Convergent total synthesis of squamostolide

Article abstract of DOI:10.1016/j.tet.2007.03.151

A convergent total synthesis of the Annonaceous acetogenin squamostolide, in a longest linear sequence of nine steps from d-mannitol, is reported. Central to the efficiency of the synthesis is a highly selective tandem ring-closing/cross metathesis step in which lactone formation and fragment coupling are accomplished.

Full text of DOI:10.1016/j.tet.2007.03.151

Tetrahedron 63 (2007) 4881–4886
Convergent total synthesis of squamostolide
*
Kevin J. Quinn, Austin G. Smith and Carolyn M. Cammarano
Department of Chemistry, College of the Holy Cross, One College Street, Worcester, MA 01610-2395, USA
Received 8 February 2007; revised 22 March 2007; accepted 23 March 2007
Available online 30 March 2007
Abstract—A convergent total synthesis of the Annonaceous acetogenin squamostolide, in a longest linear sequence of nine steps from
D-mannitol, is reported. Central to the efficiency of the synthesis is a highly selective tandem ring-closing/cross metathesis step in which
lactone formation and fragment coupling are accomplished.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
and bis(lactone) acetogenins 1–3 have received considerable
interest from the synthetic community.5–7
Squamostolide1 (1), rollicosin2 (2), and muricatacin3 (3) are
three structurally related members of the Annonaceous
acetogenin family of natural products (Scheme 1). Annona-
ceous acetogenins display a range of noteworthy biological
properties including antitumor, antimalarial, insecticidal,
and antibiotic activities. More than 400 acetogenins have
been isolated from tropical and subtropical Annonaceae
plants, with most possessing a terminal lactone and a termi-
nal aliphatic side chain connected by a linker containing one
or two tetrahydrofuran (THF) rings.4 Solamin (4) and muri-
solin (5) are representative examples of mono(THF) aceto-
genins. It is likely that truncated analogs 1–3 are formed
by oxidation of more common THF-containing acetogenins.
For example, squamostolide or muricatacin may be gener-
ated by oxidative cleavage of either the C15–C16 bond or
C19–C20 bond of solamin, respectively. As a result of their
interesting structural and biological properties as well as
their potential as structure–activity probes and intermediates
in the preparation of more complex natural products, mono-
Previously, we reported total syntheses of muricatacin and
rollicosin using a tandem ring-closing metathesis (RCM)8/
cross metathesis (CM)9 strategy for the construction of the
5-hydroxybutan-4-olide nucleus.6a,7b In this paper, we dem-
onstrate the viability of this approach in a more complex
setting than earlier reported and present a more complete
examination of the RCM/CM transformation in the context
of a highly convergent total synthesis of squamostolide.
Our synthetic strategy is based upon the observation that
acrylate esters of 1,5-hexadiene-3,4-diol (e.g., 6) undergo
size selective RCM to produce butenolides 7 in preference
to dihydropyranones 8 (Scheme 2). We have found that
tert-butyldimethylsilyl (R¼TBS) and benzyl (R¼Bn) ana-
logs of 6 give butenolides exclusively when treated with
the second-generation Grubbs’ catalyst (9).10 In a related
study, Blechert and Michaelis found that RCM of unpro-
tected (R¼H) and methoxymethyl (R¼MOM) analogs of 6
OH
O
O
R
O
O
R
O
15
HO
R = H, squamostolide, 1
R = OH, rollicosin, 2
O
O
16
O
R = H, solamin, 4
R = OH, murisolin, 5
19
O
HO
20
OH
muricatacin, 3
Scheme 1. Representative truncated and mono(THF) Annonaceous acetogenins.
Keywords: Squamostolide; Annonaceous acetogenin; Total synthesis; Olefin metathesis.
* Corresponding author. Tel.: +1 508 793 3576; fax: +1 508 793 3530; e-mail: kquinn@holycross.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.151

4882
K. J. Quinn et al. / Tetrahedron 63 (2007) 4881–4886
OR
OBn
OR
4
OR
O
PhS
( )9
RCM
or
1
O
O
O
O
O
O
O
11
O
O
6
7
8
OBn
O
PhS
( )9
RCM/CM
MesN
Cl
NMes
+
O
MesN
Cl
NMes
Ph
O
Ru
O
Cl
Ru
O
12
13
Cl
PCy3
Scheme 4. Retrosynthetic analysis of 1.
9
10
Scheme 2. Size selective RCM of trienes 6.
to their similar structural complexity and anticipated avail-
ability from simple starting materials.
with 9 or the second-generation Hoveyda–Grubbs’ catalyst
(10)11 resulted in less selective butenolide formation than
the TBS and Bn analogs with ratios of 8:7 as high as 1:2.7
being observed.12 Additionally, Virolleaud and Piva have
reported that an analog of 6 lacking substitution at C4
undergoes RCM with catalyst 9 to produce a 2:1 ratio of
butenolide to dihydropyranone.13
2. Results and discussion
The synthesis of triene 12 began with D-mannitol (14) and is
outlined in Scheme 5. Conversion of 14 to C2-symmetric
(R,R)-hexa-1,5-diene-3,4-diol (15) was achieved by bro-
moacetylation followed by reductive elimination and acetate
removal according to known protocol.15 Monobenzylation
of the stannylene acetal of 15 proved to be an efficient
method for desymmetrization,16 and acryloylation of the re-
maining hydroxyl gave metathesis substrate 12 in excellent
overall yield. The benzyl protecting group was chosen for
its compatibility and ease of removal by hydrogenolysis
(vide infra); however, it should be noted that attempts to
monoprotect the stannylene acetal of 15 with electrophiles
other than BnBr (acryloyl chloride, TBSCl, TESCl, and
MOMCl) met with failure.
In these cases, we believe that the size selectivity is most
likely governed by whether initiation by the catalyst occurs
at the C1–C2 olefin or the C5–C6 olefin (Scheme 3). Initia-
tion at the acrylate is unlikely due to its reduced reactivity.
Our results can then be rationalized by a steric preference of
initiation at the less hindered C1–C2 alkene. This rationale
is less convincing in explaining the results of Blechert and
Piva, in which one may reasonably expect a reversal of se-
lectivity due to initiation at the C5–C6 olefin due to steric
effects or directing effects of a chelating protecting group
R. The inherent selectivity for five-membered ring forma-
tion in these examples seems to indicate that a factor other
than these may also be influencing the site of initiation.
We hypothesize that coordination of the acrylate carbonyl
may be directing initiation to the proximal C1–C2 olefin
to produce intermediate A as well stabilizing the result-
ing carbene intermediate by producing the six-membered
chelate A0.
1. AcBr; Ac2O,
pyr, 67%
2. Zn, NaOAc,
HOAc
OH OH
OH
HO
OH
3. NaOMe, MeOH,
80% (2 steps)
OH OH
OH
14
15
COCl,
iPr2NEt,
CH2Cl2, 83%
Bu2SnO, Bu4NI,
PhH, -H2O;
BnBr, 88%
OBn
OR
12
OR
OR
2
6
1
LnRu
O
LnRu=
OH
LnRu
16
5
O
O
O
Scheme 5. Synthesis of triene 12.
O
O
6
A
A'
Scheme 3. Proposed rationale for size selectivity.
Synthesis of the terminal alkene CM coupling partner is
illustrated in Scheme 6. (5S)-Methyl-3-phenylsulfanyl-
dihydrofuran-2-one (19) was prepared by alkylation of the
enolate of (phenylthio)acetic acid (17) with (S)-propylene
oxide (18) followed by acid-catalyzed lactonization.17 The
12-carbon alkyl chain linker was prepared by Wittig homol-
ogation of commercially available 10-undecenal (20) fol-
lowed by hydrolysis/reduction following the procedure of
Crouch.18 Conversion to the corresponding triflate 21 and
addition to the potassium enolate of 19 produced the coupling
partner 13 as a separable 3:1 mixture of diastereomers.
Enolate alkylations such as this one, first reported by Hoye
and co-workers, have proven to be widely effective for
construction of acetogenin side chains.19 Use of the potas-
sium enolate of 19 rather than the lithium or sodium enolate
We have taken advantage of the size selectivity observed for
the RCM of trienes 6 by using this reaction in tandem with
a subsequent CM step to append a coupling partner to the un-
metathesized, exocyclic alkene. We have shown that simple
terminal olefins may be used as coupling partners in the
CM.6a,7b More recently, Hoye and co-workers reported appli-
cation of strategically similar RCM/CM approach in the total
synthesis of the bis(THF)acetogenin gigantecin.14 In order to
maximize efficiency in the synthesis of 1, we chose to pursue
a convergent approach in which triene 12 was subjected to
RCM/CM in the presence of coupling partner 13 as outlined
retrosynthetically in Scheme 4. Practically, 12 and 13 were
viewed as ideal substrates for the key metathesis step due

K. J. Quinn et al. / Tetrahedron 63 (2007) 4881–4886
4883
1. LiHMDS, THF;
results detailed in Table 1 represent our most comprehensive
study on the effect of Ru catalyst on reaction yield and
clearly indicate that the second-generation Hoveyda–
Grubbs’ catalyst (10) is optimal for promoting the RCM
and CM steps in tandem. Somewhat surprisingly, we found
that the first-generation Hoveyda–Grubbs’ catalyst resulted
in slightly higher isolated yields of 22 (RCM only) than 10
in reactions of 12 run in the absence of coupling partner 13.
O
O
18
KHMDS,
THF;
PhS
PhS
CO2H
CHO
13
O
2. TsOH, PhH,
79% (2 steps)
17
19
80%
1. Ph3P=CHOMe,
THF
2. Hg(OAc)2; NaBH4,
MeOH, 44% (2 steps)
3. Tf2O, 2,6-lutidine,
CH2Cl2, 84%
( )9
21
( )8
OTf
20
It is interesting to note that 13 undergoes dimerization by
CM at a rate much faster than that of its CM with 22, so,
in fact, the CM step is likely occurring between 22 and dimer
23 (Scheme 7). This conclusion is supported by our observa-
tion of 23 by 1H NMR and TLC analysis in which consump-
tion of 13 is not observed concomitantly with that of 22.
Rather, fast formation of 22 (from 12) and consumption of
13 (to produce 23) are observed followed by relatively
slow formation of 11. Products of CM between two molecules
of 12 and/or 22 were not observed. This is presumably due
to their reduced reactivity as a result of allylic substitution.
Scheme 6. Synthesis of terminal alkene 13.
in the alkylation was necessary to avoid the requirement
of elevated temperature and/or the use of HMPA as an
additive.
With substrates 12 and 13 in hand, the stage was set for eval-
uation of the key RCM/CM step. In previous RCM/CM stud-
ies, we employed only catalyst 9, and aside from completion
of a synthesis of squamostolide, one motivating factor for the
research presented in this article was to carry out a more
thorough evaluation of metathesis initiators for this transfor-
mation. A typical procedure involved refluxing a 0.02 M
methylene chloride or benzene solution of triene 12 in
the presence of 3 equiv of coupling partner 13 followed by
dropwise addition of 10 mol % of a metathesis catalyst as
a 0.01 M solution over 6 h via syringe pump. For consistency
in catalyst evaluation, all reactions were heated under reflux
for an additional 14 h. Our results are shown in Table 1. The
first-generation Grubbs’ catalyst20 proved incapable of ef-
fecting the tandem RCM/CM affording 22, the product of
RCM only, in poor yield (entry 1). While the second-gener-
ation Grubbs’ catalyst (9) and the first-generation Hoveyda–
Grubbs’ catalyst21 gave workable yields of 11, significant
amounts of 22 were also observed (entries 2–4). Although
11 and 22 could be separated by column chromatography
without difficulty, we felt that use of the more active sec-
ond-generation Hoveyda–Grubbs’ catalyst (10) may pro-
mote complete CM and increase our isolated yields of 11.
We were pleased to find this to be the case with yields of
11 as high as 77% being obtained (entries 5 and 6). We be-
lieve that the observed temperature dependence when cata-
lyst 10 is employed is simply the result of an increased
rate of catalyst decomposition at elevated temperature. The
O
PhS
( )9
O
PhS
( )9
O
CM
( )9
SPh
O
O
O
13
Scheme 7. Dimerization of 13 by CM.
23
The synthesis was completed by the three-step sequence out-
lined in Scheme 8. Catalytic hydrogenation/hydrogenolysis
cleanly achieved alkene reduction and benzyl group depro-
tection, and subsequent sulfide oxidation with m-CPBA
and thermolysis gave squamostolide (1) in 56% over three
steps requiring purification after only at the last. Spectral
1
data (IR, H and 13C NMR, and HRMS), optical rotation,
and melting point of synthetic 1 were consistent with those
reported in the literature.1,5
OH
1. H2, Pd/C, EtOAc
O
2. mCPBA, CH2Cl2
( )9
11
O
3. PhCH3, 110 °C,
56% (3 steps)
O
1
O
Scheme 8. Completion of the synthesis of 1.
Table 1. RCM/CM of 12 and 13
OBn
OBn
OBn
O
O
PhS
( )9
PhS
( )9
catalyst (10 mol%)
+
+
O
O
PhH, 80 °C or
CH2Cl2, 40 °C
O
O
O
O
O
O
12
13
22
11
Entry
Catalysta
Temperature (ꢀC)
Yield of 22 (%)
Yield of 11 (%)
1
2
3
4
5
6
Grubbs’ I
9
9
Hoveyda–Grubbs’ I
10
10
80
80
40
80
80
40
45
12
19
16
0
0
53
60
66
68
77
0
a
Grubbs’ I catalyst: PhCH]RuCl2(PCy3)2; Hoveyda–Grubbs’ I catalyst: o-isopropoxyPhCH]RuCl2(PCy3).

4884
K. J. Quinn et al. / Tetrahedron 63 (2007) 4881–4886
In conclusion, we have accomplished a convergent total
synthesis of squamostolide that demonstrates the scope and
power of our tandem RCM/CM strategy for preparation of
hydroxylated butenolides. The efficiency and flexibility of
this approach make it broadly useful, and we are currently
in the process of generating analogs of truncated acetoge-
nins as well as examining functionalization of RCM/CM
products for the synthesis of more complex THF-containing
acetogenins.
film) 3449, 3085, 3030, 2868 cmꢂ1 1H NMR (CDCl3,
;
400 MHz) d 7.39–7.29 (m, 5H), 5.84 (ddd, J¼17.2, 10.6,
5.7 Hz, 1H), 5.76 (ddd, J¼17.2, 10.5, 7.8 Hz, 1H), 5.39
(ddd, J¼10.6, 1.8, 0.8 Hz, 1H), 5.37 (dt, J¼17.2, 1.6 Hz,
1H), 5.34 (ddd, J¼17.2, 1.8, 0.8 Hz, 1H), 5.22 (dt, J¼10.5,
1.6 Hz, 1H), 4.67 (d, J¼11.5 Hz, 1H), 4.39 (d, J¼11.5 Hz,
1H), 4.09 (ddt, J¼7.2, 5.7, 1.4 Hz, 1H), 3.68 (br t,
J¼7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 137.9,
136.0, 134.6, 128.5, 127.9, 127.8, 120.3, 117.0, 84.0, 74.7,
70.5; HRMS calcd for C13H17O2 (MH+) 205.1229, found
205.1295.
3. Experimental
3.1.2. Acrylic acid (2R)-benzyloxy-(1R)-vinylbut-3-enyl
ester (12). To a solution of 16 (586.2 mg, 2.90 mmol) in
CH2Cl2 (29 mL) at room temperature was added i-Pr2NEt
(3.0 mL, 17.2 mmol) followed by acryloyl chloride
(0.70 mL, 8.6 mmol). The reaction mixture was stirred at
room temperature for 4 h, after which time it was quenched
with 15 mL of water and diluted with Et2O (30 mL). The
layers were separated and the aqueous phase was extracted
with Et2O (3ꢁ30 mL). The combined organic phases were
washed with satd NH4Cl (20 mL) and brine (20 mL) and
dried over MgSO4. The drying agent was removed by filtra-
tion and solvents were removed in vacuo. Purification by sil-
ica gel chromatography (6:1 pentane/Et2O) gave triene 12
(625.2 mg, 83%) as a colorless oil. Data for 12: [a]D22
+61.1 (c 1.97, CH2Cl2); IR (thin film) 3088, 3029, 2867,
3.1. General methods
Unless otherwise noted, all non-aqueous reactions were
performed in flame-dried glassware under a stream of nitro-
gen. Optical rotations were measured on a Perkin–Elmer 341
polarimeter at room temperature. Concentrations (c) are
reported in g/100 mL. Infrared spectra (IR) were obtained
on a Perkin–Elmer 1600 Series FTIR. Proton nuclear mag-
netic resonance (1H NMR) spectra and carbon nuclear mag-
netic resonance (13C NMR) spectra were recorded on a
Varian Inova-400 at 400 MHz and 100 MHz, respectively.
Chemical shifts are reported in parts per million relative to
1
CHCl3 (d 7.27) for H NMR and the central resonance of
CDCl3 (d 77.0) for 13C NMR. High resolution fast atom
bombardment mass spectra (HRMS) were obtained on a
JEOL MStation JMS-700 mass spectrometer at the University
of Massachusetts-Amherst.
1
1728 cmꢂ1; H NMR (CDCl3, 400 MHz) d 7.37–7.25 (m,
5H), 6.44 (dd, J¼17.4, 1.6 Hz, 1H), 6.17 (dd, J¼17.4,
10.4 Hz, 1H), 5.88 (ddd, J¼17.4, 10.7, 6.1 Hz, 1H), 5.84
(dd, J¼10.4, 1.6 Hz, 1H), 5.77 (ddd, J¼17.0, 10.6, 7.4 Hz,
1H), 5.50 (tt, J¼6.1, 1.4 Hz, 1H), 5.37–5.30 (m, 3H), 5.25
(tt, J¼10.7, 1.4 Hz, 1H), 4.67 (d, J¼12.1 Hz, 1H), 4.43 (d,
J¼12.1 Hz, 1H), 3.93 (br t, J¼6.7 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 165.0, 137.9, 133.9, 132.6, 130.9,
128.3, 128.1, 127.5, 127.4, 119.7, 118.1, 80.5, 75.3, 70.2;
HRMS calcd for C16H19O3 (MH+) 259.1334, found
259.1370.
EM Science DriSolvÒ solvents (CH2Cl2, PhH, THF,
pyridine, and MeOH) were used in moisture sensitive reac-
tions. (R,R)-Hexa-1,5-diene-3,4-diol (15) was prepared
from D-mannitol using the protocol reported by Burke and
Sametz.15 11-Dodecen-1-ol was prepared from 10-undecanal
according to the procedure of Crouch.18 (5S)-Methyl-3-
phenylsulfanyldihydrofuran-2-one (19) was prepared from
(phenylthio)acetic acid (17) and (S)-propylene oxide (18)
using the procedure of White.17 Commercially available
reagents and solvents were used as received without further
purification.
3.1.3. 3-Dodec-11-enyl-(5S)-methyl-3-phenylsulfanyl-
dihydrofuran-2-one (13). To a solution of 11-dodecen-
1-ol (471.0 mg, 2.53 mmol) and 2,6-lutidine (0.88 mL,
7.58 mmol) in CH2Cl2 (12 mL) at ꢂ78 ꢀC was added Tf2O
(0.64 mL, 3.80 mmol). After 10 min, the reaction mixture
was allowed to warm to 0 ꢀC and stirred for an additional
30 min. The reaction was quenched by addition of satd
NH4Cl (15 mL) and diluted with Et2O. The layers were sep-
arated and the aqueous phase was extracted with Et2O
(3ꢁ20 mL). The combined organic phases were washed
with satd NH4Cl (40 mL), H2O (20 mL), and brine
(20 mL) and dried over Na2SO4. The drying agent was
removed by filtration and the filtrate was concentrated in
vacuo. Purification by silica gel column chromatography
(6:1 hexanes/Et2O) gave triflate 21 (676.7 mg, 84%) as a
colorless oil, which was used immediately in the next step.
3.1.1. (4R)-Benzyloxyhexa-1,5-dien-(3R)-ol (16). To a
solution of (R,R)-hexa-1,5-diene-3,4-diol 15 (861.0 mg,
7.55 mmol) in PhH (75 mL) at room temperature were added
dibutyltin oxide (2.065 g, 8.30 mmol) and tetrabutylammo-
nium iodide (696 mg, 1.89 mmol). The flask was equipped
˚
with a Dean–Stark trap (filled with 4 A molecular sieves)
and a reflux condenser. The trap was filled with PhH and
the reaction mixture was heated under reflux until H2O evo-
lution appeared complete. The reaction mixture was cooled
to room temperature and BnBr (1.08 mL, 9.04 mmol) was
added. The resulting yellow solution was heated under reflux
for 18 h. The mixture was diluted with Et2O (50 mL) and
washed with 10% Na2S2O3 (30 mL). The layers were sepa-
rated and the aqueous phase was extracted with Et2O
(3ꢁ40 mL). The combined organic layers were washed
with H2O (30 mL) and dried with MgSO4. The drying agent
was removed by filtration and solvents were removed in va-
cuo. Purification by silica gel chromatography (4:1 pentane/
Et2O) provided monobenzyl ether 16 (1.36 g, 88%) as a col-
orless oil. Data for 16: [a]2D2 +42.7 (c 2.09, CH2Cl2); IR (thin
(5S)-Methyl-3-phenylsulfanyldihydrofuran-2-one
19
(554.0 mg, 2.66 mmol) in THF (2.6 mL) was cooled to
0 ꢀC, and 5.32 mL of a 0.5 M solution of KHMDS in
PhCH3 (2.66 mmol) was added. The resulting pale yellow
solution was stirred at 0 ꢀC for 10 min after which time tri-
flate 21 (676.7 mg, 2.13 mmol) in 2 mL of THF was added
via syringe. The reaction mixture was warmed to room

K. J. Quinn et al. / Tetrahedron 63 (2007) 4881–4886
4885
temperature and stirred for 16 h. The reaction was quenched
by addition of satd NH4Cl (15 mL) and diluted with EtOAc.
The layers were separated and the aqueous phase was
extracted with EtOAc (3ꢁ20 mL). The combined organic
extracts were washed with satd NH4Cl (20 mL), H2O
(20 mL), and brine (20 mL) and dried over Na2SO4. The
drying agent was removed by filtration and the filtrate was
concentrated in vacuo. Purification by silica gel column
chromatography (6:1 hexanes/EtOAc) gave terminal alkene
13 (638.3 mg, 80%) as a colorless oil. Data for 13 (major dia-
stereomer): IR (thin film) 3027, 2929, 2855, 1769 cmꢂ1; 1H
NMR (CDCl3, 400 MHz) d 7.57–7.54 (m, 3H), 7.41–7.33
(m, 2H), 5.79 (ddt, J¼16.9, 10.2, 6.6 Hz, 1H), 4.93 (dq,
J¼16.9, 1.0 Hz, 1H), 4.85 (ddt, J¼10.2, 2.3, 1.0 Hz, 1H),
4.55 (m, 1H), 2.50 (m, 1H), 2.13–1.97 (m, 5H), 1.80–1.72
(m, 2H), 1.65–1.52 (m, 2H), 1.41–1.23 (m, 13H), 1.19 (d,
J¼6.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 177.4,
139.2, 136.7, 130.4, 129.6, 129.0, 114.1, 74.2, 56.6, 34.0,
32.7, 29.7, 29.6, 29.5, 29.4, 29.1, 25.9, 25.8, 25.2, 24.7,
21.5; HRMS calcd for C23H35O2S (MH+) 375.2358, found
375.2389.
(m, 1H), 4.04 (dd, J¼8.0, 5.8 Hz, 1H), 2.61–2.47 (m, 3H),
2.33–1.94 (m, 4H), 1.80–1.72 (m, 2H), 1.65–1.52 (m, 2H),
1.41–1.23 (m, 11H), 1.16 (d, J¼6.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 177.3, 172.7, 153.6, 139.3, 137.7,
135.5, 130.4, 129.6, 129.0, 128.3, 127.6, 127.4, 126.6,
122.8, 84.5, 79.2, 73.1, 70.3, 56.3, 39.8, 36.1, 32.3, 30.3,
29.6, 29.4, 29.3, 29.2, 28.6, 25.2, 24.6, 19.9; HRMS calcd
for C35H45O5S (MH+) 577.2988, found 577.2972.
3.1.6. Squamostolide (1). To a solution of RCM/CM prod-
uct 11 (62.1 mg, 0.11 mmol) in EtOAc (3 mL) at room tem-
perature was added a spatula tip of 10 wt % Pd on activated
carbon. The reaction mixture was stirred under 1 atm of H2
for 24 h after which time it was filtered through a pad of
silica gel and concentrated invacuo to give the corresponding
saturated, debenzylated analog (50.1 mg) as a pale yellow
oil, which was carried on without purification.
To a solution of crude hydrogenation/hydrogenolysis prod-
uct (50.1 mg, 0.10 mmol) in CH2Cl2 (4 mL) at 0 ꢀC was
added m-CPBA (77% max, 25.2 mg, 0.11 mmol). After
30 min, the reaction was quenched by addition of satd
NaHCO3 (5 mL) and diluted with EtOAc. The layers were
separated and the aqueous phase was extracted with EtOAc
(2ꢁ10 mL). The combined organic extracts were washed
with satd NaHCO3 (5 mL) and brine (5 mL) and dried
over Na2SO4. The drying agent was removed by filtration
and the filtrate was concentrated in vacuo. The crude sulf-
oxide was dissolved in PhCH3 (4 mL) and heated to 110 ꢀC
for 40 min. Solvent was removed in vacuo and purification
by silica gel chromatography (5:1 PhCH3/EtOAc) gave
squamostolide 1 (22.8 mg, 56% over three steps) as a white
solid. Data for 1: [a]2D2 ꢂ3.6 (c 0.10, acetone); IR (thin film)
3.1.4. (5R)-[(1R)-Benzyloxyallyl]-5H-furan-2-one (22).
To a solution of triene 12 (51.0 mg, 0.20 mmol) and terminal
alkene 13 (218.1 mg, 0.58 mmol) in refluxing PhH (10 mL)
was added first-generation Grubbs’ catalyst (15.6 mg,
0.02 mmol) in 2 mL of PhH dropwise over 6 h by syringe
pump. Heating was continued for an additional 14 h after
addition was completed. After cooling to room temperature,
the brown solution was filtered through a short pad of silica
gel and the filtrate was concentrated in vacuo. Purification by
silica gel chromatography (4:1 pentane/Et2O) gave buteno-
lide 22 (19.7 mg, 45%) as a slightly yellow oil. Data for 3:
[a]2D2 ꢂ11.7 (c 1.11, CH2Cl2); IR (thin film) 3059, 2984,
2869, 1757 cmꢂ1; 1H NMR (CDCl3, 400 MHz) d 7.47 (dd,
J¼5.8, 1.6 Hz, 1H), 7.39–7.29 (m, 5H), 6.19 (dd, J¼5.8,
2.0 Hz, 1H), 5.65 (ddd, J¼17.2, 10.5, 7.6 Hz, 1H), 5.43–
5.36 (m, 2H), 5.13 (dt, J¼5.6, 1.6 Hz, 1H), 4.68 (d,
J¼11.9 Hz, 1H), 4.46 (d, J¼11.9 Hz, 1H), 4.11 (dd,
J¼7.6, 5.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 172.6,
153.4, 137.4, 132.4, 128.5, 127.9, 127.8, 123.0, 121.7,
83.8, 79.5, 70.8; HRMS calcd for C14H15O3 (MH+)
231.1021, found 231.0989.
3401, 2925, 2857, 1768, 1743 cmꢂ1 1H NMR (CDCl3,
;
400 MHz) d 6.99 (d, J¼1.6 Hz, 1H), 5.00 (qd, J¼6.7,
1.6 Hz, 1H), 4.41 (q, J¼7.3 Hz, 1H), 3.55 (m, 1H), 2.64–
2.53 (m, 2H), 2.30–2.21 (m, 3H), 2.09 (m, 1H), 1.87 (br s,
1H), 1.57–1.42 (m, 6H), 1.39 (d, J¼6.7 Hz, 3H), 1.37–
1.20 (m, 16H); 13C NMR (CDCl3, 100 MHz) d 177.1,
174.0, 148.9, 134.3, 82.9, 77.4, 73.6, 33.0, 29.5, 29.4,
29.2, 29.1, 28.7, 27.3, 25.4, 25.1, 24.1, 19.2; HRMS calcd
for C22H37O5 (MH+) 381.2641, found 381.2635.
3.1.5. (5R)-[(1R)-Benzyloxy-13-[(5S)-methyl-2-oxo-3-
phenylsulfanyltetrahydrofuran-3-yl]-tridec-2-enyl]-5H-
furan-2-one (11). To a solution of triene 12 (49.9 mg,
0.19 mmol) and terminal alkene 13 (215.5 mg, 0.58 mmol)
in refluxing PhH (10 mL) was added second-generation
Hoveyda–Grubbs’ catalyst 10 (12.1 mg, 0.02 mmol) in
2 mL of PhH dropwise over 6 h by syringe pump. Heating
was continued for an additional 14 h after addition was com-
pleted. After cooling to room temperature, the brown solu-
tion was filtered through a short pad of silica gel and the
filtrate was concentrated in vacuo. Purification by silica gel
chromatography (4:1 pentane/Et2O) gave RCM/CM product
11 (84.3 mg, 77%) as a yellow oil. Data for 11 (major dia-
stereomer): IR (thin film) 3053, 2928, 2859, 1765,
Acknowledgements
Acknowledgment is made to the donors of the American
Chemical Society Petroleum Research Fund for support of
this research. Additional financial support from the Simeon
J. Fortin Charitable Trust is gratefully acknowledged. Mass
spectral data were obtained at the University of Massachu-
setts Mass Spectrometry Facility, which is supported, in
part, by the National Science Foundation.
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