydroxylation of (Z)-alkenes is known to be unreliable among the various alkene
types subjected to Sharpless asymmetric dihydroxylation, becoming increasingly difficult when the
two substituents are close in size.17 Our approach was additionally disadvantaged by attempting to
override the natural bias of the system. Bearing these factors in mind, we chose to proceed with the
2.5:1 ratio of diols 31a:31b obtained.
Table 1. Sharpless cis-dihydroxylation of alkene 29
Entry Ligand
Ligand
OsO4 Temp Time Yield
dr
(31a:31b)
1:1.2
(mol%) (mol%)
(days)
1a
2b
3b
4b
NMO
n/a
0.4
0.4
1
rt
3
7
3
4
70%
(DHQ)2PHAL 1
(DHQ)2PHAL 5
(DHQ)2PHAL 5
0 °C
rt
16%c
1:1
84% 2.5:1
69% 2.3:1
1
4 °C
a
Reaction carried out in H2O/(CH3)2CO
b Reaction carried out in 1:1 t-BuOH/H2O with K3Fe(CN)6, K2CO3 and MeSO2NH2
c
43% starting material recovered

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The mixture of diols 31a and 31b was protected using 2-methoxypropene, affording acetonides
32a and 32b, which were separable by careful flash chromatography (Scheme 4). The
(R,R)-diastereomer 32a was then converted to phosphonate 25 in 86% yield by treatment with
lithiated dimethyl methylphosphonate.15 HWE reaction of chiral phosphonate 25 with aldehyde 2415
under mild aqueous conditions18 gave the desired (E)-enone 23 in 81% yield.
Reagents and conditions: (i) 2-methoxypropene, PPTS, CH2Cl2, 32a 42%, 32b 16%; (ii) MeP(O)(OMe)2,
n-BuLi, THF, -78 °C then 32a, THF, -78 °C, 86%; (iii) K2CO3, H2O/Et2O, 81%.
Scheme 4. Preparation of enone 23.
With enantiopure enone 23 in hand, attention turned to the key HK annulation to form the
pyranonaphthoquinone framework. The reaction was first attempted using the one pot annulation-
methylation conditions previously established in our lab for the synthesis of the model griseusin B
framework. This procedure enabled trapping of the unstable dihydroxynaphthalene annulation product
as a dimethyl ether.15 Annulation was effected using t-BuOK followed by biphasic methylation with
sodium hydroxide and dimethyl sulfate. However, in the present case, the product isolated was not the
desired spiroketal product 34 but the intermediate Michael addition product 33 (Scheme 5).
Reagents and conditions: (i) a. t-BuOK, THF, b. aq NaOH, Me2SO4, H2, 42%.
Scheme 5. Formation of Michael addition product 33.

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The mechanism of HK annulation involves Michael addition followed by Dieckmann-like
condensation to form the bicyclic system.19 A range of alternative bases and reaction conditions were
screened to effect complete HK annulation to afford the desired hydroquinone product 35 (Table 2).
Use of t-BuOK in THF only afforded the previously isolated Michael addition product 33 (Table 2,
entries 1-2). Attempts to cyclise the isolated Michael addition product 33 using t-BuOK, LDA or
sodium hydride resulted in no reaction or degradation. Use of DME as solvent or LDA as base were
also both unsuccessful (entries 3-4). Finally, use of t-BuOLi in THF afforded the desired
hydroquinone 35, albeit in modest yield (entry 5).
Table 2. HK annulation of enone 23 with phthalide 18.
Me
Me
OTBS
OTBS
OMe
OMe
O
O
O
OMe OH
O
O
O
TBSO
Me
O
O
conditions
or
O
O
O
+
O
OBn
OTBS
OTBS
NC
O
23
OTBS
CN
18
OH
33
35
OBn
OBn
Entry
Base
Solvent Temperature
Result
1
2
3
4
5
t-BuOK THF
t-BuOK THF
t-BuOK DME
rt
33 (33%)
33 (42%)
rt → 55 °C
100 °C
-78 °C
rt
decomposition
decomposition
35 (49%)
LDA
THF
t-BuOLi THF
Conditions for the methylation of 35 to afford the more stable trimethoxynaphthalene 22 were
next investigated (Table 3). Attempted methylation of isolated hydroquinone 35 using methyl iodide
with either cesium carbonate or sodium hydride was unsuccessful (Table 3, entries 1-2). Reaction of
35 with potassium carbonate and dimethyl sulfate in refluxing acetone produced the
trimethoxynaphthalene 22 in 24% yield over two steps (entry 3). Use of cesium carbonate resulted in
only a 5% yield of trimethoxynaphthalene 22 (entry 4). Pleasingly, an acceptable yield of
trimethoxynaphthalene 22 was obtained employing an adaptation of the one-pot annulation-
methylation from the model synthesis using t-BuOLi for the annulation in place of t-BuOK, followed
by the biphasic methylation. These conditions afforded a 41% yield of trimethoxynaphthalene 22
from enone 23 and phthalide 18 in one pot (entry 5).

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Table 3. Methylation of annulation product 35.
Entry Base
Methylating Solvent
agent
Yield
methylation of isolated hydroquinone 35
1
2
3
4
Cs2CO3
NaH
MeI
THFa
decomposition
decomposition
24%
MeI
THFa
K2CO3
Cs2CO3
Me2SO4
Me2SO4
acetoneb
acetoneb
5%
one-pot annulation/methylation of enone 23 and phthalide 18c
5
aq NaOH
Me2SO4
THFa
41%
a
b
c
room temperature
reflux
using t-BuOLi in THF for annulation step and TBAB in the methylation step
Trimethoxynaphthalene 22 could be deprotected and cyclised using HF·pyridine to afford a single
spiroketal 34 in 73% yield (Scheme 6). Subsequent progress toward the natural product proceeded in
excellent yields according to conditions established in the model synthesis.15 The benzyl ether was
deprotected by exposure to hydrogen at high pressure in the presence of Pd(OH)2/C to give alcohol
36. Two-step oxidation with IBX followed by Pinnick oxidation cleanly afforded carboxylic acid 37
(Scheme 6).
Reagents and conditions: (i) HF·pyr, THF, 73%; (ii) Pd(OH)2/C, H2 (30 psi), THF, 100%; (iii) IBX,
DMSO, 30 °C; (iv) 2-methyl-2-butene, NaClO2, KH2PO4, t-BuOH, H2O, 90% (2 steps).
Scheme 6. Preparation of advanced carboxylic acid spiroketal 37.
In the previous model synthesis, an X-ray structure was obtained showing that the spirocyclisation
gave solely the thermodynamic isomer with the C2-O1ʹ bond pseudoaxial, stabilised in part by the

ACCEPTED MANUSCRIPT
anomeric effect.15 Based on this precedent, spiroketal 34 is expected to have the anomeric
configuration shown (Figure 2). Additionally, nOe correlations from 3ʹ-H, 4ʹ-H and 7ʹ-Me to the 3-
OMe group of the pyranonaphthoquinone ring were observed, that are only possible in the
configuration shown.
Figure 2. Observed nOe correlations in spiroketal 34.
Disappointingly, initial efforts to elaborate advanced intermediate 37 to griseusin B 2 via
oxidative demethylation followed by global deprotection proved unsuccessful. The acetonide was
cleaved using aqueous HCl in THF affording diol acid 38 in 90% yield (Scheme 7). Frustratingly, all
efforts to effect oxidative demethylation of trimethoxynaphthalene 38 to form quinone 39 using a
variety of reagents (AgO, CAN, PIFA) were unsuccessful.20
Reagents and conditions: (i) 1M HCl, THF, 90%.
Scheme 7. Synthesis of advanced spiroketal diol 38.
3. Conclusion
In summary, the synthesis of advanced spiroketal 38 required to execute the total synthesis of
griseusin B 2 has been achieved. Key steps include Sharpless asymmetric dihydroxylation of (Z)-
alkene 29, HWE reaction of phosphonate 25 with aldehyde 24 and a one-pot Hauser-Kraus
annulation-methylation reaction to afford complex trimethoxynaphthalene intermediate 22. This
synthetic route is potentially adaptable to other griseusin natural products by varying the substitution
of the enone in the HK annulation step. Difficulties in achieving oxidative demethylation of advanced
trimethoxynaphthalene intermediate 38 prevented the total synthesis of griseusin B 2 and
4ʹ-deacetylgriseusin B 4. Notwithstanding this, the work reported herein demonstrates the application
of the HK annulation using a highly functionalised enone partner. The work also constitutes the

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synthesis of advanced trimethoxynaphthalene spiroketals 34, 36, 37 and 38 providing valuable
materials for biological evaluation.
4. Experimental Section
4.1 General Methods.
THF and Et2O were freshly distilled over sodium/benzophenone ketyl. CH2Cl2 was freshly
distilled from CaH2 and acetone was freshly distilled from CaCl2. Reactions were monitored by thin-
layer chromatography (TLC) using Kieselgel F254 0.2 mm (Merck) silica plates with visualisation by
ultraviolet irradiation (254 nm) followed by staining with vanillin or potassium permanganate. Optical
rotations were measured at wavelength 589 nm, with the concentration of the solution measured in
grams per 100 mL. Infrared (IR) spectra were recorded on a film ATR sampling accessory.
Absorption maxima are expressed in wavenumbers (cm-1). Nuclear magnetic resonance (NMR)
spectra were recorded operating at 300MHz for 1H nuclei and 75 MHz for 13C nuclei or 400MHz for
13
1H nuclei and 100 MHz for C nuclei, as stated. Chemical shifts were referenced to δ 7.26 and 77.0
1
13
ppm from tetramethylsilane for chloroform for H and C, respectively. All coupling constants J are
reported in hertz. All 13C NMR spectra were acquired using broadband decoupled mode, and
assignments were determined using DEPT135, DEPT90, COSY, HSQC and NOESY experiments
where required. High resolution mass spectra were obtained by electrospray ionisation in positive ion
mode at a nominal accelerating voltage of 70 eV.
Compounds 18, 24 and 28 were synthesised as described previously.15
4.2 Ethyl (R,Z)-5-(tert-butyldimethylsilyloxy)hex-2-enoate (29)
Alkyne 28 (1.59 g, 5.88 mmol) was dissolved in EtOAc (60 mL) and quinoline (60 µL). Lindlar
catalyst (314 mg, 20 wt%) was added and the reaction stirred under a H2 atmosphere for 1.5 h until
TLC showed complete consumption of 28. The reaction mixture was filtered through celite and
concentrated in vacuo. The crude oil was purified by flash chromatography (hexanes/EtOAc 19:1) to
give the title compound 29 (1.50 g, 93%) as a colourless oil; Rf (hexanes/EtOAc 19:1): 0.58;
νmax(neat)/cm-1 2957, 2930, 2858, 1720; [α]D20 -9.25 (c 1.02 in CHCl3); δH (400 MHz; CDCl3) 0.04 (s,
3H), 0.05 (s, 3H), 0.88 (s, 9 H), 1.16 (d, J = 5.9, 3H), 1.28 (t, J = 7.1, 3H), 2.79 (m, 2H), 3.96 (m,
1H), 4.15 (q, J = 7.1, 2H), 5.83 (ddd, J = 1.9, 1.9, 11.3, 1H), 6.35 (ddd, J = 7.3, 7.3, 11.7, 1H); δC
(400 MHz; CDCl3) -4.8, -4.5, 14.3, 18.0, 23.7, 25.8, 38.6, 59.8, 67.9, 120.8, 146.9, 166.4; m/z (ESI+)
[M+ + Na+] 295.1700 calcd for C14H28NaO3Si+ 295.1700.

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4.3 (R)-6-Methyl-5,6-dihydro-2H-pyran-2-one (27)
Alkene 29 (560 mg, 2.06 mmol) was dissolved in distilled THF (12 mL) and TBAF (1 M in THF,
4.1 mL, 4.1 mmol) was added. The reaction mixture was stirred for 24 h then diluted with EtOAc (6
mL), quenched with sat. aq NaHCO3 (10 mL), extracted with EtOAc (3 × 5 mL), washed with brine
(10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was
then dissolved in distilled CH2Cl2 (8 mL) and a spatula tip of (+)-camphorsulfonic acid was added.
The reaction mixture was stirred for 21 h then quenched by the addition of solid NaHCO3, filtered and
concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 1:1)
to give recovered alkyne 29 (92 mg) and the title compound 27 (90 mg, 39%, 2 steps) as colourless
oils; δH (400 MHz; CDCl3) 1.41 (d, J = 6.3, 3H), 2.31 (m, 2H), 4.55 (m, 1H), 5.98 (m, 1H), 6.85 (m,
1H); δC (400 MHz; CDCl3) 20.6, 30.9, 74.3, 121.2, 144.9, 164.4. NMR data closely matched those
previously reported.21
4.4 Ethyl (5R)-5-(tert-butyldimethylsilyloxy)-2,3-dihydroxyhexanoate (31)
(DHQ)2PHAL (313 mg, 0.40 mmol), K3Fe(CN)6 (7.94 g, 24.12 mmol), K2CO3 (3.33 mg, 24.09
mmol) and OsO4 (2.5 wt% in t-BuOH, 820 µL, 0.08 mmol) were added with stirring to H2O (40 mL)
and t-BuOH (40 mL). MeSO2NH2 (766 mg, 8.05 mmol) was added. The mixture was stirred until
clear then cooled to 0 °C and alkene 29 (2.19 g, 8.04 mmol) was added. The reaction was warmed to
rt and stirred for 3 days until TLC showed complete consumption of the starting material. The
reaction was quenched with sat. aq Na2S2O3 (40 mL) and stirred a further 30 min. The aqueous layer
was extracted with EtOAc (3 × 30 mL), the combined organic layers were washed with 2 M KOH (80
mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was
purified by flash chromatography (hexanes/EtOAc 1:1) to give the title compound 31 (2.34 g, 95%,
2.5:1 mixture of isomers) as a colourless oil; Rf (hexanes/EtOAc 1:1): 0.60; νmax(neat)/cm-1 3452,
2956, 2930, 2894, 1733; δH (400 MHz; CDCl3) 0.09 (2 × s, 2.4H*), 0.11 (2 × s, 6H), 0.89 (s, 9H), 1.20
(m, 3H), 1.31 ( m, 3H), 1.56 (m, 1H), 1.76 (m, 1H), 4.03 (m, 1H), 4.10 (m, 1H), 4.17 (m, 1H), 4.28 (q,
J = 7.5, 2H); δC (400 MHz; CDCl3) -5.1*, -4.8, -4.5*, -4.0, 14.2, 17.9, 23.1*, 24.2, 25.7, 39.4*, 40.6,
61.7, 66.4*, 69.1, 70.1*, 72.7, 74.2, 172.4; m/z (ESI+) [M+ + Na+] 329.1756 calcd for C14H30NaO5Si+
329.1755. * = denotes minor isomer.
4.5 Ethyl (4R,5R)-5-((R)-2-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl-1,3-dioxolane-4-
carboxylate (32)
Mixed diol 31 (400 mg, 1.30 mmol) was dissolved in distilled CH2Cl2 (6 mL) and 2-
methoxypropene (300 µL, 2.61 mmol) was added followed by pyridinium p-toluenesulfonic acid (26
mg, 0.10 mmol). The reaction was stirred for 1.25 h then quenched with sat. aq NaHCO3 (4 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 4 mL), the combined organic layers were washed with
brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product

ACCEPTED MANUSCRIPT
was purified by flash chromatography (hexanes/EtOAc 19:1) to give the major diastereomer 32a (190
mg, 42%) and the minor diastereomer 32b (74 mg, 16%) as colourless oils. Major isomer, 32a. Rf
(hexanes/EtOAc 19:1): 0.50; νmax(neat)/cm-1 2955, 2931, 2858, 1759; [α]D20 -13.67 (c 1.18 in CHCl3);
δH (400 MHz; CDCl3) 0.05 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 1.17 (d, J = 6.2, 3H), 1.29 (t, J = 7.0,
3H), 1.36 (s, 3H), 1.58 (m, 4H), 1.73 (m, 1H), 4.00 (m, 1H), 4.20 (m, 2H), 4.43 (m, 1H), 4.53 (d, J =
6.5, 1H); δC (400 MHz; CDCl3) -4.8, -4.4, 14.2, 18.0, 23.4, 25.6, 25.8, 27.0, 39.7, 61.0, 65.8, 74.5,
77.2, 110.3, 170.3; m/z (ESI+) [M+ + Na+] 369.2077 calcd for C17H34NaO5Si+ 369.2068. Minor
20
isomer, 32b. Rf (hexanes/EtOAc 19:1): 0.42; νmax(neat)/cm-1 2950, 2929, 2858, 1758; [α]D -9.96 (c
0.42 in CHCl3); δH (400 MHz; CDCl3) 0.05 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 1.13 (d, J = 6.3, 3H),
1.28 (t, J = 7.0, 3H), 1.35 (m, 4H), 1.59 (s, 3H), 1.64 (m, 1H), 4.00 (m, 1H), 4.19 (q, J =7.0, 2H), 4.51
(m, 2H); δC (400 MHz; CDCl3) -4.9, -4.3, 14.2, 18.0, 24.7, 25.7, 25.8, 27.0, 39.9, 60.8, 65.2, 74.2,
77.2, 110.5, 170.6; m/z (ESI+) [M+ + Na+] 369.2072 calcd for C17H34NaO5Si+ 369.2068.
4.6
Dimethyl
(2-((4R,5R)-5-((R)-2-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2-oxoethyl)phosphonate (25)
Dimethylmethylphosphonate (752 µL, 6.94 mmol) was dissolved in distilled THF (35 mL) under
a N2 atmosphere and cooled to -78 °C. n-BuLi (3.5 mL, 2.0 M in cyclohexane, 7.00 mmol) was added
and the reaction stirred for 30 min. Diastereomerically pure ester 32a (801 mg, 2.31 mmol) in distilled
THF (10 mL) was added and stirred for a further 2.5 h at -78 °C. The reaction was quenched with sat.
aq NH4Cl (20 mL), extracted with EtOAc (3 × 20 mL) then washed with brine (30 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (EtOAc neat) to give the title compound 25 (844
mg, 86%) as a colourless oil; Rf (EtOAc neat): 0.49; νmax(neat)/cm-1 2988, 2953, 2893, 2856, 1741;
20
[α]D +26.34 (c 1.51 in CHCl3); δH (400 MHz; CDCl3) 0.04 (s, 3H), 0.05 (s, 3H), 0.87 (s, 9H), 1.15
2
(d, J = 5.8, 3H), 1.37 (s, 3H), 1.58 (m, 5H), 3.03 (dd, J = 15.5, JHP = 20.9, 1H), 3.48 (dd, J = 15.3,
3
3
2JHP = 20.9, 1H), 3.78 (d, JHP = 4.8, 3H), 3.81 (d, JHP = 4.9, 3H), 3.96 (m, 1H), 4.47 (m, 2H); δC
(400 MHz; CDCl3) -4.9, -4.5, 18.0, 23.3, 24.7, 25.8, 27.0, 37.9 (d, JCP = 135.4), 39.5, 52.8 (d, 2JCP
=
6.5), 53.0 (d, 2JCP = 6.5), 65.7, 75.2, 82.5 (d, 3JCP = 3.7), 110.1, 202.9 (d, 2JCP = 7.4); m/z (ESI+) [M+
+ Na+] 447.1942 calcd forC18H37NaO7PSi+ 447.1938.
4.7 Enone (23)
Phosphonate 25 (430 mg, 1.01 mmol) was stirred in a solution of K2CO3 (2 g, 14.5 mmol) in H2O
(2 mL) for 30 min at 0 °C. Aldehyde 24 (272 mg, 0.84 mmol) in distilled Et2O (2.0 mL) was added,
the mixture warmed to rt and stirred for 18 h. The reaction mixture was diluted with Et2O (3 mL) and
H2O (2 mL) then extracted with Et2O (3 × 2 mL). The combined organic extracts were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 9:1) to give the title compound 23 (426 mg, 81%) as a colourless

ACCEPTED MANUSCRIPT
oil; Rf (hexanes/EtOAc 9:1): 0.58; νmax(neat)/cm-1 2953, 2929, 2856, 1692, 1623; [α]D +28.63 (c
1.20 in CHCl3); δH (400 MHz; CDCl3) 0.03 (s, 3H), 0.04 (s, 3H), 0.04 (s, 3H), 0.05 (s, 3H), 0.86 (s,
9H), 0.88 (s, 9H), 1.13 (d, J = 6.1, 3H), 1.37 (s, 3H), 1.46 (m, 1H), 1.59 (m, 4H), 1.74 (m, 2H), 2.41
(m, 2H), 3.52 (m, 2H), 3.95 (m, 1H), 4.02 (m, 1H), 4.47 (m, 3H), 4.55 (m, 1H), 6.52 (d, J = 15.8, 1H),
6.97 (ddd, J = 7.3, 7.3, 15.8, 1H), 7.32 (m, 5H); δC (400 MHz; CDCl3) -4.8, -4.8, -4.5, -4.5, 18.0, 23.2,
25.0, 25.8, 27.2, 37.2, 40.0, 41.0, 65.9, 66.6, 68.3, 73.0, 75.3, 82.0, 109.8, 127.5, 127.6, 127.6, 127.9,
128.3, 128.3, 129.5, 138.4, 145.4, 197.3; m/z (ESI+) [M+ + Na+] 643.3798 calcd for C34H60NaO6Si2+
643.3821.
20
4.8 Michael addition product (33)
Phthalide 18 (18 mg, 0.10 mmol) was dissolved in distilled THF (1 mL). t-BuOK (16 mg, 0.14
mmol) was added and the bright yellow mixture stirred for 20 min. Enone 23 (30 mg, 0.05 mmol) in
distilled THF (0.5 mL) was added and the solution stirred for 5 h at 55 °C until TLC showed
disappearance of the enone 23. The reaction was quenched with sat. aq NH4Cl (3 mL) and the
aqueous layer was extracted with EtOAc (3 × 2 mL). The combined organic extracts were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 2:1) to give the title compound 33 (16 mg, 42%) as a yellow oil; Rf
(hexanes/EtOAc 2:1): 0.53; δH (400 MHz; CDCl3) 0.05 (m, 12H), 0.83 (s, 9H), 0.88 (s, 9H), 1.07 (m,
1H), 1.15 (d, J = 6.3, 3H), 1.26 (m, 1H), 1.36 (s, 3H), 1.59 (s, 3H), 1.65 (m, 4H), 2.96 (m, 1H), 3.22
(m, 2H), 3.34 (m, 2H), 3.47 (m, 1H), 4.00 (m, 4H), 4.37 (m, 3H), 4.51 (m, 1H), 6.98 (d, J = 8.6, 1H),
7.13 (d, J = 7.3, 1H), 7.30 (m, 5H), 7.56 (t, J = 7.7, 1H); δC (400 MHz; CDCl3) -4.6, -4.6, -4.5, -4.5,
17.9, 18.0, 23.3, 24.8, 25.8, 27.1, 36.1, 36.5, 36.8, 39.4, 42.4, 56.2, 65.8, 66.4, 67.1, 73.0, 75.2, 80.7,
82.7, 108.5, 109.8, 113.0, 114.2, 116.3, 125.2, 127.6, 127.6, 127.7, 127.7, 128.4, 137.9, 147.6, 158.9,
165.3, 208.4; m/z (ESI+) [M+ + Na+] 832.4251 calcd for C44H67NNaO9Si2+ 832.4247.
4.9 Trimethoxynaphthalene (22)
One-pot procedure. Phthalide 18 (115 mg, 0.61 mmol) was dissolved in distilled THF (6 mL). t-
BuOLi (48 mg, 0.61 mmol) was added and the bright yellow mixture stirred for 20 min. Enone 23
(188 mg, 0.30 mmol) in distilled THF (3 mL) was added and the solution turned green. The solution
turned brown as it was stirred for 30 min until TLC showed disappearance of the enone 23. TBAB (15
mg, 0.05 mmol) and NaOH (242 mg, 6.05 mmol) in H2O (3.6 mL) were added followed by Me2SO4
(600 µL, 6.33 mmol) and the reaction was stirred for 16.5 h. The reaction was quenched with H2O (5
mL) and the aqueous layer was extracted with EtOAc (3 × 4 mL). The combined organic extracts
were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was
purified by flash chromatography (hexanes/EtOAc 9:1) to give the title compound 22 (101 mg, 41%)
20
as a yellow oil; Rf (hexanes/EtOAc 9:1): 0.46; νmax(neat)/cm-1 2938, 2856, 1703; [α]D -4.82 (c 1.10
in CHCl3); δH (400 MHz; CDCl3) -0.07 (s, 3H), 0.00 (s, 3H), 0.04 (s, 6H), 0.78 (s, 9H), 0.88 (s, 9H),

ACCEPTED MANUSCRIPT
1.14 (m, 6H), 1.28 (s, 3H), 1.77 (m, 3H), 1.97 (m, 1H), 2.66 (dd, J = 6.5, 13.5, 1H), 3.06 (dd, J = 7.8,
13.5, 1H), 3.53 (m, 2H), 3.76 (s, 3H), 3.83 (s, 3H), 3.98 (s, 3H), 4.01 (m, 1H), 4.24 (m, 1H), 4.43 (m,
3H), 4.92 (d, J = 7.0, 1H), 6.86 (d, J = 7.2, 1H), 7.28 (m, 5H), 7.44 (t, J = 7.8, 1H), 7.65 (dd, J = 0.7,
8.3, 1H); δC (400 MHz; CDCl3) -5.0, -4.8, -4.4, 17.9, 23.5, 25.6, 25.9, 26.7, 36.4, 37.3, 39.0, 56.1,
61.6, 64.2, 66.2, 67.4, 70.1, 72.8, 76.3, 82.9, 106.1, 109.2, 115.1, 119.5, 126.4, 127.3, 127.6, 127.6,
128.2, 128.2, 129.6, 131.8, 132.8, 138.7, 150.5, 151.1, 156.6, 206.3; m/z (ESI+) [M+ + Na+] 833.4430
calcd for C45H70NaO9Si2+ 833.4551.
Two-step procedure. Annulation. Phthalide 18 (49 mg, 0.26 mmol) was dissolved in distilled
THF (2.6 mL). t-BuOLi (23 mg, 0.29 mmol) was added and the bright yellow mixture stirred for 20
min. Enone 23 (80 mg, 0.13 mmol) in distilled THF (1.2 mL) was added and the solution turned
green. The solution turned brown as it was stirred for 20 min until TLC showed disappearance of the
enone 23. The reaction was quenched with sat. aq NH4Cl (3 mL) and the aqueous layer was extracted
with EtOAc (3 × 3 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered
and concentrated in vacuo to give crude annulation products which were immediately subjected to
methylation conditions.
Methylation. (i) Using K2CO3/Me2SO4. Crude annulation products were dissolved in distilled
acetone (1 mL). K2CO3 (18 mg, 0.13 mmol) and Me2SO4 (30 µL, 0.32 mmol) were added and the
mixture refluxed for 6.25 h. The reaction was quenched with sat. aq NH4Cl (1 mL) and the aqueous
layer was extracted with EtOAc (3 × 2 mL). The combined organic extracts were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo to give crude annulation products. The crude
product was purified by flash chromatography (hexanes/EtOAc 9:1) to give the title compound 22 (12
mg, 24% over 2 steps) as a yellow oil. (ii)Using Cs2CO3/Me2SO4. Crude annulation products (max.
0.14 mmol) were dissolved in distilled acetone (3 mL). Cs2CO3 (220 mg, 0.68 mmol) and Me2SO4
(130 µL, 1.37 mmol) were added and the mixture refluxed for 21 h. The reaction was quenched with
sat. aq NH4Cl (2 mL) and the aqueous layer was extracted with EtOAc (3 × 2 mL). The combined
organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude
annulation products. The crude product was purified by flash chromatography (hexanes/EtOAc 9:1) to
give the title compound 22 (5 mg, 5% over 2 steps) as a yellow oil.
4.10 Spiroketal (34)
Trimethoxynaphthalene 22 (30 mg, 0.037 mmol) was dissolved in distilled THF (2 mL) in a
plastic vial and cooled to 0 °C. HF.pyridine (70%, 50 µL, 1.53 mol) was added and the reaction
stirred at rt. After 40 min further HF.pyridine (70%, 50 µL, 1.53 mol) was added and the reaction
stirred for another 90 min. The reaction was quenched with dropwise addition of sat. aq NaHCO3 (2
mL) at 0 °C and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with
brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material
was purified by flash chromatography (hexanes/EtOAc 4:1) to give the title compound 34 (16 mg,

ACCEPTED MANUSCRIPT
73%) as a pale yellow oil; Rf (hexanes/EtOAc 4:1): 0.35; νmax(neat)/cm-1 2932, 2855, 1571; [α]D
20
+3.15 (c 2.86 in CHCl3); δH (400 MHz; CDCl3) 1.19 (d, J = 6.3, 3H), 1.30 (s, 3H), 1.60 (s, 3H), 1.90
(m, 1H), 2.09 (m, 2H), 2.16 (ddd, J = 2.0, 2.0, 14.6, 1H), 2.65 (dd, J = 11.9, 16.4, 1H), 3.06 (dd, J =
2.5, 16.4, 1H), 3.77 (m, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 4.01 (s, 3H), 4.27 (m, 1H), 4.34 (m, 1H), 4.55
(m, 3H), 5.21 (d, J = 5.8, 1H), 6.82 (d, J = 7.7, 1H), 7.32 (m, 6H), 7.65 (dd, J = 0.8, 8.1, 1H); δC (400
MHz; CDCl3) 21.2, 25.8, 26.2, 29.5, 34.4, 36.0, 56.2, 59.7, 60.8, 63.9, 64.3, 67.0, 72.8, 73.0, 74.7,
98.2, 105.5, 109.4, 114.6, 120.0, 126.2, 126.4, 127.4, 127.5, 127.5, 128.2, 128.3, 128.3, 131.1, 138.5,
148.3, 151.3, 156.4; m/z (ESI+) [M+ + Na+] 587.2613 calcd for C33H40NaO8 587.2615.
4.11 Spiroketal alcohol (36)
Benzyl ether 34 (24 mg, 0.043 mmol) was dissolved in distilled THF (30 mL) and Pd(OH)2/C
(spatula tip) was added. The mixture was shaken under H2 (30 psi) using a Parr hydrogenator for 3 h
then filtered through celite and concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 1:1) to give the title compound 36 (20 mg, 100%) as a colourless
20
oil; Rf (hexanes/EtOAc 1:1): 0.31; νmax(neat)/cm-1 3471, 2936, 2859, 1571; [α]D -9.09 (c 0.25 in
CHCl3); δH (400 MHz; CDCl3) 1.29 (m, 6H), 1.62 (s, 3H), 1.92 (m, 1H), 2.01 (m, 1H), 2.10 (m, 1H),
2.23 (ddd, J = 2.0, 2.0, 14.9, 1H), 2.70 (dd, J = 11.6, 15.8, 1H), 2.79 (m, 1H), 3.06 (dd, J = 2.1, 16.4,
1H), 3.84 (s, 3H), 3.84 (s, 3H), 3.94 (m, 2H), 4.01 (s, 3H), 4.22 (m, 1H), 4.32 (m, 1H), 4.54 (m, 1H),
5.22 (d, J = 5.9, 1H), 6.83 (d, J = 7.5, 1H), 7.38 (t, J = 7.9, 1H), 7.64 (dd, J = 0.8, 8.2, 1H); δC (400
MHz; CDCl3) 21.5, 25.8, 25.9, 29.5, 34.1, 37.9, 56.2, 60.2, 60.8, 61.6, 63.9, 67.7, 72.6, 74.2, 98.3,
105.6, 109.3, 114.6, 120.0, 125.7, 126.6, 127.3, 131.1, 148.3, 151.5, 156.4; m/z (ESI+) [M+ + H+]
475.2317 calcd for C26H35O8+ 475.2326.
4.12 Spiroketal acid (37)
Solid IBX (13 mg, 0.046 mmol) was added to alcohol 36 (13 mg, 0.028 mmol) with stirring
followed by DMSO (1.0 mL, stored over molecular sieves) and warmed to 50 °C for 4 h. The reaction
was quenched with sat. aq Na2S2O3 (2 mL) and diluted with Et2O (2 mL). The aqueous layer was
extracted with Et2O (3 × 2 mL). The combined organic layers were washed with sat. aq Na2S2O3 (4
mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a pale yellow oil. The
crude aldehyde was immediately dissolved in t-BuOH (1.5 mL) and 2-methyl-2-butene (150 µL, 1.42
mmol). A mixture of NaClO2 (22 mg, 0.24 mmol) and KH2PO4 (30 mg, 0.22 mmol) in H2O (220 µL)
was added dropwise. The reaction was warmed to 30 °C and stirred for 75 min. The reaction was
diluted with H2O (1 mL) and extracted with CH2Cl2 (4 × 1 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by
flash chromatography (EtOAc neat) to give the title compound 37 (12 mg, 90%, 2 steps) as a pale
yellow oil; Rf (EtOAc neat): 0.50; νmax(neat)/cm-1 3017, 2930, 2859, 1715, 1571, 1215; [α]D20 +7.00 (c
0.30 in CHCl3); δH (400 MHz; CDCl3) 1.25 (d, J = 6.5, 3H), 1.30 (s, 3H), 1.61 (s, 3H), 1.90 (ddd, J =

ACCEPTED MANUSCRIPT
4.5, 11.7, 15.2, 1H), 2.16 (ddd, J = 1.9, 1.9, 14.7, 1H), 2.70 (dd, J = 11.9, 16.1, 1H), 2.80 (dd, J = 4.6,
15.8, 1H), 2.89 (dd, J = 8.4, 15.8, 1H), 3.14 (dd, J = 2.5, 16.1, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4.02 (s,
3H), 4.36 (m, 1H), 4.59 (m, 2H), 5.16 (d, J = 6.2, 1H), 6.83 (d, J = 7.1, 1H), 7.39 (t, J = 8.2, 1H), 7.64
(dd, J = 0.7, 8.6, 1H); δC (400 MHz; CDCl3) 21.0, 25.8, 26.1, 28.8, 34.1, 40.3, 56.2, 60.1, 60.9, 63.9,
64.2, 72.8, 74.8, 98.4, 105.7, 109.3, 114.6, 120.1, 125.2, 126.6, 127.8, 131.1, 148.3, 151.4, 156.4,
174.7; m/z (ESI+) [M+ + Na+] 511.1939 calcd for C26H32NaO9+ 511.1939.
4.13 Spiroketal diol (38)
Acid 37 (8 mg, 0.016 mol) was stirred in distilled THF (800 µL) and aq HCl (1 M, 800 µL) for
19.5 h. The reaction was diluted with H2O (1 mL) and extracted with EtOAc (4 × 1 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to
give the title compound 38 (6.5 mg, 90%) as a pale yellow oil; Rf (CH2Cl2/CH3OH/AcOH 9:1:0.1):
0.37; νmax(neat)/cm-1 3384, 2924, 2854, 1721, 1570, 1372; [α]D -6.50 (c 0.20 in CH3OH); δH (400
20
MHz; CDCl3) 1.28 (d, J = 6.1, 3H), 1.84 (m, 1H), 2.12 (m, 1H), 2.76 (m, 3H), 3.16 (dd, J = 2.1, 15.8,
1H), 3.84 (s, 3H), 3.84 (s, 3H), 4.01 (s, 3H), 4.16 (d, J = 4.1, 1H), 4.36 (m, 1H), 4.57 (m, 1H), 4.97 (d,
J = 4.1, 1H), 6.85 (d, J = 7.3, 1H), 7.41 (t, J = 8.0, 1H), 7.64 (dd, J = 8.1, 1H); δC (400 MHz; CDCl3)
21.2, 28.9, 39.8, 40.4, 56.2, 60.9, 61.2, 63.8, 64.9, 68.4, 69.7, 102.0, 106.0, 114.5, 120.2, 124.7, 124.9,
126.9, 131.2, 148.4, 151.6, 156.6, 173.2; m/z (ESI+) [M+ + Na+] 471.1626 calcd for C23H28NaO9+
471.1626.
Acknowledgment
The authors thank The University of Auckland for financial support (BJN).
Supporting Information Available
Supplementary data for this article can be found at xxxxxxxxxxx. These include 1H NMR and 13C
NMR spectra for all novel compounds.
References
(1)
(2)
(3)
Brimble, M. A.; Nairn, M. R.; Duncalf, L. J. Nat. Prod. Rep. 1999, 16, 267.
Sperry, J.; Bachu, P.; Brimble, M. A. Nat. Prod. Rep. 2008, 25, 376.
Tsuji, N.; Kobayashi, M.; Wakisaka, Y.; Kawamura, Y.; Mayama, M.; Matsumoto,
K. J. Antibiot. 1976, 29, 7.
(4)
Maruyama, M.; Nishida, C.; Takahashi, Y.; Naganawa, H.; Hamada, M.; Takeuchi, T.
J. Antibiot. 1994, 47, 952.
(5)
Igarashi, M.; Chien, W.; Tsuchida, T.; Umekita, M.; Sawa, T.; Naganawa, H.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1995, 48, 1502.
(6)
(7)
Li, X.; Zheng, Y.; Sattler, I.; Lin, W. Arch. Pharmacal Res. 2006, 29, 942.
Li, Y.-Q.; Li, M.-G.; Li, W.; Zhao, J.-Y.; Ding, Z.-G.; Cui, X.-L.; Wen, M.-L. J.
Antibiot. 2007, 60, 757.
(8)
He, J.; Roemer, E.; Lange, C.; Huang, X.; Maier, A.; Kelter, G.; Jiang, Y.; Xu, L.-H.;
Menzel, K.-D.; Grabley, S.; Fiebig, H.-H.; Jiang, C.-L.; Sattler, I. J. Med. Chem. 2007, 50, 5168.

ACCEPTED MANUSCRIPT
(9)
(10)
(11)
Abdelfattah, M. S.; Kazufumi, T.; Ishibashi, M. J. Antibiot. 2011, 64, 729.
Abdelfattah, M. S.; Toume, K.; Ishibashi, M. J. Antibiot. 2012, 65, 245.
Ding, Z.-G.; Zhao, J.-Y.; Li, M.-G.; Huang, R.; Li, Q.-M.; Cui, X.-L.; Zhu, H.-J.;
Wen, M.-L. J. Nat. Prod. 2012, 75, 1994.
(12)
(13)
Moore, H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249.
Salaski, E. J.; Krishnamurthy, G.; Ding, W.-D.; Yu, K.; Insaf, S. S.; Eid, C.; Shim, J.;
Levin, J. I.; Tabei, K.; Toral-Barza, L.; Zhang, W.-G.; McDonald, L. A.; Honores, E.; Hanna, C.;
Yamashita, A.; Johnson, B.; Li, Z.; Laakso, L.; Powell, D.; Mansour, T. S. J. Med. Chem. 2009, 52,
2181.
(14)
(15)
(16)
(17)
(18)
(19)
(20)
Kometani, T.; Takeuchi, Y.; Yoshii, E. J. Org. Chem. 1983, 48, 2311.
Naysmith, B. J.; Brimble, M. A. Org. Lett. 2013, 15, 2006.
Ditrich, K.; Hoffmann, R. W. Tetrahedron Lett. 1985, 26, 6325.
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis 1986, 1986, 403.
Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892.
The complex mixture possibly resulted from different oxidation patterns at the
quinone ring (C3, C4) and spiroketal diol (C3ʹ, C4ʹ). Mass spectra suggested oxidation of one of the
spiroketal hydroxy groups, however no products could be isolated or identified.
(21)
Park, Y. S.; Grove, C. I.; Gonzalez-Lopez, M.; Urgaonkar, S.; Fettinger, J. C.; Shaw,
J. T. Angew. Chem., Int. Ed. 2011, 50, 3730.

ACCEPTED MANUSCRIPT
Supporting Information – NMR spectra of novel compounds
Ethyl (R,Z)-5-(tert-butyldimethylsilyloxy)hex-2-enoate, 29
OTBS
OEt
Me
29
O
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Ethyl (5R)-5-(tert-butyldimethylsilyloxy)-2,3-dihydroxyhexanoate, 31
TBSO
HO
OH
OEt
Me
31
O
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
(4R,5R)-Ethyl 5-((R)-2-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl-1,3-dioxolane-4-
carboxylate, 32a
TBSO
Me
O
O
OEt
32a
O
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
(4S,5S)-Ethyl 5-((R)-2-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl-1,3-dioxolane-4-
carboxylate, 32b
TBSO
Me
O
O
OEt
32b
O
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Dimethyl (2-((4R,5R)-5-((R)-2-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)-2-oxoethyl)phosphonate, 25
TBSO
Me
O
O
OMe
OMe
P
25
O
O
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Enone, 23
TBSO
Me
O
O
OBn
23
O
OTBS
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Michael addition product, 33
Me
OTBS
OMe
O
O
O
O
O
OTBS
NC
33
OBn
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Dimethoxynaphthalene, 22
Me
OTBS
O
MeO MeO
O
O
OTBS
MeO
22
OBn
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Spiroketal, 34
Me
O
MeO MeO
O
O
O
OBn
MeO
34
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
NOESY NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Spiroketal alcohol, 36
Me
O
MeO MeO
O
O
O
OH
MeO
36
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Spiroketal acid, 37
Me
O
MeO MeO
O
O
O
O
OH
MeO
37
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)

ACCEPTED MANUSCRIPT
Spiroketal diol, 38
Me
OH
OH
MeO MeO
O
O
O
OH
38
MeO
1H NMR (400 MHz, CDCl3)
13C NMR (400 MHz, CDCl3)