Synthesis of Curvulone B Using the 2-Chlorobenzyl Protecting Group

Article abstract of DOI:10.1055/s-0034-1379988

A total synthesis of curvulone B has been completed using a Friedel-Crafts reaction and a highly cis-selective intramolecular oxa-Michael addition. The 2-chlorobenzyl protecting group was employed and found to have much greater Lewis acid stability compared to the simple benzyl group.

Full text of DOI:10.1055/s-0034-1379988

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 751–754
letter
751
R. W. Bates et al.
Letter
Synlett
Synthesis of Curvulone B Using the 2-Chlorobenzyl Protecting
Group
Roderick W. Bates*
Kongchen Wang
Guanying Zhou
carbonylation,
Friedel–Crafts,
oxa-Michael
HO
CO2Me
CO2Me
HO
Dave Zhihong Kang
OH
H
HO
O
O
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, 637371 Singapore, Singapore
roderick@ntu.edu.sg
H
CO2Me
Received: 24.11.2014
Accepted after revision: 17.12.2014
Published online: 09.02.2015
HO
DOI: 10.1055/s-0034-1379988; Art ID: st-2014-d0964-l
H
Abstract A total synthesis of curvulone B has been completed using a
Friedel–Crafts reaction and a highly cis-selective intramolecular oxa-Mi-
chael addition. The 2-chlorobenzyl protecting group was employed and
found to have much greater Lewis acid stability compared to the simple
benzyl group.
HO
O
1
O
H
CO2Me
HO
Key words tetrahydropyran, metathesis, Friedel–Crafts, protecting
groups, cyclization
3a
HO
O
Curvulone B (1) is a cis-disubstituted tetrahydropyran
natural product and is one of a number of related com-
pounds isolated from a marine fungus.1 Given our interest
in the synthesis of such tetrahydropyrans by the combina-
tion of cross-metathesis and intramolecular oxa-Michael
addition,2,3 and the fact that this chemistry gives the cis ste-
reochemistry with high selectivity when the acceptor is a
ketone, we set out to complete the synthesis of this com-
pound (Scheme 1). During the course of these studies, a
synthesis of curvulone B (1) was reported by Takahashi et
al. using this method for THP formation.4 We wish to report
our results in which the cross-metathesis substrate is as-
sembled in an efficient manner, employing a novel phenol
protecting group.
Our synthesis began with the economical starting mate-
rial 3,5-dihydroxybenzoic acid (4, Scheme 2). Esterification5
and protection of the two phenolic hydroxy groups as their
benzyl ethers, followed by reduction of the ester and chlori-
nation with thionyl chloride gave the benzylic chloride 8a.6
Palladium-catalyzed methoxycarbonylation7 was employed
to introduce the required additional carbon atom. Although
such reactions often employ elevated pressures, this was
easily achieved with carbon monoxide at ambient pressure
2
Scheme 1 Curvulone B and its retrosynthesis
(balloon) with just 2 mol% of bis(triphenylphosphine)palla-
dium(II) chloride as the catalyst, to give ester 9a in 88%
yield.8
Our initial intention was to introduce the acryloyl side
chain required for metathesis by a palladium-catalyzed
coupling process. While, after optimization, ester 9a could
be cleanly and regioselectively iodinated α to the acetate
side chain using N-iodosuccinimide (NIS) in refluxing ace-
tonitrile, attempts to achieve a Sonogashira coupling9 with
propargyl alcohol or a carbonylative coupling with vinyl tri-
n-butyltin10 were fruitless, returning unreacted starting
material. We, therefore, resorted to a more classical C–C
bond-forming technique. The Friedel–Crafts acylation of es-
ter 9a also proceeded with complete regioselectivity to give
ketone 11a, but in only 36% yield (Table 1, entry 1). The low
yield was found to be due to extensive debenzylation.11 Rea-
soning that this premature deprotection involves the Lewis
acid mediated formation of a benzyl cation, we examined
substituted benzyl ethers. We anticipated that an electron-
withdrawing substituent would destabilize the cation and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 751–754

752
R. W. Bates et al.
Letter
Synlett
PGO
CO2Me
HO
CO2Me
HO
CO2H
SOCl2
MeOH
protection
90%
6a BnBr, K2CO3
6b 4-ClC6H4CH2Cl, NaI, K2CO3 94%
6c 2-ClC6H4CH2Cl, KI, K2CO3 99%
90%
4
6
5
PGO
OH
OH
6d 4-O2NC6H4CH2Br, K2CO3 100%
CO2Me
X
CO2Me
PGO
PGO
99%
99%
97%
BnO
CO (1 atm), MeOH,
i-Pr2NEt, (Ph3P)2PdCl2
NIS, MeCN
PG = Bn
LiAlH4, THF
a PG = Bn
b PG = 4-ClC6H4CH2
c PG = 2-ClC6H4CH2
85%
a PG = Bn
88%
I
b PG = 4-ClC6H4CH2 91%
c PG = 2-ClC6H4CH2 91%
d PG = 4-O2NC6H4CH2 90%
9
10
PGO
PGO
BnO
d PG = 4-O2NC6H4CH2 91%
SOCl2,
pyridine
Cl
7 R = CH2OH
ClOC
SnCl4
8 R = CH2Cl
see Table 1
a PG = Bn
99%
CO2Me
b PG = 4-ClC6H4CH2 85%
c PG = 2-ClC6H4CH2 98%
d PG = 4-O2NC6H4CH2 95%
CO2Me
PGO
PGO
Et3N
94–96%
Cl
PGO
O
12
11
PGO
O
CO2Me
CO2Me
PGO
PGO
SO3H
MeOH
a PG = Bn
c PG = 2-ClC6H4CH2 88%
3b
Grubbs II
OTBS
H
see Table 2
89%
13
PGO
O
OTBS
PGO
O
O
H
14
CO2Me
HO
H2, Pd(OH)2/C, EtOAc
a PG = Bn
c PG = 2-ClC6H4CH2 81%
92%
H
HO
O
O
1
H
Scheme 2 Synthesis of curvulone B
minimize the undesired deprotection pathway. Use of the
4-chlorobenzyl group12,13 resulted in only modest improve-
ment (Table 1, entry 2). This substituent exerts an inductive
effect. In contrast, use of an 2-chlorobenzyl protecting
group resulted in an increase in yield of the Friedel–Crafts
product to 89% (Table 1, entry 4).14 This is consistent with
the strong dependency of the inductive effect on distance,
amplifying the destabilization of the cation by placing the
electron-withdrawing substituent closer to the center of
positive charge. The 2-chlorobenzyl group is, therefore,
more stable under Lewis acidic conditions.15 In addition,
use of the 4-nitrobenzyl protecting group also resulted in a
high yield of the Friedel–Crafts product (Table 1, entry 3).
The mesomeric effect of the nitro group is not, of course, so
attenuated by distance. Thus, both the 2-chlorobenzyl
group and the 4-nitrobenzyl group proved to be much more
robust than the ordinary benzyl group under Lewis acidic
conditions. In all cases examined, subsequent elimination
of the β-chlorine atom of ketones 11 from the side chain
gave the desired enones 12 in high yield.
Table 1 Friedel–Crafts Reactions with Different Protecting Groupsa
Entry
Substrate 9
PG
Bn
Yield (%)
1
2
3
4
9a
9b
9c
9d
36
42
80
89
4-ClC6H4CH2
4-O2NC6H4CH2
2-ClC6H4CH2
a Reaction at –40 °C in CH2Cl2 with SnCl4 as the Lewis acid. The mixture was
quenched with one equivalent of Et3N at the same temperature.
Initial metathesis studies of enones 12 were carried out
with the benzyl-protected material 12a (Table 2). Cross-
metathesis16 of the benzyl-protected substrate 12a with
TBS ether 3b17 was found to proceed best in hexafluoroben-
zene (Table 2, entry 2).18 The yield using this solvent was
somewhat improved over the use of toluene (Table 2, entry
1). We were unable to achieve cross-metathesis of the 4-ni-
trobenzyl-protected material 12d. This failure was due to
the lack of solubility of the substrate in the solvents used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 751–754

753
R. W. Bates et al.
Letter
Synlett
The material is not sufficiently soluble in solvents which
promote the metathesis reaction, such as toluene and hexa-
fluorobenzene. Use of mixtures with more polar solvents,
such as THF, appeared to inhibit metathesis. We did not,
therefore, pursue studies with 4-nitrobenzyl-protected
compound 12d. In contrast, the 2-chlorobenzyl-protected
material 12c underwent cross-metathesis efficiently with
TBS ether 3b in 1,2-dichloroethane, although a quite high
catalyst loading was required (Table 2, entry 6). Hexafluo-
robenzene and toluene could not be used due, again, to sol-
ubility issues. 1,2-Dichloroethane was found to be the best
solvent (Table 2, entries 5 and 6).
Acknowledgment
We thank Nanyang Technological University for financial support of
this work
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379988.
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References and Notes
(1) (a) Dai, J.; Krohn, K.; Flörke, U.; Pescitelli, G.; Kerti, G.; Papp, T.;
Kövér, K. E.; Bényei, A. C.; Draeger, S.; Schulz, B.; Kurtán, T. Eur. J.
Org. Chem. 2010, 6928. Dothiolerone A, also known as phomop-
sin B, is related to this group of compounds: (b) Izuchi, Y.;
Koshino, H.; Hongo, Y.; Kanomata, N.; Takahashi, S. Org. Lett.
2011, 13, 3360.
(2) (a) Bates, R. W. Song P. Tetrahedron 2007, 63, 4497. (b) Bates, R.
W.; Song, P. Synthesis 2010, 2935. (c) Bates, R. W.; Lek, T. G. Syn-
thesis 2014, 46, 1731.
(3) For reviews of intramolecular oxa-Michael addition, see:
(a) Fuwa, H. Heterocycles 2012, 86, 1255. (b) Nising, C. F.; Bräse,
S. Chem. Soc. Rev. 2012, 41, 988. (c) Larossa, I.; Romea, P.; Urpí, F.
Tetrahedron 2008, 64, 2683. (d) Clarke, P. A.; Santos, S. Eur. J.
Org. Chem. 2006, 2045.
Table 2 Cross-Metathesis Reactions of Enone 12 with Alkene 3ba
Entry
Substrate
PG
Bn
Solvent
Yield (%)
1
2
3
4
5
6
12a
12a
12c
12c
12c
12c
toluene
62
74
39
50
55
85c
Bn
C6F6
2-ClC6H4CH2
2-ClC6H4CH2
2-ClC6H4CH2
2-ClC6H4CH2
DCE–C6F6 (1:1)
b
CH2Cl2
DCE
DCE
a Cross-metathesis reactions were carried out at 70 °C unless otherwise stat-
ed, with a continuous flow of nitrogen. The Grubbs II catalyst (5 mol% unless
stated otherwise) was added in five portions at 90 minute intervals.
b At reflux.
(4) Takahashi, S.; Akita, Y.; Nakamura, T.; Koshino, H. Tetrahedron:
Asymmetry 2012, 23, 952.
(5) Denmark, S. E.; Regens, C. S.; Kobayashi, T. J. Am. Chem. Soc.
2007, 129, 2774.
c Conditions: 10 mol% of the catalyst.
(6) Comber, M. F.; Sargent, M. V.; Skelton, B. W.; White, A. H.
J. Chem. Soc., Perkin Trans. 1 1989, 441.
(7) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39,
3318.
(8) The alternative would be three steps: substitution with cyanide,
hydrolysis, and esterification; see ref. 6.
(9) Chincilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
(10) Goure, W. F.; Wright, M. E.; Davis, P. D.; Labadie, S. S.; Stille, J. K.
J. Am. Chem. Soc. 1984, 106, 6417.
(11) Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989,
54, 1346.
(12) 4-Bromo- and 4-chlorobenzyl ethers have been found to be
more stable to TFA than simple benzyl ethers: (a) Yamashiro, D.
J. Org. Chem. 1977, 42, 523. 4-Chloro, 4-iodo, and 2-bromoben-
zyl ethers have been employed in carbohydrate chemistry. The
groups were cleaved by amination, and considered to be of
‘comparable chemical inertness’ to simple benzyl ethers:
(b) Plante, O. J.; Buchwald, S. L.; Seeburger, P. H. J. Am. Chem. Soc.
2000, 122, 7148.
(13) The yield obtained using the 4-fluorobenzyl group was similar.
(14) 2-Halobenzyl ethers, cleaved by hydrogenolysis, have been
reported in the patent literature: (a) Cao, S. X.; Feng, J.; Imaeda,
Y.; Gwaltney, S. L.; Hosfield, D. J.; Takakura, N.; Tang, M. US
2007197532 A1, 2007. (b) Alihodzic, S.; Bosnar, M.; Culic, O.;
Erakovic Haber, V.; Hutinec, A.; Jelic, D.; Kragol, G.; Marjanovic,
N.; Marusic-Istuk, Z.; Ribic, M.; Vela, V. US 2008221046 A1,
2008.
Desilyation of either the benzyl compound 13a or the 2-
chlorobenzyl compound 13c, under our usual conditions
with amberlyst-15 in methanol, gave the tetrahydropyrans
14a and 14c cleanly and directly as single cis diastereoiso-
mers. In contrast, Takahashi et al., employing mildly basic
conditions, obtained a mixture favoring the trans isomer,
which required further equilibration.19 Debenzylation of ei-
ther 14a or 14c by hydrogenation over palladium hydroxide
on carbon gave the natural product 1. The spectroscopic
and chiroptical data was in good agreement with that re-
21
25
ported: [α]D –19 (c 0.28, EtOH) {lit.: [α]D –22 (c 0.27,
EtOH),1a –15.1 (c 0.52, EtOH)4}. It is notable that, in the case
of the 2-chlorobenzyl-protected material, the carbon chlo-
rine bond was not reduced.20,21
The synthesis of curvulone B has been achieved in ten
steps and 39% overall yield from commercially available
starting material. The efficiency of the synthesis rests upon
the use of carbonylation chemistry to introduce the ester
group, the metathesis–Michael strategy to introduce the
cis-tetrahydropyran and the addition of a 2-chlorine atom
to the well-known benzyl protecting group to provide ro-
bustness under Lewis acidic conditions. We believe that
this protecting group will be of general use in organic syn-
thesis.
(15) Such ethers are still labile to strong Lewis acids, such as tin tet-
rachloride: (a) Li, N.-S.; Lu, J.; Piccirilli, J. A. Org. Lett. 2007, 9,
3009. Or zinc chloride: (b) Huston, R. C.; Gyorgy, H. H. J. Am.
Chem. Soc. 1950, 72, 4171.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 751–754

754
R. W. Bates et al.
Letter
Synlett
(16) Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900.
(17) Takahashi et al. reported that cross-metathesis does not
proceed with the unprotected alcohol 3a (ref. 4). We also found
this to be the case. We propose that an unreactive chelate
forms.
(18) (a) Samojłowicz, C.; Bieniek, M.; Pazio, A.; Makal, A.; Woźniak,
K.; Poater, A.; Cavallo, L.; Wójcik, J.; Zdanowski, K.; Grela, K.
Chem. Eur. J. 2011, 17, 12981. For a helpful discussion of metath-
esis conditions, see: (b) Bieniek, M.; Michrowska, A.; Usanov, D.
L.; Grela, K. Chem. Eur. J. 2008, 14, 806.
(19) For the specific production of trans-THPs in this way, see:
(a) Banwell, M. G.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W. J.
Chem. Soc., Perkin Trans. 1 1996, 967. (b) Banwell, M. G.; Bissett,
B. D.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W. Aust. J. Chem.
1998, 51, 9.
(21) A solution of compound 14c (69 mg, 0.128 mmol) in EtOAc (5
mL) containing 20% Pd(OH)2 on carbon (30 mg) was stirred
overnight under hydrogen (balloon). The mixture was filtered
through Celite and concentrated. Purification by flash chroma-
tography on silica eluting with 50% EtOAc–hexane gave 1 as a
25
colorless oil (42 mg, 81%). [α]D21 –19 (c 0.28, EtOH) {lit.:1a,4 [α]D
–22 (c 0.27, EtOH), –15.1 (c 0.52, EtOH)]. 1H NMR (400 MHz,
CDCl3): δ = 9.77 (s, 1 H), 6.27 (d, J = 2.3 Hz, 1 H), 6.21 (d, J = 2.3
Hz, 1 H), 4.13 (m, 1 H), 3.94 (d, J = 16.5 Hz, 1 H), 3.70 (s, 3 H),
3.57 (m, 1 H), 3.51 (d, J = 16.5 Hz, 1 H), 3.30 (dd, J = 14.2, 10.3
Hz, 1 H), 2.57 (dd, J = 14.3, 3.2 Hz, 1 H), 1.84 (m, 1 H), 1.67 (m, 1
H), 1.63 (m, 1 H), 1.57 (m, 1 H), 1.44 (m, 1 H), 1.27 (m, 1 H), 1.17
(d, J = 5.9 Hz, 3 H). 13C NMR (100 MHz, CDCl3): J = 204.24,
172.44, 159.51, 159.41, 135.77, 120.88, 111.73, 104.05, 77.90,
74.87, 52.10, 49.04, 39.74, 32.68, 30.73, 23.11, 21.50.
(20) 2-Chlorotoluene was detected in the crude reaction mixture.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 751–754

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