Synthetic study of versipelostatin A: Synthesis of the spirotetronate unit starting from pulegone

Article abstract of DOI:10.1055/s-0031-1290204

The synthesis of the spirotetronate unit of versipelostatin A, a down-regulator of molecular chaperone GRP78, was achieved in ten steps starting from pulegone, via the Johnson-Claisen rearrangement. A model study of the coupling reaction with the octalin unit was also performed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290204

LETTER
397
Synthetic Study of Versipelostatin A: Synthesis of the Spirotetronate Unit
Starting from Pulegone
S
ynthetic Study o
y
f
V
ersipelos
o
tatin A Katsuta,* Kazuya Arai, Arata Yajima, Tomoo Nukada
Faculty of Applied Biosciences, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan
Fax +81(3)54772264; E-mail: r3katsut@nodai.ac.jp
Received 9 November 2011
Abstract: The synthesis of the spirotetronate unit of versipelostatin
A, a down-regulator of molecular chaperone GRP78, was achieved
27
O
O
O
in ten steps starting from pulegone, via the Johnson–Claisen rear-
rangement. A model study of the coupling reaction with the octalin
unit was also performed.
O
O
HO
HO
O
O
OH
O
MeO
OH
O
HO
Key words: versipelostatin A, natural products, spiro compounds,
Claisen rearrangement
H
H
O
In 2002, Shin-ya and co-workers isolated versipelostatin
A (1; Figure 1) from the culture broth of Streptomyces
versipellis and identified it as a down-regulator of grp78
gene expression.1 In the endoplasmic reticulum (ER) of
OH
versipelostatin A (1)
Figure 1 Structure of versipelostatin A (1)
solid tumor cells, the expression of the GRP78 protein en- gone by introduction of the tetronate ring and oxidative
hances the ER stress response, which plays a role in the re- cleavage of the double bond.
sistance to chemotherapy and hypoglycaemic stress.2
We synthesized the enantiomeric spirotetronate unit ent-
B, with the aim of establishing a synthetic route towards
versipelostatin A. Although the stereochemistry of the
natural spirotetronate unit is 27R, which corresponds to
9R in the intermediate B, we selected the more economi-
cal (R)-pulegone as the starting material for our model
Thus, a specific down-regulator of GRP78 would hold
promise as an alternative to cancer chemotherapy.3 The
structure of versipelostatin A, including its stereochemis-
try, was determined to be that of 1 by analysis of its spec-
troscopic data and on the basis of synthetic studies of the
sugar moieties.4,5 Versipelostatin A consists of a trisac-
study.
charide attached to a seventeen-membered macrocycle
The initial stage of the synthesis is shown in Scheme 2.
fused to spirotetronate and octalin units. Our interest in
Alkylation of lithiated methyl propiolate with (R)-pule-
gone afforded the adduct 3 stereoselectively via axial at-
the unique structure and biological activity of ver-
sipelostatin A led us to pursue its synthesis. Herein, we re-
tack.15 The sequential 1,4-addition of the methoxide ion
port the efficient synthesis of the spirotetronate unit of
followed by spirolactone formation13 gave the desired
versipelostatin A. To date, several synthetic studies of
spirotetronate-related compounds,6,7 such as tetronolide,8–
11 quartromicin,12,13 and spirohexenolide,14 have been re-
ported, and some of these synthetic approaches are cur-
rently used for the total synthesis of natural products.
tetronate derivative 4. The yield of 4 was 69% for the two
steps based on (R)-pulegone; elimination of the methyl
propiolate group under basic conditions caused regenera-
tion of (R)-pulegone (16%).15 Tetronate derivative 4 was
converted into ketone 5 by ozonolysis of the isopropy-
lidene moiety. The a,b-dehydrogenation of ketone 5
proved to be somewhat challenging. Saegusa oxidation, 2-
iodoxybenzoic acid (IBX) oxidation, phenylsulfanylation,
or phenylselenenylation and oxidation were all attempted,
but in each case either no or very little of the desired enone
was obtained. However, dehydrogenation following
Mukaiyama’s protocol [LHMDS, PhS(Cl)=N(t-Bu)]16 af-
forded enone 6 in satisfactory yield. The 1,2-addition of
methylmagnesium bromide to 7-en-6-one 6 gave the cor-
responding allylic alcohol as a single isomer.17 Subse-
quent oxidation and allylic rearrangement was achieved
simultaneously using pyridinium chlorochromate (PCC)
and silica gel to give 6-en-8-one 8. This enone was further
treated with methylmagnesium bromide to give two dia-
stereomeric adducts, 9 and 10, in an approximately 2:1 ra-
Our synthetic plan for 1 is illustrated in Scheme 1. The
synthetic features include anion-mediated coupling reac-
tions of fragments B, C, and D, macrocyclization by ring-
closing metathesis (RCM) between C-10 and C-11, fol-
lowed by formation of the octalin system by an intramo-
lecular Diels–Alder reaction of A. The spirotetronate
fragment B was envisioned to be prepared from allylic al-
cohol E via a [3,3]-sigmatropic rearrangement. Com-
pound E, in turn, was thought to be accessible from
spirolactone F, which could be synthesized from (S)-pule-
SYNLETT 2012, 23, 397–400
x
x.
x
x.
2
0
1
2
Advanced online publication: 26.01.2012
DOI: 10.1055/s-0031-1290204; Art ID: U64711ST
© Georg Thieme Verlag Stuttgart · New York

398
R. Katsuta et al.
LETTER
HO
X
9
27
O
MeO
RO
RO
RO
O
MeO
O
MeO
O
MeO
O
SO2Ph
F
O
O
O
1
B
E
O
O
Et
RO
X = leaving group
or OTBS
O
OHC
O
C
10
intramolecular
Diels–Alder reaction
11
10
11
O
D
Ar
OR
O
A
RCM
(S)-pulegone
Scheme 1 Synthetic route to versipelostatin A (1) and its spirotetronate unit
tio. Nucleophilic attack from the opposite side of the C-9 instead of propionic acid afforded the desired Johnson–
methyl group gave the major adduct 9, which was the de- Claisen rearrangement product 11 (36%), accompanied
sired product. Unfortunately, the use of methyllithium as by 12 (36%) and unreacted 9 (23%) within 16 hours. The
a nucleophile accelerated an axial attack and decreased yield of 11 was not improved by extending the reaction
the formation of 9 (9/10 = 1:3).
time. Microwave irradiation accelerated both the rear-
rangement and the elimination (11: 33%, 12: 36%, 9: 36%
in 15 min). The best result was obtained when the reaction
was carried out in a sealed tube at a high temperature
(Scheme 3).19–22
LDA, THF
methyl propiolate
–78 °C to 0 °C
NaOMe
MeOH, r.t.
2 steps 69%
(+ 2, 16%)
OH
O
MeO2C
2
3
O3, CH2Cl2
–78 °C
MeC(OEt)3
LHMDS, THF
PhS(Cl)=N(t-Bu)
–78 °C
2-nitrophenol
EtO2C
then Me2S
9
+
O
MeO
sealed tube
160 °C
MeO
O
O
O
MeO
O
MeO
O
90%
95%
O
O
O
4
5
11 (56%)
12 (31%)
Scheme 3 Synthesis of 11 by Johnson–Claisen rearrangement
HO
MeMgBr
THF, 0 °C
PCC, silica gel
6
6
CH2
Cl2, r.t.
O
MeO
MeO
O
O
O
The synthesis of key intermediate 14 (ent-B) is shown in
Scheme 4. The synthesized ester 11 was treated with
LiAlH4, followed by protection of the hydroxy group as a
TBS ether to give 14, the stereochemistry of which was
confirmed by NOE experiments (Figure 2) and by the
similarity of the 1H NMR spectra of the synthesized com-
pound 14 to the reported spectra of related spirotetr-
onates.11,23,24 Following the stereoselective construction
of the spirotetoronate unit, we subsequently addressed the
coupling reaction using synthesized 14 and benzaldehyde
as a model compound for the acylated octalin unit.
70%
82%
O
6
7
O
HO
HO
MeMgBr
THF, 0 °C
8
9
+
MeO
O
MeO
O
MeO
O
O
O
O
9 (67%)
10 (33%)
8
Scheme 2 Synthesis of allylic alcohol 9
Using established protocols,9,14 spirotetronate 14 was
lithiated with t-BuLi, followed by treatment with benzal-
dehyde to afford a product predicted to be 15.25
The stereochemistries of the adducts were confirmed by
NOE experiments (vide infra). After chromatographic
separation of the two diastereomers, the required com-
pound 9 was subjected to [3,3]-sigmatropic rearrange-
ment to install a C2 unit at the C-6 position. Attempted
vinyl ether formation, oxy-Michael addition to vinyl sul-
fone and acetylation followed by Ireland–Claisen
rearrangement18 were all unsuccessful. Refluxing in tri-
ethyl orthoacetate with propionic acid as a catalyst only
resulted in the formation of the undesired exo-selective
dehydration product 12. In contrast, using 2-nitrophenol
NOEs
OTBS
H
H2C
H
Me
Me
O
Me
O
H
MeO
14
Figure 2 NOE study of compound 14
Synlett 2012, 23, 397–400
© Thieme Stuttgart · New York

LETTER
Synthetic Study of Versipelostatin A
399
(10) Roush, W. R.; Reilly, M. L.; Koyama, K.; Brown, B. B.
J. Org. Chem. 1997, 62, 8708.
TBSCl, imidazole
DMF, r.t.
LiAlH4, THF
0 °C
(11) Boeckmann, R. K.; Shao, P.; Wrobleski, S. T.; Boehmler,
D. J.; Heintzelman, G. R.; Barbosa, A. J. J. Am. Chem. Soc.
2006, 128, 10572.
11
HO
2 steps 70%
MeO
O
(12) Roush, W. R.; Barda, D. A. Tetrahedron Lett. 1997, 38,
O
8781.
13
(13) Roush, W. R.; Barda, D. A. Tetrahedron Lett. 1997, 38,
8785.
t-BuLi, THF
PhCHO
(14) Jones, B. D.; La Clair, J. J.; Moore, C. E.; Rheingold, A. L.;
Burkart, M. D. Org. Lett. 2010, 12, 4516.
TBSO
–78 °C to 0 °C
MeO
HO
O
(15) The 1H NMR spectrum of crude 3 indicated that this material
is present as a single diastereomer. Complete consumption
of (R)-pulegone was also confirmed
TBSO
63%
MeO
O
O
O
(16) Mukaiyama, T.; Matsuo, J.; Kitagawa, H. Chem. Lett. 2000,
11, 1250.
14
(17) NOESY correlations were observed between 6-Me, 9-Me
and 10-Hb of compound 7
15
Scheme 4 Synthesis of key intermediate 14 and its alkylation
(18) Ireland–Claisen rearrangements of acetates of tertiary
alcohols have been reported, see: (a) Giró-Mañas, C.;
Paddock, V. L.; Bochet, C. G.; Spivey, A. C.; White, A. J.
P.; Mann, I.; Oppolzer, W. J. Am. Chem. Soc. 2010, 132,
5176. (b) Haning, H.; Giró-Mañas, C.; Paddock, V. L.;
Bochet, C. G.; White, A. J. P.; Bernardinelli, G.; Mann, I.;
Oppolzer, W.; Spivey, A. C. Org. Biomol. Chem. 2011, 9,
2809.
In summary, we have achieved an efficient stereoselective
synthesis of the enantiomeric spirotetronate unit 14 of ver-
sipelostatin A (1). The overall yield was 8.9% in ten steps
starting from commercially available (R)-pulegone. This
synthetic method is thought to be applicable to other
spirotetronate-based natural products. In addition, we per-
formed a model study of the coupling reaction of the
spirotetronate unit and the acylated octalin unit using ben-
zaldehyde as an electrophile. Our continuing research to-
wards the synthesis of versipelostatin A, including the
synthesis of other coupling partners and studies on cy-
clizations, is in progress.
(19) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem.
Soc. 1970, 92, 741.
(20) Fukazawa, T.; Shimoji, Y.; Hashimoto, T. Tetrahedron:
Asymmetry 1996, 6, 1649.
(21) Bohno, M.; Sugie, K.; Imase, H.; Yusof, Y. B.; Oishi, T.;
Chida, N. Tetrahedron 2007, 63, 6977.
(22) Tanimoto, H.; Kato, H.; Chida, N. Tetrahedron Lett. 2007,
48, 6267.
(23) Analytical data for (5R,6S,9S)-6-[2-(tert-butyldimethyl-
silyloxy)ethyl]-4-methoxy-6,8,9-trimethyl-1-oxaspiro-
[4.5]deca-3,7-dien-2-one (14): [a]D26 –16 (c 0.46, CHCl3);
IR (Nujol): 2956, 1760, 1628, 1089, 962 cm–1; 1H NMR (400
MHz, CDCl3): d = 0.04 (s, 6 H), 0.88 (s, 9 H), 0.89 (s, 3 H),
1.04 (d, J = 7.3 Hz, 3 H), 1.66 (s, 3 H), 1.72–1.83 (m, 2 H),
1.85 (dd, J = 13.7, 6.4 Hz, 1 H), 2.03 (dd, J = 13.7, 10.0 Hz,
1 H), 2.37 (m, 1 H), 3.67–3.75 (m, 2 H), 3.78 (s, 3 H), 4.99
(s, 1 H), 5.10 (s, 1 H); 13C NMR (100 MHz, CDCl3): d =
–5.3, –5.3, 18.2, 19.5, 20.9, 21.2, 25.9, 32.6, 37.6, 39.8, 42.2,
59.2, 60.0, 88.5, 88.9, 127.4, 136.2, 171.9, 186.0; MS (ESI-
TOF): m/z [M + Na]+ calcd for C21H36NaO4Si: 403.2275;
found: 403.2247
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We gratefully acknowledge Prof. Dr. H. Watanabe, Prof. Dr. K.
Ishigami and Mr. M. Yamamoto at the University of Tokyo for re-
cording the HRMS spectra. This work was partially supported by a
Grant-in-Aid for Scientific Research (23780121) from the Japanese
Ministry of Education, Culture, Sports, Science and Technology.
(24) Roush, W. R.; Barda, D. A.; Limberakis, C.; Kunz, R. K.
Tetrahedron 2002, 58, 6433.
References and Notes
(25) Preparation of (5R,6S,9S)-6-[2-(tert-butyldimethylsilyl-
oxy)ethyl]-3-[(RS)-1-hydroxybenzyl]-4-methoxy-6,8,9-
trimethyl-1-oxaspiro[4.5]deca-3,7-dien-2-one (15): To a
solution of tetronate 14 (21 mg, 0.066 mmol) in THF (2 mL),
was added a solution of tert-butyllithium (1.0 M in pentane,
49 mL, 0.085 mmol) at –78 °C under argon and the mixture
was stirred for 10 min. To the mixture was then added
benzaldehyde (8.6 mL, 0.085 mmol). After stirring for 20
min, the reaction mixture was poured into saturated aqueous
NH4Cl and extracted with EtOAc. The organic layer was
washed with water and brine, dried over anhydrous MgSO4
and concentrated in vacuo. The residue was subjected to
flash chromatography over silica gel (hexanes–acetone,
12:1) to give a 6:4 mixture of diastereomers of 15 (17 mg,
63%) as an amorphous solid. [a]D26 –11 (c 0.46, CHCl3); IR
(Nujol): 3423, 1725, 1635, 1067, 836 cm–1; 1H NMR (400
MHz, CDCl3): d = 0.04, 0.04, 0.05 (3 × s, total 6 H, TBS),
(1) Park, H.-R.; Furihata, K.; Hayakawa, Y.; Shin-ya, K.
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© Thieme Stuttgart · New York
Synlett 2012, 23, 397–400

400
R. Katsuta et al.
LETTER
0.88 (s, 3.6 H, TBS), 0.89 (s, 5.4 H, TBS), 0.95 (s, 1.2 H, 6-
Me), 0.97 (s, 1.8 H, 6-Me), 1.05 (d, J = 7.3 Hz, 1.8 H, 9-
Me), 1.05 (d, J = 6.9 Hz, 1.2 H, 9-Me), 1.63–1.68 (m, 3 H,
8-Me), 1.74–1.83 (m, 2 H, 6-CH2-), 1.88 (dd, J = 13.7,
6.8 Hz, 0.6 H, 10-Ha), 1.94 (dd, J = 13.8, 6.9 Hz, 0.4 H, 10-
Ha), 2.05 (m, 1 H, 10-Hb), 2.38 (m, 1 H, 9-H), 3.69–3.77 (m,
2 H, 6-CH2-CH2-), 3.88 (s, 1.8 H, 4-OMe), 3.94 (s, 1.2 H, 4-
OMe), 4.14 (d, J = 10.0 Hz, 0.6 H), 4.33 (d, J = 10.0 Hz,
0.4 H), 5.10 (m, 1 H, 7-H), 5.96 (s, 0.6 H, OH), 5.98 (s, 0.4,
OH), 7.25–7.43 (m, 5 H, ArH); 13C NMR (100 MHz,
CDCl3): d = –5.3 (1.2 C), –5.3 (0.8 C), 18.2 (0.4 C), 18.2
(0.6 C), 19.5 (0.4 C), 19.6 (0.6 C), 20.9 (1 C), 21.6 (0.6 C),
21.6 (0.4 C), 25.9 (3 C), 32.6 (1 C), 37.7 (0.6 C), 37.9
(0.4 C), 49.2 (1 C), 42.3 (0.4 C), 42.4 (0.6 C), 59.9 (0.4 C),
59.9 (0.6 C), 60.3 (0.6 C), 60.4 (0.4 C), 67.2 (0.6 C), 67.7
(0.4 C), 87.7 (0.6 C), 87.9 (0.4 C), 103.1 (0.4 C), 103.2
(0.6 C), 125.8 (1.2 C), 125.9 (0.8 C), 127.2 (0.4 C), 127.3
(0.6 C), 127.5 (0.6 C), 127.6 (0.4 C), 128.6 (2 C), 136.0
(0.6 C), 136.2 (0.4 C), 142.9 (0.4 C), 143.1 (0.6 C), 173.5
(0.4 C), 173.7 (0.6 C), 177.9 (0.4 C), 178.4 (0.6 C); MS
(ESI-TOF): m/z [M + Na]+ calcd for C28H42N2NaO5Si:
509.2694; found: 509.2661
Synlett 2012, 23, 397–400
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