Asymmetric synthesis of (+)-chloriolide

Article abstract of DOI:10.1016/j.tetlet.2010.03.028

An asymmetric synthesis of 12-membered ring macrolide, chloriolide has been accomplished by adopting a linear strategy. Lipase-catalyzed enzymatic kinetic resolution (EKR), asymmetric alkynylation using Trost pro-phenol catalyst followed by Yamaguchi macr

Full text of DOI:10.1016/j.tetlet.2010.03.028

Tetrahedron Letters 51 (2010) 2644–2647
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Tetrahedron Letters
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Asymmetric synthesis of (+)-chloriolide
*
Tapas Das, Nandan Jana, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric synthesis of 12-membered ring macrolide, chloriolide has been accomplished by adopting
a linear strategy. Lipase-catalyzed enzymatic kinetic resolution (EKR), asymmetric alkynylation using
Trost pro-phenol catalyst followed by Yamaguchi macrolactonization has been successfully employed
to achieve the target molecule.
Received 9 February 2010
Revised 2 March 2010
Accepted 9 March 2010
Available online 12 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Medium ring macrolides
Enzymatic kinetic resolution (EKR)
Asymmetric alkynylation
Macrolactonization
Asymmetric total synthesis
Chloriolide is a 12-membered ring macrolide which was ob-
tained from solid substrate fermentation cultures of Chloridium
virescens var. chlamydosporum (NRRL 37636) that was originally
isolated from decayed wood by Jiao et al.1 Chloriolide belongs to
family of polyketide-derived fungal macrolactones (Scheme 1).
Although the related cladospolides and patulolides have been
reported to show antifungal and antibacterial activities, chloriolide
was inactive against Aspergillus flavus and Fusarium verticillioides.
Chloriolide was also inactive in antibacterial disk assays against
Staphylococcus aureus, Bacillus subtilis. The antifungal activity of
the original extract was attributed to the presence of the well-
known antifungal metabolite monorden. Monorden (also known
as radicicol) is produced by Monicillium nordinii, a mycoparasite
isolated from fungi that attack forest trees, as well as a variety of
other fungi.2
Total synthesis of structurally related patulolide has been re-
ported in the literature.3 In this Letter we would like to present
asymmetric synthesis of (+)-chloriolide. During the course of our
study the first asymmetric synthesis of the parent molecule has
been reported by Haug and Kirsch4 The retrosynthetic analysis is
shown in Scheme 2. The main highlights of our synthetic strategy
are Yamaguchi macrolactonization of properly functionalized seco
acid in the penultimate step. The seco acid in turn can be easily
constructed from two iterative three carbon homologation (alky-
nylation reaction with properly protected propargyl alcohol) reac-
tion with hydroxyl protected aldehyde. The required hydroxyl
protected aldehyde is thought to be constructed by an enzymatic
kinetic resolution (EKR) strategy (Scheme 2).
The synthesis starts from 1,3-butane diol (1). Selective mono
protection with TBSCl (tert-butyldimethylsilyl chloride) by Mc-
Dougals protocol,5 yielded the mono TBS protected ether 2 in
90% yield. With this racemic mono protected ether, enzymatic ki-
netic resolution (EKR) was achieved using vinyl acetate, CAL-B
(Candida antartica lipase) and DIPE (diisopropyl ether) as solvents
to afford the corresponding (R)-acetate 3 (yield = 48%, ee = 99%)
and (S)-alcohol 4 (yield = 48%, ee = 97%) according to Kazlauskas
empirical rule.6 The (S)-alcohol 4 was required for our synthetic
exercise, hence the ent-3 obtained from methanolic hydrolysis of
(R)-3 was inverted by Mitsunobu inversion followed by acetate
group deprotection afforded the required (S)-4 in good yield (93%
in two steps). The alcohol functionality in (S)-4 was protected as
its PMB (para-methoxybenzyl) ether by treating with PMB-imi-
date7 in the presence of a catalytic amount of CSA (camphorsulfo-
nic acid) to yield compound 5 in 82% yield. Removal of the TBS
group was achieved by treating compound 5 with PPTS (pyridini-
um paratoluene sulfonate) in MeOH, followed by oxidation of the
(CH2)n
(CH2)n
O
OH
O
O
O
O
OH
HO
OH
O
n = 2, (Z)-norisopatulolide C
n = 3, (Z)-isopatulolide C
n = 4, (Z)-homoisopatulolide C
n = 2, (E)-norpatulolide C
n = 3, (E)-patulolide C
n = 4, (E)-homopatulolide C
chloriolide
* Corresponding author. Tel.: +91 3222 283328; fax: +91 3222 282252.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
Scheme 1. Naturally occurring chloriolide and related macrolides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.028

T. Das et al. / Tetrahedron Letters 51 (2010) 2644–2647
2645
12
O
O
HO
OH
1
S
O
10
Macrolactonisation
OP3
OP2
9
Asymmetric
alkynylation
S
R
HO
OP1
OH
OP1
OHC
OP2
OP2
5
6
P1 = TBDPS
P2 = TBS
3 = PMB
chloriolide
P
EKR
OH
EKR
CHO
OP2
PO
Scheme 2. Retrosynthetic analysis of chloriolide.
primary alcohol functionality under Swern condition8 afforded the
corresponding aldehyde 6 with 80% yield (in two steps). Then the
aldehyde 6 was subjected to HWE (Horner–Wadsworth–Emmons)
reaction with ethoxy carbonylmethylen-triphenylphosphorane to
12 obtained from the fast reacting diastereomer was deacetylated
and subjected to Mitsunobu inversion/hydrolysis protocol to afford
the required diastereomeric alcohol 11 in 70% overall yield from
12. The secondary alcohol functionality in 11 was protected as its
TBDPS ether using imidazole and TBDPSCl (tert-butyldiphenylsilyl
chloride) in DCM (dichloromethane) afforded the compound 13
in 80% yield. Selective removal of TBS group in the presence of
TBDPS group was achieved by treating compound 13 with PPTS
in MeOH,10 afforded the corresponding propargylic alcohol in
70% yield. Then the acetylenic triple bond was converted to its cor-
responding cis(Z) double bond using Lindlar’s catalyst under H2
atmosphere with a small amount of quinoline afforded the com-
pound 14 in 92% yield (Scheme 3).
Compound 14 was then oxidized to its corresponding (Z) alde-
hyde 15 by Dess–Martin periodinane (DMP) oxidation11 in 85%
yield. Aldehyde 15 was then subjected to asymmetric alkynylation
protocol with tert-Butyl-dimethyl-prop-2-ynyloxy-silane by using
(R,R)-pro-phenol catalyst developed by Trost et al.12 to afford the
compound 16 in 72% yield (dr = 10:1). The free secondary hydroxy
group in 16 was protected as its TBDPS ether by treatment with
imidazole and TBDPSCl at room temperature afforded the corre-
afford the a,b unsaturated ester 7 in 98% yield. The olefinic double
bond in compound 7 was reduced by using NiCl2, NaBH4 in MeOH9
to afford the corresponding saturated ester in 97% yield. Reduction
of ester functionality was achieved by using LiAlH4 in ether to af-
ford the alcohol 8 in 88% yield. Swern oxidation of compound 8
afforded the desired aldehyde 9 in 80% yield. Then the aldehyde
9 was subjected to alkynylation reaction with the anion generated
from TBS protected propargyl alcohol using n-BuLi as a base at
ꢀ78 °C afforded the compound 10 in 80% yield. Compound 10
was obtained as mixtures of diastereomers. But we could not sep-
arate the diastereomers as their polarity remains same on TLC
plate. Therefore we have decided to carry out a further round of
EKR of compound 10 using CAL-B and vinyl acetate as the acyl do-
nor. The transesterification reaction afforded the corresponding (R)
alcohol 11 (yield = 47%) and (S) acetate 12 (yield = 48%) according
to the Kazlauskas rule. Our required substrate was the slow react-
ing diastereomer 11 for the next synthetic steps. Hence the acetate
OH
OH
OAc
OH
a
b
+
OH
OTBS
OTBS
OTBS
1
2
3
4
c
4
OPMB
OPMB
OPMB
OPMB
d
e
f
g
CHO
CO2Et
OTBS
OH
6
5
7
8
HO
OH
L
OPMB
h
i
OTBS
CHO
M
BMPO
9
10
Fast reacting enantiomer
Kazlauskas model
j
AcO
HO
OTBS
OTBS
BMPO
BMPO
11
+
12
11
k
l
SPDBTO
OPMB
OTBDPS
OTBS
m
BMPO
13
OH
14
Scheme 3. Reagents and conditions. (a) NaH, THF, TBS-Cl, 90%; (b) CAL-B, DIPE, vinylacetate, 1 h; (c) (i) K2CO3/MeOH; (ii) Ph3P/DIAD/AcOH; (iii) K2CO3/MeOH; (d)
PMBO(C@NH)CCl3, CSA, 82%; (e) (i) PPTS, MeOH; (ii) (COCl)2, DMSO, Et3N, ꢀ78 °C; (f) Ph3P@CHCO2Et, DCM, rt, 98%; (g) (i) NiCl2, NaBH4, MeOH, 97%; (ii) LiAlH4, 45 min, 88%;
(h) (COCl)2, DMSO, Et3N, ꢀ78 °C; (i) tert-butyl-dimethyl-prop-2-ynyloxy-silane, n-BuLi, ꢀ78 °C, 80%; (j) CAL-B, DIPE, vinylacetate, 72 h; (k) (i) K2CO3/MeOH; (ii) Ph3P/DIAD/
AcOH; (iii) K2CO3/MeOH, 70%; (l) TBDPS-Cl, imidazole, 90%; (m) (i) PPTS, MeOH, 78%; (ii) H2, Lindlar’s catalyst, 92%.

2646
T. Das et al. / Tetrahedron Letters 51 (2010) 2644–2647
OPMB
OTBS
OPMB
OTBDPS
b
a
16, R = H, dr = 10:1
17, R = TBDPS
14
c
CHO
15
OTBDPS
RO
HO
Ph
OH
Ph
d
N
OH
N
OPMB
OPMB
X
Ph
Ph OH
O
e
19, X = H
20, X = OH
(R,R)-ProPhenol ligand
OTBDPS
OTBDPS
SPDBTO
SPDBTO
18
f
O
O
O
O
g
OH
OTBDPS
HO
SPDBTO
21
Chloriolide
Scheme 4. Reagents and conditions. (a) Dess–Martin periodinane, 93%; (b) tert-butyl-dimethyl-prop-2-ynyloxy-silane, Me2Zn, (R,R)-pro-phenol ligand, 72%; (c) TBDPS-Cl,
imidazole, 88%; (d) (i) PPTS, MeOH; (ii) Red-Al, THF, ꢀ78 °C, 70% in two steps; (e) (i) DMP, DCM, 92%; (ii) NaH2PO4, NaClO2, t-BuOH, 2-methyl-2-butene, H2O, rt, 1 h, 92%; (f) (i)
DDQ, DCM/H2O (20:1), 78%; (ii) 2,4,6-trichlorobenzoylchloride, DIPEA (diisopropylethyl amine), DMAP, toluene 60 °C, 24 h, 64%; (g) NH4F/MeOH, rt, 48 h, 55%.
Wicklow, D. T.; Dowd, P. F. Org. Lett. 2002, 4, 3095; (d) Che, Y.; Gloer, J. B.;
Wicklow, D. T. J. Nat. Prod. 2002, 65, 399; (e) Hawksworth, D. L.. In Biology of
Conidial Fungi; Cole, G. T., Kendrick, B., Eds.; Academic Press: New York, 1981;
sponding TBDPS ether 17 in 80% yield. Selective removal of the TBS
ether was achieved by treating compound 17 with PPTS/MeOH fol-
lowed by reducing the acetylenic triple bond to its corresponding
trans double bond using red-Al{sodiumdihydro-bis(2-methoxyeth-
oxy)aluminate)}13 in THF afforded the compound 18 in 75% yield.
Then this (E) alcohol 18 on oxidation using DMP in DCM afforded
the corresponding (E) aldehyde 19 in 92% yield. Then the aldehyde
19 was converted to the corresponding acid 20 by Pinnic oxida-
tion14 in 70% yield (Scheme 4). Removal of PMB group was
achieved by treating 20 with DDQ15 in DCM/H2O (20:1), to afford
the seco acid in 78% yield. The hydroxyacid when subjected to mac-
rolactonization reaction under Yamaguchi condition,16 compound
21 was obtained in 64% yield. Removal of the TBDPS group in 21
was achieved by using NH4F/MeOH to afford the target molecule
chloriolide in 2.2% overall yield (Scheme 4).17 The spectral charac-
teristic values (1H and 13C NMR) of our synthesized chloriolide are
in perfect agreement with those of the reported value in the liter-
ature.1,18–29
Vol. 1, pp 171–244.
3. (a) Babu, K. V.; Sharma, G. V. M. Tetrahedron Asymmetry 2008, 19, 577; (b) Rao,
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Tetrahedron Lett. 1989, 30, 2153; (r) Mori, K.; Sakai, T. Liebigs Annalen der
Chemie 1988, 13; (s) Makita, A.; Yamada, Y.; Okade, H. J. Antibiot. 1986, 39,
1257.
In conclusion we have reported the asymmetric synthesis of the
12-membered macrolide (+)-chloriolide in an efficient way. Enzy-
matic kinetic resolution/Mitsunobu inversion has been success-
fully employed to fix two of the hydroxy stereocenters (7R and
11S) in the target molecule. Whereas asymmetric alkynylation
reaction by using Trost pro-phenol catalyst has been applied to
fix the 4S-hydroxy stereocenter. Finally Yamaguchi macrolacton-
ization of the properly functionalized seco acid afforded the target
molecule.
4. Haug, T. T.; Kirsch, S. F. Org. Biomol. Chem. 2010, 8, 991.
5. McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J. Org. Chem. 1986, 51, 3388.
6. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis. Wiley-VCH,
1999, Weinheim. ISBN: 3-527-30104-6.
7. Iversen, T.; Bundle, K. R. J. Chem. Soc., Chem. Commun. 1981, 1240.
8. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1979, 44, 4148.
9. Nagasawa, T.; Kuwahara, S. Org. Lett. 2009, 11, 761.
10. Prakash, S.; Saleh, A.; Blair, A. I. Tetrahedron Lett. 1989, 30, 19.
11. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
12. (a) Trost, B. M.; Weiss, A. H.; Von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8;
(b) Trost, B. M.; Weiss, A. H. Org. Lett. 2006, 8, 4461.
13. Raghavan, S.; Mustafa, S.; Sridhar, B. J. Org. Chem. 2009, 74, 4499.
14. Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
15. Horita, K.; Yoshioka, T.; Tanaka, Y.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986,
42, 3021.
Acknowledgments
16. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989.
We are thankful to CSIR (New Delhi, India; Grant No.: 01-2109/
07/EMR-II) for providing financial support. We are also thankful to
DST (New Delhi) for providing the departmental NMR facility un-
der the DST-IRPHA programme. Two of the authors, T.D. and N.J.
is thankful to CSIR (New Delhi, India) for a research fellowship.
17. (a) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.; Roberts, S. M.
Tetrahedron Lett. 1979, 20, 3981; (b) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J.
Am. Chem. Soc. 1981, 103, 1224.
18. 1H NMR of compound 6 (200 MHz, CDCl3), d: 9.76 (t, J = 2.4 Hz, 1H), 7.22 (d,
J = 7.2 Hz, 2H), 6.9 (d, J = 7.2 Hz, 2H), 4.52 (d, J = 11.2 Hz, 1H), 4.38 (d,
J = 11.2 Hz, 1H), 4.1 (m, 1H), 3.8 (s, 3H), 2.8–2.5 (m, 2H), 1.27 (d, J = 6.0 Hz, 3H).
13C NMR (50 MHz), d: 201.72, 159.48, 130.53, 129.51, 114.07, 70.51, 70.1, 55.5,
50.74, 20.05.
References and notes
½ ꢁ +10.9 (c 1.0, CHCl3).
a 2D5
1. Jiao, P.; Swenson, D. C.; Gloer, J. B.; Wicklow, D. T. J. Nat. Prod. 2006, 69, 636.
2. (a) Wicklow, D. T.; Joshi, B. K.; Gamble, W. R.; Gloer, J. B.; Dowd, P. F. Appl.
Environ. Microbiol. 1998, 64, 4482; (b) Soman, A. G.; Gloer, J. B.; Angawi, R. F.;
Wicklow, D. T.; Dowd, P. F. J. Nat. Prod. 2001, 64, 189; (c) Li, C.; Gloer, J. B.;
19. 1H NMR of compound 7 (200 MHz, CDCl3), d: 7.24 (d, J = 8.0 Hz, 2H), 7.1 (td,
J = 16.0, 7.4 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 5.88 (td, J = 16.0, 2.8 Hz, 1H), 4.5 (d,
J = 11.2 Hz, 1H), 4.39 (d, J = 11.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.8 (s, 3H), 3.66
(m, 1H), 2.5–2.3 (m, 2H), 1.3 (t, J = 7.2 Hz, 3H), 1.26 (d, J = 6.0 Hz, 3H).

T. Das et al. / Tetrahedron Letters 51 (2010) 2644–2647
2647
13C NMR (50 MHz), d: 167.89, 159.33, 145.56, 130.79, 129.37, 123.55, 113.98,
25. 1H NMR of compound 18 (400 MHz, CDCl3), d: 7.66 (m, 8H), 7.5–7.2 (m, 14H),
6.88 (d, J = 8.0 Hz, 2H), 5.55 (m, 2H), 5.3 m, 1H), 4.94 (m, 1H), 4.6 (m, 1H), 4.5–
4.3 (m, 3H), 3.77 (s, 3H), 3.6–3.4 (m, 3H), 1.4–1.2 (m, 6H), 1.2–1.0 (21H).
13C NMR (100 MHz), d: 159.08, 135.97, 135.83, 135.74, 134.79, 134.34, 134.23,
133.51, 132.73, 132.55, 131.17, 130.97, 130.83, 130.04, 129.91, 129.62, 129.47,
129.32, 129.19, 128.56, 127.46, 127.3, 126.97, 113.7, 74.62, 71.12, 69.9, 65.39,
62.55, 55.27, 38.42, 36.36, 36.19, 27.01, 26.89, 20.48, 19.5, 19.23.
73.41, 70.35, 60.38, 55.45, 39.47, 19.88, 14.46.
½ ꢁ +39.2 (c 1.0, CHCl3).
a 2D5
20. 1H NMR of compound 9 (200 MHz, CDCl3), d: 9.75 (t, J = 2.4 Hz, 1H), 7.24 (d,
J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 4.48 (d, J = 12.0 Hz, 1H), 4.34 (d,
J = 12.0 Hz, 1H), 3.84 (s, 3H), 3.5 (m, 1H), 2.5–2.4 (m, 2H), 1.8–1.4 (m, 4H), 1.28
(d, J = 6.4 Hz, 3H).
13C NMR (50 MHz), d: 202.67, 159.09, 130.96, 129.25, 113.77, 73.95, 70.0,
55.28, 43.81, 36.08, 19.53, 18.19.
½ ꢁ +11.26 (c 0.8, CHCl3).
a 2D5
26. 1H NMR of compound 19 (400 MHz, CDCl3), d: 9.08 (dd, J = 8.0, 3.6 Hz, 1H), 7.5
(m, 8H), 7.4–7.2 (m, 14H), 6.87 (d, J = 8.0 Hz, 2H), 6.3 (td, J = 16, 5.2 Hz, 1H), 5.7
(m, 2H), 5.46 (m, 1H), 4.9 (m, 1H), 4.4 (d, J = 11.2 Hz, 1H), 4.32 (d, J = 11.2 Hz,
1H), 4.2 (m, 1H), 3.78 (s, 3H), 3.38 (m, 1H), 1.4–1.2 (m, 6H), 1.0 (21H).
13C NMR (100 MHz), d: 193.39, 158.93, 136.19, 135.77, 135.61, 135.28, 135.25,
134.73, 133.96, 133.77, 133.0, 132.98, 131.1, 130.03, 129.85, 129.77, 129.61,
129.54, 128.98, 128.6, 128.56, 127.62, 127.58, 127.46, 113.64, 74.33, 70.15,
69.9, 69.77, 55.21, 38.35, 36.57, 26.95, 26.71, 20.64, 20.47, 19.44, 19.13.
½ ꢁ +9.2 (c 0.5, CHCl3).
a 2D5
21. 1H NMR of compound 11 (400 MHz, CDCl3), d: 7.25 (d, J = 8.0 Hz, 2H), 6.86 (d,
J = 8.0 Hz, 2H), 4.49 (d, J = 11.2 Hz, 1H), 4.38 (d, J = 11.2 Hz, 1H), 4.36 (s, 2H),
4.34 (m, 1H), 3.79 (s, 3H), 3.50 (m, 1H), 1.6–1.5 m, 6H), 1.18 (d, J = 6.0 Hz, 3H),
0.9 (s, 9H), 0.11 (s, 6H).
13C NMR (100 MHz), d: 159.08, 131.13, 129.21, 113.78, 85.88, 83.46, 74.40,
70.0, 62.39, 55.28, 51.74, 37.69, 36.24, 25.83, 21.21, 19.60, 18.30, ꢀ5.1.
½
a 2D5
ꢁ
ꢀ11.06 (c 1.8, CHCl3).
½ ꢁ +101.2 (c 0.5, CHCl3).
a 2D5
22. 1H NMR of compound 14 (400 MHz, CDCl3), d: 7.66 (m, 4H), 7.5–7.3 (m, 6H),
7.23 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 5.44 (m, 1H), 5.34 (m, 1H), 4.45
(d, J = 11.2 Hz, 1H), 4.36 (m, 1H), 4.33 (d, J = 11.2 Hz, 1H), 3.78 (s, 3H), 3.59 (m,
2H), 3.4 (m, 1H), 1.6–1.3 (m, 6H), 1.18 d, J = 6.0 Hz, 3H), 1.0 (s, 9H).
13C NMR (100 MHz), d: 159.09, 130.68, 135.94, 134.59, 134.27, 131.05, 129.70,
129.63, 129.26, 128.53, 128.35, 127.58, 127.41, 113.76, 74.34, 69.98, 69.15,
58.51, 55.29, 37.99, 36.58, 26.99, 21.07, 19.64, 19.27.
27. 1H NMR of compound 20 (400 MHz, CDCl3), d: 7.54 (m, 8H), 7.4–7.2 (m, 14H),
6.86 (d, J = 8.0 Hz, 2H), 6.6 (td, J = 16.0, 5.6 Hz, 1H), 5.57 (m, 1H), 5.44 (m, 2H),
4.72 (m, 1H), 4.42 (d, J = 11.2 Hz, 1H), 4.38 (d, J = 11.2 Hz, 1H), 4.1 (br, 1H), 3.78
(s, 3H), 3.33 (m, 1H), 1.4–1.3 (m, 6H), 1.16 (d, J = 6.0 Hz, 3H), 1.0 (s, 18H).
13C NMR (100 MHz), d: 191.31, 158.9, 150.21, 135.74, 135.71, 135.69, 135.59,
135.13, 133.94, 133.89, 133.23, 132.99, 131.08, 129.79, 129.67, 129.49, 129.45,
129.06, 128.71, 127.56, 127.53, 127.43, 127.41, 118.98, 113.62, 74.45, 69.93,
69.81, 69.68, 55.19, 38.33, 36.34, 29.63, 26.93, 26.8, 20.53, 19.45, 19.39.
½ ꢁ +3.1 (c 0.8, CHCl3).
a 2D5
23. 1H NMR of compound 15 (400 MHz, CDCl3), d: 9.34 (d, J = 2.2 Hz, 1H), 7.65 (m,
4H), 7.5–7.4 (m, 6H), 7.2 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 6.5 (m, 1H),
5.7 (dd, J = 11.2, 2.2 Hz, 1H), 4.94 (m, 1H), 4.45–4.32 (m, 2H), 3.82 (s, 3H), 3.45
(m, 1H), 1.8–1.3 (m, 6H), 1.18 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H).
½ ꢁ +33.8 (c 1.0, CHCl3).
a 2D5
28. 1H NMR of compound 21 (400 MHz, CDCl3), d: 7.52–7.18 (m, 20H), 6.42 (dd,
J = 16.0, 4.8 Hz, 1H), 5.7 (d, J = 16.0 Hz, 1H), 5.3–5.2 (m, 2H), 4.75 (m, 1H), 4.33
(m, 1H), 4.11 (m, 1H), 1.4–1.2 (m, 6H), 1.16 (d, J = 6.4 Hz, 3H), 1.08 (s, 9H), 0.91
(s, 9H).
13C NMR (100 MHz), d: 190.53, 159.09, 153.09, 135.87, 135.81, 133.42, 133.35,
131.06, 130.32, 129.99, 129.17, 128.31, 127.79, 127.71, 113.78, 74.23, 69.94,
69.02, 55.29, 37.95, 36.55, 26.97, 20.9, 19.55, 19.25.
13C NMR (100 MHz), d: 166.7, 150.1, 135.81, 135.73, 135.68, 134.51, 133.9,
133.8, 133.42, 132.99, 131.58, 130.83, 129.78, 129.74, 129.57, 129.45, 128.74,
127.6, 127.41, 127.3, 119.94, 72.58, 71.27, 70.22, 35.72, 33.53, 29.64, 26.97,
20.99, 20.89, 19.22, 19.13.
½ ꢁ ꢀ4.8 (c 0.9, CHCl3).
a 2D5
24. 1H NMR of compound 16 (400 MHz, CDCl3), d: 7.66 (m, 4H), 7.45 (m, 6H), 7.25
(d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 5.5 (m, 1H), 5.3 (m, 1H), 4.5–4.4 (m,
4H), 4.25 (s, 2H), 3.78 (s, 3H), 3.44 (m, 1H), 1.6–1.4 (m, 6H), 1.18 (d, J = 6.0 Hz,
3H), 1.0 (s, 9H), 0.88 (s, 9H), 0.1 (s, 6H).
½ ꢁ +92.1 (c 0.3, CHCl3).
a 2D5
29. 1H NMR of (+)-Chloriolide (400 MHz, CDCl3), d: 7.15 (dd, J = 15.8, 2.6 Hz, 1H),
6.12 (dd, J = 15.8, 2.6 Hz, 1H), 5.7–5.5 (m, 2H), 5.22 (m, 1H), 4.78 (m, 1H), 4.55
(m, 1H), 1.82–1.25 (m, 6H), 1.32 (d, J = 6.4 Hz, 3H).
13C NMR (100 MHz), d: 159.05, 136.09, 135.95, 134.64, 134.12, 134.03, 131.26,
129.82, 129.76, 129.13, 128.32, 127.66, 127.50, 113.77, 83.78, 83.63, 74.61,
70.04, 69.43, 58.17, 55.29, 51.65, 38.18, 36.60, 26.97, 25.81, 20.96, 19.63, 19.28,
18.24, ꢀ5.13.
13C NMR (100 MHz), d: 167.0, 152.7, 140.4, 126.9, 119.6, 74.2, 69.8, 68.3, 36.8,
34.5, 21.5, 19.7.
½
a 2D5
ꢁ
+105.9 (c 0.2, CHCl3). Lit ½a D25
ꢁ
+107.0 (c 0.2, CHCl3).
½ ꢁ +77.2 (c 0.4, CHCl3).
a 2D5