Enantioselective total synthesis of macrosphelides A and e

Article abstract of DOI:10.1016/j.tet.2011.04.099

Enantioselective synthesis of 16-membered trilactone macrolides, macrosphelide A and E from (S)-lactic acid is described. Key features of the synthesis include the utility of a hitherto unexplored β-ketophosphonate derived from lactic acid and Yamaguchi lactonization leading to the title compounds.

Full text of DOI:10.1016/j.tet.2011.04.099

Tetrahedron 67 (2011) 4514e4520
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Enantioselective total synthesis of macrosphelides A and E
*
Kavirayani R. Prasad , Phaneendra Gutala
Department of Organic Chemistry, Indian Institute of Science, Sir C.V. Raman Avenue, Bangalore 560 012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective synthesis of 16-membered trilactone macrolides, macrosphelide A and E from (S)-lactic
Received 8 February 2011
Received in revised form 21 April 2011
Accepted 28 April 2011
acid is described. Key features of the synthesis include the utility of a hitherto unexplored
phosphonate derived from lactic acid and Yamaguchi lactonization leading to the title compounds.
b-keto-
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 5 May 2011
Keywords:
Total synthesis
Macrolactone
Lactic acid
Macrosphelides
1. Introduction
O
O
Me
9
O
O
Me
9
OH
OH
O
O
Macrosphelides AeM are a class of 16-membered trilactones
isolated from a culture broth of Microsphaeropsis sp. FO-5050 and
from the strain Periconia byssoides.1 Macrosphelide A 1a, is reported
to inhibit the adhesion of human leukemia HL-60 cells to human-
umbilical-vein endothelial cells. The adhesion of tumor cells ap-
parently is the crucial step in tumor metastasis and 1a is found to be
orally active against lung metastasis of B16/BL6 melanoma in mice
(50 mg/kg) without being toxic to normal mammalian cells.1a
Macrosphelide E 1b is structurally similar to macrosphelide A 1a
and is epimeric at the third position (Fig. 1). Recently, hybrid struc-
tures based on macrosphelides have also been shown to exhibit
potent apoptosis-inducing activity toward human lymphoma cells.2
Owing to the diverse bio-activity of the macrosphelides, they are
considered as good lead compounds for anti-cancer drug
development.
HO
Me
HO
Me
Me
Me
O
3
O
O
O
3
O
O
macrosphelide A 1a
macrosphelide E 1b
Fig. 1. Macrosphelides A and E.
OPG
O
OPG
OMe
OMe
Me
OAllyl
Me
P
O
O
Me
OH
O
4
OH
2
O
8
14
HO
Me
O
1
Me
+
3
O
O
O
OH
Several approaches for the synthesis of 1a and 1b have been
reported, which mainly rely on either asymmetric dihydroxylation
or modification of lactic acid or carbohydrates for the source of
chirality.3 Herein, we report a concise and facile synthesis of mac-
rosphelides A and E from (S)-lactic acid. Our approach (Scheme 1) is
O
1
Me
OPG
1a
OEt
Me
HO
O
3
5
Scheme 1. Retrosynthesis for macrosphelide A.
based on the elaboration of b-ketophosphonate 4, which is easily
derived from (S)-lactic acid. Synthesis of the key orthogonally
protected diol acid fragment 2 is expected from WittigeHorner
2. Results and discussion
homologation of
transformations.
4
with allylglyoxalate and subsequent
Our synthetic sequence commenced with addition of the lith-
ium anion generated from dimethyl methylphosphonate to ethyl-
(S)-trityloxy lactate 64 to afford the
b
-ketophosphonate 7 in 89%
yield. Treatment of the phosphonate 7 with allylglyoxalate5 under
mild basic conditions afforded the -unsaturated esters (E)-8 and
* Corresponding author. Fax: þ91 8023600529; e-mail address: prasad@org-
chem.iisc.ernet.in (K.R. Prasad).
a,b
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.099

K.R. Prasad, P. Gutala / Tetrahedron 67 (2011) 4514e4520
4515
(Z)-8 in 75% and 19% yields, respectively, which were separated on
silica gel column chromatography. Reduction of 8 with NaBH4 in
MeOH produced a separable mixture of diastereomeric alcohols 9
and 10 in 60:40 ratio, while reduction with NaBH4/CeCl3 increased
the ratio to 67:33. Employing either LiBH4 or Zn(BH4)2 as the re-
ducing agent furnished the alcohols in 55:45 ratio.6 All these results
are summarized in Table 1. Mitsunobu inversion7 of 9 furnished the
p-nitrobenzoate of 10, which was treated with K2CO3 in presence of
allyl alcohol to give 10 in 88% yield for two steps, thus enabling an
efficient sequence for the synthesis of 10 (Scheme 2).
by Paek et al.3k allyl ester 18a was transformed into the free acid 19a8
by reaction with Pd(PPh3)4, which on Yamaguchi lactonization fur-
nished the macro trilactone 20a in 70% yield (for two steps). Final
deprotection of the MOM ethers to the corresponding hydroxy
groups was accomplished by treating 20a with TFA resulting in
macrosphelide A 1a in 88% yield. The spectral data of 1a is identical
to that reported for the natural product in literature (Scheme 4).1a
Following the same sequence, synthesis of macrosphelide E was
accomplished from 15 employing (R)-silyloxybutanoic acid
(Scheme 5). The spectral data of 1b is identical to that reported in
literature for the natural product.1e
Table 1
Reduction of 8 with various reducing agents
S. No
Reducing agent
Solvent
Temp
Time
dr 9:10a
3. Conclusions
1
2
3
4
NaBH4
NaBH4/CeCl3
LiBH4
MeOH
MeOH
THF
ꢀ50 ꢁC
ꢀ40 ꢁC
ꢀ78 ꢁC
ꢀ78 ꢁC
1 h
2 h
1 h
3 h
60:40
67:33
55:45
55:45
In conclusion, a facile strategy for the synthesis of macro-
sphelides A and E is presented from (S)-ethyl lactate in almost 19%
overall yield via the corresponding b-ketophosphonate. The pro-
cedure is operationally simple, high yielding and is amenable for
the synthesis of a number of analogues.
Zn (BH4)2
THF
a
Diastereomeric ratio was estimated by 1H NMR.
OTr
OTr
MeP(O)(OMe)2
n-BuLi/THF,
−78 °C to rt, 1 h
89%
allyl glyoxalate/ Cs2CO3
OMe
OEt
Me
Me
Me
P
O
MeCN :THF, −15 °C, 30 min
OMe
O
6
O
75%
7
Tr = trityl
OTr
O
OTr
O
OTr
O
NaBH4/CeCl3, MeOH
−40 °C, 2 h, 96%
Me
Me
Oallyl
Oallyl +
Oallyl
OH
10 (32%)
OH
9 (64%)
O
8
i) PPh3, DIAD, PNBA
THF, 0 °C to rt, 1 h, 90%
ii) K2CO3, allyl alcohol
rt, 2 h, 98%
Scheme 2. Synthesis of 10.
Allyl ester 10 served as the key unit for the synthesis of the
required acid 12 and alcohol 13 fragments. The free hydroxy group
in 10 was protected as the MOM ether 11, which on saponification
with NaOH resulted in the free acid 12 in 94% yield, while reaction
with amberlyst resin produced the alcohol 13 in 91% yield
(Scheme 3).
4. Experimental section
4.1. General procedures
Column chromatography was performed on silica gel, Acme grade
100e200 mesh. TLC plates were visualized either with UV, in an
OTr
O
MeOH:THF (3:1)
0.5N NaOH, rt
3 h, 94%
Me
Me
OH
OMOM
12
OTr
O
I
MOMCl/ Pr2NEt
Me
10
Oallyl
DCM, DMAP
rt, 8 h, 93%
OH
O
OMOM
11
Amberlyst
MeOH, rt, 2 h
91%
Oallyl
OMOM
13
Scheme 3. Synthesis of acid and alcohol fragments 12 and 13.
After successfully obtaining the required acid and alcohol units,
DCC coupling of 12 and 13 under standard conditions afforded the
ester 14 in 84% yield. Deprotectionof the trityl group is accomplished
by treating 14 with PPTS in methanol to furnish the diester 15 in 90%
yield. Esterification of the free alcohol in 15 with (S)-silylox-
ybutanoic acid 16a3a produced the ester 17a in 91% yield. Depro-
tection of the silyl group in 17a with PPTS in methanol resulted in the
allyl ester 18a in 89% yield. Following a similar sequence described
iodine chamber, or with phosphomolybdic acid spray, unless noted
otherwise. Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification. THF
was freshly distilled over Na-benzophenoneketyl. Melting points
were uncorrected. Unless stated otherwise, 1H NMR and 13C NMR
spectra were recorded either on a bruker AC400 in CDCl3 as solvent
with TMS as reference unless otherwise indicated. Unless stated
otherwise, all the reactions were performed under inert atmosphere.

4516
K.R. Prasad, P. Gutala / Tetrahedron 67 (2011) 4514e4520
O
Me
O
Me
OMOM
PPTS, MeOH
OMOM
O
O
O
DCC, DMAP
CSA, DCM, rt
3 h, 84%
MOMO
Me
12+13
MOMO
Me
rt, 6 h, 90%
OTr
allylO
O
OH
allylO
Me
14
15
O
O
O
Me
OMOM
OAllyl
OMOM
TBSO
Me
O
O
O
MOMO
Me
MOMO
Me
OH
PPTS/MeOH
rt, 24 h, 89%
O
16a
DCC, DMAP, CSA
DCM, rt, 12 h
91%
O
O
OAllyl
O
O
Me
OTBS
17a
Me
OH
18a
O
Me
O
O
Me
OMOM
OMOM
O
O
2,4,6-trichloro
benzoyl chloride
Et3N, DMAP
tolune, 80 °C
MOMO
Me
MOMO
Me
O
Me
Pd(PPh3)4
morpholine, THF
rt, 14 h
O
HO
OH
O
O
O
O
70% for two steps
20a
Me
19a
O
O
Me
OH
O
HO
Me
TFA, DCM
rt, 5 h, 88%
Me
O
macrosphelide A 1a
O
O
Scheme 4. Synthesis of macrosphelide A.
O
Me
O
Me
OMOM
TBSO
Me
O
O
OMOM
O
O
MOMO
Me
OH
O
16b
PPTS/MeOH
rt, 24 h, 93%
MOMO
Me
DCC, DMAP, CSA
DCM, rt, 12 h
88%
O
O
OAllyl
OH
allylO
Me
Me
17b
OTBS
15
O
O
O
Me
OMOM
OAllyl
OMOM
2,4,6-trichloro
benzoyl chloride
Et3N, DMAP
tolune, 80 °C
O
O
MOMO
Me
MOMO
Me
Pd(PPh3)4
morpholine, THF
rt, 14 h
O
O
O
O
HO
OH
O
70% for two steps
Me
OH
18b
Me
19b
O
Me
O
Me
OH
OMOM
O
O
HO
Me
MOMO
Me
O
Me
TFA, DCM
rt, 5 h, 88%
O
Me
O
macrosphelide E 1b
O
O
O
O
O
20b
Scheme 5. Total synthesis of macrosphelide E.
4.1.1. (S)-Ethyl 2-(trityloxy)propionate (6). To a stirred solution of
chlorotriphenylmethane (1.17 g, 4.25 mmol) and DBU (0.9 mL,
5.92 mmol) in dichloromethane (5 mL), a solution of (S)-ethyl
lactate 5 (0.5 g, 4.25 mmol) in dichloromethane (3 mL) was added
and the reaction mixture was stirred at room temperature for
48 h. After completion of the reaction, the reaction mixture was
poured into ice cold water (10 mL) and extracted with diethyl
ether (3ꢂ20 mL). The combined ether layers were washed with

K.R. Prasad, P. Gutala / Tetrahedron 67 (2011) 4514e4520
4517
brine (2ꢂ10 mL) and dried over Na2SO4. Evaporation of solvent
gave the crude residue, which was purified by silica gel column
at room temperature. The reaction mixture was cooled to ꢀ40 ꢁC,
and NaBH4 (0.12 g, 3.17 mmol) was added portionwise for over
10 min and stirred for 2 h. After completion of the reaction (mon-
itored by TLC), the reaction mixture was quenched by the addition
of water (1 mL) at ꢀ40 ꢁC, slowly allowed to warm up to room
temperature, and stirred for further 30 min. It was then poured into
water (10 mL) and extracted with diethyl ether (3ꢂ20 mL). Com-
bined organic layers were washed with brine (2ꢂ5 mL) and dried
over Na2SO4. Evaporation of solvent followed by silica gel column
chromatography of the resulting residue using petroleum ether/
Et2O (4:1) as eluent furnished 10 (minor isomer, less polar com-
pound) (0.29 g, 32%) as a colorless sticky mass and 9 (major isomer,
chromatography using petroleum ether/Et2O (10:1) to give tri-
24
phenylmethylether (1.25 g, 82%) as a colorless sticky mass. [a]
D
24
ꢀ38.7 (c 2.1, CH2Cl2); lit.4
[a
]
ꢀ37.0 (c 1.0, CH2Cl2); IR (Neat)
D
2983, 1752, 1732, 1491, 1448, 1131, 705 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d 7.51e7.49 (m, 6H), 7.35e7.23 (m, 9H), 4.21 (q, 1H,
J¼6.7 Hz), 3.69 (q, 2H, J¼7.2 Hz), 1.38 (d, 3H, J¼6.7 Hz), 1.06 (t, 3H,
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3)
d 173.5 (Cq), 143.9 (Cq), 129.0
(CH), 127.7 (CH), 127.2 (CH), 87.9 (Cq), 69.7 (CH), 60.2 (CH2), 20.1
(CH3), 13.9 (CH3); HRMS (MþNa) found 383.1650. C24H24O3þNa
requires 383.1623.
more polar compound) (0.58 g, 64%) as a colorless sticky mass.
24
4.1.2. Dimethyl (S)-2-oxo-3-(trityloxy)butylphosphonate (7). To
a THF (5 mL) solution of dimethyl methylphosphonate (0.75 mL,
6.9 mmol) placed in a 50 mL round bottom flask, cooled to ꢀ78 ꢁC,
was added n-BuLi (2.4 mL of a 2.2 M solution in hexanes,
5.28 mmol) drop wise. The reaction mixture was stirred at ꢀ78 ꢁC
for 30 min and a solution of 6 (1.24 g, 3.44 mmol) in THF (10 mL)
was added drop wise and stirred for 1 h. After completion of the
reaction (monitored by TLC), the reaction mixture was cautiously
quenched by the addition of saturated NH4Cl (10 mL). It was then
poured into water (20 mL) and extracted with EtOAc (3ꢂ20 mL).
Combined organic layers were washed with brine (2ꢂ10 mL) and
dried over Na2SO4. Evaporation of solvent followed by silica gel
column chromatography of the resultant residue with diethyl ether
as eluent furnished 7 (1.34 g, 89%) as a colorless sticky mass.
Compound 9: [
a
]
ꢀ42.0 (c 0.9, CHCl3); IR (Neat) 3460, 3058,
D
2855, 1716, 1704, 1652, 1268, 1070, 707 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d
7.49e7.47 (m, 6H), 7.31e7.22 (m, 9H), 6.99 (dd, 1H, J¼15.8,
4.1 Hz), 6.05 (dd, 1H, J¼15.7, 1.5 Hz), 5.93 (ddt, 1H, J¼16.3, 11.0,
5.6 Hz), 5.32 (dd, 1H, J¼17.2, 1.1 Hz), 5.23 (d, 1H, J¼10.4 Hz), 4.63
(d, 2H, J¼5.6 Hz), 3.77 (d, 1H, J¼3.8 Hz), 3.57 (quintet, 1H, J¼6.0 Hz),
2.04 (br s, 1H), 0.94 (d, 3H, J¼6.2 Hz); 13C NMR (100 MHz, CDCl3)
d
165.9 (Cq),147.5 (CH),144.6 (Cq),132.2 (CH), 128.8 (CH),127.8 (CH),
127.2 (CH), 121.4 (CH), 118.0 (CH2), 87.2 (Cq), 73.4 (CH), 72.6 (CH),
65.0 (CH2), 16.8 (CH3); HRMS (MþNa) found 451.1889.
C28H28O4þNa requires 451.1885.
Compound 10: [
a
]
24 þ25.7 (c 2.3, CHCl3); IR (Neat) 3469, 3086,
D
2934, 1719, 1656, 1490, 931 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.52e7.50 (m, 6H), 7.33e7.24 (m, 9H), 6.60 (dd, 1H, J¼15.7, 4.1 Hz),
[
a]
24 ꢀ25.3 (c 4.0, CHCl3); IR (Neat) 3468, 2955, 1721, 1449, 1056,
5.96e5.86 (m, 2H), 5.30 (d, 1H, J¼17.2 Hz), 5.22 (d, 1H, J¼10.5 Hz)
4.60 (d, 2H, J¼5.5 Hz), 3.81 (dq, 1H, J¼12.6, 2.6 Hz), 3.35 (br s, 1H),
2.31 (br s, 1H),1.04 (d, 3H, J¼6.3 Hz); 13C NMR (100 MHz, CDCl3)
D
706 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.42e7.24 (m, 15H), 4.2
(q,1H, J¼6.9 Hz), 3.69 (d, 3H, J¼11.2 Hz), 3.66 (d, 3H, J¼11.2 Hz), 3.30
(dd, 1H, J¼18.0, 15.6 Hz), 1.74 (dd, 1H, J¼24.0, 15.5 Hz), 1.38 (d, 3H,
d
165.9 (Cq), 146.2 (CH), 144.4 (Cq), 132.1 (CH), 128.7 (CH), 128.0
J¼6.9 Hz); 13C NMR (100 MHz, CDCl3)
d
205.2 (Cq), 143.5 (Cq), 128.9
(CH), 127.4 (CH), 120.6 (CH), 118.1 (CH2), 87.5 (Cq), 72.7 (CH), 72.0
(CH), 65.0 (CH2), 15.3 (CH3).
(CH), 128.1 (CH), 127.6 (CH), 88.2 (Cq), 53.0 (CH3), 52.9 (CH3), 52.7
(CH3), 52.6 (CH3), 34.3 (CH2), 33.0 (CH2), 19.0 (CH3); HRMS (MþNa)
found 461.1493. C25H27O5PþNa requires 461.1494.
4.1.5. Synthesis of 10 from 9. To a pre-cooled (0 ꢁC) solution of
triphenylphosphine (0.7 g, 2.7 mmol), DIAD (0.38 mL, 2 mmol) in
THF, a solution of 9 (0.58 g, 1.35 mmol) in THF was added and
stirred for 10 min at the same temperature. Solid p-nitrobenzoic
acid (0.34 g, 2.7 mmol) was added at once to the reaction mixture
and slowly allowed to warm up to room temperature and stirred for
1 h. After completion of the reaction (monitored by TLC) most of the
solvent was evaporated under vacuum and the residue obtained
was purified by silica gel column chromatography using petroleum
4.1.3. (S,E)-Allyl 4-oxo-5-(trityloxy)hex-2-enoate (8). In a 50 mL
two-neck round bottom flask equipped with Argon balloon was
placed a solution of 7 (1.33 g, 3.04 mmol) in MeCN (5 mL). Solid
Cs2CO3 (1.98 g, 6.08 mmol) was then introduced into the flask and
stirred for 45 min at room temperature. The reaction mixture was
cooled to ꢀ15 ꢁC, and a solution of allylglyoxalate (0.69 g,
6.08 mmol) in MeCN (5 mL) was added drop wise and stirred for
30 min. After completion of the reaction (monitored by TLC), the
reaction mixture was cautiously quenched by the addition of sat-
urated citric acid (10 mL), poured into water (20 mL) and extracted
with diethyl ether (3ꢂ20 mL). Combined organic layers were
washed with brine (2ꢂ10 mL) and dried over Na2SO4. Evaporation
of solvent gave the crude residue, which was purified on silica gel
column chromatography using petroleum ether/Et2O (10:1) as el-
uent to furnish 8 (E-isomer) (0.97 g, 75%) as a colorless sticky mass
and Z-8 (Z-isomer) (0.25 g, 19%) as a colorless sticky mass. E-8:
ether/diethyl ether (5:1) as eluent to give p-nitrobenzoate as
24
a colorless sticky mass (0.7 g, 90%). [
a
]
þ3.1 (c 1.9, CHCl3); IR
(Neat) 3058, 2360, 1727, 1529, 1269, 10D15, 707 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d
8.28 (ABq, 4H, J¼8.8 Hz), 7.49e7.46 (m, 6H),
7.30e7.25 (m, 9H), 6.79 (dd, 1H, J¼15.8, 5.1 Hz), 5.92 (ddt, 1H,
J¼16.3, 11.0, 5.8 Hz), 5.85 (dd, 1H, J¼15.7, 1.3 Hz), 5.32 (dd, 1H,
J¼17.3, 1.3 Hz), 5.25 (d, 1H, J¼10.3 Hz), 5.18e5.17(m, 1H), 4.62 (d, 1H,
J¼5.7 Hz), 3.92 (qd, 1H, J¼6.3, 2.3 Hz), 1.10 (d, 3H, J¼6.4 Hz); 13C
NMR (100 MHz, CDCl3) d 165.1 (Cq), 163.4 (Cq), 150.7 (Cq), 144.3 (Cq),
[
a
]
24 ꢀ93.6 (c 2.6, CHCl3); IR (Neat) 3058, 3024, 2978, 2930, 1726,
142.3 (CH), 135.3 (Cq), 131.8 (CH), 130.8 (CH), 128.9 (CH), 127.8 (CH),
127.3 (CH), 123.7 (CH), 122.5 (CH), 118.6 (CH2), 87.5 (Cq), 77.1 (CH),
70.7 (CH), 65.4 (CH2), 16.5 (CH3); HRMS (MþNa) found 600.1998.
C35H31NO7þNa requires 600.1998.
170D0, 1623, 1364, 977 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.42e7.40
(m, 6H), 7.27e7.21 (m, 9H), 7.11 (d, 1H, J¼15.8 Hz), 6.22 (d, 1H,
J¼15.8 Hz), 5.91 (ddt, 1H, J¼16.1, 10.9, 5.6 Hz), 5.32 (d, 1H,
J¼17.2 Hz), 5.26 (d, 1H, J¼10.4 Hz), 4.63 (d, 2H, J¼5.5 Hz), 4.32e4.27
To a solution of the p-nitrobenzoate (0.7 g, 1.21 mmol) (obtained
above) in allyl alcohol (5 mL) was added K2CO3 (0.32 g, 2.42 mmol)
and stirred for 2 h at room temperature. After completion of re-
action (monitored by TLC) the reaction mixture was poured into
water (10 mL) and extracted with diethyl ether (3ꢂ20 mL). Com-
bined organic layers were washed with brine (2ꢂ5 mL) and dried
over Na2SO4. Evaporation of solvent gave the crude residue, which
was purified by silica gel column chromatography using petroleum
ether/Et2O (4:1) as eluent to furnish 10 (0.51 g, 98%) as a colorless
(m, 1H), 1.38 (d, 3H, J¼6.9 Hz); 13C NMR (100 MHz, CDCl3)
d 201.1
(Cq), 165.0 (Cq), 143.6 (Cq), 133.6 (CH), 131.6 (CH), 129.0 (CH), 128.0
(CH), 127.9 (CH), 127.5 (CH), 118.5 (CH2), 88.1 (Cq), 75.7 (CH), 65.5
(CH2), 19.5 (CH3); HRMS (MþNa) found 449.1716. C28H26O4þNa
requires 449.1729.
4.1.4. (E,5S)-Allyl 4-hydroxy-5-(trityloxy)hex-2-enoate (9 and 10). To
a stirred solution of E-8 (0.9 g, 2.1 mmol) in MeOH (5 mL), was
added CeCl3$7H2O (1.18 g, 3.17 mmol) and allowed to stir for 45 min
sticky mass. [
a
]
24 þ25.7 (c 2.3, CHCl3); IR (Neat) 3469, 3086, 2934,
D

4518
K.R. Prasad, P. Gutala / Tetrahedron 67 (2011) 4514e4520
1719, 1656, 1490, 931 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.52e7.50
2977, 2893, 1722, 1715, 1682, 1454, 1276 cmꢀ1; 1H NMR (400 MHz,
CDCl3) 6.88 (dd, 1H, J¼15.8, 6.3 Hz), 6.07 (dd, 1H, J¼15.8, 1.2 Hz),
5.93 (ddt, 1H, J¼16.2, 10.6, 5.8 Hz), 5.32 (dd, 1H, J¼17.2, 1.4 Hz), 5.23
(dd, 1H, J¼10.4, 1.1 Hz), 4.65e4.62 (m, 4H), 4.15 (dq, 1H, J¼6.0,
1.1 Hz), 3.92e3.91 (m, 1H), 3.38 (s, 3H), 2.59 (br s, 1H), 1.14 (d, 3H,
(m, 6H), 7.33e7.24 (m, 9H), 6.60 (dd, 1H, J¼15.7, 4.1 Hz), 5.96e5.86
(m, 2H), 5.30 (d, 1H, J¼17.2 Hz), 5.22 (d, 1H, J¼10.5 Hz), 4.60 (d, 2H,
J¼5.5 Hz), 3.81 (dq, 1H, J¼12.6, 2.6 Hz), 3.35 (br s, 1H), 2.31 (br s,
1H), 1.04 (d, 3H, 6.3 Hz); 13C NMR (100 MHz, CDCl3)
d 165.9 (Cq),
146.2 (CH), 144.4 (Cq), 132.1 (CH), 128.7 (CH), 128.0 (CH), 127.4 (CH),
120.6 (CH), 118.1 (CH2), 87.5 (Cq), 72.7 (CH), 72.0 (CH), 65.0 (CH2),
15.3 (CH3); HRMS (MþNa) found 451.1675. C28H28O4þNa requires
451.1885.
J¼6.5 Hz); 13C NMR (100 MHz, CDCl3)
d 165.4 (Cq), 144.1 (CH), 132.0
(CH), 123.7 (CH), 118.3 (CH2), 95.4 (CH2), 80.2 (CH), 69.1 (CH), 65.2
(CH2), 55.8 (CH3), 17.8 (CH3); HRMS (MþNa) found 253.1047.
C11H18O5þNa requires 253.1052.
4.1.6. Allyl (E,4R,5S)-4-(methoxymethoxy)-5-(trityloxy)hex-2-enoate
(11). To a pre-cooled (0 ꢁC) solution of 10 (0.8 g, 1.87 mmol) and
DMAP (0.03 g, 0.187 mmol) in DCM (5 mL), was added N,N diiso-
propylethylamine (1.5 mL, 9.35 mmol) drop wise and stirred for
15 min. MOMCl (0.45 mL, 5.61 mmol) was introduced into the re-
action mixture and slowly allowed to warm up to room tempera-
ture and stirred for 8 h. After completion of the reaction (indicated
by TLC) the reaction mixture was then poured into water (10 mL)
and extracted with diethyl ether (3ꢂ20 mL). Combined organic
layers were washed with brine (2ꢂ5 mL) and dried over Na2SO4.
Evaporation of solvent gave the crude residue, which was purified
by silica gel column chromatography using petroleum ether/diethyl
ether (5:1) as eluent to furnish 11 (0.82 g, 93%) as a colorless oil
4.1.9. Preparation of diester (14). In a 25 mL single neck round
bottom flask was placed a solution of the acid 12 (0.32 g,
0.74 mmol) in DCM (2 mL) under argon atmosphere. A solution of
the alcohol 13 (0.13 g, 0.56 mmol) in DCM (2 mL) was introduced
via syringe into the flask. Solid DMAP (0.014 g, 0.112 mmol), DCC
(0.23 g, 1.12 mmol), and camphorsulfonic acid (0.007 g, 0.03 mmol)
were added to the reaction mixture at once, and stirred for 3 h at
room temperature. After completion of the reaction (indicated by
TLC), the reaction mixture was diluted with diethyl ether (10 mL)
and was filtered through a short pad of Celite and the Celite pad
was washed with diethyl ether (3ꢂ5 mL). Evaporation of solvent
followed by silica gel column chromatography of the resulting
residue using petroleum ether/Et2O (5:1) as eluent yielded 14
(sticky mass). [
a
]
24 þ8.2 (c 3.5, CHCl3); IR (Neat) 3058, 2936, 1722,
(0.3 g, 84%) as a colorless oil. [
a
]
24 ꢀ19.0 (c 2.3, CHCl3); IR (Neat)
D
D
1656, 1448, 1033, 921 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.54e7.53
3059, 2986, 1723, 1659, 1449, 1154, 709 cmꢀ1; 1H NMR (400 MHz,
(m, 6H), 7.33e7.23 (m, 9H), 6.56 (dd, 1H, J¼15.7, 5.3 Hz), 5.92 (ddt,
1H, J¼16.2, 10.7, 5.6 Hz), 5.82 (dd, 1H, J¼15.7, 1.5 Hz), 5.31 (dd, 1H,
J¼17.2, 12.0 Hz), 5.23 (d, 1H, J¼10.4 Hz), 4.61 (ABq, 2H, J¼6.5 Hz),
4.61 (d, 2H, J¼5.6 Hz), 3.74 (dq, 1H, J¼12.6, 2.0 Hz), 3.51e3.50 (m,
1H), 3.32 (s, 3H), 1.05 (d, 3H, 6.3 Hz); 13C NMR (100 MHz, CDCl3)
CDCl3)
d
7.53e7.51 (m, 6H), 7.32e7.22 (m, 9H), 6.85 (dd, 1H, J¼15.7,
6.0 Hz), 6.52 (dd, 1H, J¼15.7, 5.3 Hz), 6.10 (dd, 1H, J¼15.8, 1.2 Hz),
5.94 (ddt, 1H, J¼17.0, 10.6, 4.9 Hz), 5.75 (dd, 1H, J¼15.7, 1.5 Hz), 5.34
(dd, 1H, J¼17.2, 1.4 Hz), 5.25 (dd, 1H, J¼10.4, 1.0 Hz) 5.06e5.03 (m,
1H), 4.67e4.54 (m, 6H), 4.35e4.32 (m, 1H), 3.73e3.71 (m, 1H),
3.48e3.46 (m, 1H), 3.34 (s, 3H), 3.31 (s, 3H), 1.23 (d, 3H, J¼6.5 Hz)
d
165.7 (Cq),146.3 (CH),144.7 (Cq),132.1 (CH),129.0 (CH),127.8 (CH),
127.2 (CH), 121.6 (CH), 118.2 (CH2), 95.5 (CH2), 87.3 (Cq), 78.1 (CH),
72.1 (CH), 65.1 (CH2), 55.6 (CH3), 15.7 (CH3); HRMS (MþNa) found
495.2144. C30H32O5þNa requires 495.2147.
1.04 (d, 3H, J¼6.3 Hz); 13C NMR (100 MHz, CDCl3)
d 165.3 (Cq), 146.4
(CH), 144.6 (Cq), 143.8 (CH), 132.0 (CH), 128.9 (CH), 127.8 (CH), 127.2
(CH), 123.7 (CH), 121.7 (CH), 118.4 (CH2), 95.5 (CH2), 94.8 (CH2), 87.3
(Cq), 78.2 (CH), 76.5 (CH), 72.0 (CH), 71.3(CH), 65.2 (CH2), 55.7 (CH3),
55.6 (CH3), 15.6 (CH3), 14.9 (CH3); HRMS (MþNa) found 667.2885.
C38H44O9þNa requires 667.2883.
4.1.7. (E,4R,5S)-4-(Methoxymethoxy)-5-(trityloxy)hex-2-enoic acid
(12). A solution of 11 (0.5 g, 1.06 mmol) in MeOH/THF (3:1, 5 mL)
was added 0.5 N NaOH (2 mL) and stirred for 3 h. After completion
of the reaction (indicated by TLC), the reaction mixture was neu-
tralized with 0.2 N HCl (5 mL) at 0 ꢁC. The reaction mixture was
then poured into water (10 mL) and extracted with CHCl3
(3ꢂ15 mL). Combined organic layers were washed with brine
(2ꢂ5 mL) and dried over Na2SO4. Evaporation of solvent gave the
crude residue, which was purified by silica gel column chroma-
tography using petroleum ether/diethyl ether (2:3) as eluent to
4.1.10. Preparation of hydroxydiester (15). To a stirred solution of 14
(0.29 g, 0.45 mmol) in MeOH (5 mL) was added PPTS (0.15 g,
0.9 mmol) and stirred at room temperature for 6 h. After comple-
tion of the reaction (indicated by TLC), MeOH was evaporated un-
der vacuum and the reaction mixture was diluted with DCM (5 mL).
Solid NaHCO3 (0.08 g, 0.9 mmol) was added and stirred for further
15 min. The reaction mixture was then filtered through a short pad
of Celite and the Celite pad was washed with DCM (3ꢂ5 mL).
Evaporation of solvent followed by silica gel column chromatog-
raphy of the resulting residue using petroleum ether/EtOAc (1:1) as
furnish 12 (0.43 g, 94%) as a colorless oil (sticky mass). [
a
]
24 þ11.5
D
(c 2.2, CHCl3); IR (Neat) 3059, 3034, 2935, 2825, 1698, 1449, 1282,
708 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.53e7.51 (m, 6H),
7.32e7.23 (m, 9H), 6.61 (dd, 1H, J¼15.7, 5.1 Hz), 5.77 (dd, 1H, J¼15.7,
1.3 Hz), 4.60 (ABq, 2H, J¼6.6 Hz), 3.75e3.73 (m, 1H), 3.48e3.46
(m, 1H), 3.31 (s, 3H), 1.04 (d, 3H, J¼6.3 Hz); 13C NMR (100 MHz,
eluent yielded 15 (0.162 g, 90%) as a colorless oil. [
a
]
2D4 ꢀ71.0 (c 1.0,
CHCl3); IR (Neat) 3474, 2940, 1722, 1659, 1451, 1271, 1033 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d
6.88 (dd, 1H, J¼6.1, 2.0 Hz), 6.84 (dd, 1H,
CDCl3)
d
171.2 (Cq), 147.0 (CH), 144.6 (Cq), 128.9 (CH), 127.8 (CH),
J¼6.0, 2.0 Hz), 6.08 (dd, 2H, J¼21.3, 15.7 Hz), 5.93 (ddt, 1H, J¼16.5,
10.9, 5.8 Hz), 5.32 (d, 1H, J¼17.2 Hz), 5.24 (d, 1H, J¼10.4 Hz), 5.09
(dq, 1H, J¼12.7, 6.4 Hz), 4.67e4.60 (m, 6H), 4.36e4.34 (m, 1H),
4.17e4.14 (m, 1H), 3.93e3.90 (m, 1H), 3.39 (s, 3H), 3.36 (s, 3H), 2.51
(br s, 1H), 1.25 (d, 3H, 6.5 Hz) 1.14 (d, 3H, 6.5 Hz); 13C NMR
127.2 (CH), 122.4 (CH), 95.4 (CH2), 87.3 (Cq), 78.1 (CH), 72.0 (CH),
55.6 (CH3), 15.6 (CH3); HRMS (MþNa) found 455.1832.
C27H28O5þNa requires 455.1834.
4.1.8. (E,4R,5S)-Allyl 5-(hydroxy)-4-(methoxymethoxy)hex-2-enoate
(13). To a stirred solution of 11 (0.3 g, 0.63 mmol) in MeOH (5 mL)
was added Amberlyst-15 (0.3 g) at room temperature and stirred
for 2 h. After completion of the reaction (indicated by TLC), the
reaction mixture was diluted with diethyl ether (10 mL) and was
then filtered through a short pad of Celite and the Celite pad was
washed with diethyl ether (3ꢂ5 mL). Evaporation of solvent fol-
lowed by silica gel column chromatography of the resulting residue
(100 MHz, CDCl3) d 165.4 (Cq), 165.0 (Cq), 144.3 (CH), 143.8 (CH),
132.0 (CH), 123.8 (2 CH), 118.4 (CH2), 95.5 (CH2), 95.0 (CH2), 80.4
(CH), 76.6 (CH), 71.5 (CH), 69.2 (CH), 65.3 (CH2), 55.9 (CH3), 55.8
(CH3), 17.9 (CH3), 15.0 (CH3); HRMS (MþNa) found 425.1787.
C19H30O9þNa requires 425.1788.
4.1.11. Preparation of triester 17a and 17b. The following procedure
for 17a is representative. To a solution of 15 (0.08 g, 0.20 mmol) in
DCM (2 mL) in a 25 mL round bottom flask, was added a solution of
the acid S-16 (0.069 g, 0.30 mmol) in DCM (2 mL). Solid DMAP
using petroleum ether/EtOAc (1:1) as eluent yielded 13 (0.133 g,
24
D
91%) as a colorless oil. [
a
]
ꢀ74.9 (c 3.8, CHCl3); IR (Neat) 3471,

K.R. Prasad, P. Gutala / Tetrahedron 67 (2011) 4514e4520
4519
(0.005 g, 0.04 mmol), DCC (0.083 g, 0.40 mmol), and cam-
phorsulfonic acid (0.004 g, 0.02 mmol) were introduced at once in to
the flask and stirred for 12 h at room temperature. After completion
of the reaction (indicated by TLC), the reaction mixture was diluted
with diethyl ether (10 mL) and was filtered through a short pad of
Celite and the Celite pad was washed with diethyl ether (3ꢂ5 mL).
Evaporation of solvent followed by silica gel column chromatogra-
phy of the resulting residue using petroleum ether/EtOAc (5:1) as
CDCl3)
d
6.85 (dd, 1H, J¼12.4, 6.0 Hz), 6.81 (dd, 1H, J¼12.5, 6.1 Hz),
6.07 (td, 2H, J¼15.7, 1.2 Hz), 5.92 (ddt, 1H, J¼16.3, 10.6, 5.8 Hz), 5.31
(dd, 1H, J¼17.2, 1.4 Hz), 5.22 (dd, 1H, J¼10.4, 1.0 Hz), 5.07(dq, 2H,
J¼12.9, 2.7 Hz), 4.63e4.57 (m, 6H), 4.35e4.32 (m, 1H), 4.29e4.26
(m,1H), 4.17 (m,1H), 3.35 (s, 3H), 3.34 (s, 3H), 3.08 (br s,1H), 2.47 (dd,
1H, J¼16.1, 3.7 Hz), 2.39 (dd,1H, J¼16.1, 8.7 Hz) 1.24 (d, 3H, J¼6.5 Hz),
1.21 (d, 3H, J¼7.0 Hz), 1.19 (d, 3H, J¼6.5 Hz); 13C NMR (100 MHz,
CDCl3)
d 171.7 (Cq), 165.3 (Cq), 164.8 (Cq), 143.6 (2CH), 131.9 (CH),
eluent yielded 17a (0.11 g, 91%) as a colorless oil. [
a
]
2D4 ꢀ41.9 (c 2.7,
124.0 (CH), 123.8 (CH), 118.4 (CH2), 94.9 (CH2), 94.8 (CH2), 76.6 (CH),
76.5 (CH), 71.6 (CH), 71.3 (CH), 65.3 (CH2), 64.1 (CH), 55.7 (CH3), 55.6
(CH3), 43.3 (CH2), 22.3 (CH3), 15.1 (CH3), 14.9 (CH3); HRMS (MþNa)
found 511.2191. C23H36O11þNa requires 511.2155.
CHCl3); IR (Neat) 3085, 2857, 1727, 1661, 1463, 1281, 1034 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d
6.87 (dd, 1H, J¼12.7, 6.0 Hz), 6.83 (dd, 1H,
J¼9.8, 3.1 Hz), 6.09 (td, 2H, J¼17.0, 1.0 Hz), 5.92e5.82 (m, 1H), 5.33
(dd, 1H, J¼17.2, 1.1 Hz), 5.25 (dd, 1H, J¼10.5, 1.0 Hz), 5.11e5.08 (m,
1H), 5.03e5.01 (m, 1H), 4.66e4.60 (m, 6H), 4.38e4.36 (m, 1H),
4.32e4.30 (m, 1H), 4.26e4.21 (m, 1H), 3.37 (s, 3H), 3.36 (s, 3H), 2.49
(dd, 1H, J¼14.7, 6.7 Hz), 2.36 (dd, 1H, J¼14.7, 6.1 Hz), 1.26 (d, 3H,
J¼6.6 Hz), 1.21 (d, 3H, J¼6.6 Hz), 1.18 (d, 3H, J¼6.2 Hz), 0.85 (s, 9H),
4.1.13. Macrolactone 20a and 20b. The following procedure for 20a
is representative. Pd(PPh3)4 (0.165 g, 0.143 mmol) and morpholine
(0.012 mL, 0.143mmol) were added to a stirred solutionof 18a (0.07 g,
0.143 mmol) in THF (5 mL) and stirred for 12 h at room temperature.
The reaction mixture was quenched with 1 N HCl (2 mL), and poured
into water (10 mL). The reaction mixture was extracted with EtOAc
(3ꢂ20 mL) and the combined organic layers were washed with brine
(2ꢂ5 mL) and dried over Na2SO4. Evaporation of solvent gave crude
residue of the hydroxy acid 19a. It was cumbersome to purify the
seco-acid from an unidentifiable impurity on column chromatogra-
phy. Hencethesecoacid(0.064 g, 0.143mmol)wasusedassuchinthe
next step without further purification.
0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 170.7 (Cq),
165.3 (Cq), 164.9 (Cq), 144.0 (CH), 143.7 (CH), 132.0 (CH), 123.8 (CH),
123.7 (CH), 118.7 (CH2), 94.9 (2CH2), 76.5 (CH), 71.6 (CH), 71.2 (CH),
65.6 (CH), 65.3 (CH2), 55.7 (2CH3), 44.9 (CH2), 25.7 (3CH3), 23.7
(CH3), 17.9 (Cq), 14.8 (CH3), ꢀ4.6 (CH3), ꢀ4.9 (CH3); HRMS (MþNa)
found 625.3019. C29H50O11SiþNa requires 625.3020.
Compound 17b: yield: 88% [
a
]
24 ꢀ60.5 (c 1.8, CHCl3); IR (Neat)
D
3086, 2955, 1728, 1661, 1473, 1281, 1035 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d
6.84 (td, 2H, J¼15.6, 6.0 Hz), 6.1 (dd, 1H, J¼15.8, 1.2 Hz),
Triethylamine (0.12 mL, 0.86 mmol) and 2,4,6-trichlorobenzoyl
chloride (0.12 mL, 0.86 mmol) were added to a stirred solution of
19a (0.064 g, 0.143 mmol) in dry toluene (5 mL) and stirred for 1 h
at room temperature. It was diluted with toluene (30 mL) and was
6.06 (dd, 1H, J¼15.9, 1.4 Hz), 5.94 (ddt, 1H, J¼16.1, 11.3, 5.7 Hz), 5.33
(dd, 1H, J¼17.2, 1.3 Hz), 5.24 (dd, 1H, J¼10.4, 1.2 Hz), 5.09 (dq, 1H,
J¼12.8, 6.3 Hz), 5.01 (dq, 1H, J¼12.8, 6.3 Hz), 4.65e4.59 (m, 6H),
4.37e4.35 (m, 1H), 4.31e4.22 (m, 2H), 3.36 (s, 3H), 3.36 (s, 3H), 2.48
(dd, 1H, J¼14.8, 7.2 Hz), 2.35 (dd, 1H, J¼14.8, 5.6 Hz) 1.26 (d, 3H,
J¼6.5 Hz), 1.21 (d, 3H, J¼6.5 Hz), 1.17 (d, 3H, J¼6.1 Hz), 0.85 (s, 9H),
added to
a pre-heated solution of 4-dimethylaminopyridine
(0.435 g, 3.6 mmol) in toluene at 80 ꢁC for over 3 h. The reaction
mixture was stirred for 4 h at 80 ꢁC, and after completion of the
reaction (monitored by TLC) it was poured into saturated NaHCO3
(20 mL) and extracted with EtOAc (3ꢂ20 mL). Combined organic
layers were washed with brine (2ꢂ5 mL) and dried over Na2SO4.
Evaporation of solvent gave the crude residue, which was purified
by silica gel column chromatography using petroleum ether/EtOAc
(4:1) as eluent to furnish 20a (0.043 g, 70% over two steps) as
0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 170.8 (Cq),
165.3 (Cq), 164.9 (Cq), 144.0 (CH), 143.7 (CH), 132.0 (CH), 123.8 (CH),
123.7 (CH), 118.4 (CH2), 94.9 (2CH2), 76.5 (CH), 71.5 (CH), 71.0 (CH),
65.6 (CH), 65.2 (CH2), 55.6 (2CH3), 44.8 (CH2), 25.7 (3CH3), 23.8
(CH3), 17.9 (Cq), 14.9 (CH3), 14.8 (CH3), ꢀ4.6 (CH3), ꢀ5.0 (CH3);
HRMS (MþNa) found 625.3018. C29H50O11SiþNa requires
625.3020.
a colorless oil. [
a
]
D ꢀ102.2 (c 2.3, CHCl3); IR (Neat) 2982, 2826,1734,
1724, 1656, 1458, 1251, 1032 cmꢀ1; 1H NMR (400 MHz, CDCl3)
4.1.12. Preparation of hydroxytriester (18a and 18b). The following
procedure for 18a is representative. To a stirred solution of 17a
(0.10 g, 0.166 mmol) in MeOH (4 mL) was added PPTS (0.055 g,
0.33 mmol) at room temperature and stirred for 24 h. After com-
pletion of the reaction (indicated by TLC), MeOH was evaporated
under vacuum and the reaction mixture was diluted with DCM
(5 mL). Solid NaHCO3 (0.028 g, 0.33 mmol) was added and stirred for
further 15 min. The reaction mixture was then filtered through
a short pad of Celite and the Celite pad was washed with DCM
(3ꢂ5 mL). Evaporation of solvent followed by silica gel column
d
6.74e6.67(m, 2H), 5.96 (d, 1H, J¼15.8 Hz), 5.9 (d, 1H, J¼15.8 Hz),
5.31e5.28 (m, 1H), 5.03e4.90 (m, 2H), 4.65e4.53 (m, 4H),
4.10e4.00(m, 2H), 3.36 (s, 3H), 3.35 (s, 3H), 2.57 (dd, 1H, J¼15.0,
2.5 Hz), 2.48 (dd, 1H, J¼15.0, 8.7 Hz) 1.40 (d, 3H, J¼6.2 Hz), 1.30
(d, 3H, J¼6.3 Hz), 1.28 (d, 3H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3)
d
169.5 (Cq), 164.2 (Cq), 145.1 (CH), 144.0 (CH), 124.3 (CH), 124.2
(CH), 94.9 (CH2), 94.3 (CH2), 78.4 (CH), 76.3 (CH), 71.7 (CH), 70.6
(CH), 67.5 (CH), 55.9 (CH3), 55.8 (CH3), 40.8 (CH2), 19.5 (CH3), 17.8
(CH3), 17.6 (CH3); HRMS (MþNa) found 453.1735. C20H30O10þNa
requires 453.1737.
chromatography of the resulting residue using petroleum ether/
Compound 20b: [
a]
ꢀ65.2 (c 2.0, CHCl3); IR (Neat) 2983, 2827,
D
24
D
EtOAc(1:1) as eluentyielded 18a (0.072 g, 89%) asa colorlessoil. [
a]
1722, 1655, 1453, 1273, 1030 cmꢀ1; 1H NMR (400 MHz, CDCl3)
ꢀ57.4 (c 2.4, CHCl3); IR (Neat) 3514, 2983, 1725, 1660, 1409, 1252,
d
6.84 (dd, 1H, J¼15.7, 6.1 Hz), 6.78 (dd, 1H, J¼15.8, 6.6 Hz), 6.13
1033 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
6.85 (td, 2H, J¼15.8, 6.0 Hz),
(d, 1H, J¼15.8 Hz), 5.96 (d, 1H, 15.8 Hz), 5.24 (td, 1H, J¼6.6, 3.1 Hz),
5.11 (dq, 2H, J¼12.9, 4.6 Hz), 4.62 (d, 4H, J¼2.0 Hz), 4.25e4.22 (m,
1H), 4.10e4.07 (m, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 2.76 (dd, 1H,
J¼14.8, 3.0 Hz), 2.55 (dd, 1H, J¼14.9, 6.5 Hz) 1.41 (d, 3H, J¼6.5 Hz),
1.38 (d, 3H, J¼6.5 Hz), 1.22 (d, 3H, J¼6.5 Hz); 13C NMR (100 MHz,
6.09 (td, 2H, J¼17.1, 1.2 Hz), 5.94 (ddt, 1H, J¼16.2, 11.2, 5.7 Hz), 5.33
(dd, 1H, J¼17.2, 1.4 Hz), 5.25 (dd, 1H, J¼10.4, 1.0 Hz), 5.09(m, 2H),
4.66e4.60 (m, 6H), 4.37e4.35 (m, 1H), 4.31e4.28 (m, 1H), 4.18e4.16
(m, 1H), 3.37 (s, 3H), 3.37 (s, 3H), 3.03 (br d, 1H, J¼3.0 Hz), 2.48 (dd,
1H, J¼12.1, 4.2 Hz), 2.42 (dd, 1H, J¼16.0, 8.3 Hz) 1.27e1.21 (m, 9H);
CDCl3)
d 169.4 (Cq), 165.0 (Cq), 164.4 (Cq), 143.2 (CH), 143.1 (CH),
13C NMR (100 MHz, CDCl3)
d
172.0 (Cq), 165.3 (Cq), 164.9 (Cq), 143.7
124.9 (CH), 124.5 (CH), 94.6 (CH2), 94.5 (CH2), 77.6 (CH), 76.5 (CH),
72.0 (CH), 71.3 (CH), 67.3 (CH), 55.9 (CH3), 55.8 (CH3), 40.6 (CH2),
19.3 (CH3), 17.5 (CH3), 17.2 (CH3); HRMS (MþNa) found 453.1737.
C20H30O10þNa requires 453.1737.
(CH), 131.9 (CH), 124.0 (CH), 123.8 (CH), 118.4 (CH2), 94.9 (CH2), 94.9
(CH2), 76.6 (CH), 76.5 (CH), 71.6 (CH), 71.4 (CH), 65.3 (CH2), 64.3 (CH),
55.7 (CH3), 43.1 (CH2), 22.5 (CH3), 15.1 (CH3), 14.8 (CH3); HRMS
(MþNa) found 511.2152. C23H36O11þNa requires 511.2155.
Compound 18b: yield: 93%; [
a
]
D
ꢀ75.7 (c 4.3, CHCl3); IR (Neat)
4.1.14. Macrosphelides A and E (1a and 1b). A stirred solution of 20a
(0.040 g, 0.093 mmol) in DCM (5 mL) was treated with TFA (2.5 mL)
3501, 2939, 1724, 1660, 1454, 1173, 1033 cmꢀ1; 1H NMR (400 MHz,

4520
K.R. Prasad, P. Gutala / Tetrahedron 67 (2011) 4514e4520
for 5 h at room temperature. After completion of the reaction (in-
dicated by TLC), TFA was removed under reduced pressure. Silica gel
column chromatography of the resulting residue using petroleum
ether/EtOAc (1:1) as eluent yielded macrosphelide A 1a (0.028 g,
References and notes
1. (a) Hayashi, M.; Kim, Y.-P.; Hiraoka, H.; Natori, M.; Takamatsu, S.; Kawakubo, T.;
Masuma, R.; Komiyama, K.; Omura, S. J. Antibiot. 1995, 48, 1435; (b) Takamatsu,
S.; Kim, Y.-P.; Hayashi, M.; Hiraoka, H.; Natori, M.; Komiyama, K.; Omura, S. J.
Antibiot. 1996, 49, 95; (c) Takamatsu, S.; Hiraoka, H.; Kim, Y.-P.; Hayashi, M.;
Natori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1997, 50, 878; (d) Fukami, A.;
Taniguchi, Y.; Nakamura, T.; Rho, M.-C.; Kawaguchi, K.; Hayashi, M.; Komiyama,
K.; Omura, S. J. Antibiot. 1999, 52, 501; (e) Numata, A.; Iritani, M.; Yamada, T.;
Minoura, K.; Matsumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38,
8215; (f) Yamada, T.; Iritani, M.; Doi, M.; Minoura, K.; Ito, T.; Numata, A. J. Chem.
Soc., Perkin Trans. 1 2001, 3046; (g) Yamada, T.; Iritani, M.; Minoura, K.; Numata,
A.; Kobayashi, Y.; Wang, Y.-G. J. Antibiot. 2002, 55, 147; (h) Yamada, T.; Minoura,
K.; Tanaka, R.; Numata, A. J. Antibiot. 2007, 60, 370.
88%) as white needles. [
a
]
þ74.3 (c 0.75, MeOH); lit.1a
[
a
]
þ84.1
D
D
(c 0.59, MeOH); mp 142e143 ꢁC; lit.1a mp 141e142 ꢁC; IR (KBr) 3434,
2936, 1732, 1704, 1648, 1458, 1290, 1049 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d
6.88 (dt, 2H, J¼15.7, 3.7 Hz), 6.06 (d, 1H, J¼15.7 Hz), 6.04
(dd, 1H, J¼15.7, 1.1 Hz), 5.43e5.35 (m, 1H), 5.00e4.94 (m, 1H),
4.90e4.83 (m, 1H), 4.24e4.23 (m, 1H), 4.15e4.13 (m, 1H), 2.63 (dd,
1H, J¼15.5, 8.7 Hz), 2.58 (dd, 1H, J¼15.6, 3.6 Hz) 1.46 (d, 3H,
J¼6.5 Hz), 1.37 (d, 3H, J¼6.3 Hz), 1.33 (d, 3H, J¼6.3 Hz); 13C NMR
2. (a) Matsuya, Y.; Kawaguchi, T.; Ishihara, K.; Ahmed, K.; Zhao, Q.-L.; Kondo, T.;
Nemoto, H. Org. Lett. 2006, 8, 4609; (b) Matsuya, Y.; Kobayashi, Y.; Kawaguchi, T.;
Hori, A.; Watanabe, Y.; Ishihara, K.; Ahmed, K.; Wei, Z.-L.; Yu, D.-A.; Zhao, Q.-L.;
Kondo, T.; Nemoto, H. Chem.dEur. J. 2009, 15, 5799.
(100 MHz, CDCl3) d 170.1 (Cq),165.7 (Cq),164.8 (Cq),146.3 (CH),145.4
(CH), 122.6 (CH), 122.1 (CH), 74.6 (CH), 73.7 (CH), 72.9 (CH), 67.6
(CH), 40.9 (CH2), 19.6 (CH3), 17.8 (CH3), 17.7 (CH3); HRMS (MþNa)
found 365.1212. C16H22O8þNa requires 365.1212. Anal. Calcd for
C16H22O8 (365.1212): Found: C, 55.99; H, 6.36. C16H22O8 requires C,
56.13; H, 6.48.
3. Synthesis of macrosphelides A and E: (a) Sunazuka, T.; Hirose, T.; Harigaya, Y.;
Takamatsu, S.; Hayashi, M.; Komiyama, K.; Omura, S.; Sprengeler, P. A.; Smith, A.
B., III. J. Am. Chem. Soc. 1997, 119, 10247; (b) Kobayashi, Y.; Kumar, B. G.; Kurachi,
T. Tetrahedron Lett. 2000, 41, 1559; (c) Ono, M.; Nakamura, H.; Konno, F.; Akita, H.
Tetrahedron: Asymmetry 2000, 11, 2753; (d) Kobayashi, Y.; Kumar, G. B.; Kurachi,
T.; Acharya, H. P.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 2001, 66, 2011; (e)
Sharma, G. V. M.; Mouli, C. C. Tetrahedron Lett. 2002, 43, 9159; (f) Takahashi, T.;
Kusaka, S.-I.; Doi, T.; Sunazuka, T.; Omura, S. Angew. Chem., Int. Ed. 2003, 42,
5230; (g) Kusaka, S.-I.; Dohi, S.; Doi, T.; Takahashi, T. Tetrahedron Lett. 2003, 44,
8857; (h) Matsuya, Y.; Kawaguchi, T.; Nemoto, H. Org. Lett. 2003, 5, 2939; (i)
Kawaguchi, T.; Funamori, N.; Matsuya, Y.; Nemoto, H. J. Org. Chem. 2004, 69, 505;
(j) Paek, S.-M.; Yun, H.; Kim, N.-J.; Jung, J. W.; Chang, D.-J.; Lee, S.; Yoo, J.; Park,
H.-J.; Suh, Y.-G. J. Org. Chem. 2009, 74, 554; (k) Paek, S.-M.; Seo, S.-Y.; Kim, S.-H.;
Jung, J.-W.; Lee, Y.-S.; Jung, J.-K.; Suh, Y.-G. Org. Lett. 2005, 7, 3159.
Similarly reaction with 20b produced macrosphelide E 1b in
88% yield: [
a
]
þ58.1 (c 0.75, EtOH); lit.1e
[
a
]
þ56.8 (c 0.46,
D
D
EtOH); IR (Neat) 3449, 2984, 1718, 1663, 1277, 1053, 984 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d
7.02 (dd, 1H, J¼15.6, 4.2 Hz), 6.81 (dd,
1H, J¼15.6, 5.3 Hz), 6.13 (dd, 1H, J¼15.6, 1.1 Hz), 6.06 (dd, 1H,
J¼15.6, 1.2 Hz), 5.34e5.26 (m, 1H), 5.11 (dq, 1H, J¼11.6, 4.9 Hz),
4.97 (dq, 1H, J¼12.8, 6.4 Hz), 4.36e4.35 (m, 1H), 4.18e4.15 (m,
1H), 2.73 (dd, 1H, J¼15.9, 3.1 Hz), 2.59 (dd, 1H, J¼15.9, 7.0 Hz) 1.41
(d, 3H, J¼7.2 Hz), 1.38 (d, 3H, J¼7.4 Hz), 1.3 (d, 3H, J¼6.5 Hz); 13C
4. Colin-Messager, S.; Girard, J.-P.; Rossi, J.-C. Tetrahedron Lett. 1992, 33, 2689.
5. Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.;
Christensen, B. G. J. Med. Chem. 1987, 30, 871.
6. Diastereomeric ratio of the alcohols was estimated by 1H NMR. Reduction of the
corresponding TBS analogue gave the diastereomeric alcohols in 80:20 ratio,
which are non separable.
NMR (100 MHz, CDCl3)
d 170.8 (Cq), 166.6 (Cq), 165.3 (Cq), 145.4
(CH), 145.1 (CH), 123.0 (CH), 122.3 (CH), 75.8 (CH), 75.1 (CH), 75.0
(CH), 73.6 (CH), 66.7 (CH), 40.4 (CH2), 19.5 (CH3), 17.6 (CH3), 17.3
(CH3); HRMS (MþNa) found 365.1213.C16H22O8þNa requires
365.1212.
Acknowledgements
7. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Swamy, K. C. K.; Kumar, N. N. B.;
Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551.
8. It was cumbersome to purify the acid from an unidentifiable impurity. Silica gel
column chromatography of the acid always furnished the required acid 19 ad-
mixed with the impurity; hence the crude acid obtained was used as such in the
next step without further purification.
We thank the Department of Science and Technology (DST),
New Delhi for funding. K.R.P. is a Swarnajayanthi fellow of DST, New
Delhi. P.G. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a senior research fellowship.