A new synthesis of the phytotoxic 10-membered lactone herbarumin I

Article abstract of DOI:10.1016/j.tetasy.2009.03.034

Herbarumin I a phytotoxic 10-membered lactone has been synthesized from d-(-)-isoascorbic acid in 12 steps with an overall yield of 16.8%. The methodology involved in generating the stereogenic center at C-8 is a Sharpless asymmetric epoxidation, as well 1,2-asymmetric induction followed by macrolactonization via RCM.

Full text of DOI:10.1016/j.tetasy.2009.03.034

Tetrahedron: Asymmetry 20 (2009) 1115–1119
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A new synthesis of the phytotoxic 10-membered lactone herbarumin I
*
J. Jon Paul Selvam, K. Rajesh, V. Suresh, D. Chanti Babu, Y. Venkateswarlu
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herbarumin I a phytotoxic 10-membered lactone has been synthesized from
D
-(ꢀ)-isoascorbic acid in 12
Received 12 January 2009
Accepted 10 March 2009
Available online 6 May 2009
steps with an overall yield of 16.8%. The methodology involved in generating the stereogenic center at C-8
is a Sharpless asymmetric epoxidation, as well 1,2-asymmetric induction followed by macrolactonization
via RCM.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
DIBAL-H in DCM at ꢀ78 °C followed by the two carbon Wittig olef-
ination to afford the unsaturated ester 15 (E/Z ratio 85:15). This
Herbarumin I, a 10-membered macrolide was isolated from the
culture of Phoma herbarum fungus by Mata and co-workers in
2000.1 Since then, a series of other related 10-membered lactones
have been isolated with phytotoxic activity. Herbarumin I remains
to be the most phytotoxicity of the series on the seeding of Ama-
ranthus hypochondriacus1, holding promises as a lead compound
for the discovery of new herbicides. The initial structural and ste-
reochemical assignment of herbarumin I was established by Fürst-
ner et al. through total synthesis.2 Since then different total
syntheses3 have been reported. Herein we report an enantioselec-
tive total synthesis of herbarumin I from commercially available
unsaturated ester was further reduced to allylic alcohol 16 using
DIBAL-H and was subjected to a Sharpless asymmetric epoxidation
to afford epoxide 17. Opening of epoxide7 was carried out when 17
was refluxed with TPP in CCl4 followed by treatment with sodium
metal in ether to produce allylic alcohol 18. Deprotection of the
TBDMS group followed by a benzyl protection of diol 19 afforded 7.
Compound 7 prepared by both methods was matched in rota-
tion and spectral values. Deprotection of primary acetonide in
compound 7 with pTSA in MeOH furnished diol 8 in quantitative
yield, which was further subjected to mono-tosylation in the pres-
ence of a catalytic amount of dibutyltin oxide to give 9 followed by
subsequent exposure to K2CO3 to afford epoxide 10. Treatment of
10 with EtMgBr in the presence of CuBr afforded alcohol 11, which
was esterified with hex-5-enoic acid using a Yamaguchi protocol8
to furnish compound 12 in good yield. The RCM of 12 in the pres-
ence of Grubbs II generation catalyst3a,9 led to the required pro-
tected lactone 13 in 84% yield. The ring closure metathesis was
very smooth and benzyl protection did not hinder the formation
of the required compound 13. In previous reports the required E-
isomer was achieved through Grubbs I catalyst whereas, Grubbs
II led to the Z-isomer. In the present study the E-isomer was
achieved in good yield when we used Grubbs II catalyst.
D
-(ꢀ)-isoascorbic acid as a chiral source.
2. Results and discussion
Our retro synthetic approach is outlined in Scheme 1. The ste-
reochemistry of the two contiguous stereogenic centers can be
matched by the pattern displayed by
D
-(ꢀ)-isoascorbic acid. There-
fore, this was chosen as a readily accessible starting material,
which was converted on a gram scale into esters 3 and 14 using
a known protocol.4 This follows an effective route in the prepara-
tion of hex-5-enoic ester 12 and RCM resulted in herbarumin I
(Scheme 1).
In fact, compared to the previous approaches3 this reaction has
given a higher yield and selectivity of the required E-isomer in
90:10 (E/Z ratio). Deprotection of the benzyl groups was achieved
using TiCl4 in DCM at 0 °C to provide the natural product herbaru-
min I 1 in 74% yield.10 The physical and spectral data of synthetic
herbarumin I are identical with those of the natural product.
Using ester 2 as the starting material the chiral center at C-8
was generated by two different routes. Strategy one involves con-
version of ester 2 into vinyl ketone 5 using Weinreb amide 4 fol-
lowed by treatment with vinyl magnesium bromide.5 Ketone 5
was reduced selectively by zincborohydride6 with good diastere-
oselectivity (94:6) to afford alcohol 6 (Scheme 3). The intermediate
6 was also prepared starting from compound 2 involving the
sequential functional group manipulations as shown in Scheme
2. This includes the reduction of TBS protected ester 14 using
3. Conclusion
In conclusion, we have reported an asymmetric total synthesis
of herbarumin I, from
ent strategies with an overall yield of 16.8%. The alcohol fragment
D
-(ꢀ)-isoascorbic acid involving two differ-
* Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
6 was synthesized in enantiomerically pure form by different
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.034

1116
J. Jon Paul Selvam et al. / Tetrahedron: Asymmetry 20 (2009) 1115–1119
O
OBn
HO
HO
O
O
OBn
O
OBn
O
OBn
10
12
1
O
O
COOEt
OTBS
14
OBn
O
O
O
O
O
OH
OBn
OTBS
7
17
O
OH
O
O
COOEt
O
D
-(-)-isoascorbic acid
OBn
OBn
3
6
Scheme 1. Retro synthesis of herbarumin I.
O
Ref. 4
O
O
a
b
D
-(-)-isoascorbic acid
O
O
O
COOEt
OH
COOEt
OTBS
COOEt
OTBS
2
14
15
c
O
OBn
O
OH
O
O
g
e
d
O
O
O
O
O
OH
OH
OBn
OR
OTBS
OTBS
7
17
16
R = TBS 18
R = H 19
f
Scheme 2. Reagents and conditions: (a) TBDMS-Cl, imidazole, DCM, rt, 3 h 96%; (b) (i) DIBAL-H, DCM, ꢀ78 °C, 30 min; (ii) two carbon ylide, DCM, 2 h, 82% (for two steps); (c)
DIBAL-H, DCM, ꢀ78 °C, 30 min, 89%; (d) (ꢀ)-DET, Ti(OPri)4, TBHP, molecular sieves 4 Å, DCM, ꢀ20 °C, 15 h, 76%; (e) (i) PPh3, CCl4, 80 °C, 6 h; (ii) sodium metal, ether, 8 h, 68%
(for two steps); (f) TBAF, THF, 1.5 h, 97%; (g) NaH, BnBr, THF, rt, 2 h, 95%.
routes from the same chiron. The synthesis also featured epoxide
opening with sodium metal in preparation of compound 18 and
stereoselective induction of a 1,2-anti chiral alcohol using zinc-
borohydride in the preparation of compound 6. Opening of epoxide
10 with EtMgBr followed by a lactonization of 12 by RCM led to
herbarumin I in enantiomerically pure form. The present synthesis
will provide an access to a synthesis of variety of structural ana-
logues of herbarumin I for biological studies.
on HORIBA SEPA-300 polarimeter, 10 ml cell. 1H and 13C NMR
spectra were recorded in CDCl3 solution on a Varian Gemini 200
and Brucker Avance 300. Chemical shifts were reported in parts
per million with respect to internal TMS. Coupling constants (J)
are quoted in hertz. Mass spectra were obtained on MS-ESI, HRMS
mass spectrometers.
4.1.1. (R)-Ethyl 2-(benzyloxy)-2-((R)-2,2-dimethyl-1,3-dioxalan-
4-yl)acetate 3
4. Experimental
To a solution of ascorbate 2 (5 g, 24.5 mmol) in dry DCM
(50 mL) was added silver oxide (8.5 g, 36.7 mmol) followed by ben-
zyl bromide (3.59 mL, 26.2 mmol). The reaction mixture was stir-
red for 12 h at room temperature and was filtered through a pad
of Celite. The filtrate was evaporated to dry and was purified over
silica gel column chromatography (92:8 hexane–EtOAc) to furnish
4.1. General methods
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel of 60-120 mesh. IR (FT-IR) spectra were measured as KBr pel-
lets or as films between KBr plates. Optical rotations were recorded
a pure compound 3 (6.26 g, 87%) as a colorless liquid. ½a D20
ꢁ
¼ þ26:5
(c 2.0, MeOH); IR: 2933, 1743, 1254, 1076, 840 cmꢀ1
;
1H NMR

J. Jon Paul Selvam et al. / Tetrahedron: Asymmetry 20 (2009) 1115–1119
1117
O
O
O
O
O
O
h
j
i
O
COOEt
OH
O
Me
COOEt
OBn
O
O
N
OBn
OBn
OMe
2
3
4
5
k
OBn
O
RO
OBn
O
OBn
o
O
OH
m
l
R'O
O
O
OBn
OBn
R, R' = H
OBn
OBn
10
7
6
8
n
R = H, R' = Ts 9
p
O
BnO
BnO
HO
HO
OH OBn
OBn
O
OBn
q
r
s
O
O
OBn
O
O
11
12
13
1
Scheme 3. Reagents and conditions: (h) BnBr, Ag2O, DCM, rt, 12 h, 87%; (i) NH(Me)(OMe), C3H7MgBr, THF, ꢀ10 °C, 1 h, 90%; (j) vinyl magnesium bromide, THF, ꢀ78 °C then rt,
2 h, 78%; (k) ZnBH4, ether, ꢀ50 °C, 1 h, 86%; (l) NaH, BnBr, 0 °C to rt 2 h, 95%; (m) PTSA, MeOH, 2 h, 98%; (n) TsCl, Et3N, Bu2SnO, rt, 4 h; (o) K2CO3, MeOH, 1 h, 85% (for the two
steps); (p) C2H5MgBr, Cu2Br2, THF, ꢀ30 °C, 75%; (q) Hex-5-enoic acid, Et3N, 2,4,6-trichloro benzoyl chloride, DMAP, toluene, 3 h, 87%; (r) Grubb’s II catalyst, DCM, reflux, 12 h,
84%; (s) TiCl4, DCM, 0 °C, 1 h, 74%.
(300 MHz, CDCl3): d 7.26–7.39 (m, 5H); 4.62–4.65 (d, J = 11.70 Hz,
1H); 4.44–4.48 (d, J = 11.70 Hz, 1H); 4.14–4.30 (m, 3H); 3.92–4.01
(m, 2H); 3.86 (d, J = 6.61 Hz, 1H); 1.38 (s, 3H); 1.31 (s, 3H); 1.27–
1.32 (t, J = 7.17 Hz, 3H); 13C NMR (300 MHz, CDCl3): 170.1, 137.0,
128.3, 128.0, 128.0, 109.7, 96.2, 79.1, 75.9, 77.7, 66.2, 60.8, 26.7,
25.5, 14.3; ESI-MS: 317 [(M+Na)+]; HRMS calcd for C16H22O5Na
317.1365, found 317.1354.
was stirred at the same temperature for 1 h and then slowly
warmed to room temperature over 2 h. The reaction was quenched
by the addition of saturated NH4Cl. The organic layer was extracted
with EtOAc. Combined organic extract was successively washed
with brine, dried over anhydrous Na2SO4, and evaporated in vacuo.
Purification upon silica gel chromatography (95:5 hexane–EtOAc)
furnished a pure compound 5 (2.7 g, 78%) as
a yellow oil.
½
a 2D0
ꢁ
¼ þ22:1 (c 1.2, MeOH); IR: 2917, 1757, 1713,1634,1110 cmꢀ1
;
4.1.2. (R)-2-(Benzyloxy)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
N-methoxy-N-methylacetamide 4
1H NMR (300 MHz, CDCl3): d 7.28–7.38 (m, 5H); 6.74–6.85 (dd,
J = 17.37, 10.57 Hz, 1H); 6.37–6.45 (dd, J = 17.37, 1.70 Hz, 1H);
5.76–6.45 (dd, J = 10.57, 1.70 Hz, 1H); 4.58–4.62 (d, J = 11.52 Hz,
1H); 4.46–4.51 (d, J = 11.52 Hz, 1H); 4.29–4.35 (q, J = 11.89,
6.23 Hz, 1H); 3.93–4.08 (m, 3H); 1.40 (s, 3H); 1.32 (s, 3H); 13C
NMR (300 MHz, CDCl3): 198.7, 136.9, 132.1, 129.7, 128.5, 128.1,
110.0, 83.7, 75.8, 72.9, 66.4, 26.4, 25.1; ESI-MS: 299 [(M+Na)+];
HRMS calcd for C16H20O4Na 299.1259, found 299.1247.
A solution of dried THF (50 mL) containing a mixture of ester 3
(5 g, 17 mmol) and Weinreb’s salt (2.5 g, 25.5 mmol) was cooled to
ꢀ10 °C and was added a solution of isopropyl magnesium bromide
(25.5 mL of a 1 M soln in THF, 25.5 mmol). The reaction mixture
was stirred at the same temperature for 1 h and was quenched
with saturated NH4Cl. The organic layer was extracted with EtOAc.
Combined extract was washed with brine, dried over anhydrous
Na2SO4. Removal of solvent under reduced pressure afforded a
crude reaction mixture, which was purified using silica gel chro-
matography (90:10 hexane–EtOAc) and furnished a pure com-
4.1.4. (1S,2S)-1-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-
4-yl)but-3-en-2-ol 6
A solution of ketone 5 (2 g, 7.24 mmol) in 20 mL dry diethyl
ether under N2 atmosphere was cooled to ꢀ50 °C and ZnBH4
(2.7 mL of a 2 M solution in THF, 5.43 mmol) was added slowly
for the period of 10 min. After stirring for 1 h at the same temper-
ature, the reaction mixture was quenched by addition of saturated
NH4Cl. The resulting mixture was extracted with diethyl ether.
Combined organic layer was washed with brine, dried over Na2SO4,
evaporated in vacuo. The residue was chromatographed on silica
gel (90:10 hexane–EtOAc) to give 6 (1.7 g, 86%) as a colorless oil.
pound 4 (4.7 g, 90%) as a colorless liquid. ½a D20
¼ þ14:7 (c 1.8,
ꢁ
MeOH); IR: 2933, 1667, 1073 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
7.22–7.33 (m, 5H); 4.59–4.63 (d, J = 12.08 Hz, 1H); 4.47–4.52 (d,
J = 12.08 Hz, 1H); 4.29–4.40 (m, 2H); 3.96–4.08 (m, 2H); 3.61 (s,
3H); 3.19 (s, 3H); 1.39 (s, 3H); 1.31 (s, 3H); 13C NMR (300 MHz,
CDCl3): 170.6, 137.5, 128.2, 127.8, 127.7, 109.2, 96.2, 75.5, 72.1,
66.3, 61.3, 32.2, 26.4, 25.2; ESI-MS: 332 [(M+Na)+]; HRMS calcd
for C16H23NO5Na 332.1474, found 332.1462.
½
a 2D0
ꢁ
¼ þ6:9 (c 1.3, MeOH); IR: 3473, 2955, 2858, 1727; 1H NMR
4.1.3. (R)-1-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxalan-4-yl)
but-3-en-2-one 5
To a solution of amide 4 (4 g, 12.9 mmol) in dry THF (60 mL) at
ꢀ78 °C was added vinyl magnesium bromide (15.5 mL of a 1 M
soln in THF, 15.5 mmol) slowly over 20 min. The reaction mixture
(300 MHz, CDCl3): d 7.18–7.32 (m, 5H); 5.32–5. 96 (m, 3H);
4.58–4.63 (d, J = 12.08 Hz, 1H); 4.31–4.40 (d, J = 12.08 Hz, 1H);
3.77–4.11 (m, 5H); 2.45 (s, 1H); 1.33 (s, 3H); 1.28 (s, 3H); 13C
NMR (300 MHz, CDCl3): 141.0, 134.0, 128.4, 127.4, 126.9, 120.0,
108.8, 81.0, 75.1, 73.8, 70.3, 66.3, 26.8, 25.4; ESI-MS:

1118
J. Jon Paul Selvam et al. / Tetrahedron: Asymmetry 20 (2009) 1115–1119
301[(M+Na)+]; HRMS calcd for C16H22O4Na 301.1415, found
301.1405.
quid. ½a 2D0
ꢁ
¼ þ26:2 (c 2.6, MeOH); IR: 3063, 2925, 1724, 1453,
1H NMR (200 MHz, CDCl3):
7.24–7. 38
1270, 1099 cmꢀ1
;
d
(m,1H); 5.8–5.94 (m, 1H); 5.32–5.40 (dd, J = 13.59, 2.26 Hz, 2H);
4.81–4.86 (d, J = 12.08 Hz, 1H); 4.61–4.68 (dd, J = 11.39, 9.06 Hz,
2H); 4.22–4.46 (d, J = 1.08 Hz, 1H); 3.93–3.97 (t, J = 6.79,
12.84 Hz, 1H); 3.06–3.11 (m, 2H); 2.77–2.79 (m, 1H); 2.57–2.59
(dd, J = 2.26, 4.53 Hz, 1H); 13C NMR (300 MHz, CDCl3): 134.50,
127.81, 127.78, 127.29, 127.12, 127.00, 119.03, 81.11, 79.30,
72.86, 69.90, 50.74, 44.50; ESI-MS: 333 [(M+Na)+]; HRMS calcd
for C20H22O3Na 333.1467, found 333.1456.
4.1.5. (R)-4-((1S,2S)-1,2-Bis(benzyloxy)but-3-enyl)-2,2-dimethyl-
1,3-dioxolane 7
Alcohol 6 (1.2 g, 4.32 mmol) in dry THF (20 mL) was added to a
solution containing NaH (207 mg, 8.63 mmol) dry THF (15 mL) at
0 °C followed by benzyl bromide (0.63 mL, 5.179 mmol). The reac-
tion mixture was allowed to stir for 2 h at room temperature. The
reaction mixture was quenched with saturated NH4Cl. The organic
layer was extracted with EtOAc. The combined organic layer
washed with brine, dried over Na2SO4, solvent was removed under
reduced pressure. Purification of the crude mass using silica gel
column chromatography (95:5 hexane–EtOAc) furnished pure ben-
4.1.8. (4R,5R,6S)-5,6-Bis(benzyloxy)oct-7-en-4-ol 11
A solution of EtMgBr (5.79 mL of a 1 M soln in THF, 5.79 mmol)
was added dropwise to a stirred and cooled (-30 °C) solution of
Cu2Br2 (333 mg) in dry THF (20 mL). After stirring for 10 min, epox-
ide 10 (600 mg, 1.93 mmol) in THF (10 mL) was added. Stirring was
continued for 10 h, slowly warming the mixture to 0 °C. The mix-
ture was poured into saturated NH4Cl. The organic layer was ex-
tracted with diethyl ether. The organic layer was successively
washed with brine and dried over anhydrous Na2SO4. Removal of
a solvent under reduced pressure afforded a crude reaction mix-
ture. Purification of crude mass using silica gel column chromatog-
zylated ether 7 (1.5 g, 95%) as a colorless liquid. ½a D20
¼ þ31:8 (c
ꢁ
2.7, MeOH); IR: 3063, 2928, 1735, 1604, 1454, 1213, 1066 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.21–7.33 (m, 10H); 5.79–6.0 (m,
1H); 5.28–5.37 (m, 2H); 4.76–4.87 (d, J = 11.75 Hz, 1H); 4.65–
4.71 (d, J = 7.34 Hz, 1H); 4.62–4.65 (d, J = 7.34 Hz, 1H); 4.35–4.41
(d, J = 11.75 Hz, 1H); 3.99–4.17 (m, 2H); 3.91–3.95 (dd, J = 5.87,
2.93 Hz, 1H); 3.71–3.76 (dd, J = 6.61, 2.93 Hz, 1H); 1.37 (s, 3H);
1.31 (s, 3H); 13C NMR (300 MHz, CDCl3): 138.5, 134.7, 128.2,
127.9, 127.5, 127.4, 127.3, 119.3, 108.7, 81.5, 81.4, 75.1, 74.0,
70.4, 66.3, 26.6, 25.4; ESI-MS: 391 [(M+Na)+]; HRMS calcd for
C23H28O4Na 391.1885, found 391.1875.
raphy (85:15 hexane–EtOAc) afforded
a
pure compound 11
¼ þ9:1 (c 3.0, MeOH);
1H
(480 mg, 75%) as a colorless liquid. ½a D20
ꢁ
IR: 3449, 2958, 2924, 1722, 1454, 1271, 1069, 749, 699 cmꢀ1
;
NMR (300 MHz, CDCl3): d 7.32–7.20 (m, 10H); 5.96–5.82 (m, 1H);
5.35–5.20 (m, 2H); 4.74–4.70 (d, J = 11.33 Hz, 1H); 4.63–4.59 (d,
J = 11.70 Hz, 1H); 4.51–4.48 (d, J = 11.33 Hz, 1H); 4.39–4.33 (d,
J = 11.70 Hz, 1H); 4.03–3.96 (m, 1H); 3.69–3.65 (m, 1H); 3.34–
3.31 (dd, J = 5.47, 3.77 Hz, 1H); 2.46 (br s, 1H); 1.56–1.20 (m,
4H); 0.94–0.83 (t, J = 6.98 Hz, 3H); 13C NMR (300 MHz, CDCl3):
135.55, 128.34, 128.28, 128.03, 127.78, 127.73, 127.63, 119.29,
82.55, 80.73, 73.84, 70.52, 35.55, 18.93, 14.01; ESI-MS:
363 [(M+Na)+]; HRMS calcd for C22H28O3Na 363.1936, found
363.1924.
4.1.6. (2R,3S,4S)-3,4-Bis(benzyloxy)hex-5-ene-1,2-diol 8
To a solution of compound 7 (1.2 g, 3.26 mmol) in MeOH
(20 mL) was added PTSA (18 mg, 5 mol %) and was stirred at room
temperature for 2 h. After completion of reaction, NaHCO3 was
added and stirred for additional 15 min. The compound was ex-
tracted into DCM and the organic layer was washed with water,
brine, dried over anhydrous Na2SO4. Removal of the solvent under
reduced pressure followed by column chromatographic purifica-
tion (80:20 hexane–EtOAc) afforded a pure compound 8 (1 g,
98%) as a colorless liquid. ½a D20
ꢁ
¼ þ47:8 (c 0.7, CHCl3); IR: 3420,
3064, 2925, 1722, 1453, 1274, 1093 cmꢀ1
;
1H NMR (300 MHz,
4.1.9. (4R,5R,6S)-5,6-Bis(benzyloxy)oct-7-en-4-yl hex-5-enoate 12
Et3N (0.13 mL, 0.94 mmol) and 2,4,6-trichlorobenzoyl chloride
(0.13 mL, 0.88 mmol) were added to a stirred solution of hex-5-
enoic acid (0.1 mL, 0.88 mmol) in anhydrous THF (10 mL) under
N2 at room temperature. The resulting mixture was allowed to stir
for 2 h before it was filtered through a pad of silica gel. The filtrate
was concentrated to dryness. The residue was dissolved in toluene
(10 mL) and alcohol 11 (300 mg, 0.88 mmol) and DMAP (538 mg,
4.41 mmol) were added. The mixture was stirred at room temper-
ature for 3 h and was diluted with EtOAc, and the organic layer was
separated. The aqueous layer was extracted with EtOAc. The com-
bined organic extracts were washed with saturated NaHCO3, brine,
and dried over anhydrous Na2SO4. The resulting mixture was fil-
tered, and the solvent was evaporated in vacuo to afford a residue.
The residue was purified by silica gel column chromatography
(96:4 hexane–EtOAc) afforded pure product 12 (335 mg, 87%) as
CDCl3): d 7.42–7. 20 (m, 10H); 5.93–5.82 (dd, J = 15.86, 9.06 Hz,
1H); 5.54–5.40 (m, 1H); 5.06–4.97 (d, J = 11.33 Hz, 1H); 4.93–
4.86 (dd, J = 9.06, 4.53 Hz, 1H); 4.76–4.72 (d, J = 12.08 Hz, 1H);
4.61–4.57 (d, J = 11.34 Hz, 1H); 4.26–4.22 (d, J = 12.08 Hz, 1H);
3.78–3.71 (m, 2H); 2.43–1.56 (m, 6H); 1.35–0.96 (m, 4H); 0.84–
0.80 (t, J = 7.55 Hz, 3H); 13C NMR (300 MHz, CDCl3): 138.1, 137.9,
135.3, 128.4, 128.2, 128.0, 127.8, 127.7, 119.6, 96.2, 82.0, 81.1,
74.0, 72.1, 70.5, 63.2; ESI-MS: 351[(M+Na)+]; HRMS calcd for
C20H24O4Na 351.1572, found 351.1580.
4.1.7. (R)-2-((1S,2S)-1,2-Bis(benzyloxy)but-3-enyl)oxirane 10
To a solution of 8 (900 mg, 2.74 mmol), dibutyltin oxide (13 mg,
0.05 mmol), and Et3N (0.39 mL, 2.74 mmol) in dry DCM was added
p-toluenesulfonyl chloride (340 mg, 2.74 mmol) at 0 °C under N2
atmosphere. After stirring for 4 h at room temperature, the reac-
tion mixture was extracted with DCM. The organic extract was suc-
cessively washed with water, brine, and dried over anhydrous
Na2SO4. Removal of solvent under reduced under reduced pressure
afforded a crude mass which was then carried out to next step
without any purification.
To a stirred solution of monotosylate derivative 9 in dry MeOH
(15 mL) was added K2CO3 (1.13 g, 8.22 mmol) under a N2 atmo-
sphere. After being stirred for 1 h, MeOH was evaporated under re-
duced pressure keeping the temperature below 30 °C. The residue
was extracted with DCM. The organic extract was washed with
water, brine, and dried over anhydrous Na2SO4. Removal of a sol-
vent under reduced pressure afforded a crude mass. Purification
of the crude mass by silica gel column chromatography (90:10 hex-
ane–EtOAc) afforded epoxide 10 (730 mg, 85%) as a colorless li-
a colorless liquid. ½a D20
ꢁ
¼ þ6:4 (c 2.6, MeOH); IR: 3068, 2930,
1733, 1641, 1455, 1093 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.36–
7.25 (m, 10H); 6.05–5.84 (m, 1H); 5.82–5.63 (m, 1H); 5.41–5.37
(d, J = 2.93 Hz, 1H); 5.37–5.31 (dd, J = 1.46, 11.02 Hz, 1H); 5.25–
5.17 (m, 1H); 5.05–4.94 (m, 2H); 4.81-4.75 (d, J = 11.75 Hz, 1H);
4.61–4.59 (d, J = 3.67 Hz, 1H); 4.55–4.54 (d, J = 2.93 Hz, 1H);
4.32–4.22 (d, J = 11.02 Hz, 1H); 3.92 -3.80 (dd, J = 5.87, 7.34 Hz,
1H); 3.59–3.55 (dd, J = 3.67, 5.87 Hz, 1H); 2.29–2.20 (m, 2H);
2.12–2.0 (m, 2H); 1.75–1.42 (m, 5H); 1.37–1.06 (m, 2H); 0.89–
0.78 (t, J = 7.34 Hz, 3H); 13C NMR (300 MHz, CDCl3): 173.11,
138.24, 138.14, 137.76, 128.99, 128.29, 128.20, 128.08, 127.96,
127.59, 127.53, 119.43, 115.20, 81.32, 80.58, 74.30, 72.80, 70.27,
33.63, 33.08, 24.03, 18.68, 13.90; ESI-MS: 460 [(M+Na)+]; HRMS
calcd for C28H36O4Na 459.2511, found 459.2522.

J. Jon Paul Selvam et al. / Tetrahedron: Asymmetry 20 (2009) 1115–1119
1119
4.1.10. (8S,9R,10R,E)-8,9-Bis(benzyloxy)-10-propyl-3,4,5,8,9,
10-hexahydro-2H-oxecin-2-one 13
6H); 13C NMR (300 MHz, CDCl3): 109.4, 77.1, 70.3, 66.1, 61.3,
55.8, 54.4, 26.5, 25.7, 25.2, 18.1; ESI-MS: 341 [(M+Na)+]; HRMS
calcd for C15H30O5NaSi 341.1760, found 341.1749.
A solution of 12 (100 mg, 0.23 mmol) and Grubb’s II catalyst
(19 mg, 0.02 mmol) in degassed anhydrous DCM (250 mL) was re-
fluxed for 12 h. Then the mixture was quenched with ethyl vinyl
ether (5 mL) and concentrated in vacuo. The residue was purified
by silica gel column chromatography (95:5 hexane–EtOAc) affor-
4.1.10.5. (1S,2S)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,
2-dimethyl-1,3-dioxolan-4-yl)but-3-en-2-ol 18. Colorless liquid;
½
a 2D0
ꢁ
¼ þ27:7 (c 1.5, MeOH); IR: 3473, 2955, 2858, 1727, 1254,
ded
a
pure product 13 (78 mg, 84%) as
¼ þ13:5 (c 1.1, MeOH); IR: 3030, 2927, 1726, 1452, 1200,
1093 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.42–7. 20 (m, 10H);
a
colorless liquid.
1073 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.80–5.92 (m, 1H);
;
½
a 2D0
ꢁ
5.28–5.35 (td, J = 15.67, 1.51 Hz, 1H); 5.18–5.22 (td, J = 10.57,
1.51 Hz, 1H); 4.20–4.24 (m, 1H); 4.00–4.06 (m, 1H); 3.92–3.97 (t,
J = 7.93 Hz, 1H); 3.85–3.89 (dd, J = 4.72, 3.39 Hz, 1H); 3.79–3.84
(t, J = 7.74 Hz, 1H); 2.38 (br s, 1H); 1.37 (s, 3H); 1.30 (s, 3H); 0.88
(s, 9H); 0.10 (s, 6H); 13C NMR (300 MHz, CDCl3): 135.8, 116.8,
108.2, 75.8, 75.0, 72.3, 65.7, 26.5, 25.8, 19.6; ESI-MS: 325
[(M+Na)+]; HRMS calcd for C15H30O4NaSi 325.1811, found
325.1800.
;
5.93–5.82 (dd, J = 9.06, 15.86 Hz, 1H); 5.54–5.40 (m, 1H); 5.06–
4.97 (d, J = 11.33 Hz, 1H,); 4.93–4.86 (dd, J = 4.53, 9.06 Hz, 1H);
4.76–4.72 (d, J = 12.08 Hz, 1H); 4.61- 4.57 (d, J = 11.34 Hz, 1H);
4.26–4.22 (d, J = 12.08 Hz, 1H); 3.78–3.71 (m, 2H); 2.43–1.56 (m,
6H); 1.35–0.96 (m, 4H); 0.84–0.80 (t, J = 7.55 Hz, 3H); 13C NMR
(300 MHz, CDCl3): 175.38, 138.67, 138.56, 135.07, 129.65, 129.33,
128.87, 128.70, 128.22, 128.06, 127.51, 127.34, 127.27, 96.09,
84.08, 79.88, 74.85, 73.24, 69.06, 34.33, 33.90, 33.52, 29.64,
26.08, 18.33, 13.75; ESI-MS: 432 [(M+Na)+]; HRMS calcd for
C26H32O4Na 431.2198, found 431.2192.
4.1.11. Herbarumin I 1
To a solution of 13 (50 mg, 0.12 mmol) in dry DCM (10 mL) was
added a solution of TiCl4 (0.039 mL, 0.36 mmol) in dry DCM (2 mL)
under N2 at 0 °C. The reaction was monitored by TLC until the start-
ing material was consumed. Water was added and the compound
was extracted into DCM. The combined organic extract was
washed with brine, dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and the crude mass purified
by silica gel chromatography and (80:20 hexane–EtOAc) afforded
4.1.10.1. (R)-Ethyl 2-(tert-butyldimethylsilyloxy)-2-((R)-2,2-di-
methyl-1,3-dioxolan-4-yl)acetate 14. Colorless liquid;
þ24 (c 1.5, CHCl3); IR: 2933, 2859, 1750, 1473, 1371, 1256, 1155,
1074, 840, 779 cmꢀ1 1H NMR (300 MHz, CDCl3): d 3.96–4.26 (m,
½
a 2D0
ꢁ
¼
;
6H); 1.41 (s, 3H); 1.33 (s, 3H); 1.25–1.32 (t, J = 7.17 Hz, 3H); 0.89 (s,
9H); 0.08 (s, 3H); 0.07 (s, 3H); 13C NMR (300 MHz, CDCl3): 171.4,
109.5, 72.6, 65.3, 60.9, 26.6, 25.6, 25.3, 18.1, 14.1; ESI-MS: 341
[(M+Na)+]; HRMS calcd for C15H30O5NaSi 341.1760, found 341.1756.
pure compound 1 (20 mg, 74%) as a colorless solid. ½a D20
ꢁ
¼ þ11:5
(c 0.5, EtOH); IR: 3030, 2927, 1726, 1452, 1200, 1093 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): d 5.57 (d, J = 15.8 Hz, 1H); 5.50 (m, 1H);
4.87 (td, J = 9.4, 2.2 Hz, 1H); 4.35 (br s, 1H), 3.41 (d, J = 9.4 Hz,
1H); 2.43 (br s, OH, 1H); 2.22–2.33 (m, 2H); 2.07–1.80 (m, 3H);
1.48–1.70 (m, 3H); 1.30–1.20 (m, 3H); 0.92 (t, J = 7.3 Hz, 3H); 13C
NMR (300 MHz, CDCl3): 176.3, 130.7, 124.5, 73.5, 73.2, 70.13,
34.4, 33.6, 33.08, 24.6, 17.9, 13.82; ESI-MS: 251 [(M+Na)+]; HRMS
calcd for C12H20O4Na 251.1259, found 251.1251.
4.1.10.2. (S,E)-Ethyl 4-(tert-butyldimethylsilyloxy)-4-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-2-enoate 15. Colorless liquid;
½
a 2D0
ꢁ
¼ ꢀ3:1 (c 5.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.83–
6.95 (dd, J = 15.62, 4.68 Hz, 1H); 5.92–6.02 (dd, J = 15.62, 1.56 Hz,
1H); 3.82–4.30 (m, 6H); 1.39 (s, 3H); 1.31 (s, 3H); 1.25–1.34 (t,
J = 7.03 Hz, 3H); 0.92 (s, 9H); 0.09 (s, 3H); 0.05 (s, 3H). 13C NMR
(300 MHz, CDCl3): 200.3, 165.6, 147.3, 121.8, 109.5, 96.2, 78.3,
72.3, 65.8, 60.2, 26.8, 26.0, 25.4, 18.3, 14.4. IR: 2935, 1723, 1659,
1258, 1075, 839 cmꢀ1; ESI-MS: 341 [(M+Na)+]. HRMS calcd for
C17H32O5NaSi 318.1863, found 318.1858.
References
1. Rivero-Cruz, J. F.; Garcia-Aguieee, G.; Cerda-Garcia-Rojas, C. M.; Mata, R.
Tetrahedron 2000, 56, 5337–5344.
2. Fürstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R.
J. Am. Chem. Soc. 2002, 124, 7061–7069.
4.1.10.3. (S,E)-4-(tert-Butyldimethylsilyloxy)-4-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)but-2-en-1-ol 16. Yellow liquid; ½a D20
ꢁ
¼ þ6:9 (c
4.0, MeOH); IR: 3449, 2924, 1628, 1219,772 cmꢀ1
;
1H NMR
3. (a) Furstner, A.; Radkowski, K. Chem. Commun. 2001, 671–672; (b) Aparecido
Sabino, A.; Pilli, R. A. Tetrahedron Lett. 2002, 43, 2819–2821; (c) Diez, E.; Dixon,
D. J.; Ley, S. V.; Polara, A.; Rodriguez, F. Helv. Chim. Acta 2003, 86, 3717–3729;
(d) Gurjar, M. K.; Karmakar, S.; Mohapatra, D. K. Tetrahedron Lett. 2004, 45,
4525–4526; (e) Nanda, S. Tetrahedron Lett. 2005, 46, 3661–3663; (f) Salaskar,
A.; Sharma, A.; Chattopadhyay, S. Tetrahedron: Asymmetry 2006, 17, 325–329;
(g) Nagaiah, K.; Sreenu, D.; Srinivasa Rao, R.; Yadav, J. S. Tetrahedron Lett. 2007,
48, 7173–7176.
4. Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu,
D. C. J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598–2602.
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Moessner, C. Angew. Chem., Int. Ed. 2008, 47, 3016–3020.
6. Narasimhan, S.; Balakumar, R. Aldrichim. Acta 1998, 31, 19–26.
7. Sharma, G. V. M.; Laxmi Reddy, K. Tetrahedron: Asymmetry 2006, 17, 3197–
3202.
8. Jnanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
(300 MHz, CDCl3): d 5.76–5.86 (td, J = 4.53, 9.82, 15.86 Hz, 1H).
5.60–5.69 (dd, J = 5.28, 15.86 Hz, 1H); 3.80–4.13 (m, 6H); 2.89 (br
s, 1H); 1.38 (s, 3H); 1.30 (s, 3H); 0.89 (s, 9H); 0.08 (s, 3H); 0.04
(s, 3H); 13C NMR (300 MHz, CDCl3): 131.4, 109.3, 78.9, 73.1, 66.1,
62.7, 26.6, 25.7, 18.0; ESI-MS: 325 [(M+Na)+]; HRMS calcd for
C15H30O4NaSi 325.1811, found 325.1804.
4.1.10.4. ((2R,3S)-3-((R)-(tert-Butyldimethylsilyloxy)((R)-2,
2-dimethyl-1,3-dioxolan-4-yl)methyl)oxiran-2-yl)methanol
17. Colorless oil; ½a D20
ꢁ
¼ þ15:5 (c 4.0, MeOH); IR: 3449, 2932, 2859,
1744, 1472, 1376, 1254, 1071, 837, 778 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 4.00–4.08 (m, 2H); 3.82–3.94 (m, 3H); 3.60–3.66 (dd,
J = 12.65, 3.96 Hz, 1H); 3.15–3.18 (m, 1H); 3.10–3.12 (m, 1H);
2.37 (br s, 1H); 1.42 (s, 3H); 1.35 (s, 3H); 0.87 (s, 9H); 0.08 (s,
9. Fürstner, A.; Langemann, K. Synthesis 1997, 792–803.
10. Sharma, G. V. M.; Janardhan Reddy, J.; Laxmi Reddy, K. Tetrahedron Lett. 2006,
47, 6531–6535.