Total synthesis of umuravumbolide and hyptolide through silicon-tethered ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201300302

The total synthesis of umuravumbolide and hyptolide has been achieved in a efficient manner by using temporary silicon-tethered ring-closing metathesis and cross-coupling reactions as key steps. The stereogenic centres were generated by means of proline-catalysed α-aminoxylation of aldehydes and Brown's asymmetric allylation method. An efficient total synthesis of umuravumbolide and hyptolide has been achieved by using temporary silicon-tethered ring-closing metathesis. The stereogenic centres were generated by using asymmetric allyl boration and proline-catalysed α-aminoxylation with high degrees of enantioselectivity. Copyright

Full text of DOI:10.1002/ejoc.201300302

FULL PAPER
DOI: 10.1002/ejoc.201300302
Total Synthesis of Umuravumbolide and Hyptolide Through Silicon-Tethered
Ring-Closing Metathesis
Partha Sarathi Chowdhury[a] and Pradeep Kumar*[a]
Keywords: Synthetic methods / Total synthesis / Lactones / Silanes / Metathesis / Wittig reactions
The total synthesis of umuravumbolide and hyptolide has
been achieved in a efficient manner by using temporary sili-
actions as key steps. The stereogenic centres were generated
by means of proline-catalysed α-aminoxylation of aldehydes
con-tethered ring-closing metathesis and cross-coupling re- and Brown’s asymmetric allylation method.
closing metathesis reaction for construction of the lactone
ring.
As a part of our current interest in naturally occurring
Introduction
Desacetylumuravumbolide[1a] (1a) and umuravumbol-
ide[1a] (1b) and structurally related hyptolide[1b] (2), isolated
from species of Tetradenia and Hyptis, are representative
members of the Lamiaceae family (Figure 1). These com-
pounds have a common structural feature, the polyacylated-
6-heptenyl-5,6-dihydro-2H-pyran-2-one framework, con-
taining an α,β-unsaturated δ-lactone that is known to bind
protein thiol groups as a result of their ability to act as a
Michael acceptor. These compounds show a wide range of
pharmacological activities such as cytotoxicity against hu-
man tumour cells, and antimicrobial and antifungal ac-
tivity. Furthermore, several compounds from the La-
miaceae family have been shown to be an emetic that can
be used to treat loss of appetite.
pharmacologically active α,β-unsaturated δ-lactones,[3] we
have accomplished the total synthesis of umuravumbolide
(1b) and hyptolide (2) by a highly convergent strategy.
We note in advance that our approach is both concise
and versatile, exploiting temporary silicon-tethered ring-
closing metathesis (TST-RCM)[4] and Ando’s protocol[5] to
construct the olefins. Furthermore, the strategy provides
convergent synthetic access to all members of the La-
miaceae family. The general retrosynthetic analysis is de-
picted in Scheme 1. We aimed to construct the side chain
Z-olefin of both umuravumbolide 1b and hyptolide 2
through ring-closing metathesis of bis-siloxane intermedi-
ates 3 and 4, respectively. The latter intermediates would
Figure 1. Structures of deacetylumuravumbolide (1a), umuravum-
bolide (1b) and hyptolide (2).
Synthetic studies toward 1 and 2 have been reported by
Ramachandran,[2a] Marco,[2b] Chakraborty,[2c] Venkates-
warlu[2d] and Sabitha[2e] et al. However, to the best of our
knowledge, all attempts have involved linear approaches in-
volving semihydrogenation of the alkyne part using Lind-
Alar’s catalyst to generate the side chain olefin, and ring-
[a] Division of Organic Chemistry, CSIR – National Chemical
Laboratory,
Pune 411008, India
Fax: +91-20-25902629
E-mail: pk.tripathi@ncl.res.in
Homepage: http://newhome.ncl.res.in/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300302.
Scheme 1. Retrosynthetic analysis of umuravumbolide (1b) and
hyptolide (2).
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Total Synthesis of Umuravumbolide and Hyptolide
originate from coupling of allylic alcohols 5, 6 and 6, 7, known homoallylic alcohol 17[2b] was performed with
respectively, whereas the requisite fragments 5–7 could be Brown’s B-allyl diisopinocampheylborane, followed by
prepared from hexanal 8, 4-(4-methoxybenzyloxy)butanal treatment with benzyl bromide (BnBr) to afford 18 in 97%
(9)[6] and TBS-protected l-lactaldehyde 10, respectively.
yield. We next examined the proline-catalyzed α-aminoxyl-
ation reaction of aldehyde to generate the third stereogenic
centre. Towards this end, we converted olefin 18 into
alcohol 19 in 95% yield by the hydroboration oxidation
technique. Thus, compound 19 was oxidized by using 2-
iodoxybenzoic acid (IBX) to furnish the corresponding al-
dehyde, which was directly subjected to α-aminoxylation
catalyzed by d-proline, followed by reduction in situ using
NaBH4 to give the required O-amino-substituted diol,
which, on treatment with a catalytic amount of copper sulf-
ate, afforded diol 20 in 80% yield along with the minor
diastereomer (10%), which could be easily separated by
chromatography. The stereochemistry of the major dia-
stereomer 20 was confirmed by 13C NMR spectroscopic
analysis.[14] Diol 20, on selective monotosylation and base
treatment, furnished 21 in 90% yield. Finally, dimethylsulf-
onium methylide mediated (Corey–Chaykovsky’s condi-
tions)[9] ring opening of epoxide 21 gave fragment 7 in 80%
yield.
Results and Discussion
Our synthesis started with the preparation of fragment
5. The sequence developed to prepare fragment 5 is summa-
rized in Scheme 2. Thus, aldehyde 8 was exposed to sequen-
tial α-aminoxylation[7] catalyzed by d-proline, followed by
reduction in situ using NaBH4 to furnish O-amino-substi-
tuted diol 11. Compound 11 was subjected to reductive hy-
drogenation conditions to afford the known diol 12[8] in
85% yield, which, on selective monotosylation and base
treatment, furnished epoxide 13[8] in 80% yield. Finally, di-
methylsulfonium methylide mediated[9] ring opening of ep-
oxide 13 generated fragment 5[10] in 72% yield.
Scheme 2. Reagents and conditions: (a) i. d-proline, nitrosobenzene,
DMSO; ii. NaBH4, MeOH, 0.5 h; (b) H2/Pd-C, EtOAc, 8 h, 85%
(over two steps); (c) i. TsCl, Bu2SnO, Et3N, 2 h; ii. K2CO3, MeOH,
room temp., 1 h, 80%; (d) (CH3)3SI, 2 h, nBuLi, THF, 72%.
The synthesis of fragment 6 commenced from 4-(4-meth-
oxybenzyloxy)butanal (9) as illustrated in Scheme 3. Alde-
hyde 9 was subjected to α-aminoxylation catalyzed by l-
proline, under a similar set of reaction conditions to those
used in Scheme 2, to afford diol 15[11] in 83% yield and in
97% ee;[12] on selective monotosylation and base treatment
of 15, epoxide 16[11] was furnished in 83% yield. This epox-
ide was also opened with dimethylsulfonium methylide to
afford the allylic alcohol fragment 6[13] in 75% yield.
Scheme 4. Reagents and conditions: (a) BnBr, NaH, DMF, 0 °C to
room temp., 2 h, 97%; (b) BH3·DMS, THF, room temp., 4 h then
H2O2, NaOH, EtOH, room temp., 12 h, 95%; (c) i. IBX, EtOAc,
reflux, 3 h, ii. d-proline, PhN=O, DMSO then NaBH4, MeOH,
10 min; iii. CuSO4, 80% (over three steps); (d) i. TsCl, Bu2SnO,
Et3N, CH2Cl2, 1 h; ii. K2CO3, MeOH, room temp., 1 h, 90% (over
two steps); (e) (CH3)3SI, –20 °C, nBuLi, THF, 3 h, 80%.
With the cross-coupling partners in hand, the crucial sili-
con-tethered coupling to construct disiloxane 3 was exam-
ined (Table 1). Initial attempts using a range of silicon teth-
ering reagents such as Me2SiCl2 and Ph2SiCl2 proved un-
successful. We then considered using (iPr)2SiCl2 as the teth-
ering reagent under the reaction conditions reported by Ev-
ans and co-workers.[15] Accordingly, the addition of frag-
ment 5 to (iPr)2SiCl2 followed by further addition of a sec-
Scheme 3. Reagents and conditions: (a) i. l-proline, nitrosobenzene, ond fragment 6 after 24 h, led to the exclusive formation of
DMSO; ii. NaBH4, MeOH, 0.5 h; (b) H2/Pd-C, EtOAc, 7 h, 83%
the homodimer of 5 (Table 1; entry 1). We attributed this
(over two steps); (c) i. TsCl, Bu2SnO, Et3N, 2 h; ii. K2CO3, MeOH,
failure to the use of excess tethering reagent and to the pro-
room temp., 0.5 h, 83%; (d) (CH3)3SI, 2 h, nBuLi, THF, 75%.
longed reaction time after the addition of the first fragment
The sequence developed to prepare fragment 7 is summa- 5. Consequently, the reaction was performed with 5 equiv.
rized in Scheme 4. As our point of departure, asymmetric of tethering reagent, but again with no product formation
allylation of TBS-protected l-lactaldehyde 10 to generate being observed (entry 2). Nevertheless, we could isolate a
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small amount (5%) of coupled product 3 when the amount
We then reduced the time interval between the addition
of tethering reagent was reduced to 1.1 equivalent (entry 3). of fragment 5 and fragment 6 from 24 h to 5 h, but this did
not lead to any improvement in the yield of coupled prod-
uct 3 (Table 1, entry 4), yields of more than 25% were ob-
tained when the reaction time was reduced to 1 h (entry 5),
Table 1. Optimization of the coupling reaction of fragments 5 and
and the best yield (87%) was achieved when fragment 6 was
added 15 min after the addition of fragment 5 (entry 6).
Thus, coupled product 3 could be synthesized in excellent
yield by reducing the amount of tethering reagent from 10
to 1.1 equivalents as well as reducing time interval between
the addition of the two fragments from 24 h to 15 min.
Clearly, the reduction in the amount of tethering reagent
also improves the cost effectiveness of the reaction. With
disiloxane intermediates 3 and 4 in hand, we turned our
attention to its further elaboration to umuravumbolide (1b)
and hyptolide (2) by transforming the disiloxane moieties
(3 and 4) into the corresponding cyclic intermediates 22 and
23, respectively, and subsequent synthetic manipulations
(Scheme 5). The ring-closing metathesis reaction of disilox-
ane 3 using Grubbs’ second generation catalyst in toluene
at 80 °C proceeded smoothly to generate the required cyclic
intermediate 22 in 88% yield. However, cyclisation of 4 un-
der similar conditions furnished the required cyclic interme-
6.
Entry
Fragment 5
[equiv.]
(iPr)2SiCl2
[equiv.]
Time[a] Yield of 3
[%]
[b]
1
2
3
4
5
6
1
1
1
1
1
1
10
5
1.1
1.1
1.1
1.1
24 h
24 h
24 h
5 h
–
–
[b]
5[c]
5[c]
1 h
30[c]
15 min 87[d]
[a] Time between the addition of first fragment and second frag-
ment. [b] Only homodimer of 5 formed. [c] Obtained along with
homodimer of 5. [d] Obtained along with 5% homodimer of 5 and
unreacted 6.
Scheme 5. Reagents and conditions: (a) 1st fragment (5 or 6), (iPr)2SiCl2, imidazole, CH2Cl2, 0 °C, 15 min, then 2nd fragment (6 or 7),
14 h; (b) Grubbs-II (5 mol-%), 80 °C, toluene, 16 h, 88%; (c) Grubbs–Hoveyda-II (5 mol-%), 80 °C, toluene, 16 h, 75%; (d) DDQ, CH2Cl2/
H2O, 0 °C to room temp., 10 min; (e) i. DMP, pyridine, CH2Cl2, 0 °C, 0.5 h; ii. (PhO)2P(O)CH2COOEt, NaH, NaI, THF, –78 °C, 2 h;
(f) i. TBAF, THF, room temp. ii.. Ti(O-iPr)4, benzene, reflux, 1 h; (g) Ac2O, Et3N, cat. DMAP, CH2Cl2, room temp., 9 h, 90%; (h) i. TiCl4,
CH2Cl2, 0 °C to room temp., 30 min; ii. Ac2O, Et3N, cat. DMAP, CH2Cl2, room temp., overnight, 90% (over two steps).
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Total Synthesis of Umuravumbolide and Hyptolide
diate 23 in only low yield. Hence, the ring-closing metathe- application of this methodology to the synthesis of other
sis (RCM) of disiloxane 4 was examined by using Grubbs structurally related biologically active compounds for struc-
catalyst under a variety of reaction conditions; as a result ture-activity studies is underway in our laboratory.
of this study, the cis-product was obtained exclusively in
appreciable yield (Table 2).
Experimental Section
Table 2. Optimization of RCM conditions for disiloxane 4.
General Methods: All reactions requiring anhydrous conditions
Entry Catalyst
Solvent
Temp. [°C] Yield [%]
were performed under a positive pressure of argon using oven-dried
glassware (110 °C), which was cooled under argon. Solvents used
for chromatography were distilled at their respective boiling points
using known procedures. All commercial reagents were obtained
from Sigma–Aldrich Chemical Co. or Lancaster Chemical Co.
(UK). Petroleum ether (PE), where used, had a boiling range of
60–90 °C.
1
2
3
4
Grubbs II
Grubbs II
Grubbs II
CH2Cl2
DCE
toluene
40
10
10
20
75
84
110
110
Grubbs–Hoveyda II toluene
Our next objective towards the completion of the synthe-
sis was to form the requisite unsaturated lactone rings.
Towards this end, compounds 22 and 23 were subjected to
removal of the PMB groups using 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ), producing the corresponding
alcohols 24 and 25, respectively, in excellent yields. Subse-
quent Dess–Martin periodinane mediated oxidation of the
alcohol group led to formation of the corresponding alde-
hydes, which were directly subjected to two-carbon homolo-
gation under Ando conditions[5] to give (Z)-unsaturated es-
ter 26 and 27 in 90% and 93% yields, respectively, with
excellent stereoselectivity.
With substantial amounts of 26 and 27 in hand, the plat-
form was then set to construct the lactone ring of the target
molecules. Initially, simultaneous deprotection of the silyl
groups and cyclization to prepare the lactones 1a and 28
using pTSA in MeOH was attempted. However, the reac-
tion led to the formation of some unidentified products.
Hence, the clear choice was a two-step procedure; we first
deprotected the silyl groups using tetrabutylammonium
fluoride (TBAF) in tetrahydrofuran (THF) and the crude
polyols thus obtained were eventually cyclized to give the
six-membered lactones desacetylumuravumbolide (1a) and
28 in 92% and 96% yielsd, respectively, upon treatment
with a catalytic amount of Ti(OiPr)4 in benzene at reflux.
Desacetylumuravumbolide (1a) was further acetylated to
furnish umuravumbolide 1b.
Progress of the reactions was monitored by TLC using precoated
aluminium plates (Merck silica gel 60 F254). Column chromatog-
raphy was performed on silica gel 60–120/100–200/230–400 mesh
obtained from S. D. Fine Chemical Co. India or Spectrochem In-
dia. Standard syringe and cannula techniques were used to transfer
air- and moisture-sensitive reagents. IR spectra were recorded with
a Perkin–Elmer infrared spectrometer model 599-B and model 1620
FTIR. 1H NMR spectra were recorded with Bruker AC-200,
Bruker AV-400 or Bruker DRX-500 instruments using deuterated
solvent. Chemical shifts are reported in ppm; 1H coupling con-
stants (J) are reported as absolute values in Hz and multiplicity
[broad (br.), singlet (s), doublet (d), triplet (t), multiplet (m)]. 13C
NMR spectra were recorded with Bruker AC-200, Bruker AV-400
or Bruker DRX-500 instruments operating at 50, 100 and
125 MHz, respectively. 13C NMR chemical shifts are reported in
ppm relative to the central line of CDCl3 (δ = 77.0 ppm). Mass
spectra were recorded with a PE SCIEX API QSTAR pulsar (LC-
MS) instrument. All melting points were recorded with a Büchi B-
540 electrothermal melting point apparatus, yields refer to chro-
matographically and spectroscopically pure compounds.
(S)-Hexane-1,2-diol (12): To a stirred solution of aldehyde 8 (1.0 g,
9.98 mmol) and nitrosobenzene (1.06 g, 9.98 mmol) in DMSO
(9 mL) was added d-proline (0.23 g, 1.9 mmol, 20 mol-%) in one
portion at 25 °C. After 1 h, the temperature was lowered to 0 °C,
followed by dilution with anhyd. MeOH (10 mL) and careful ad-
dition of excess NaBH4 (1.32 g, 35 mmol). The reaction was
quenched after 10 min by pouring the reaction mixture into a vig-
orously stirred biphasic solution of Et2O and aqueous HCl (1 m).
The organic layer was separated, and the aqueous phase was ex-
tracted with EtOAc (3ϫ 20 mL). The combined organic phase was
dried with anhyd Na2SO4, concentrated, and purified by column
chromatography over silica gel (EtOAc/PE, 40:60) to give pure ami-
noxy alcohol 11. Aminoxy alcohol 11 (1.0 g, 4.7 mmol) was dis-
solved in EtOAc (10 mL) and 10% Pd/C (0.050 g) was added to
the solution and the reaction mixture was stirred in a hydrogen
atmosphere (1 atm, balloon pressure) for 12 h. After completion of
the reaction (monitored by TLC) the reaction mixture was filtered
through a Celite pad, concentrated, and the crude product was then
purified by silica gel chromatography (EtOAc/PE, 40:60) to give
pure diol 12 (0.48 g, 85%) as a colourless liquid. [α]2D5 = –14.3 (c =
The spectroscopic and physical data of desacetylumura-
vumbolide (1a) and umuravumbolide (1b) were identical in
all respects to those reported in the literature.[1a] Towards
the synthesis of target molecule 2, compound 28 was sub-
jected to debenzylation followed by acetylation of the sec-
ondary hydroxyl group to furnish the target molecule hyp-
tolide 2 in excellent yield. The spectroscopic and physical
data of compound 2 were identical in all respects to those
reported in the literature.[1b]
1.0, methanol) {ref.[8] [α]2D0 = –16.4 (c = 1.0, methanol)}. IR
Conclusions
1
(CHCl ): ν
= 3372, 2925 cm–1. H NMR (200 MHz, CDCl3): δ
˜
3
max
An efficient synthesis of umuravumbolide (1b) and hyp-
tolide (2) has been achieved through the application of tem-
porary silicon-tethered ring-closing metathesis (TST-RCM)
and Ando olefination reaction. The stereogenic centres were
installed by using proline-catalysed α-aminoxylation reac-
= 4.38–3.36 (m, 5 H), 1.32–1.22 (m, 6 H), 0.84–0.82 (m, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 71.9, 66.2, 33.1, 27.7, 22.6,
13.8 ppm. HRMS (ESI+): m/z calcd. for C6H14O2 [M + Na]+
141.0891; found 141.0893.
(S)-2-Butyloxirane (13): To a mixture of diol 12 (0.21 g, 1.77 mmol)
tions and by Brown’s asymmetric allyl boration. Further in anhydrous CH2Cl2 (5 mL) was added dibutyltin oxide (0.008 mg,
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P. S. Chowdhury, P. Kumar
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0.035 mol) followed by p-toluenesulfonyl chloride (0.337 g,
1.77 mmol) and triethylamine (0.25 mL, 1.77 mmol), and reaction
was stirred at room temperature under nitrogen and the progress
of the reaction was monitored by TLC. Upon completion of the
reaction, the mixture was quenched by adding water. The solution
was extracted with CH2Cl2 (3ϫ 10 mL) and the combined organic
phase was washed with water, dried (Na2SO4), and concentrated.
To this crude mixture in MeOH at 0 °C was added K2CO3 (0.5 g,
3.61 mmol) and the resultant mixture was stirred for 1 h at the
same temp. Upon completion of the reaction, as indicated by TLC,
the reaction was quenched by addition of ice pieces and methanol
was evaporated. The concentrated reaction mixture was then ex-
tracted with ethyl acetate (3ϫ 20 mL), the combined organic layer
was washed with brine, dried (Na2SO4) and concentrated. Column
chromatography of the crude product (PE/ethyl acetate, 70:30) gave
epoxide 13 (0.14 g, 80%) as a colourless liquid. [α]2D5 = –16.5 (c =
1.0, pentane) {ref.[8] [α]2D4 = –18.7 (c = 0.93, pentane)}. IR (CHCl3):
158.7, 128.8, 128.5, 112.3, 73.3, 67.5, 55.5, 50.1, 47.3, 33.8 ppm.
HRMS (ESI+): m/z calcd. for C12H16O3 [M + Na]+ 231.0997;
found 231.0993.
(R)-5-(4-Methoxybenzyloxy)pent-1-en-3-ol (6): Compound 6 was
prepared by following the procedure described for 5, yield 75%;
colourless liquid; [α]2D5 = –10.0 (c = 1.4, CHCl3) {ref.[12] [α]1D9 = –9.2
(c 1.0, CHCl )}. IR (CHCl ): ν
= 3414, 1613, 1586 cm–1. 1H
˜
max
3
3
NMR (200 MHz, CDCl3): δ = 7.31–7.24 (m, 2 H), 6.93–6.86 (m, 2
H), 5.97–5.80 (m, 1 H), 5.33–5.08 (m, 2 H), 4.46 (s, 2 H), 3.82 (s,
3 H), 3.76–3.57 (m, 2 H), 2.99 (s. 1 H), 1.94–1.79 (m, 2 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 159.1, 140.5, 129.9, 129.2, 114.2,
113.7, 72.8, 71.7, 67.8, 55.1, 36.1 ppm. HRMS (ESI+): m/z calcd.
for C13H18O3 [M + Na]+ 245.1154; found 245.1158.
{[(2S,3R)-3-(Benzyloxy)hex-5-en-2-yl]oxy}(tert-butyl)dimethylsilane
(18): To the known homoallylic alcohol 17 (2 g, 8.67 mmol) in
DMF (7.5 mL) at 0 °C was added NaH (60% in mineral oil, 0.38 g,
9.54 mmol). After 15 min, benzyl bromide (1.63 g, 1.13 mL,
9.54 mmol) was introduced and the reaction mixture was stirred for
2 h at room temperature. Water was carefully added to the reaction
mixture, which was then extracted with diethyl ether, washed with
water, and dried (Na2SO4). Silica gel column chromatography of
the crude product (petroleum ether/EtOAc, 95:5) afforded benzyl-
protected compound 18 (2.69 g, 97%). [α]2D5 = +10.16 (c = 0.9,
ν
= 2989, 2925, 2870 cm–1. 1H NMR (200 MHz, CDCl3): δ =
˜
max
2.71–2.67 (m, 1 H), 2.57–2.52 (m, 1 H), 2.28–2.25 (m, 1 H), 1.34–
1.10 (m, 6 H), 0.78–0.71 (t, J = 6.13 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 51.9, 46.6, 31.9, 27.8, 22.2, 13.6 ppm.
HRMS (ESI+): m/z calcd. for C6H12O [M + Na]+ 123.0786; found
123.0784.
(S)-Hept-1-en-3-ol (5): To a suspension of trimethylsulfonium iod-
ide (5.44 g, 26.5 mmol) in anhydrous THF (10 mL) at –20 °C was
added nBuLi (1.6 m in hexane, 16.68 mL, 26.5 mmol) dropwise over
20 min and the mixture was stirred for 30 min. Epoxide 13 (0.5 g,
4.37 mmol) in anhydrous THF (5 mL) was added to the above reac-
tion mixture, which was then slowly warmed to 0 °C over 1 h. The
reaction mixture was stirred at ambient temperature for 2 h and,
after consumption of the starting material, the reaction was
quenched by the addition of H2O (10 mL) and extracted with
EtOAc (4ϫ 10 mL). The combined extracts were washed with
brine, dried with Na2SO4 and concentrated. Column chromatog-
raphy of the crude product (PE/ethyl acetate, 70:30) gave 5 (0.45 g,
80%) as a colourless liquid. [α]2D5 = +9.5 (c = 1.4, pentane) {ref.[10]
CHCl ). IR (CHCl ): ν = 2933, 2867, 1613, 1514, 1464, 1248,
˜
max
3
3
1039, 920, 885 cm–1. H NMR (CDCl3, 400 MHz): δ = 7.30–7.19
(m, 5 H), 5.92–5.75 (m, 1 H), 5.08–4.93 (m, 2 H), 4.64–4.45 (m, 2
H), 3.92–3.61 (m, 1 H), 3.31–3.21 (m, 1 H), 2.25 (t, J = 6.53 Hz, 2
H), 1.13 (d, J = 6.42 Hz, 3 H), 0.83–0.80 (m, 9 H), –0.01–0.06 (m,
6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 138.9, 135.6, 128.2,
127.8, 127.3, 116.6, 83.6, 72.7, 70.4, 35.7, 33.7, 25.9, 19.3, –4.3,
–4.7 ppm. HRMS (ESI+): m/z calcd. for C19H33O2Si [M + H]
321.2250; found 321.2254.
1
(4R,5S)-4-(Benzyloxy)-5-[(tert-butyldimethylsilyl)oxy]hexan-1-ol
(19): A solution of olefin 18 (2.5 g, 7.8 mmol) in anhydrous THF
(30 mL) was treated under N2 with BH3·DMS (0.75 mL, 7.8 mmol,
d = 0.8 g/mL). The reaction mixture was stirred for 4 h at room
temperature and then quenched by addition of MeOH (25 mL),
6 m aqueous NaOH (9 mL), and 30% H2O2 (15 mL) and stirred
for an additional 12 h. The resulting mixture was stirred for 1 h
and worked up (extraction with EtOAc). Column chromatography
on silica gel (PE/EtOAc, 90:10) afforded 19 (2.5 g, 95%) as a light-
[α]2D5 = +10.3 (c = 1.45, pentane)}; IR (CHCl ): νmax = 3485, 1613,
˜
3
1586 cm–1. H NMR (200 MHz, CDCl3): δ = 5.88–5.71 (m, 1 H),
1
5.19–4.99 (m, 1 H), 4.08–3.96 (m, 1 H), 2.34 (s, 1 H), 1.48–1.22 (m,
6 H), 0.88–0.81 (m, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
141.3, 114.2, 73.0, 36.6, 27.4, 22.5, 13.8 ppm. HRMS (ESI+): m/z
calcd. for C7H14O [M
+
Na]+ 137.0942; found 137.0945.
yellow oil. [α]2D5 = +9.31 (c = 0.9, CHCl ). IR (CHCl ): νmax = 3377,
˜
3
3
C24H50O2Si (398.74): C 72.29, H 12.64; found C 72.27, H 12.63.
1
3019, 2400, 1501, 1427, 1230, 1070, 993, 857, 725 cm–1. H NMR
(CDCl3, 400 MHz): δ = 7.27–7.18 (m, 5 H), 4.73–4.37 (m, 2 H),
4.01–3.73 (m, 1 H), 3.63–3.47 (m, 2 H), 3.35–3.15 (m, 1 H), 1.61–
1.50 (m, 4 H), 1.11 (d, J = 6.19 Hz, 3 H), 0.81–0.79 (m, 9 H),
–0.01–0.07 (m, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 138.7,
128.3, 127.9, 127.5, 83.8, 72.9, 70.8, 63.0, 29.6, 29.0, 27.4, 25.8,
19.2, –4.3, –4.7 ppm. HRMS (ESI+): m/z calcd. for C19H35O3Si [M
+ H] 339.2355; found 339.2354.
(R)-4-(4-Methoxybenzyloxy)butane-1,2-diol (15): Compound 15
was prepared from compound 9 using l-proline as catalyst by fol-
lowing the procedure described for 12, yield 83%; colourless liquid;
[α]2D5 = –1.03 (c = 1.0, CHCl3) {ref.[11] [α]2D5 = –2.6 (c = 1.4, CHCl3)}.
1
IR (CHCl ): ν
= 3384, 2934, 1613, 1514, 1249 cm–1. H NMR
˜
3
max
(200 MHz, CDCl3): δ = 7.27–7.20 (m, 2 H), 6.90–6.84 (m, 2 H),
4.44 (s, 2 H), 3.93–3.82 (m, 1 H), 3.79 (s, 3 H), 3.69–342 (m, 4 H),
1.89–1.62 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 159.3,
129.8, 129.4, 113.8, 72.9, 71.3, 67.8, 66.5, 55.23, 32.7 ppm. HRMS
(ESI+): m/z calcd. for C12H18O4 [M + Na]+ 249.1103; found
249.1106.
(2S,4R,5S)-4-(Benzyloxy)-5-[(tert-butyldimethylsilyl)oxy]hexane-
1,2-diol (20): To a solution of 19 (2 g, 5.9 mmol) in EtOAc (10 mL)
was added IBX (4.6 g, 17.7 mmol) and the mixture was heated to
80 °C for 3 h. The mixture was cooled to room temp. and filtered
through a pad of Celite, the filtrate was concentrated, and the crude
aldehyde was used for the next step without purification.
(R)-2-[2-(4-Methoxybenzyloxy)ethyl]oxirane (16): Compound 16
was prepared by following the procedure described for 13, yield
83%; colourless liquid; [α]2D5 = +13.82 (c = 1.0 CHCl3) {ref.[11]
To a stirred solution of the above aldehyde (1.5 g, 4.45 mmol) and
nitrosobenzene (0.48 g, 4.45 mmol) in DMSO (4 mL) was added d-
[α]2D5 = +12.0 (c = 1.0, CHCl )}. IR (CHCl ): ν
= 2997, 2924,
˜
max
3
3
2860, 1613, 1513 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.29–7.24 proline (0.1 g, 0.89 mmol, 20 mol-%) in one portion at 25 °C. After
(m,2 H), 6.91–6.85 (m, 2 H), 4.47 (s, 2 H), 3.81 (s, 3 H), 3.63–3.57
(m, 2 H), 3.11–3.02 (m, 1 H), 2.81–2.76 (m, 1 H), 2.54–2.50 (m, 1
1 h, the temperature was lowered to 0 °C, the reaction mixture was
diluted with anhyd. MeOH (5 mL) and excess NaBH4 (0.6 g,
H), 1.99–1.71 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 15.6 mmol) was carefully added. The reaction was quenched after
4590
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4586–4593

Total Synthesis of Umuravumbolide and Hyptolide
10 min by addition of satd. NH4Cl. The organic layer was sepa-
rated and the aqueous phase was extracted with EtOAc (3 ϫ
10 mL). The combined organic phase was dried with anhyd
3.82 (s, 3 H), 3.63–3.44 (m, 2 H), 2.02–1.76 (m, 2 H), 1.35–1.23 (m,
7 H), 1.05–1.04 (m, 12 H), 0.97–0.93 (m, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 159.0, 141.4, 141.1, 129.4, 129.2, 113.9,
Na2SO4, concentrated, and purified by column chromatography 113.7, 113.7, 73.6, 72.6, 70.9, 66.4, 55.3, 38.0, 37.7, 22.8, 22.6, 17.4,
over silica gel (EtOAc/PE, 40:60) to give pure aminoxy alcohol
(1.5 g, 80%). The aminoxy alcohol (1.5 g, 3.5 mmol) was dissolved
in MeOH (10 mL) , 3% copper sulfate was added and the reaction
mixture was stirred for 12 h. After completion of the reaction
(monitored by TLC) it was quenched by addition of satd. NH4Cl.
The organic layer was separated and the aqueous phase was ex-
tracted with EtOAc (3ϫ 10 mL). The combined organic phase was
dried with anhyd Na2SO4, concentrated, and purified by silica gel
chromatography (EtOAc/PE, 50:50) to give pure diol 20 (0.66 g,
80%) as a colourless liquid. [α]2D5 = +41.86 (c = 0.2, CHCl3). IR
17.2, 14.3 ppm. HRMS (ESI+): m/z calcd. for C26H44O4Si [M +
Na]+ 471.2907; found 471.2907.
(5R,9S,11R,12S)-11-(Benzyloxy)-7,7-diisopropyl-1-(4-methoxyphen-
yl)-12,14,14,15,15-pentamethyl-5,9-divinyl-2,6,8,13-tetraoxa-7,14-
disilahexadecane (4): Compound 4 was prepared from coupling
fragments 6 and 7 by following the procedure described for 3, yield
87%; colourless liquid; [α]2D5 = 26.86 (c = 0.2, CHCl3). IR (CHCl3):
ν
˜
= 2935, 2856, 1713, 1600, 1504, 1265, 1065, 1071, 920,
max
885 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.27–7.15 (m, 7 H),
6.82–6.77 (m, 2 H), 5.84–5.62 (m, 2 H), 5.12–4.91 (m. 4 H), 4.48–
4.19 (m, 6 H), 4.03–3.79 (m, 1 H), 3.73 (s, 3 H), 3.66–3.26 (m, 3
H), 1.68–1.66 (m, 4 H), 1.53–1.33 (m, 2 H), 1.07 (d, J = 6.31 Hz,
3 H), 0.95–0.94 (m, 12 H), 0.83 (s, 9 H), –0.02 (s, 6 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 159.0, 140.9, 139.3, 139.1, 130.8,
129.1, 128.2, 127.6, 127.3, 127.2, 114.6, 113.7, 81.6, 72.9, 72.7, 71.6,
71.2, 70.6, 55.2, 39.9, 26.0, 25.8, 18.0, 17.4, 17.3, –4.6, –4.7 ppm.
HRMS (ESI+): m/z calcd. for C39H646Si2 [M + Na]+ 707.4139;
found 707.4139.
(CHCl ): νmax = 3412, 3020, 2978, 1652, 1534, 1248, 1237 cm–1. 1H
˜
3
NMR (CDCl3, 400 MHz): δ = 7.31–7.19 (m, 5 H), 4.77–4.41 (m, 2
H), 3.99–3.78 (m, 3 H), 3.56–3.47 (m, 2 H), 3.41–3.29 (m, 1 H),
1.58–1.54 (m, 2 H), 1.10–1.07 (m, 3 H), 0.82–0.81 (m, 9 H), –0.01
(s, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 138.0, 128.5,
127.9, 83.0, 72.4, 70.5, 70.1, 66.8, 33.0, 29.6, 25.8, 18.9, –4.8 ppm.
HRMS (ESI+): m/z calcd. for C19H35O4Si [M + H] 355.2305; found
355.2301.
(2S,3R)-3-(Benzyloxy)-4-[(S)-oxiran-2-yl]butan-2-yloxy(tert-butyl)di-
methylsilane (21): Compound 21 was prepared by following the
(4S,7R)-4-Butyl-2,2-diisopropyl-7-[2-(4-methoxybenzyloxy)ethyl]-
4,7-dihydro-1,3,2-dioxasilepine (22): A solution of 3 (0.1 g,
0.22 mmol) in toluene (50 mL) was degassed for 5 min with argon,
then Grubbs-II catalyst (0.006 g, 0.006 mmol) was added and the
solution was degassed again. The mixture was stirred at 80 °C for
18 h, before the solvent was removed in vacuo and the residue was
purified by flash chromatography (PE/ethyl acetate, 95:5) to give
cyclised product 22 (0.082 g, 88%); [α]2D5 = +3.00 (c = 0.65, CHCl3).
procedure described for 13, yield 90%; colourless liquid; [α]2D5
=
+12.8 (c = 0.5, CHCl ). IR (CHCl ): νmax = 2930, 2856, 1620, 1600,
˜
3
3
1557, 1501, 1310 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.30–7.21
(m, 5 H), 4.74–4.45 (m, 2 H), 3.87–3.79 (m, 1 H), 3.51–3.30 (m, 1
H), 3.05–2.95 (m, 1 H), 2.73–2.61 (m, 1 H), 2.44–2.35 (m, 1 H),
1.92–1.37 (m, 2 H), 1.10 (t, J = 6.22 Hz, 3 H), 0.81–0.79 (m, 9 H),
–0.02–0.04 (m, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 138.8,
135.6, 128.3, 127.8, 127.5, 81.7, 73.1, 70.5, 50.1, 47.8, 34.5, 34.0,
25.8, 19.2, –4.4, –4.7 ppm. HRMS (ESI+): m/z calcd. for
C19H33O3Si [M + H] 337.2199; found 337.2196.
IR (CHCl ): ν
= 2929, 2865, 1612, 1513, 1465, 1248, 1092,
˜
3
max
884 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.23–7.21 (m, 2 H),
6.91–6.88 (m, 2 H), 5.92–5.45 (m, 2 H), 4.88–4.48 (m, 2 H), 3.79
(s, 3 H), 3.75–3.43 (m, 4 H), 1.40–1.29 (m, 10 H), 1.03 (s, 12 H),
0.89–0.87 (m, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 159.1,
135.5, 134.8, 133.9, 129.32, 113.7, 72.8, 71.0, 67.9, 66.7, 55.3, 38.6,
38.3, 22.6, 22.5, 17.6, 17.2, 14.1 ppm. HRMS (ESI+): m/z calcd.
for C24H41O4Si [M + H]+421.2774; found 421.2775.
(3S,5R,6S)-5-(Benzyloxy)-6-[(tert-butyldimethylsilyl)oxy]hept-1-en-
3-ol (7): Compound 7 was prepared by following the procedure
described for 5, yield 80%; colourless liquid; [α]2D5 = +26.42 (c =
1.1, CHCl ). IR (CHCl ): ν = 3290, 3032, 2430, 1652, 1561,
˜
max
3
3
1504, 1215, 1012, 901, 876 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
7.27–7.16 (m, 5 H), 5.83–5.67 (m, 1 H), 5.21–4.96 (m, 2 H), 4.77–
4.41 (m, 2 H), 4.25–4.18 (m, 1 H), 3.93–3.77 (m, 1 H), 3.56–3.46
(m, 1 H), 1.74–1.59 (m, 2 H), 1.09 (d, J = 6.42 Hz, 3 H), 0.83–0.82
(m, 9 H), –0.01 (s, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
140.8, 138.2, 128.4, 127.9, 127.7, 114.2, 83.2, 72.5, 71.3, 76.6, 40.1,
37.5, 25.7, 18.9, –4.6, –4.7 ppm. HRMS (ESI+): m/z calcd. for
C20H34O3Si [M + H] 351.2355; found 351.2350.
(4S,7R)-4-{(2R,3S)-2-(Benzyloxy)-3-[(tert-butyldimethylsil-
yl)oxy]butyl}-2,2-diisopropyl-7-{2-[(4-methoxybenzyl)oxy]ethyl}-4,7-
dihydro-1,3,2-dioxasilepine (23): A solution of 4 (0.075 g,
0.109 mmol) in toluene (18 mL) was degassed for 5 min with argon,
then Hoveyda–Grubbs second-generation catalyst (2 mg,
3.28 μmol) was added and the solution was degassed again. The
mixture was stirred at 80 °C for 18 h, before the solvent was re-
moved in vacuo and the residue was purified by flash chromatog-
raphy (PE/ethyl acetate, 90:10) to give cyclised product 23 (0.054 g,
(5R,9S)-7,7-Diisopropyl-1-(4-methoxyphenyl)-5,9-divinyl-2,6,8-
trioxa-7-silatridecane (3): Dichlorodiisopropylsilane (0.085 mL,
0.48 mmol) was added to imidazole (0.089 g, 1.31 mmol) in CH2Cl2
(0.24 mL) at 0 °C. The solution was stirred for 5 min, then frag-
ment 5 (0.05 g, 0.437 mmol) in CH2Cl2 (0.18 mL) was added drop-
wise over 1 h at 0 °C. The mixture was stirred for a further 15 min
at 0 °C, then a solution of fragment 6 (0.097 g, 0.437 mmol) in
CH2Cl2 (0.035 mL) was added at 0 °C. The reaction mixture was
warmed to room temperature and stirred for 14 h, then filtered and
washed with hexane. Concentration in vacuo afforded a crude oil,
which was purified by flash chromatography on silica gel (PE/ethyl
acetate, 95:5) to afford bis-alkoxysilane 3 (0.196 g, 87 %) as a
75%); [α]2D5 = 27.98 (c = 0.8, CHCl ). IR (CHCl ): ν
= 2931,
˜
max
3
3
2901, 2301, 1800, 1654, 1466, 885, 847, 770, 681 cm–1. 1H NMR
(CDCl3, 400 MHz): δ = 7.27–7.18 (m, 7 H), 6.83–6.78 (m, 2 H),
5.60–4.63 (m, 2 H), 4.61–4.36 (m, 4 H), 4.16–3.97 (m, 1 H), 3.87–
3.78 (m, 1 H), 3.73 (s, 3 H), 3.65–3.35 (m, 3 H), 2.36–1.46 (m, 7
H), 1.11 (d, J = 6.19 Hz, 3 H), 0.98–0.94 (m, 12 H), 0.83 (s, 9 H),
–0.01 (s, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 159.2, 138.7,
129.4, 128.2, 128.0, 127.8, 127.5, 113.7, 80.9, 72.9, 72.7, 71.0, 68.5,
67.9, 64.9, 55.2, 39.1, 39.0, 30.2, 25.8, 18.0, 17.2, 16.9, –4.5,
–4.6 ppm. HRMS (ESI+): m/z calcd. for C37H60O6Si2 [M + H]+
657.4007; found 657.4007.
colourless oil. [α]2D5 = –1.98 (c = 1.3, CHCl ). IR (CHCl ): ν
=
˜
max
2-[(4R,7S)-7-Butyl-2,2-diisopropyl-4,7-dihydro-1,3,2-dioxasilepin-4-
yl]ethanol (24): To a stirring solution of PMB ether 22 (0.070 g,
0.164 mmol) in CH2Cl2/H2O (0.5:0.03) was added DDQ (0.046 g,
0.199 mmol). The resulting mixture was stirred for 10 min at room
3
3
2933, 2867, 1613, 1514, 1464, 1248, 1089, 1039, 920, 885 cm–1. H
NMR (CDCl3, 400 MHz): δ = 7.31–7.24 (m, 2 H), 6.92–6.85 (m, 2
H), 5.95–5.74 (m, 2 H), 5.23–5.01 (m, 4 H), 4.55–4.24 (m, 4 H),
1
Eur. J. Org. Chem. 2013, 4586–4593
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4591

P. S. Chowdhury, P. Kumar
quid; [α]2D5 = 18.06 (c = 0.6, CHCl ). IR (CHCl ): ν
= 2932,
FULL PAPER
temp., then the mixture was poured into saturated aqueous
NaHCO3 and further diluted with CH2Cl2. The layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (2 ϫ
10 mL). The combined organic layers were dried (Na2SO4), filtered,
and concentrated. The solvents were removed under reduced pres-
sure to give the crude product mixture as a yellow oil. Silica gel
column chromatography of the crude product (PE/ethyl acetate,
˜
max
3
3
2867, 1742, 1705, 1422, 1302, 1274, 1101, 965, 889, 773 cm–1. 1H
NMR (CDCl3, 400 MHz): δ = 7.33–7.25 (m, 5 H), 6.46–6.36 (m, 1
H), 5.86 (d, J = 11.76 Hz, 1 H), 5.67–5.48 (m, 2 H), 4.92–4.46 (m,
5 H), 4.16 (q, J = 7.15 Hz, 2 H), 3.94–3.83 (m, 1 H), 1.79–1.57 (m,
4 H), 1.27–1.24 (m, 5 H), 1.18–1.15 (m, 3 H), 1.02–098 (m, 12 H),
0.88 (s, 9 H), 0.06 (m, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 166.4, 146.3, 139.0, 128.2, 127.8, 127.7, 127.4, 121.0, 80.5, 72.5,
70.2, 68.4, 59.8, 40.8, 37.5, 29.7, 25.8, 19.1, 17.4, 17.2, 14.3, –4.5,
–4.7 ppm. HRMS (ESI+): m/z calcd. for C33H56O6Si2 [M + H]+
80:20) gave 24 (0.046 g, 93%); [α]2D5 = –6.18 (c = 1.0, CHCl3). IR
1
(CHCl ): ν
= 3456, 2929, 2865, 1465, 1248, 1092, 884 cm–1. H
˜
3
max
NMR (CDCl3, 500 MHz): δ = 5.68–5.45 (m, 2 H), 3.89–3.83 (m, 2
H), 3.66–3.62 (m, 2 H), 1.35–1.29 (m, 10 H), 0.92–0.80 (m, 15 605.3694; found 605.3696.
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 135.2, 132.8, 71.8, 71.0,
61.3, 39.1, 37.7, 22.7, 22.6, 19.8, 17.2, 14.1 ppm. LC–MS: m/z =
323 [M + Na]+. HRMS (ESI+): m/z calcd. for C16H32O3Si [M +
Na]+ 323.2018; found 323.2018.
Desacetylumuravumbolide (1a): To a stirred solution of compound
26 (25 mg, 67.8 μmol) in THF (0.6 mL) was added TBAF (40 μL,
0.13 mmol) at room temperature and the yellow solution was
stirred overnight at the same temperature. Water was added, the
organic layer was separated and the aqueous layer was extracted
with EtOAc. The combined organic layers were dried with Na2SO4
and concentrated to give the crude triol, which was used for the
next step without purification.
2-((4R,7S)-7-{(2R,3S)-2-(Benzyloxy)-3-[(tert-butyldimethylsil-
yl)oxy]butyl}-2,2-diisopropyl-4,7-dihydro-1,3,2-dioxasilepin-4-yl)eth-
anol (25): Compound 25 was prepared from 23 by following the
procedure described for 24, yield 92%; colourless liquid; [α]2D5
=
12.43 (c = 0.8, CHCl ). IR (CHCl ): νmax = 2967, 2861, 1582, 1513,
˜
3
3
The diol was dissolved in benzene (0.4 mL) and Ti(OiPr)4 (2 μL,
6 μmol) was added. The yellow solution was heated to reflux for
1 h, then the solution was cooled to room temp. and the solvent
was removed in vacuo. The residue was purified by flash
chromatography (100 g silica gel; CH2Cl2/MeOH, 98:2) to give lac-
tone 1a (16 mg, 92%) as a colourless oil; [α]2D5 = –2.3 (c = 0.5,
1445, 1348, 1092, 889 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.33–
7.25 (m, 5 H), 5.70–5.46 (m, 2 H), 5.00–4.82 (m, 2 H), 4.78–4.63
(m, 1 H), 4.60–4.45 (m, 1 H), 3.94–3.83 (m, 3 H), 3.76–3.40 (m, 1
H), 1.96–1.58 (m, 6 H), 1.18–1.15 (m, 3 H), 1.06–0.99 (m, 12 H),
0.89 (s, 9 H), 0.06–0.01 (m, 6 H) ppm. 13C NMR (CDCl3,
120 MHz): δ = 138.9, 135.7, 135.4, 134.9, 128.2, 127.8, 80.5, 73.3,
72.5, 69.3, 68.4, 61.3, 39.4, 39.2, 29.7, 25.8, 18.5, 17.4, 17.1, –4.5,
–4.7 ppm. HRMS (ESI+): m/z calcd. for C29H52O5Si2 [M + Na]+
559.3251; found 559.3252.
CHCl3) {ref.[2] [α]2D5 = –5.3 (c = 1.3, CHCl )}. IR (CHCl ): ν
=
˜
max
3
3
3456, 1720, 1685, 1390, 1060 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 6.89–6.87 (m, 1 H), 6.00–5.97 (m, 1 H), 5.78–5.65 (m, 1 H),
4.62–4.34 (m, 1 H), 2.41–2.19 (m. 2 H), 1.56–1.47 (m, 2 H), 1.45–
1.26 (m, 4 H), 0.93 (m, 3 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 164.1, 146.6, 135.8, 127.4, 123.1, 72.8, 67.2, 37.0, 29.9, 27.0,
23.1, 14.0 ppm. HRMS (ESI+): m/z calcd. for C12H18O3 [M +
Na]+ 233.1154; found 233.1155.
(Z)-Ethyl 4-[(4R,7S)-7-Butyl-2,2-diisopropyl-4,7-dihydro-1,3,2-dioxa-
silepin-4-yl]but-2-enoate (26): Dess–Martin periodinane (0.046 g,
0.109 mmol) was added to a solution of 24 (0.030 g, 0.099 mmol)
and pyridine (0.04 mL, 0.49 mmol) in CH2Cl2 (0.8 mL) at 0 °C.
The reaction was stirred at room temp. for 30 min, then quenched
by addition of saturated aqueous Na2S2O3 and saturated aqueous
NaHCO3. The organic layer was washed with satd NaCl solution,
dried with Na2SO4, and concentrated to afford the aldehyde, which
was used immediately in the next step without further purification.
Umuravumbolide (1b): Prepared from desacetylumuravumbolide
(1a) according to ref.[2a] [α]2D5 = +15 (c = 0.3, CHCl3) {ref.[2] [α]2D5
= +30 (c = 2.1, CDCl )}. IR (CHCl ): ν = 1745, 1730, 1685,
˜
max
3
3
1
1256 cm–1. H NMR (CDCl3, 400 MHz): δ = 6.88–6.86 (m, 1 H),
6.03–5.99 (m, 1 H), 5.93–5.66 (m, 1 H), 5.42–5.08 (m, 3 H), 2.31–
2.29 (m, 2 H), 2.02 (s, 3 H), 1.41–1.35 (m, 6 H), 0.87 (m, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 169.7, 163.5, 146.4, 130.9, 130.5,
123.7, 72.8, 69.9, 34.5, 30.2, 28.9, 22.2, 21.9, 14.0 ppm. HRMS
(ESI+): m/z calcd. for C14H20O4 [M + Na]+ 275.1259; found
275.1258.
To a solution of (PhO)2P(O)CH2COOEt (0.043 g, 0.108 mmol) in
THF (0.6 mL) at 0 °C was added NaI (0.012 g, 0.084 mmol). After
5 min, NaH (60% dispersion in mineral oil, 0.002 g, 0.108 mmol)
was added, and the resulting solution was cooled to –78 °C. The
aldehyde (0.026 g, 0.084 mmol) dissolved in THF (0.6 mL) was
then added dropwise. After 2 h at –78 °C, saturated NH4Cl
(0.7 mL) was added and the reaction mixture was extracted with
Et2O (3 ϫ 5 mL). The combined organic extracts were dried
(Na2SO4) and concentrated. The crude product was purified by
flash chromatography (PE/ethyl acetate, 85:15) to give 26 (0.033 g,
(R)-6-[(3S,5R,6S,Z)-5-(Benzyloxy)-3,6-dihydroxyhept-1-en-1-yl]-
5,6-dihydro-2H-pyran-2-one (28): Prepared from 27 by following the
procedure described for 1a, yield 96%; colourless liquid; [α]2D5
=
–1.7 (c = 0.7, CHCl ). IR (CHCl ): ν = 3330, 2937, 1823, 1470,
˜
max
3
3
1320, 1245, 1076, 872 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.30–
7.23 (m, 5 H), 6.40–6.31 (m, 1 H), 5.80 (d, J = 11.87 Hz, 1 H),
5.62–5.43 (m, 2 H), 4.87–4.54 (m, 3 H), 3.88–3.79 (m, 1 H), 1.74–
1.52 (m, 4 H), 1.13–1.10 (m, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 172.6, 144.2, 139.0, 130.7, 129.8, 128.5, 127.9, 127.7,
127.6, 126.7, 84.0, 70.3, 67.1, 66.6, 64.7, 41.6, 31.6, 22.4 ppm.
HRMS (ESI+): m/z calcd. for C19H24O5 [M + Na]+ 355.1521;
found 355.1521.
90%). [α]2D5 = –7.60 (c = 0.3, CHCl ). IR (CHCl ): ν
= 2930,
˜
max
3
3
2861, 1650, 1610, 1512, 1460, 1241, 1092, 885 cm–1 1H NMR
.
(CDCl3, 400 MHz): δ = 6.46–6.39 (m, 1 H), 5.87–5.84 (m, 1 H),
5.66–5.58 (m, 1 H), 5.51–5.44 (m, 1 H), 4.82–4.54 (m, 2 H), 4.18–
4.14 (m, 2 H), 3.08–2.99 (m, 1 H), 2.90–2.80 (m, 1 H), 1.32–1.26
(m, 1 H), 1.03–0.98 (m, 12 H), 0.90–0.88 (m, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 166.5, 146.5, 135.1, 132.9, 120.9, 71.1, 70.2,
59.9, 38.3, 37.3, 22.7, 22.5, 17.6, 17.1, 14.3, 14.1 ppm. HRMS
(ESI+): m/z calcd. for C20H37O4Si [M + H]+ 369.2461; found
369.2464.
Hyptolide (2): To a solution of 28 (10 mg, 30 μmol) in anhydrous
CH2Cl2 (0.35 mL) under nitrogen at 0 °C was added TiCl4 (28 mg,
16 μL, 0.15 mmol). After 20 min, excess reagent was quenched by
the addition of water, and the mixture was extracted with CH2Cl2,
washed with water, dried (Na2SO4), and evaporated to afford the
triol, which was used immediately in the next step without further
purification.
(Z)-Ethyl 4-((4R,7S)-7-{(2R,3S)-2-(Benzyloxy)-3-[(tert-butyldi-
methylsilyl)oxy]butyl}-2,2-diisopropyl-4,7-dihydro-1,3,2-dioxasil-
epin-4-yl)but-2-enoate (27): Compound 27 was prepared from 25 by
following the procedure described for 26, yield 93%; colourless li-
4592
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Eur. J. Org. Chem. 2013, 4586–4593

Total Synthesis of Umuravumbolide and Hyptolide
The triol was then dissolved in anhydrous CH2Cl2 (0.12 mL) and
treated with Et3N (33 μL, 0.24 mmol), acetic anhydride (20 μL,
0.2 mmol) and DMAP (1.4 mg, 12 μmol). After stirring overnight,
the reaction mixture was worked up (extraction with CH2Cl2) and
purified by chromatography on a silica gel column (PE/ethyl acet-
ate, 70:30) to give hyptolide 2 (7 mg, 90%) as a colourless solid;
m.p. 83–86 °C (ref.[2b] m.p. 87–88 °C); [α]2D5 = +12.3 (c = 0.7,
[1] a) L. Van Puyvelde, S. Dube, E. Uwimana, C. Uwera, R. A.
Dommisse, E. L. Esmans, O. Van Schoor, A. J. Vlietinck, Phy-
tochemistry 1979, 18, 1215–1218; b) A. J. Birch, D. N. Butler,
J. Chem. Soc. 1964, 4167–4168.
[2] a) V. R. Ramachandran, M. V. R. Reddy, J. P. Rearick, N.
Hoch, Org. Lett. 2001, 3, 19–20; b) S. Diaz-Oltra, J. Murga, E.
Falomir, M. Carda, J. A. Marco, Tetrahedron 2004, 60, 2979–
2985; c) S. Purkait, T. K. Chakraborty, Tetrahedron Lett. 2008,
49, 5502–5504; d) V. Shekhar, D. K. Reddy, S. P. Reddy, P.
Prabhakar, Y. Venkateswarlu, Eur. J. Org. Chem. 2011, 4460–
4464; e) G. Sabitha, D. V. Reddy, S. S. S. Reddy, J. S. Yadav, G.
Kumar, P. Sujitha, RSC Adv. 2012, 2, 7241–7247.
[3] a) P. Kumar, S. V. Naidu, J. Org. Chem. 2006, 71, 3935–3941;
b) P. Kumar, M. Pandey, P. Gupta, S. V. Naidu, D. D. Dhavale,
Eur. J. Org. Chem. 2010, 36, 6993–7004; c) P. Kumar, M. Pan-
dey, P. Gupta, D. D. Dhavale, Org. Biomol. Chem. 2012, 10,
1820–1825.
CHCl3) {ref.[2b] [α]2D5 = +11.2 (c = 0.6, CHCl )}. IR (CHCl ): ν
˜
3
3
max
1
= 1737, 1645, 1280 cm–1. H NMR (CDCl3, 400 MHz): δ = 6.86–
6.84 (m, 1 H), 6.09–6.03 (m, 1 H), 5.73–5.71 (m, 1 H), 5.52–5.50
(m, 2 H), 5.11–5.07 (m, 1 H), 5.03–4.80 (m, 2 H), 2.36–2.33 (m, 2
H), 2.04–2.02 (m, 10 H), 1.81 (s, 1 H), 1.15–1.11 (m, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 169.7, 169.0, 164.8, 139.2, 129.5,
126.5, 124.0, 72.8, 70.5, 69.9, 67.2, 61.5, 33.7, 22.6, 14.0 ppm.
HRMS (ESI+): m/z calcd. for C18H24O8 [M + Na]+ 511.2492;
found 511.2495.
[4] For examples of silicon-tethered ring-closing metathesis cross-
coupling reactions, see: a) T. R. Hoye, M. A. Promo, Tetrahe-
dron Lett. 1999, 40, 1429–1432; b) P. Van de Weghe, D. Aoun,
J. G. Boiteau, J. Eustache, Org. Lett. 2002, 4, 4105–4108, and
related references cited therein.
[5] K. Ando, J. Org. Chem. 1997, 62, 1934–1939.
[6] a) P. Kumar, M. S. Bodas, J. Org. Chem. 2005, 70, 360–363; b)
P. Kumar, S. V. Naidu, P. Gupta, J. Org. Chem. 2005, 70, 2843–
2846.
tert-Butyl{(S)-1-[(4R,6S)-2,2-Dimethyl-6-vinyl-1,3-dioxan-4-
yl]ethoxy}dimethylsilane (29): To a dark-blue solution of sodium-
ammonia prepared from excess sodium and liquid ammonia
(30 mL), was added a solution of 7 (0.05 g, 0.14 mmol) in THF
(5 mL) at –78 °C. The solution was warmed to –50 °C and stirred
for 1 h. The reaction was quenched by the addition of ammonium
chloride. The cooling bath was removed and, after all ammonia
was evaporated, the mixture was diluted with water and the aque-
ous layer was extracted with EtOAc. The extract was washed with
water and concentrated under reduced pressure.
[7] G. Zhong, Angew. Chem. 2003, 115, 4379; Angew. Chem. Int.
Ed. 2003, 42, 4247–4250.
[8] C. A. G. M. Weijers, A. K. Botes, M. S. van Dyk, I. A. M.
de Bont, Tetrahedron: Asymmetry 1998, 9, 467–473.
[9] L. Alcaraz, J. J. Harnett, C. Mioskowski, J. P. Martel, T.
Le Gall, D. S. Shin, J. R. Falck, Tetrahedron Lett. 1994, 35,
5449–5452.
To a solution of the above compound in CH2Cl2 (5 mL) at 25 °C
was added 2-methoxy-propene (40 μL, 0.42 mmol), followed by
PPTS (2.5 mg, 10 μmol) portionwise. The reaction mixture was
stirred at 25 °C for 15 min, then quenched by the addition of solid
NaHCO3 and stirred for 30 min. The reaction mixture was filtered
through a pad of Celite and concentrated. Silica gel column
chromatography (PE/ethyl acetate, 24:1) gave 29 (0.036 g, 85%) as
[10] F. Felluga, C. Forzato, F. Ghelfi, P. Nitti, G. Pitacco, U. M.
Pagnoni, F. Roncagliab, Tetrahedron: Asymmetry 2007, 18,
527–536.
[11] K. Zhang, V. Gudipati, D. P. Curran, Synlett 2010, 667–671.
[12] The enantiomeric excess of diol 15 was determined by con-
verting its derivative allylic alcohol 6 into the Mosher ester and
analyzing the 19F NMR spectrum (see the Supporting Infor-
mation).
a colourless liquid; [α]2D5 = +11.50 (c = 0.5, CHCl3). IR (CHCl3):
1
ν
= 2901, 2823, 1580, 1545, 1309, 745 cm–1. H NMR (CDCl3,
˜
max
400 MHz): δ = 5.92–5.79 (m, 1 H), 5.27–5.18 (m, 1 H), 5.13–5.04
(m, 1 H), 4.39–4.18 (m, 1 H), 3.98–3.70 (m, 1 H), 3.64–3.55 (m, 1
H), 1.92–1.64 (m, 2 H), 1.57 (s, 6 H), 1.15–1.11 (m, 3 H), 0.88–0.86
(m, 9 H), 0.05 (m, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
139.0, 115.3, 114.2, 98.5, 73.4, 71.3, 70.2, 32.7, 30.1, 29.7, 25.8,
19.9, –4.4, –4.6 ppm. HRMS (ESI+): m/z calcd. for C16H33O3Si [M
+ H] 301.2199; found 303.2197.
[13] L. A. Paquette, S. Dong, G. D. Parker, J. Org. Chem. 2007, 72,
7135–7147.
[14] The stereochemistry of 20 was confirmed on the basis of 13C
NMR spectra by converting 7 (derived from 20, Scheme 4) into
compound 29 through the following sequence of reaction.
Compound 7 was subjected to Birch reaction conditions fol-
lowed by acetonide protection of 1,3-diol to give the cyclic moi-
ety 29. The appearance of methyl resonance peaks at δ = 19.8
and 30.0 ppm and the acetal carbon resonating at δ = 98.5 ppm
(see the Supporting Information) confirmed the presence of
syn-acetonide 29.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data of synthetic intermediates of umura-
vumbolide 1b and hyptolide 2, and 1H and 13C NMR spectra of
all new compounds.
Acknowledgments
P. S. C. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for the award of a senior research fellowship.
Financial support from the Department of Science and Technology
(DST), New Delhi (grant number SR/S1/OC-44/2009) is gratefully
acknowledged.
[15] P. A. Evans, J. Cui, S. J. Gharpure, A. Polosukhin, H. R.
Zhang, J. Am. Chem. Soc. 2003, 125, 14702–14703.
Received: February 28, 2013
Published Online: June 12, 2013
Eur. J. Org. Chem. 2013, 4586–4593
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4593