Stereoselective synthesis of macrosphelide i

Article abstract of DOI:10.1055/s-0033-1338657

An efficient total synthesis of macrosphelide I, has been achieved starting from commercially available chiral materials, ethyl (S)-lactate and methyl (R)-3-hydroxybutyrate. Titanium(IV) promoted the regioselective nucleophilic opening reaction of epoxy a

Full text of DOI:10.1055/s-0033-1338657

LETTER
▌2039
lSettteer reoselective Synthesis of Macrosphelide I
Stereoselective Synthesis of Macrosphelide I
Bacchu Veena,* Gangavaram V. M. Sharma
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR, Indian Institute of Chemical Technology, Hyderabad
500007, India
Fax +91(40)27160387; E-mail: bveena9@gmail.com
Received: 02.05.2014; Accepted after revision: 31.05.2014
1 by using regioselective opening of an epoxy alcohol and
Abstract: An efficient total synthesis of macrosphelide I, has been
ring-closing metathesis as the key steps.
achieved starting from commercially available chiral materials, eth-
yl (S)-lactate and methyl (R)-3-hydroxybutyrate. Titanium(IV) pro-
moted the regioselective nucleophilic opening reaction of epoxy
alcohol with benzoic acid, Sharpless epoxidation, ring-closing me-
18
O
OH
tathesis and Yamaguchi esterification as key steps for the construc-
tion of the 16-membered macrotriolide.
12
13
11
9
O
8
7
10
HO
6
O
Key words: macrosphelide I, regioselective opening, Yamaguchi
esterification, ring-closing metathesis
14
5
1
3
15
O
O
O
17
2
16
Figure 1 Macrosphelide I (1)
The interesting biological properties and complex molec-
ular architecture of the macrosphelides have attracted the
attention of organic chemists.1 Macrosphelides A–L are
unique 16-membered macrocyclic trislactones that were
isolated from various natural sources.2 Macrosphelides
A–L showed activity as inhibitors of the adhesion of HL-
60 cells to a monolayer of LPS-activated human-umbili-
cal-vein endothelial cells and this class of macrotriolides
has attracted attention as lead compounds for the develop-
ment of novel anticancer drugs.1,2
The retrosynthetic analysis of 1 is presented in Scheme 1.
Macrocyclization of 2 was envisaged to give 1, while the
bisolefin 2 was proposed to be available from alcohol 3
and acid 4. Alcohol 3 was in turn envisaged to be derived
from 5 and 6, with both fragments being formed from 7 as
a common starting material. Thus, the main synthetic
strategy involves regioselective nucleophilic opening of
an epoxy alcohol, RCM-mediated macrocyclization and
Yamaguchi esterification.
Macrosphelide I (1; Figure 1) is a 16-membered trislac-
tone, isolated from a strain of Periconia byssoides by the
Numata group.3 It was found to be cytotoxic against P388
lymphocytic leukaemia cells and HL-60 cell in vitro while
its ED50 was found to be 20 μg cm–1 against P388 cells.
The stereochemistry of 1 was confirmed by spectroscopic
analysis.3 Prior to this work there has been only one ap-
proach to the synthesis of macrosphelide I (1) reported in
the literature.4 In continuation of our interest in the syn-
thesis of macrolides,5 we herein describe the synthesis of
The macrosphelide I, fragment 5, with two contiguous ste-
reogenic centers and an ester group correlating to C(11)–
O(16), and 6, with two stereogenic centers correlating to
the C(6)–O(10) unit of macrosphelide I (1) were obtained
from ethyl L-(+)-lactate, which provided one stereogenic
center. The other stereocenter was created by a regioselec-
tive nucleophilic opening reaction of an epoxy alcohol
with benzoic acid.6 Fragment 4, which constitutes the
O
O
OMEM
OMEM
O
O
PMBO
TBSO
TBSO
O
1
3
+
OH
4
O
O
O
OH
3
2
OPMB
O
OPMB
OH
OEt
+
O
OBz
OBz
O
5
6
7
Scheme 1 Retrosynthesis of macrosphelide I (1)
SYNLETT 2014, 25, 2039–2043
Advanced online publication: 16.07.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338657; Art ID: st-2014-d0371-l
© Georg Thieme Verlag Stuttgart · New York

2040
B. Veena, G. V. Sharma
LETTER
OPMB
a
OPMB
ref . 2
O
OH
8
O
7
OPMB
O
O
c
OBz
10
PMBO
H
PMBO
OH
OPMB
b
d
e
OH
OH
O
H
OBz
OBz
9
9a
6
OPMB
OBz
O
OPMB
f
CHO
OEt
OBz
5
9b
Scheme 2 Reagents and conditions: (a) (–)-DIPT, Ti(Oi-Pr)4, TBHP, 4 Å MS, CH2Cl2, –20 °C, 12 h, 88%; (b) Ti(Oi-Pr)4, benzoic acid,
CH2Cl2, 0 °C to r.t., 2 h; (c) 2,2-DMP, cat. PTSA, 0 °C to r.t., 2 h (83% in two steps); (d) Ph3P, I2, imidazole, CH2Cl2, 0 °C to r.t., 4 h, (68% in
two steps); (e) NaIO4, acetone–H2O, 0 °C to r.t., 1 h; (f) Ph3P=CHCOOEt, benzene, reflux, 2 h, (77% in three steps).
C(1)–O(4) unit of macrosphelide I (1), was prepared from temperature for 30 minutes furnished alcohol 129 in 84%
(R)-3-hydroxybutyrate 16.
yield.
According to the synthetic strategy, the known allylic al-
cohol 87 was subjected to Sharpless epoxidation on treat-
ment with (–)-DIPT, Ti(Oi-Pr)4 and TBHP in anhydrous
CH2Cl2 at –20 °C for 12 hours to furnish epoxide 9 in 88%
yield (Scheme 2).
OPMB
OH
OPMB
a, b
c
OR
OMEM
12
OBz
6
11a R = H
11b R = MEM
Regioselective ring opening of the epoxide 9 with benzoic
acid and Ti(Oi-Pr)4 in anhydrous CH2Cl2 at room temper-
ature for 24 hours afforded the 1,2-diol as the exclusive
product. In order to overcome difficulties in separation of
the diol from the reaction mixture (as the epoxide and diol
have the same Rf value) and to verify whether the ring
opening of the epoxy alcohol had favored the formation of
the 1,2-diol or 1,3-diol, the crude diol was converted into
10.
Scheme 3 Reagents and conditions: (a) K2CO3, MeOH, r.t., 1 h,
89%; (b) MEMCl, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 12 h, 76%;
(c) DDQ, CH2Cl2, 0 °C to r.t., 84%.
Benzoate 5 on mild base hydrolysis with K2CO3 in MeOH
at room temperature for one hour gave alcohol 13a in 78%
yield (Scheme 4). Treatment of 13a with TBSCl and im-
idazole in CH2Cl2 at room temperature for two hours gave
13b in 86% yield.
Thus, treatment of 9a with 2,2-dimethoxypropane and
PTSA in CH2Cl2 at 0 °C to room temperature for two
hours gave 10 in 83% of overall yield. Diol 9a was used
as common intermediate for the synthesis of 5 and 6. Ac-
cordingly, diol 9a, on treatment with Ph3P, imidazole and
OPMB
O
OPMB
O
a, b
c
OEt
OEt
OBz
OR
8
I2 at room temperature for four hours gave olefin 6 in
5
13a R = H
13b R = TBS
68% yield (Scheme 2). Equally, diol 9a, on oxidative
cleavage with NaIO4 in acetone/water at room tempera-
ture for one hour, gave the corresponding aldehyde 9b,
which on subsequent treatment with (ethoxycarbonyl-
methylene)triphenyl phosphorane in benzene at reflux for
two hours afforded 5 in 77% yield.
OPMB
O
OPMB
O
d
OH
OEt
OTBS
15
OTBS
14
Scheme 4 Reagents and conditions: (a) K2CO3, MeOH, r.t., 1 h,
78%; (b) TBSCl, imidazole, CH2Cl2, 0 °C to r.t., 2 h, 86%; (c) PtO2,
H2, EtOAc, r.t., 3 h, 88%; (d) LiOH, THF–MeOH–H2O (3:1:1), r.t.,
3 h, 89%.
Base hydrolysis of benzoate 6 with K2CO3 in MeOH at
room temperature for one hour afforded the allyl alcohol
11a5f in 89% yield. Further, treatment of 11a with MEMCl
and DIPEA in CH2Cl2 at room temperature for 12 hours
gave 11b in 76% yield (Scheme 3). Finally, oxidative de-
protection of 11 with DDQ in CH2Cl2 and H2O at room
Subsequently, catalytic hydrogenation of 13 with PtO2 in
EtOAc under hydrogen atmosphere at room temperature
Synlett 2014, 25, 2039–2043
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of Macrosphelide I
2041
for three hours gave 14 in 88% yield. Ester 14, on hydro- minutes furnished the bisolefin 2 in 80% yield. Bisolefin
lysis with LiOH in THF–MeOH–H2O (3:1:1) at room 2 on macrocyclization by RCM reaction in the presence of
temperature for three hours, afforded acid 15 in 89% Grubbs II catalyst12 (5 mol%) in CH2Cl2 at reflux for 18
yield.
hours gave 21 in 74% yield (Scheme 6).
Having synthesized 12 and 15, the next goal was the syn- Reaction of 21 with CF3COOH in CH2Cl2 at room temper-
thesis of 4. Accordingly, commercially available methyl ature for 24 hours afforded 1 in 67% yield (Scheme 6).
(R)-3-hydroxybutyrate (16), on reaction with p-methoxy- The specific rotation value of the synthetic 1 {[α]22D +12.4
benzyl trichloroacetimidate and PTSA (cat.) in CH2Cl2, (c = 0.09, CHCl3)}, was in good accordance with that of
gave 17 in 72% yield (Scheme 5). Hydrolysis of ester 17 the natural product {[α]22D +10.3 (c = 0.31, EtOH)}.3 The
with LiOH in THF–MeOH–H2O (3:1:1) at room temper- IR, mass, 1H NMR and 13C NMR data of the synthetic ma-
ature for three hours afforded acid 410 in 82% yield crosphelide I (1)13 were also in good accordance with
(Scheme 5).
those of the natural product.3
In conclusion, the synthesis of macrosphelide I (1)3 has
been achieved from ethyl L-(+)-lactate (7) and methyl (R)-
3-hydroxybutyrate (16), wherein the required stereo-
chemical configurations at C-8 and C-14 were successful-
ly secured by using regioselective nucleophilic opening
reaction of an epoxy alcohol with benzoic acid. The
Yamaguchi protocol was quite efficient for the triester
formation, while, the triester bisolefin was very effective-
ly transformed into the target natural product 1 using a
RCM method under Grubbs’ reaction conditions.
OH
O
O
O
PMBO
PMBO
b
a
OMe
OMe
OH
16
17
4
Scheme 5 Reagents and conditions: (a) PMBOC(=NH)Cl3, PTSA,
CH2Cl2, 0 °C to r.t., 72%; (b) LiOH, THF–MeOH–H2O (3:1:1), r.t.,
3 h, 82%.
Having synthesized all the three fragments 12, 15 and 4,
our next aim was their further conversion into the macro-
sphelide I (1) core structure. Accordingly, coupling of
acid 15 with alcohol 12 was achieved using Yamaguchi
esterification11 conditions in the presence of 2,4,6-trichlo-
robenzoyl chloride and Et3N in THF through the anhy-
dride prepared from 15 in the presence of DMAP in
toluene to afford ester 18 in 73% yield (Scheme 6). Ester
18 on oxidative deprotection with DDQ in aqueous
CH2Cl2 gave alcohol 3 in 82% yield.
Acknowledgment
B.V. thanks the CSIR, New Delhi, for financial support in the form
of a fellowship.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
Yamaguchi esterification of acid 4 with alcohol 3 by the
use of 2,4,6-trichlorobenzoyl chloride and Et3N in THF in
the presence of DMAP in toluene afforded ester 19 in 62%
yield. Reaction of 19 with DDQ in aqueous CH2Cl2 at
room temperature for one hour furnished alcohol 20 in
88% yield and esterification of alcohol 20 with acryloyl
chloride and DIPEA in CH2Cl2 at room temperature for 40
References and Notes
(1) (a) Nakumara, H.; Ono, M.; Shida, Y.; Akita, H.
Tetrahedron: Asymmetry 2002, 13, 703. (b) Kobayashi, Y.;
Wang, Y. G. Tetrahedron Lett. 2002, 43, 4381. (c) Akita, H.;
Nakamura, H.; Ono, M. Chirality 2003, 15, 352.
(d) Kawaguchi, T.; Funamori, N.; Matsuya, Y.; Nemoto, H.
O
O
OMEM
O
OMEM
O
4, c, d
e
a, b
15
+ 12
TBSO
TBSO
O
O
OR
OR
19 R = PMB
20 R = H
18 R = PMB
3 R = H
O
O
O
O
O
O
O
OMEM
O
OH
OMEM
O
O
O
g
f
TBSO
HO
TBSO
O
O
O
O
O
O
O
21
1
2
Scheme 6 Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 2 h, DMAP, toluene, 0 °C to r.t., 5 h, 73%; (b) DDQ,
CH2Cl2–H2O (19:1), 0 °C to r.t., 1 h, 82%; (c) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 2 h, then alcohol 3, DMAP, toluene, 0 °C to r.t., 5
h, 62%; (d) DDQ, CH2Cl2–H2O (19:1), 0 °C to r.t., 1 h, 88%; (e) acryloyl chloride, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 40 min, 80%; (f) Grubbs
II, CH2Cl2, reflux, 18 h, 74%; (g) TFA, CH2Cl2, 0 °C, 24 h, 67%.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2039–2043

2042
B. Veena, G. V. Sharma
LETTER
J. Org. Chem. 2004, 69, 505. (e) Matsuya, Y.; Nemoto, H.
Heterocycles 2005, 65, 1741.
7.27 (m, 2 H, ArH), 6.81 (d, J = 8.4 Hz, 2 H, ArH), 5.93–
6.05 (m, 1 H, =CH), 5.59–5.62 (m, 1 H, CHOBz), 5.29–5.41
(m, 2 H, =CH2), 4.60 (dd, J = 11.3 Hz, 2 H, CH2Ar), 3.74–
(2) (a) Hayashi, M.; Kim, Y. P.; Hiraoka, H.; Natori, M.;
Takamatsu, S.; Kawakubo, T.; Masuma, R.; Komiyama, K.
S.; Omura, S. J. Antibiot. 1995, 48, 1435. (b) Takamatsu, S.;
Kim, Y. P.; Hayashi, M.; Hiraoka, H.; Natori, M.;
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(c) Takamatsu, S.; Hiraoka, H.; Kim, Y. P.; Hayashi, M.;
Natori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1997, 50,
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Minoura, K.; Numata, A.; Kobayashi, Y.; Wang, Y. G.
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Heterocycles 2010, 81, 57.
3.85 (m, 4 H, OCH, OMe), 1.25 (d, J = 6.4 Hz, 3 H, Me). 13
NMR (75 MHz, CDCl3): δ = 165.5, 159.1, 132.9, 130.4,
129.6, 129.2, 128.3, 118.3, 113.7, 76.5, 75.4, 70.8, 55.1,
C
15.8. IR (neat): 3396, 3067, 2967, 2969, 1721, 1597, 1453,
1279, 1113 cm–1. HRMS: m/z [M + Na]+ calcd for
C20H22O4Na: 349.1416; found: 349.3761.
(4R,5S)-4-(tert-Butyldimethylsilyloxy)-5-(4-methoxy-
benzyloxy)hexanoic Acid (15): colorless oil; [α]D25 +44.6 (c
= 1.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J =
7.9 Hz, 2 H, ArH), 6.85 (d, 2 H, J = 8.4 Hz, ArH), 4.48 (dd,
J = 11.3 Hz, 2 H, CH2Ar), 3.79 (s, 3 H, OMe), 3.67–3.71 (m,
1 H, OCH), 3.38–3.44 (m, 1 H, OCH), 2.36–2.44 (m, 2 H,
CH2CO), 1.88–1.96 (m, 1 H, CH), 1.75–1.82 (m, 1 H, CH),
1.16 (d, J = 6.4 Hz, 3 H, Me), 0.89 (br s, 9 H, 3 × Me), 0.05
(s, 6 H, 2 × Me). 13C NMR (75 MHz, CDCl3): δ = 159.0,
130.7, 129.2, 113.7, 76.9, 74.1, 70.6, 60.2, 55.2, 29.4, 27.8,
25.9 (3 × C), 18.1, 15.6, –4.2, –4.6. IR (neat): 3031, 2930,
2857, 1710, 1097 cm–1. HRMS: m/z [M + Na]+ calcd for
C20H34O5NaSi: 405.2091; found: 405.2073.
(3) (a) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.;
Matusumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett.
1997, 38, 8215. (b) Yamada, T.; Iritani, M.; Doi, M.;
Minoura, K.; Ito, T.; Numata, A. J. Chem. Soc., Perkin
Trans. 1 2001, 3046.
(4) Sharma, G. V. M.; Veera Babu, K. Tetrahedron: Asymmetry
2007, 18, 2175.
(5) (a) Sharma, G. V. M.; Chandra Mouli, C. Tetrahedron Lett.
2002, 43, 9159. (b) Sharma, G. V. M.; Chandra Mouli, C.
Tetrahedron Lett. 2003, 44, 8161. (c) Sharma, G. V.M.;
Reddy, C. G. Tetrahedron Lett. 2004, 45, 7483. (d) Sharma,
G. V. M.; Reddy, J. J.; Reddy, K. L. Tetrahedron Lett. 2006,
47, 6531. (e) Sharma, G. V. M.; Reddy, K. L.; Reddy, J. J.
Tetrahedron Lett. 2006, 47, 6537. (f) Sharma, G. V. M.;
Reddy, P. S. Eur. J. Org. Chem. 2012, 2414.
(6) (a) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50,
1557. (b) Moreno, M.; Riera, A. Molecules 2010, 15, 1041.
(c) Krishna, R. P.; Ramana, V. D. J. Org. Chem. 2012, 77,
674.
(4R,5S)-{(2S,3R)-3-[(2-Methoxyethoxy)methoxy]pent-4-
en-2-yl}-4-(tert-butyldimethylsilyloxy)-5-hydroxy-
hexanoate (3): colorless liquid; [α]D25 –145.0 (c = 0.65,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.68–5.74 (m, 1
H, =CH=CH2), 5.30 (d, J = 12.5 Hz, 2 H, =CH2), 5.00–5.05
(m, 1 H, CHCO), 4.69–4.76 (m, 2 H, OCH2), 4.07–4.11 (m,
1 H, OCH), 3.76–3.83 (m, 1 H, OCH), 3.71–3.72 (m, 1 H,
OCH), 3.60–3.68 (m, 2 H, OCH2), 3.54–3.56 (m, 2 H,
OCH2), 3.39 (s, 3 H, OMe), 2.42–2.50 (m, 1 H, CHC=O),
2.28–2.35 (m, 1 H, CHCO), 1.84–1.91 (m, 1 H, CH), 1.71–
1.78 (m, 1 H, CH), 1.23 (d, J = 6.5 Hz, 3 H, Me), 1.13 (d,
J = 6.5 Hz, 3 H, Me), 0.91 (s, 9 H, 3 × Me), 0.09 (s, 6 H, 2 ×
Me). 13C NMR (75 MHz, CDCl3): δ = 173.3, 133.9, 119.7,
92.8, 78.7, 74.9, 71.6 (2 × C), 69.8, 66.9, 58.9, 29.8, 25.8 (3
× C), 25.6, 18.0, 17.7, 15.3, –4.5 (2 × C). IR (neat): 3430,
2957, 2930, 2856, 1719, 1654, 1465 cm–1. HRMS: m/z [M +
Na]+ calcd for C21H42O7NaSi: 457.2592; found: 457.2590.
(4R,5S)-{(2S,3R)-3-[(2-Methoxyethoxy)methoxy]pent-4-
en-2-yl}-4-(tert-butyldimethylsilyloxy)-5-[(R)-3-
hydroxybutanoyloxy]hexanoate (20): colorless liquid;
[α]D25 –127.8(c = 0.5, CHCl3). 1H NMR (500 MHz, CDCl3):
δ = 5.63–5.77 (m, 1 H, CH=CH2), 5.25–5.33 (m, 2 H, =CH2),
4.98–5.05 (m, 1 H, CHCO), 4.85–4.93 (m, 1 H, CHCO),
4.77 (d, J = 6.7 Hz, 1 H, OCH), 4.67 (d, J = 6.7 Hz, 2 H,
OCH2), 4.14–4.26 (m, 2 H, OCH2), 4.04–4.15 (m, 2 H,
OCH2), 3.70–3.98 (m, 2 H, OCH2), 3.58–3.67 (m, 1 H,
OCH), 3.51–3.58 (m, 1 H, OCH), 3.39 (s, 3 H, OMe), 3.07–
3.13 (m, 1 H, OCH), 2.29–2.48 (m, 4 H, CH2CO, CH2CO),
1.73–1.83 (m, 2 H, CH2), 1.17–1.26 (m, 9 H, 3 × Me), 0.89
(s, 9 H, 3 × Me), 0.05 (s, 6 H, 2 × Me). 13C NMR (75 MHz,
CDCl3): δ = 172.7, 172.1, 133.9, 129.1, 119.8, 92.8, 78.7,
73.2, 72.9, 71.6 (2 × C), 66.9, 64.1, 59.0, 43.1, 30.1, 28.0,
25.8 (3 × C), 22.3, 18.1, 15.4, 14.6, –4.4, –4.6. IR (neat):
3352, 2983, 2842, 1719, 1654, 1553, 1402 cm–1. HRMS: m/z
[M + Na]+ calcd for C25H48O9NaSi: 543.2959; found:
543.2963.
(7) Sabitha, G.; Nayak, S.; Bhikshapathi, M.; Maruthi, C.;
Yadav, J. S. Synthesis 2011, 3661.
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8780. (b) Donglu, B.; Li, S.; Xu, R. Tetrahedron Lett. 2000,
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S.; Toshiaki, S. Angew. Chem. Int. Ed. 2003, 42, 5230.
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M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
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1999, 1, 953. (b) Love, J. A.; Sanford, M. S.; Day, M. W.;
Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 10103.
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(13) Spectroscopic Data for Selected Compounds:
(2S,3R,E)-6-Ethoxy-2-(4-methoxybenzyloxy)-6-oxohex-
4-en-3-ylbenzoate (5): yellow syrup; [α]D25 +91.7 (c = 0.25,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 7.7
Hz, 2 H, ArH), 7.58 (t, J = 7.7 Hz, 1 H, ArH), 7.46 (t, J = 7.7
Hz, 2 H, ArH), 7.23–7.25 (m, 3 H, ArH), 7.04 (dd, J = 5.0,
15.5 Hz, 1 H, ArH), 6.82 (d, J = 8.6 Hz, 2 H, =CH), 6.04 (d,
J = 16.0 Hz, 1 H, =CH), 5.77–5.78 (m, 1 H, OCHBz), 4.55
(dd, J = 11.4 Hz, 2 H, CH2Ar), 4.19 (q, J = 6.8 Hz, 2 H,
OCH), 3.76–3.84 (m, 4 H, OCH2, OCH2), 1.21–1.33 (m, 6 H,
2 × Me). 13C NMR (75 MHz, CDCl3): δ = 165.7, 165.3,
159.2, 142.2, 133.2, 130.0, 129.7, 129.3, 128.4, 123.0,
113.7, 75.0, 74.6, 70.9, 60.5, 55.1, 15.9, 14.1. IR (neat):
3396, 3032, 2941, 1721, 1453, 1112 cm–1. HRMS: m/z [M +
Na]+ calcd for C23H26O6Na: 421.1652; found: 421.4387.
(3R,4S)-4-(4-Methoxybenzyloxy)pent-1-en-3-ylbenzoate
(6): colorless syrup; [α]D25 +43.7 (c = 1.5, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 8.06 (d, J = 6.9 Hz, 2 H, ArH), 7.57
(t, J = 7.1 Hz, 1 H, ArH), 7.42–7.47 (m, 2 H, ArH), 7.25–
(4R,9R,10S,15R,16S,E)-15-(tert-Butyldimethylsilyloxy)-
9-[(2-methoxyethoxy)methoxy]-4,10,16-trimethyl-
1,5,11-trioxacyclohexadec-7-ene-2,6,12-trione (21):
yellow liquid; [α]D25 –84.0(c = 0.45, CHCl3). 1H NMR (500
MHz, CDCl3): δ = 6.77 (dd, J = 6.9, 15.4 Hz, 1 H, CH=CH),
6.02 (dd, J = 15.4 Hz, 1 H, CH=CH), 5.23–5.29 (m, 1 H,
CHCO), 5.07–5.12 (m, 1 H, CHCO), 4.80–4.86 (m, 1 H,
CHCO), 4.69 (dd, J = 16.9 Hz, 2 H, OCH2), 4.19–4.21 (m, 1
H, OCH), 3.74–3.78 (m, 1 H, OCH), 3.61–3.67 (m, 2 H,
Synlett 2014, 25, 2039–2043
© Georg Thieme Verlag Stuttgart · New York

LETTER
OCH2), 3.53–3.54 (m, 2 H, OCH2), 3.38 (s, 3 H, OMe), 2.74
Stereoselective Synthesis of Macrosphelide I
2043
Macrosphelide I (1): colorless syrup; [α]D25 +12.4 (c = 0.09,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.18 (d, J = 6.6 Hz,
3 H, Me), 1.32 (d, J = 6.6 Hz, 3 H, Me), 1.46–1.47 (m, 1 H,
CH), 1.47 (d, J = 6.6 Hz, 3 H, Me), 1.68–1.74 (m, 1 H, CH),
2.36 (dt, J = 5.1, 14.7 Hz, 1 H, CH), 2.53 (br s, 1 H, OH),
2.62–2.68 (m, 2 H, CH2), 2.70 (dd, J = 2.9, 16.1 Hz, 1 H,
CH), 3.25 (d, J = 11.4 Hz, 1 H, CH), 3.83 (br s, 1 H, OH),
4.29 (br s, 1 H, CH), 4.83–4.87 (m, 2 H, 2 × CH), 5.65 (m, 1
H, CH), 6.24 (dd, J = 2.2, 15.4 Hz, 1 H, HC=CH), 7.21 (dd,
J = 2.9, 15.4 Hz, 1 H, CH=CH). 13C NMR (150 MHz,
CDCl3): δ = 12.70, 18.60, 20.10, 27.50, 30.40, 41.80, 67.00,
71.10, 74.40, 74.80, 78.30, 121.90, 147.80, 166.90, 168.60,
175.30. IR (neat): 3447, 2925, 1628 cm–1. HRMS: m/z [M +
Na]+ calcd for C16H24O8Na: 367.1368; found: 367.1383.
(dd, J = 3.9, 14.4 Hz, 1 H, =CHCH), 2.53 (dd, J = 6.4, 14.9
Hz, 1 H, =CHCH), 2.29–2.44 (m, 2 H, =CHCH2), 1.55–1.79
(m, 2 H, CH2), 1.43 (d, J = 6.4 Hz, 3 H, Me), 1.30 (d, J = 6.4
Hz, 3 H, Me), 1.17 (d, J = 6.4 Hz, 3 H, Me), 0.88 (s, 9 H, 3
× Me), 0.07 (d, J = 15.4 Hz, 6 H, 2 × Me). 13C NMR (75
MHz, CDCl3): δ = 172.2, 169.3, 164.6, 143.0, 125.0, 93.3,
77.5, 73.7, 73.1, 71.5, 71.1, 67.5, 67.2, 59.0, 40.5, 30.7, 29.6,
28.3, 25.7 (3 × C), 19.5, 17.3, 15.5, –4.4, –4.6. IR (neat):
2856, 1734, 1657, 1615, 1517, 1466, 1093 cm–1. HRMS: m/z
[M + Na]+ calcd for C26H46O10NaSi: 569.2752; found:
569.2763.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2039–2043

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