Synthetic studies on cytotoxic macrolides cruentarens A and B: Stereoselective synthesis of the C8C19 segment of cruentarens A and B

Article abstract of DOI:10.1016/j.tetasy.2010.04.068

A stereoselective synthesis of the C₈C₁₉ segment of cruentarens A and B, cytotoxic natural products, has been accomplished. The key steps involve a stereoselective radical cyclization, stereospecific methylation of a c, d-epoxy acrylate, nucleophilic epoxide ring opening and a cis-Wittig olefination.

Full text of DOI:10.1016/j.tetasy.2010.04.068

Tetrahedron: Asymmetry 21 (2010) 1837–1844
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Tetrahedron: Asymmetry
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Synthetic studies on cytotoxic macrolides cruentarens A and B: stereoselective
synthesis of the C8–C19 segment of cruentarens A and B
*
Busam Ramalinga Vara Prasad, Harshadas Mitaram Meshram
Discovery Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the C8–C19 segment of cruentarens A and B, cytotoxic natural products, has
been accomplished. The key steps involve a stereoselective radical cyclization, stereospecific methylation
Received 5 April 2010
Accepted 20 April 2010
Available online 23 July 2010
of a
c
, d-epoxy acrylate, nucleophilic epoxide ring opening and a cis-Wittig olefination.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
As summarized in Scheme 2, the synthesis of phosphonium salt
6 commenced with known allyl alcohol 8.10 Treatment of alcohol 8
with N-bromosuccinimide and ethyl vinyl ether11 in dichlorometh-
ane resulted in the formation of bromo acetal 912 as an inseparable
1:1 diastereomeric mixture in 93% yield, which stereoselective rad-
ical cyclization in refluxing benzene using n-tributyl tin hydride
and AIBN13 furnished the lactol ether 1012 (96:4 trans–cis ratio).
The preferential trans geometry13 of the resulting new stereogenic
centre was set from earlier studies and also according to one of the
Beckwith guidelines, which states that 2- or 4-substituted radicals
give mainly trans-disubstituted cyclopentyl derivatives, we pro-
ceeded further. The hydrolysis of lactol ether 10 using 80% acetic
acid under reflux conditions afforded the lactol 1112 which was
converted into diol 1214 with NaBH4/CH3OH. The primary hydroxyl
group of the diol 12 was protected as its TBS ether 13 by using TBS
chloride and imidazole and later the secondary group was pro-
tected with TBDPS chloride to give the disilyl ether 14. Selective
deprotection of the TBS with catalytic CSA in a 1:1 mixture of
DCM and CH3OH furnished primary alcohol 15 which was sub-
jected to iodination using triphenyl phosphine (TPP), imidazole
and iodine to give the iodo compound 16. The phosphonium salt
6 was obtained by refluxing a 1:1.1 mixture of iodo compound
16 and TPP in benzene for 48 h.
Cruentarens A and B are cytotoxic macrolides isolated from
myxobacterium, Byssovorax cruenta1,2 (Fig. 1). While cruentaren A
shows strong cytotoxicity against the L929 cell line with an IC50
value of 1.2 ngm Lꢀ1, cruentaren B showed only marginal cytotox-
icity and no antifungal activity.2 Structurally, cruentaren A resem-
bles the benzlactones apicularen A3 and salicylihalimide A.4
Considering their novel structures and the biological activities5 of
cruentarens, many groups focussed their attention towards the
synthesis of these targets. Synthesis of cruentaren A has been
achieved by Maier et al.6 and also by Fürstner et al.7 Chakraborthy
et al.8 reported a convergent total synthesis of cruentaren B.
Recently Maier et al.9 reported the synthesis of some cruentaren
A analogues. The unique structural features of cruentarens coupled
with their activity attracted our interest in their synthesis. Herein,
we report the synthesis of the C8–C19 segment of cruentarens A and
B in which the key steps involve radical cyclization, epoxide open-
ing with trimethyl aluminium, methyl lithium and a cis-Wittig
olefination.
2. Results and discussion
Synthesis of aldehyde 7 began with the known cis epoxy alcohol
1715 (Scheme 3). The hydroxyl group was oxidized using Swern
conditions16 to afford an aldehyde which on Wittig olefination17
with the stable ylide carboethoxymethylenetriphenylphosphorane
As shown in Scheme 1, our synthetic strategy involves macrol-
actonization between the C1-carboxylic acid and C15-hydroxy
group (cruentaren A) and C9-hydroxy group (cruentaren B) of seg-
ment 1 which involves the assembly of three fragments, aryl boro-
nic acid 2, bromo compound 3 and propargyl amide 4. The
fragment 3 could in turn be obtained from a cis-Wittig olefination
of phosphonium salt 6 and aldehyde 7. The target molecules could
be achieved from the common intermediate 5.
produced
c
, d-epoxy acrylate 1818 in 92% yield over two steps.
Upon treatment of 18 with excess of trimethyl aluminium in the
presence of water in dichloromethane at ꢀ40 °C,19 methylation
took place at the c-position with complete regio- and stereoselec-
tivity to afford the syn alcohol 1918 as the sole product in 92% iso-
lated yield. The hydroxyl group of 19 was protected as the TBS
ether followed by treatment with DIBAL reduction provided the al-
lyl alcohol 21, which set the platform for introducing two more ste-
reogenic centres via Sharpless asymmetric epoxidation.20Thus the
* Corresponding author. Fax: +91 (40)27160512.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.068

1838
B. R. V. Prasad, H. M. Meshram / Tetrahedron: Asymmetry 21 (2010) 1837–1844
32
20
O
21
OH
HO
28
24
17
23
N
H
19
25
OH
3
O
31
33
1
15
O
13
12
5
8
29 MeO
11
7
9
HO
I
30
33
25
H
N
28
23
24
OH
OH
OH
O
19
3
5
1
O
OH
21
15
17
31
O
20
11
32
13
29
MeO
9
8
12
30
II
Figure 1. Structures of cruentarens A I and B II.
allyl alcohol 21 on treatment with
L
-(+)-DIPT, Ti(OiPr)4 and TBHP
without purification except NBS which was freshly recrystallized
from hot water before use. The progress of all the reactions was
monitored by thin-layer chromatography (TLC) using glass plates
precoated with Silica Gel 60 F254 to a thickness of 0.5 mm (Merck).
Column chromatography was carried out using silica gel (60–
120 mesh). Optical rotation values were measured with JASCO
DIP-360 digital polarimeter at 25 °C and IR spectra were recorded
with a Perkin–Elmer FT-IR spectrophotometer. 1H and 13C NMR
spectra were recorded with Varian Gemini 200 MHz, Bruker
Avance 300 MHz, Varian Unity 400 MHz or Varian Inova
500 MHz spectrometer using trimethylsilane as an internal stan-
dard in CDCl3.
yielded epoxy alcohol 22 which was regioselectively opened with
the Gillmann cuprate21 generated from MeLi and CuI at ꢀ40 °C to
furnish the diol 23. Further, the diol was protected as acetonide
24 with 2,2-dimethoxy propane and PPTS in dry DCM in 93% yield.
Cleavage of the benzyl ether in the acetonide with lithium in liquid
ammonia22 at ꢀ33 °C afforded the primary alcohol 25, which on
subsequent oxidation with TEMPO/BIAB23 gave the aldehyde 7 in
77% yield (two steps).
With the phosphonium salt 6 and aldehyde 7 in hand, we ex-
plored the possibilities for the synthesis of the C8–C19 fragment
by employing a cis-Wittig olefination procedure. The Z olefin, with-
in the C8–C19 fragment, was formed by a Wittig reaction8 between
the phosphonium salt 6 and aldehyde 7 using substoichiometric
amount of n-BuLi as the base and THF as solvent at ꢀ78 °C for
12 h in 75% yield with Z/E = 10:1 selectivity. The Z configuration
of the double bond was confirmed by the coupling constant
(J = 11.1 Hz) of the two olefinic protons. An excess of this base or
use of other bases and variation in temperature resulted in lower
selectivity and elimination products.
4.1.1. (S)-((2-(2-Bromo-1-ethoxyethoxy)but-3-enyloxy)-
methyl)benzene 9
Ethyl vinyl ether (5.71 mL, 59.65 mmol) was added to a stirred
solution of alcohol
8 (4.45 g, 25 mmol) and NBS (5.34 g,
29.99 mmol) in dry CH2Cl2 (187 mL) under a nitrogen atmosphere
at 0 °C. The reaction mixture was then brought to room tempera-
ture and stirred for 3 h. Solvent was removed at reduced pressure
and residue was chromatographed on silica gel column as quickly
as possible to give the pure bromo acetal 9 (7.4 g, 90%) as a
3. Conclusion
colourless oil. Rf = 0.6 (10% EtOAc/hexane). IR (neat):
m
2976,
2922, 2865, 1421, 1364, 1108, 1058, 1027, 730 cmꢀ1
;
1H NMR
In conclusion, we succeeded in accomplishing the stereoselec-
tive synthesis of the C8–C19 fragment of cuentarens A and B. Key
features of the synthesis of our target include radical cyclization,
(CDCl3, 300 MHz): d 7.35–7.22 (m, 5H), 5.9–5.7 (m, 1H), 5.40–5.19
(m, 2H), 4.9–4.7 (m, 1H), 4.55–4.5 (m, 2H), 4.3–4.2 (m, 1H), 3.79–
3.4 (m, 4H) 3.4–3.29 (m, 2H), 1.25–1.1 (m, 3H); MS (ESI): m/z 353
[M+Na]+; HRMS (ESI): [M+Na]+ calcd for C15H21O3NaBr: 351.0570;
found: 351.0564.
regioselective methylation of a c, d-epoxy acrylate and a cis-Wittig
olefination. Research towards the total synthesis of cruentarens A
and B is in progress in our laboratory. This approach is readily
applicable for the synthesis of cruentarens A and B as well as addi-
tional analogues.
4.1.2. (2S,3S)-2-(Benzyloxymethyl)-5-ethoxy-3-methyl
tetrahydrofuran 10
4. Experimental section
4.1. General remarks
Tri n-butyl-tin hydride (7.22 mL, 26.86 mmol) was added drop-
wise to a refluxing solution of bromo acetal 9 (5.89 g, 17.91 mmol)
in dry benzene (72 mL) with catalytic AIBN under a nitrogen atmo-
sphere. The reduction completed within 30 min as indicated by TLC
analysis. Benzene was stripped-off; the crude residue was charged
on silica gel column and eluted first with petroleum ether to re-
move excess tri-n-butyl-tin hydride and n-Bu3SnBr formed in the
reaction. Then the product was eluted with 3% ethyl acetate/
All air- or moisture-sensitive reactions were carried out under a
nitrogen atmosphere. Solvents were distilled over Na/benzophe-
none for THF, over P2O5 followed by CaH2 for DCM, DMF and over
P2O5 for benzene. Commercially available reagents were used

B. R. V. Prasad, H. M. Meshram / Tetrahedron: Asymmetry 21 (2010) 1837–1844
1839
cruentaren A (I) and B (II)
H
N
O
O
TBSO
OPMB
O
O
OTBS
OTBDPS
MeO
1
O
TBSO
OPMB
O
H
N
O
OTBDPS
OTs
O
OTBS
Br
4
B(OH)2
MeO
3
2
TBSO
O
O
OTBDPS
BnO
5
TBSO
O
O
OTBDPS
+
PPh3
BnO
_
I
OHC
6
7
TBSO
OH
COOEt
BnO
8
BnO
20
Scheme 1.
hexane after complete removal of tin impurities to give the pure
lactol ether 10 (4.16 g, 93%) as a colourless liquid. Rf = 0.5 (10%
4.1.3. (4S,5S)-5-(Benzyloxymethyl)-4-methyltetrahydro furan-2-
ol 11
EtOAc/hexane). IR (neat):
m
2971, 2929, 2902, 2872, 1452, 1372,
The solution of lactol ether 10 (3.35 g, 13.43 mmol) in 80% aq
AcOH (60 mL) solution was refluxed for 4 h. The mixture was
cooled to 0 °C, neutralized by solid NaHCO3 and extracted with
ethyl acetate (2 ꢁ 100 mL). The organic extracts were washed with
water (2 ꢁ 50 mL) followed by brine (1 ꢁ 50 mL) and dried over
anhydrous Na2SO4. Filtration and evaporation of the solvent
1110, 991, 739 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 7.38ꢀ7.2 (m,
5H), 5.1–5.0 (m, 1H), 4.57–4.55 (m, 2H), 3.8–3.3 (m, 5H), 2.4–2.0
(m, 2H), 1.6–1.44 (m, 1H), 1.17 (t, J = 6.7 Hz, 3H), 1.06 (d,
J = 6.7 Hz, 3H); MS (ESI): m/z 273 [M+Na]+; HRMS (ESI): [M+Na]+
calcd for C15H22O3Na: 273.1466; found: 273.1472.

1840
B. R. V. Prasad, H. M. Meshram / Tetrahedron: Asymmetry 21 (2010) 1837–1844
EtO
OH
OEt
O
OH
O
Br
O
a
b
c
BnO
BnO
BnO
BnO
11
8
10
9
OR
OTBDPS
OH
e
d
g
OTBS
BnO
OH
BnO
BnO
OH
12
13: R=H
15
f
14: R=TBDPS
OTBDPS
OTBDPS
+
i
h
PPh3
BnO
I
BnO
_
I
16
6
Scheme 2. Reagents and conditions: (a) NBS, ethyl vinyl ether, CH2Cl2, 0 °C to rt, 3 h, 90%; (b) n-Bu3SnH, AIBN, benzene, reflux, 30 min, 93%; (c) 80% AcOH, reflux, 4 h, 90%; (d)
NaBH4, CH3OH, 0 °C to rt, 2.5 h, 90%; (e) TBSCl, imidazole, CH2Cl2, 0 °C to rt, 30 min, 95%; (f) TBDPSCl, imidazole, cat DMAP, DMF, 0 °C to rt 6 h, 98%; (g) CSA, CH3OH/CH2Cl2
(1:1), 0 °C to rt, 1.5 h, 90%; (h) TPP, I2, imidazole, THF, 0 °C to rt, 1 h, 89%; (i) TPP, benzene, reflux, 48 h, 92%.
followed by purification (column chromatography) afforded pure
Na2SO4. Concentration in vacuo and purification by flash column
lactol 11 (2.68 g, 90% yield) as a colourless oil. Rf = 0.3 (30%
chromatography gave silyl ether 13 (2.86 g, 95%) as a pale yellow
EtOAc/hexane). IR (neat):
m
3418, 2927, 2866, 1453, 1092, 981,
oil. Rf = 0.6 (10% EtOAc/hexane). ½a D25
¼ þ1:0 (c 1.0, CHCl3); IR
ꢂ
739 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.35–7.22 (m, 5H), 5.5–
;
(neat): m ;
3453, 2954, 2929, 2858, 1252, 1093, 834, 774 cmꢀ1
5.35 (m, 1H), 4.6–4.5 (m, 2H), 3.77–3.4 (m, 3H), 2.4 (m, 1H),
1.65–1.45 (m, 2H), 1.14–1.05 (m, 3H); MS (ESI): m/z 245
[M+Na]+; HRMS (ESI): [M+Na]+ calcd for C13H18O3Na: 245.1153;
found: 245.1163.
1H NMR (CDCl3, 300 MHz): d 7.35–7.24 (m, 5H), 4.55 (s, 2H),
3.75–3.35 (m, 5H), 1.85–1.65 (m, 2H), 1.5–1.42 (m, 1H), 0.91 (d,
J = 6.7 hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (CDCl3,
300 MHz): d 138.09, 128.28, 127.59, 74.23, 73.26, 72.55, 61.06,
35.23, 33.21, 25.85, 18.2, 16.0, ꢀ5.45; MS (ESI): m/z 339
[M+H]+; HRMS (ESI): [M+Na]+ calcd for C19H34O3NaSi: 361.2174;
found: 361.2189.
4.1.4. (3S,4S)-5-(Benzyloxy)-3-methylpentane-1,4-diol 12
Treatment of a solution of lactol 11 (2.47 g, 11.15 mmol) in
CH2Cl2/EtOH (1:1, 6 mL) with NaBH4 (932 mg, 24.53 mmol) at
0 °C for 30 min and stirring at room temperature for 2 h and after
workup in the usual manner yielded the diol 12 (2.24 g, 90%) as a
4.1.6. (5S,6S)-5-(Benzyloxymethyl)-2,2,6,10,10,11,11-
heptamethyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodecane 14
Alcohol 13 (2.7 g, 8.02 mmol) was combined with imidazole
(1.09 g, 16.04 mmol), 4-(dimethylamino)pyridine (97.8 mg,
0.8 mmol) and DMF (10 mL). The solution was cooled to 0 °C and
treated with TBDPSCl (2.746 g, 10.02 mmol). The reaction mixture
was stirred at room temperature for 6 h and the reaction was
quenched with satd aq NaHCO3 (50 mL). The aqueous phase was
extracted with Et2O (3 ꢁ 30 mL). The combined organic layers
were washed with water (2 ꢁ 50 mL), brine, dried over MgSO4, fil-
tered and concentrated. Purification of the crude product by flash
column chromatography afforded disilyl ether 14 (4.527 g, 98%)
colourless oil. Rf = 0.3 (50% EtOAc/hexane). ½a D25
¼ þ2:2 (c 1.0,
ꢂ
CHCl3); IR (neat):
m 3385, 2922, 2871, 1454, 1100, 1065,
742 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.35–7.15 (m, 5H), 4.55
;
(s, 2H), 3.8–3.35 (m, 5H), 1.85–1.5 (m, 3H), 0.91 (d, J = 6.7 Hz,
3H); 13C NMR (CDCl3, 300 MHz): d 137.8, 128.4, 127.7, 74.3,
73.5, 72.7, 60.5, 36.3, 33.8, 16.4; MS (ESI): m/z 247 [M+Na]+;
HRMS (ESI): [M+Na]+ calcd for C13H20O3Na: 247.1310; found:
247.1315.
4.1.5. (2S,3S)-1-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
3-methylpentan-2-ol 13
as
a
colourless viscous liquid. Rf = 0.7 (5% EtOAc/hexane).
¼ ꢀ5:1 (c 1.0, CHCl3); IR (neat): 2955, 2931, 2858, 1466,
1103, 1046, 834, 701 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.7–
Diol 12 (2.0 g, 8.92 mmol) was added into a round-bottomed
flask followed by CH2Cl2 (36 mL) and cooled to 0 °C. Imidazole
(1.33 g, 18.04 mmol) was added and allowed to stir for 5 min.
TBSCl (1.47 g, 9.8 mmol) was added in one portion and continued
the stirring for 30 min. The reaction was quenched with 20 mL of
water. Organic layer was separated and dried over anhydrous
½
a 2D5
ꢂ
m
;
7.63 (m, 4H), 7.41–7.2 (m, 9H), 7.07–7.03 (m, 2H), 4.21–4.15 (m,
2H), 3.82–3.78 (m, 1H), 3.6–3.47 (m, 2H), 3.39 (d, J = 5.2 Hz, 2H),
1.9–1.8 (m, 1H), 1.72–1.62 (m, 1H), 1.4–1.3 (m, 1H), 1.05 (s,
9H),0.95 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR

B. R. V. Prasad, H. M. Meshram / Tetrahedron: Asymmetry 21 (2010) 1837–1844
1841
OR
COOEt
O
O
OH
a
b
BnO
BnO
COOEt
BnO
17
19: R= H
20: R=TBS
18
c
OTBS
OTBS
O
d
e
f
OH
OH
BnO
BnO
21
22
TBSO
O
O
OTBS
OH
i
g
OH
RO
BnO
23
24
: R=Bn
25: R=H
h
j
O
O
TBSO
O
O
TBSO
OTBDPS
BnO
OHC
5
7
Scheme 3. Reagents and conditions: (a) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C; (ii) Ph3PCHCO2Et, benzene, reflux, 4 h, 92% (for two steps).; (b) Me3Al, CH2Cl2,H2O, ꢀ40 °C,
1.5 h, 92%; (c) TBSCl, Et3N, DMAP, CH2Cl2, rt, 24 h, 95%; (d) DIBAL-H, Et2O, ꢀ78 °C to ꢀ20 °C, 1 h, 90%; (e)
L
-(+)-DIPT, Ti(OiPr)4,TBHP, CH2Cl2, ꢀ20 °C, 8 h, 89%; (f) CH3Li, CuI,
Et2O, ꢀ40 °C, 2 h, 80%; (g) PPTS, CH2Cl2, 1 h, 93%; (h) Li, liq. NH3, THF, ꢀ33 °C, 1 h, 91%; (i) TEMPO, BAIB, CH2Cl2, 0 °C to rt, 2 h, 85%; (j) 6, n-BuLi, THF, ꢀ78 °C to 23 °C, 12 h, 75%
(Z/E = 10:1).
(CDCl3, 300 MHz):
d
138.30, 136.06, 135.88, 134.81, 133.94,
m/z 485 [M+Na]+; HRMS (ESI): [M+Na]+ calcd for C29H38O3NaSi:
129.43, 129.24, 128.07, 127.53, 127.4, 127.22, 76.19, 72.86, 72.26,
61.65, 34.84, 33.68, 27.07, 25.96, 19.54, 18.29, 15.53, -5.29; MS
(ESI): m/z 599 [M+Na]+; HRMS (ESI): [M+Na]+ calcd for C35H52O3N-
aSi2: 599.3352; found: 599.3351.
485.2487; found: 485.2487.
4.1.8. ((2S,3S)-1-(Benzyloxy)-5-iodo-3-methylpentan-
2-yloxy)(tert-butyl)diphenylsilane 16
To a stirred solution of alcohol 15 (2.52 g, 5.46 mmol) in dry THF
(22 mL) was added triphenyl phosphine (1.71 g, 6.55 mmol), imid-
azole (928 mg, 13.65 mmol) and iodine (1.795 g, 7.09 mmol) at
0 °C under nitrogen atmosphere. After 1 h the reaction mixture
was diluted with diethyl ether (10 mL), washed with 10% Na2S2O3,
brine and dried over anhydrous Na2SO4. Concentration in vacuo
and column chromatography through a short pad of silica gel
afforded iodo compound 16 (2.78 g, 89%) as a pale yellow liquid.
4.1.7. (3S,4S)-5-(Benzyloxy)-4-(tert-butyldiphenylsilyloxy)-
3-methylpentan-1-ol 15
Camphorsulfonic acid (491 mg, 2.11 mmol) was added to a stir-
red 0 °C solution of the disilyl ether 14 (3.69 g, 6.42 mmol) in
25 mL of dichloromethane and 25 mL of methanol. After 1.5 h the
reaction was quenched with satd NaHCO3, extracted three times
with dichloromethane and dried over Na2SO4. Concentration in va-
cuo and purification by flash column chromatography yielded alco-
hol 15 (2.67 g, 90%) as a colourless viscous oil. Rf = 0.4 (20% EtOAc/
Rf = 0.7 (5% EtOAc/hexane). ½a D25
ꢂ
¼ ꢀ6:0 (c 1.0, CHCl3); IR (neat):
m
2959, 2931, 2858, 1427, 1109, 739, 701 cmꢀ1
;
1H NMR (CDCl3,
hexane). ½a 2D5
ꢂ
¼ ꢀ8:5 (c 1.0, CHCl3); IR (neat):
m
3423, 2929, 2857,
300 MHz): d 7.65–7.6 (m, 4H), 7.4–7.2 (m, 9H), 7.06–7.02 (m, 2H),
4.2 (d, J = 3.7 Hz, 2H), 3.75–3.7 (m, 1H), 3.36–3.32 (m, 2H), 3.2–3.1
(m, 1H), 3.04–2.94 (m, 1H), 2.05–1.95 (m, 1H), 1.82–1.63 (m, 2H),
1.05 (s, 9H), 0.9 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 300 MHz): d
138.01, 135.98, 135.77, 134.46, 133.48, 129.55, 129.35, 128.1,
127.53, 127.5, 127.28, 75.25, 72.88, 71.87, 37.83, 35.80, 27.05,
19.46, 14.8, 5.5; MS (ESI): m/z 595 [M+Na]+; HRMS (ESI): [M+Na]+
calcd for C29H37O2NaSiI: 595.1505; found: 595.1520.
1460, 1107, 700 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 7.65–7.6 (m,
4H), 7.4–7.2 (m, 9H), 7.05–7.04 (m, 2H), 4.2 (s, 2H), 3.85–3.75
(m, 1H), 3.60–3.38 (m, 4H), 1.84–1.75 (m, 1H) 1.62–1.59 (m, 1H),
1.45–1.4 (m, 1H), 1.05 (s, 9H), 0.94 (d, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 300 MHz):
d 138.06, 136.07, 135.83, 134.44, 133.61,
129.58, 129.38, 128.13, 127.61, 127.46, 127.35, 127.28, 75.76,
72.92, 72.03, 60.78, 34.43, 33.47, 27.06, 19.49, 15.79; MS (ESI):

1842
B. R. V. Prasad, H. M. Meshram / Tetrahedron: Asymmetry 21 (2010) 1837–1844
4.1.9. Preparation of phosphonium salt 6
(179 mg, 1.47 mmol) and TBSCl (2.64 g, 17.64 mmol). This solution
was stirred for 24 h and then the reaction was quenched with satd
aq sodium bicarbonate. The layers were separated and the aqueous
layer was extracted with ether (3 ꢁ 60 mL). The combined organic
layers were washed with brine (60 mL) and dried over anhydrous
sodium sulfate. After removal of the solvent in vacuo, flash chro-
matography on silica gel afforded the ester 20 (5.67 g, 95%) as a
To a solution of iodo compound 16 (2.5 g, 4.37 mmol) in 5 mL of
benzene was added triphenylphosphine (1.26 g, 4.8 mmol) in 1 mL
of benzene under argon atmosphere and stirred for 48 h. During
this time the solution forms a thick precipitate. The reaction mix-
ture was cooled to 0 °C and diluted with ether (10 mL). The precip-
itate was collected by filtration and washed with hexane. The solid
was dried under reduced pressure to give the phosphonium salt 6
(3.3 g, 92%) as a pale yellow solid.
pale yellow oil. Rf = 0.6 (10% EtOAc/hexane). ½a D25
¼ ꢀ34:5 (c 1.0,
ꢂ
CHCl3); IR (neat):
m 2955, 2857, 1720, 1651, 1257, 1096, 1033,
837, 775 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.35–7.20 (m, 5H),
;
4.1.10. (E)-Ethyl 3-((2R,3S)-3-(2-(benzyloxy)ethyl)oxiran-
2-yl)acrylate 18
6.99 (dd, J = 15.8 Hz, 7.5 Hz, 1H), 5.76 (dd, J = 15.8 Hz, 1.5 Hz, 1H),
4.45 (m, 2H), 4.15 (q, J = 6.7 Hz, 2H), 3.84 (dt, J = 7.5 Hz, 4.5 Hz,
1H), 3.52–3.42 (m, 2H), 2.44–2.36 (m, 1H), 1.8–1.6 (m, 2H), 1.3
(t, J = 6.7 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.03 (d,
6H); 13C NMR (CDCl3, 300 MHz): d 166.6, 151.3, 138.3, 128.3,
127.6, 127.5, 121.0, 72.9, 72.2, 66.7, 60.0, 41.9, 33.7, 25.8, 18.0,
14.2, 13.9, ꢀ4.4, ꢀ4.6; MS (ESI): m/z 407 [M+H]+; HRMS (ESI):
[M+Na]+ calcd for C23H38O4NaSi: 429.2437; found: 429.2436.
To oxalyl chloride (3.848 mL, 44.82 mmol) in CH2Cl2 (144 mL) at
ꢀ78 °C was added dimethyl sulfoxide (6.78 mL, 95.63 mmol) over
15 min. The reaction mixture was stirred for an additional 15 min
before epoxy alcohol 17 (6.22 g, 29.88 mmol) dissolved in CH2Cl2
(28 mL) was added via a cannula. The mixture was stirred for
30 min before triethylamine (20.77 mL, 150 mmol) was added drop-
wise. The reaction mixturewas allowed to warm up to room temper-
ature for 30 min and water (172 mL) was added and the aqueous
phase was extracted with CH2Cl2 (2 ꢁ 160 mL). The combined or-
ganic layers were washed with brine and dried over anhydrous
Na2SO4. The resulting aldehyde obtained after concentration was
used immediately for the next step without further purification.
To a stirred solution of the aldehyde in 144 mL of benzene was
added Ph3PCHCO2Et (10.92 g, 31.2 mmol) in one portion. The reac-
tion mixture was concentrated in vacuo after stirring at 80 °C for
4 h. Purification by flash column chromatography gave epoxy
acrylate 18 6.61 g (92%) as a colourless liquid. Rf = 0.7 (30% EtOAc/
4.1.13. (4S,5S,E)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
4-methylhept-2-en-1-ol 21
To a ꢀ78 °C solution of ester 20 (5.37 g, 13.23 mmol) in Et2O
(78 mL) was added DIBAL-H (33.07 mL of a 1.0 M solution in hex-
anes, 33.07 mmol) dropwise. The mixture was allowed to warm up
to ꢀ20 °C for 1 h and then the reaction was quenched with satd aq
sodium potassium tartrate (Rochelle’s salt, 70 mL) and diluted with
Et2O. The mixture was stirred at room temperature for 12 h. The
aqueous phase was extracted with Et2O (3 ꢁ 40 mL), dried over
anhydrous MgSO4, filtered and concentrated to provide pure allyl
alcohol 21 (4.33 g, 90%) as a colourless oil. Rf = 0.5 (30% EtOAc/hex-
hexane). ½a 2D5
ꢂ
¼ ꢀ7:2 (c 1.0, CHCl3); IR (neat):
m
;
2924, 2856, 1718,
1306, 1265, 1183, 1100, 1033, 977 cmꢀ1
1H NMR (CDCl3,
ane). ½a 2D5
ꢂ
¼ ꢀ26:5 (c 1.0, CHCl3); IR (neat):
m
;
3415, 2955, 2929,
200 MHz): d 7.37–7.20 (m, 5H), 6.77 (dd, J = 15.6, 6.3 Hz, 1H), 6.06
(d, J = 15.6 Hz, 1H), 4.50 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.65–3.55
(m, 2H), 3.54–3.47 (m, 1H), 3.38–3.29 (m, 1H), 1.88–1.76 (m, 2H),
1.30 (t, J = 7 Hz, 3H); 13C NMR (CDCl3, 200 MHz): d 165.28, 141.60,
138.04, 128.22, 127.45, 127.39, 125.12, 72.89, 66.98, 60.40, 57.16,
54.87, 28.17, 14.04; MS (ESI): m/z 299 [M+Na]+; HRMS (ESI):
[M+Na]+ calcd for C16H20O4Na: 299.1259; found: 299.1254.
2856, 1461, 1253, 1097, 837, 773 cmꢀ1 1H NMR (CDCl3,
300 MHz): d 7.39ꢀ7.2 (m, 5H), 5.75–5.55 (m, 2H), 4.5–4.39 (m,
2H), 4.1–4.05 (m, 2H), 3.8–3.7 (m, 1H), 3.5–3.42 (m, 2H), 2.34–
2.25 (m, 1H), 1.8–1.6 (m, 2H), 0.97 (d, J = 7.5 Hz, 3H), 0.88 (s, 9H),
0.01 (s, 6H); 13C NMR (CDCl3, 300 MHz): d 138.1, 135.6, 128.3,
128.2, 127.7, 127.5, 73.4, 72.9, 66.5, 58.2, 37.6, 34.0, 25.8, 18.0,
17.1, ꢀ4.4, ꢀ4.5; MS (ESI): m/z 387 [M+Na]+; HRMS (ESI):
[M+Na]+ calcd for C21H36O3NaSi: 387.2331; found: 387.2337.
4.1.11. (4S,5S,E)-Ethyl 7-(benzyloxy)-5-hydroxy-4-methylhept-
2-enoate 19
4.1.14. ((2S,3S)-3-((2S,3S)-5-(Benzyloxy)-3-(tert-
Epoxy acrylate 18 (5.79 g, 21 mmol) was added into a round-
bottomed flask followed by CH2Cl2 (210 mL) and cooled to
ꢀ40 °C. Me3Al (2 M in toluene, 105 mL, 210 mmol) was added
and allowed to stir for 5 min. Then H2O (2.25 mL, 125.9 mmol)
was added and continued the reaction at same temperature for
1.5 h before it was quenched with satd aq NH4Cl solution. Organic
layer was separated and dried over anhydrous Na2SO4. Concentra-
tion in vacuo and purification by flash column chromatography
gave the hydroxyl ester 19 (5.64 g, 92%) as a colourless liquid.
butyldimethylsilyloxy)pentan-2-yl)oxiran-2-yl)methanol 22
Dry CH2Cl2 (77 mL) was added to 2.2 g of 4 Å powdered acti-
vated molecular sieves and the suspension mixture was cooled to
ꢀ20 °C under nitrogen atmosphere.
L-(+)-DIPT (0.26 mL,
1.26 mmol) and Ti(OiPr)4 (0.3 mL, 1.05 mmol) were added subse-
quently with stirring and the resulting mixture was stirred for
30 min at ꢀ20 °C. The allyl alcohol 21 (3.84 g, 10.55 mmol) in dry
CH2Cl2 (20 mL) was added and the resulting mixture was stirred
for another 30 min at ꢀ20 °C. TBHP (9.89 mL, 3.2 M in toluene,
31.65 mmol) was then added and the resulting mixture was stirred
at the same temperature for 8 h. It was then warmed to 0 °C, the
reaction was quenched with 10 mL of water and the reaction mix-
ture was stirred for 2 h at room temperature. 30% aq NaOH solu-
tion saturated with NaCl (15 mL) was then added and the
resulting mixture was stirred vigorously for another 30 min at
room temperature. The resulting mixture was filtered through Cel-
ite pad and the filter cake was washed well with CH2Cl2. The organ-
ic phase was separated and the aqueous phase was extracted with
CH2Cl2 (3 ꢁ 30 mL). Combined organic phases were washed with
brine and dried over Na2SO4. Removal of solvent under reduced
pressure and purification afforded epoxy alcohol 22 (3.56 g, 89%)
Rf = 0.3 (20% EtOAc/hexane). ½a D25
ꢂ
¼ ꢀ14:4 (c 1.0, CHCl3); IR (neat):
m
3480, 2973, 2868, 1716, 1454, 1368, 1271, 1182, 1096, 1033,
987 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 7.36–7.22 (m, 5H), 6.88
(dd, J = 15.9, 8.3 Hz, 1H), 5.79 (dd, J = 15.9, 1.5 Hz, 1H), 4.50 (s,
2H), 4.16 (q, J = 6.8 Hz, 2H), 3.75–3.67 (m, 2H), 3.61 (dt, J = 9.0,
6.8 Hz, 1H), 3.03 (d, J = 2.3 Hz, 1H), 2.45–2.31 (m, 1H), 1.74–1.66
(m, 2H), 1.29 (t, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 200 MHz):
d 166.52, 150.75, 137.69, 128.40, 127.77,
127.62, 121.52, 74.21, 73.37, 69.30, 60.15, 42.59, 33.56, 14.57,
14.18; MS (ESI): m/z 315 [M+Na]+; HRMS (ESI): [M+Na]+ calcd for
C17H24O4Na: 315.1572; found: 315.1562.
4.1.12. (4S,5S,E)-Ethyl-7-(benzyloxy)-5-(tert-butyldimethyl
silyloxy)-4-methylhept-2-enoate 20
To a solution of hydroxyl ester 19 (4.29 g, 14.7 mmol) in CH2Cl2
(58 mL) were added Et3N (4.09 mL, 29.4), dimethylaminopyridine
as a pale yellow liquid. Rf = 0.3 (30% EtOAc/hexane). ½a D25
¼ ꢀ24:5
ꢂ
(c 1.0, CHCl3); IR (neat):
m 3346, 2954, 2930, 2857, 1463, 1253,
1091, 1024, 836, 773 cmꢀ1
;
1H NMR (CDCl3, 400 MHz): d 7.38–
7.22 (m, 5H), 4.45–4.35 (m, 2H), 3.89–3.8 (m, 2H), 3.61–3.54 (m,

B. R. V. Prasad, H. M. Meshram / Tetrahedron: Asymmetry 21 (2010) 1837–1844
1843
1H), 3.45–3.38 (m, 2H), 2.95–2.8 (m, 2H), 1.8–1.7 (m, 1H), 1.66–1.6
(m, 1H) 1.5–1.4 (m, 1H), 0.98 (d, J = 7.3 Hz, 3H), 0.89 (s, 9H), 0.04 (s,
6H); 13C NMR (CDCl3, 300 MHz): d 138.2, 128.2, 127.6, 127.5, 72.9,
72.0, 66.78, 61.72, 58.0, 57.8, 41.0, 33.6, 25.7, 21.6, 17.9, ꢀ4.5,
ꢀ4.6; MS (ESI): m/z 403 [M+Na]+; HRMS (ESI): [M+Na]+ calcd for
1464,, 1381, 1256, 1064, 1006, 835, 772 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 3.8–3.6 (m, 5H), 3.5–3.4 (m, 1H), 1.9–1.7 (m, 4H),
1.4 (s, 3H), 1.3 (s, 3H), 0.92 (s, 9H), 0.9 (d, J = 4.1 Hz, 3H), 0.7 (d,
J = 6.6 Hz, 3H), 0.1 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3,
300 MHz): d 97.9, 73.8, 72.8, 66.4, 60.4, 38.2, 34.5, 30.7, 29.6,
25.8, 25.4, 18.9, 12.5, 9.8, ꢀ4.4, ꢀ4.6; MS (ESI): m/z 369 [M+Na]+;
HRMS (ESI): [M+Na]+ calcd for C18H3804NaSi: 369.2437; found:
369.2442.
C
21H3604NaSi: 403.2280; found: 403.2292.
4.1.15. (2R,3R,4S,5S)-7-(Benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-2,4-dimethylheptane-1,3-diol 23
To a cold (ꢀ23 °C) suspension of copper(I) iodide (6.58 g,
34.56 mmol) in dry ether (20 mL), MeLi (34.56 mL, 69.12 mmol,
2.0 M) in ether was added dropwise until it become a clear solu-
tion. After 30 min. at this temperature the solution was cooled to
ꢀ40 °C and then epoxy alcohol 22 (3.14 g, 8.64 mmol) in ether
(50 mL) was added dropwise. After being stirred for 2 h at ꢀ40 °C
and then for 30 min at ꢀ23 °C, the mixture was poured into satd
aq NH4Cl (30 mL) and the blue aqueous layer was thoroughly ex-
tracted with CH2Cl2 (3 ꢁ 20 mL). The combined organic layers were
washed with brine (20 mL), dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. The contamination of the 1,2-
diol was eliminated by exposing the crude reaction mixture to aq
NaIO4 followed by silica gel column chromatography using petro-
leum ether/EtOAc to give pure 1,3-diol 23 (2.73 g, 80%) as a colour-
4.1.18. (3S,4S)-3-(tert-Butyldimethylsilyloxy)-4-((4R,5R)-2,2,5-
trimethyl-1,3-dioxan-4-yl)pentanal 7
To a stirred solution of 25 (830 mg, 2.4 mmol) in CH2Cl2 (24 mL)
was added TEMPO (113 mg, 0.72 mmol) followed by iodobenzene
diacetate (2.3 g, 7.2 mmol). After stirring for 2 h at rt, the reaction
mixture was treated with 5% aq Na2S2O3 solution (3 mL) and satd
aq NaHCO3 solution (3 mL). After 15 min, the organic phase was
separated and the aqueous phase was extracted with Et2O
(3 ꢁ 8 mL). The combined organic extracts were dried over anhy-
drous Na2SO4 and concentrated under reduced pressure to get
the corresponding aldehyde (701 mg, 85%) as viscous colourless
oil, which was immediately used for the olefination reaction.
4.1.19. (5S,10S,11S,Z)-11-(Benzyloxymethyl)-2,2,3,3,10,14,14-
heptamethyl-13,13-diphenyl-5-((S)-1-((4R,5R)-2,2,5-trimethyl-
1,3-dioxan-4-yl)ethyl)-4,12-dioxa-3,13 disilapentadec-7-ene 5
In a flame-dried 10-mL flask, phosphonium salt 6 (242 mg,
0.29 mmol) was dried under high vacuum for 1 h. Under argon, it
was dissolved in fresh, dry THF (1 mL) and n-BuLi (0.11 mL of a
2.4 M solution in hexane, 0.29 mmol) was added dropwise. After
stirring for 1 h at 23 °C, the flask containing the deep-red suspen-
sion was cooled to ꢀ78 °C and a precooled (ꢀ78 °C) solution of
freshly prepared aldehyde 7 (99.6 mg, 0.29 mmol) in THF (1.9 mL)
was added dropwise. After stirring for an additional 12 h, the reac-
tion mixture was allowed to slowly warm to 23 °C overnight. The
reaction was quenched with satd aq NH4Cl and some H2O and the
reaction mixture was extracted (1 ꢁ Et2O, 2 ꢁ CH2Cl2). The com-
bined organic phase was dried (MgSO4), filtered and concentrated.
The residue was purified by column chromatography to give pure
olefin (168 mg, 75%, Z/E=10:1) as a yellow liquid. Rf = 0.8 (2%
less syrup. Rf = 0.3 (40% EtOAc/hexane).
½
a 2D5
ꢂ
¼ ꢀ14:5 (c 1.0,
CHCl3); IR (neat):
m
3413, 2931, 2858, 1462, 1254, 1090, 1026,
976, 836, 774 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 7.3–7.22 (m,
5H), 4.5–4.4 (m, 2H), 4.1–4.0 (m, 1H), 3.65–3.5 (m, 3H) 3.5–3.39
(m, 3H), 1.9–1.8 (m, 3H), 1.7–1.6 (m, 1H), 0.90 (s, 9H), 0.88 (d,
J = 5.2 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H), 0.1 (d, 6H); 13C NMR (CDCl3,
300 MHz): d 138.1, 128.3, 127.6, 127.5, 81.0, 75.4, 73.0, 68.6, 66.7,
37.5, 37.4, 34.6, 25.7, 17.8, 13.5, 5.9, ꢀ3.8, ꢀ4.6; MS (ESI): m/z 397
[M+H]+; HRMS (ESI): [M+Na]+ calcd for C22H40O4NaSi: 419.2593;
found: 419.2591.
4.1.16. ((3S,4S)-1-(Benzyloxy)-4-((4R,5R)-2,2,5-trimethyl-1,3-
dioxan-4-yl)pentan-3-yloxy)(tert-butyl)dimethylsilane 24
To a solution of diol 23 (2.39 g, 6.04 mmol) in dry CH2Cl2
(30 mL), 2,2-dimethoxy propane (3.69 mL, 30.2 mmol) and PPTS
(770 mg) were added. The mixture was stirred at the same temper-
ature for 1 h. Sodium bicarbonate was added to neutralize PPTS
and filtered. Removal of solvent and purification by silica gel col-
umn chromatography afforded the acetonide 24 (2.44 g, 93%) as
EtOAc/hexane). ½a D25
ꢂ
¼ ꢀ15:5 (c 1.0, CHCl3); IR (neat):
m
3303,
2920, 2850, 1689, 1563, 1508, 1343, 1209, 747 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz): d 7.68–7.62 (m, 4H), 7.34–7.2 (m, 11H), 5.61
(dt, J = 11.1, 6.0 Hz, 1H), 5.48 (ddd, J = 11.1, 10.0, 7.2 Hz, 1H), 4.2
(d, J = 6.7 Hz, 2H), 3.9–3.8 (m, 2H), 3.6–3.38 (m, 5H), 2.4–2.3 (m,
4H), 2.2–2.1 (m, 1H), 2.0–1.75 (m, 2H), 1.34 (s, 3H), 1.3 (s, 3H),
1.08 (d, J = 6.7 Hz, 3H), 1.02 (s, 9H), 0.9 (s, 9H), 0.78 (d, J = 7.5 Hz,
3H), 0.6 (d, J = 6.7 Hz, 3H), 0.05 (s, 6H); 13C NMR (CDCl3,
300 MHz): d 139.4, 135.8, 135.7, 133.9, 131.6, 129.5, 128.4, 128.2,
127.6, 127.1, 126.8, 126.6, 126.0, 97.9, 76.1, 73.5, 72.9, 66.3, 63.1,
59.5, 38.2, 37.0, 30.3, 29.9, 28.3, 27.0, 26.9, 26.1, 22.6, 19.6, 19.2,
16.0, 12.4, 9.9, ꢀ5.0, ꢀ5.2; MS (ESI): m/z 796 [M+Na]+.
a colourless syrup. Rf = 0.6 (5% EtOAc/hexane). ½a D25
¼ ꢀ23:5 (c
ꢂ
1.0, CHCl3); (neat):
m 2932, 2856, 1461, 1378, 1254, 1111, 1005,
835, 772 cmꢀ1 1H NMR (CDCl3, 500 MHz): d 7.3–7.24 (m, 5H),
;
4.45 (m, 2H), 3.8–3.7 (m, 2H), 3.6–3.58 (m, 1H), 3.5–3.4 (m, 2H),
1.9–1.7 (m, 4H), 1.4 (s, 3H) 1.3 (s, 3H), 0.9 (s, 9H), 0.83 (d,
J = 5.8 Hz, 3H), 0.62 (d, J = 6.8 Hz, 3H), 0.02 (s, 6H); 13C NMR (CDCl3,
300 MHz): d 138.6, 128.2, 127.6, 127.4, 97.6, 72.7, 72.6, 72.0, 67.0,
66.5, 38.7, 32.9, 30.7, 29.7, 25.9, 19.0, 17.9, 12.5, 9.9, ꢀ4.2, ꢀ4.7 MS
(ESI): m/z 459 [M+Na]+; HRMS (ESI): [M+Na]+ calcd for C25H44O4
NaSi: 459.2906; found: 459.2896.
Acknowledgement
4.1.17. (3S,4S)-3-(tert-Butyldimethylsilyloxy)-4-((4R,5R)-2,2,5-
trimethyl-1,3-dioxan-4-yl)pentan-1-ol 25
B.R.V.P. thanks CSIR, New Delhi, for the award of fellowship.
To a solution of lithium (0.167 g, 23.8 mmol) in liquid NH3
(28 mL) was added compound 24 (2.09 g, 4.8 mmol) in dry THF
(2 mL) at ꢀ33 °C. The reaction mixture was stirred for 1 h at the
same temperature and the reaction was quenched with solid NH4Cl
till blue colour disappears. Ammonia was allowed to evaporate and
the residual mixture was taken in ethyl acetate (10 mL), washed
with water (2 ꢁ 5 mL) and brine (1 ꢁ 3 mL) and dried over anhy-
drous Na2SO4. Evaporation of the solvent and purification of the
residue by silica gel column chromatography afforded alcohol 25
(1.51 g, 91%) as a pale yellow syrup. Rf = 0.3 (20% EtOAc/hexane).
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a 2D5
ꢂ
¼ ꢀ30:5 (c 1.0, CHCl3); IR (neat):
m 3444, 2955, 2933, 2857,

1844
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