Toward the total syntheses of pepluanin A and euphosalicin: Concise route to a highly oxygenated cyclopentane as a common intermediate

Article abstract of DOI:10.1055/s-2004-834822

A substrate controlled asymmetric synthesis is described of a highly functionalized cyclopentanyl vinyl triflate which serves as an advanced intermediate in the total synthesis of the novel multidrug resistance reversing jatrophanes pepluanin A and euphosalicin. Key steps are a Claisen-Eschenmoser rearrangement followed by hydroxy-lactonization, intramolecular trans-lactonization, Davis hydroxylation and regioselective enoltriflate formation.

Full text of DOI:10.1055/s-2004-834822

2558
LETTER
Toward the Total Syntheses of Pepluanin A and Euphosalicin: Concise Route
to a Highly Oxygenated Cyclopentane as a Common Intermediate
T
oward the Total Synt
i
heses o
c
f
Pepluanin
h
A
a
nd Euph
a
osalicin el W. Gilbert, Anna Galkina, Johann Mulzer*
Institut für Organische Chemie, Währingerstrasse 38, 1090 Wien, Austria
Fax +43(1)427752189; E-mail: johann.mulzer@univie.ac.at
Received 22 September 2004
isolated, including pepluanin A (1) and euphosalicin (2,
Figure 1).
Abstract: A substrate controlled asymmetric synthesis is described
of a highly functionalized cyclopentanyl vinyl triflate which serves
as an advanced intermediate in the total synthesis of the novel mul-
tidrug resistance reversing jatrophanes pepluanin A and euphosali-
cin. Key steps are a Claisen–Eschenmoser rearrangement followed
by hydroxy-lactonization, intramolecular trans-lactonization, Davis
hydroxylation and regioselective enoltriflate formation.
To allow for a more detailed study of the MDR-related
activities and to further analyze the structure activity
relationships, it is highly desirable to develop a general
synthetic access to pepluanin A (1) and euphosalicin (2)
as well as other structurally related jatrophane natural
products.4 Structural analysis of 1 and 2 revealed that the
differences in the oxygenation patterns and carbon skele-
tons primarily lie in the C7-14 segment of the larger ring.
Retrosynthetic analysis suggested that at a late stage for-
mation of bonds C14-15 and C6-7 might be achieved via
pinacol and Nozaki–Hiyama–Kishi (NHK) type cou-
plings, respectively (Scheme 1). Triflate 3 could thus
serve as a versatile coupling partner and allow synthetic
access to several natural products upon preparation of the
corresponding C7-14 segments. It was envisaged that tri-
flate 3 should be available from the bicyclic lactone 4 via
stereoselective a-hydroxylation and ring-opening of the
lactone. We hoped to prepare 4 from alcohol 5 and estab-
lish the synthetically challenging oxygenation pattern via
a series of transformations including an epoxide-opening
step to introduce the trans-1,2-diol moiety on the ring.
Keywords: oxygenated cyclopentanes, Eschenmoser–Claisen
rearrangement, lactonization, Davis oxidation, enol triflate
One of the major problems of cancer chemotherapy is in-
trinsic or acquired multi-drug resistance (MDR). A prima-
ry mechanism of MDR is attributed to the overexpression
of P-glycoprotein (P-gp) in the plasma membrane or resis-
tant cells where the P-gp acts as an energy-dependent
efflux pump, reducing intracellular accumulation of anti-
cancer drugs.1 A number of drugs, such as calcium chan-
nel blockers, calmodulin inhibitors, and indole alkaloids
are known to reverse MDR by competing with anticancer
drugs for binding to P-gp. However, they have not been
proven clinically useful yet. For example, verapamil, the
most extensively studied MDR reversing agent, induces
cardiovascular toxicity at the concentration that it reverses
MDR.2 Thus, there remains a need to develop new classes
of MDR reversing agents with less toxicity to the host.
pinacol
OAc
HO
15
AcO
OMOM
OTES
OTf
O
OAc
14
AcO
16
NicO
HO
AcO
15
15
14
BzO
H
AcO
MOMO
6
7
PMBO
AcO
BzO
H
AcO
H
AcO
OAc
6
6
ONic
7
7
3
NHK
OAc
OAc
ONic
OAc
ONic
OAc
1
OAc
2
1
OMOM
HO
OTBS
Figure 1 Pepluanin A (1) and euphosalicin (2).
O
3
O
MOMO
The Euphorbiaceae (spurge) family is known to produce
various highly functionalized, structurally unique macro-
cyclic diterpenes. The MDR-reversing effect of lipophilic
extracts of Euphorbia esula L., E. peplus L., E. salicifolia,
and E. serrulata was tested on mouse lymphoma cells.3
From the active extracts, a series of structurally related
compounds with significant P-gp inhibitory activity was
4
5
Scheme 1 Retrosynthetic analysis.
Prior to tackling the synthesis of 3, we first investigated
alternative preparations of the known alcohol 5.5 Follow-
ing a protocol by Curran and co-workers,6 commercially
available furfuryl alcohol (6) was elaborated into a sepa-
rable mixture of acetate 7 (13%, 98% ee) and alcohol 8
(13%, 98% ee, Scheme 2). Using well-established chem-
istry,7 compounds 7 and 8 were then converted to a
SYNLETT 2004, No. 14, pp 2558–2562
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834822; Art ID: G36704ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Toward the Total Syntheses of Pepluanin A and Euphosalicin
2559
common intermediate, ketone 9, in two and five steps, re-
spectively.8,9 Finally, treatment of 9 with MeLi furnished
the desired tertiary alcohol 5 in good yield.5
OTBS
HO
OTBS
b
a
O
With multigram quantities of enantiomerically enriched
alcohol 5 in hand, the first steps in the elaboration of the
5-membered ring were investigated. Subjection of the
allylic alcohol 5 to the Claisen–Eschenmoser rearrange-
ment protocol10 afforded N,N-dimethyl amide 11 in good
yield (Scheme 3). A completely stereoselective epoxida-
tion of the double bond in 11 from the less hindered b-face
was then accomplished by treatment of 11 with in situ
generated DMDO.11
5
N
11
OR
O
OTBS
OTBS
O
O
N
O
13 R = H
14 R = MOM
c
OH
O
12
HO
OTBS
AcO
OTBS
Scheme 3 Reagents: (a) (MeO)2C(Me)NMe2 (85%); (b) oxone, ace-
tone, 18-crown-6, NaHCO3, (80%); (c) MOMCl, EtNi-Pr2 (81%).
6
8
7
c–e
a,b
AcO
O
O
OMOM
OMOM
OTBS
OTBS
h
f, g
5
a,b
O
c–e
14
9
10
O
O
AcO
15
HO
Scheme 2 Reagents: (a) K2CO3, MeOH (94%); (b) PDC (88%);
(c) Ac2O, Et3N, DMAP (99%); (d) TBAF (82%); (e) PDC (96%);
(f) K2CO3, MeOH (99%); (g) TBSCl, Et3N, DMAP (86%); (h) MeLi
(89%).
16
N
f
O
O
Fortuitously, the next step in our synthesis, regioselective
opening of the epoxide, occurred spontaneously upon
flash chromatography of the unstable epoxide 12. NMR
analysis of the product confirmed the bicyclic lactone
structure 13. Thus, the newly formed epoxide had been
opened by an internal attack of the neighboring amide car-
bonyl group, affording the desired trans-1,2-diol moiety.
The tertiary alcohol in 13 was then protected as the MOM
ether (14). The next series of steps were intended for the
migration of the lactone function in 14 from the oxygen-
ated C2 position on the cyclopentyl ring to the oxygenated
C5 position (Scheme 4). The lactone in 14 was opened
with pyrrolidine and the resulting alcohol was protected as
an acetate 15. Upon optimization of our synthesis, this
five-step sequence was replaced by one simple high yield-
ing step. Removal of the TBS protection group liberated
the C5 alcohol in 15, which was utilized in the desired lac-
tonization. Subsequent deacetylation afforded alcohol 16.
Indeed, treatment of 14 with TBAF for 18 hours at room
temperature directly afforded the desired lactone 16 in
88% yield. From a mechanistic point of view, the alkoxide
generated upon TBAF-desilylation of 14 apparently
adopted conformation 17 suitable for an intramolecular
trans-lactonization. Protonation of the resulting alkoxide
18 would then directly give alcohol 16. Upon MOM pro-
tection of the sterically hindered free hydroxyl at C2 in 16
to give 4, the stage was set to introduce the last point of
oxygenation (Scheme 5). The topology of the cis-fused
bicycle 16 exposes a convex face, which appears to be
significantly less sterically hindered than the correspond-
ing face.
O
O
O
O
MOMO
MOMO
17
18
Scheme 4 Reagents: (a) Pyrrolidine (97%); (b) Ac2O, pyridine
(92%); (c) TBAF (73%); (d) CSA (79%); (e) K2CO3, MeOH (89%);
(f) TBAF (88%).
This difference was thought to be sufficient to direct the
stereoselective introduction of a hydroxyl group next to
the carbonyl. Indeed, the hydroxylation step was smooth-
ly achieved by treatment of 4 with KHMDS at –78 °C
followed by addition of a cold solution of Davis’
oxaziridine12 yielding the desired alcohol 19. The relative
configuration of the newly introduced hydroxyl group in
19 was confirmed by 1H 2D NOESY experiments. Among
the noted cross peaks, strong correlations were detected
between the proton adjacent to the newly introduced
hydroxyl, Ha, and the ring methyl group, Mea (Figure 2).
OMOM
OMOM
O
O
b
O
O
MOMO
RO
a
OH
16 R = H
R = MOM
19
4
Scheme 5 Reagents: (a) MOMCl, NaI, EtNi-Pr2 (86%);
(b) KHMDS, Davis’ reagent; CSA (74%).
Synlett 2004, No. 14, 2558–2562 © Thieme Stuttgart · New York

2560
M. W. Gilbert et al.
LETTER
NOE
Mea
References
MOMO
MOMO
(1) (a) Lehnert, M. Int. J. Cancer 1998, 76, 857.
Ha
Ha : δ = 4.59 ppm (d, J = 3.3 Hz)
Mea: δ = 1.33 ppm
O
(b) Anuchapreeda, S. L. P.; Smith, M. M.; Ambudkar, S. V.;
Limtrakul, P. Biochem. Pharmacol. 2002, 64, 573.
(2) Candussio, L.; Decorti, G.; Crivellato, E.; Granzotto, M.;
Rosati, A.; Giraldi, T.; Bartoli, F. Life Sciences 2002, 71,
3109.
H
H
O
OH
H
19
(3) (a) Hohmann, J.; Molnar, J.; Redei, D.; Evanics, F.; Forgo,
P.; Kalman, A.; Argay, G.; Szabo, P. J. Med. Chem. 2002,
45, 2425. (b) Hohmann, J.; Evanics, F.; Dombi, G.; Szabo,
P. Tetrahedron 2001, 57, 211. (c) Corea, G.; Fattorusso, E.;
Lanzotti, V.; Motti, R.; Simon, P. N.; Dumontet, C.; Di
Pietro, A. J. Med. Chem. 2004, 47, 988.
(4) Helmboldt, H.; Rehbein, J.; Hiersemann, M. Tetrahedron
Lett. 2004, 45, 289.
(5) Roy, A.; Schneller, S. W. J. Org. Chem. 2003, 68, 9269.
(6) Curran, T. T.; Hay, D. A. Tetrahedron: Asymmetry 1996, 7,
2791.
(7) Barsa, S. K.; Drew, M. G. B.; Mann, J.; Kane, P. D. J. Chem.
Soc., Perkin Trans. 1 2000, 3592.
(8) All spectra obtained for intermediates 7–10 matched those
previously reported in the literature.
(9) For other preparations of 9 please refer to: Myers, A. G.;
Hammond, M.; Wu, Y. Tetrahedron Lett. 1996, 37, 3083;
and references therein.
(10) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv.
Chim. Acta 1964, 47, 2425.
Figure 2
The final steps in the preparation of our target intermedi-
ate 3 began with a PMB protection of the newly intro-
duced hydroxyl to give 20 (Scheme 6). The lactone in 20
was then opened with pyrrolidine to give amide 21 and the
resulting free hydroxl group was then TES protected to
give 22. The pyrrolidine amide 22 was then converted to
the corresponding methyl ketone 23 by addition of two
equivalents of methyl lithium at 0 °C. Although more than
one equivalent of MeLi was required for this reaction to
go to completion, none of the double addition product was
detected. The final step in this sequence, regioselective vi-
nyl triflate formation, was accomplished by first deproto-
nating the methyl ketone 23 under kinetically controlled
conditions. The resulting enolate was then quenched with
PhNTf2 to give 3 in excellent yield.
(11) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(12) Davis, F. A.; Chaltophadhyay, S.; Towson, T. C.; Lol, S.;
Reddy, T. J. Org. Chem. 1988, 53, 2087.
In summary, we have prepared the highly functionalized
triflate 3 from enantiomerically enriched alcohol 5 via an
eleven-step sequence13 that incorporates highly stereose-
lective epoxidation and subsequent intramolecular ring-
opening reactions, allowing for the establishment of the
oxygenation pattern with the desired relative and absolute
configuration. The advanced intermediate 3 should allow
synthetic access to a multitude of jatrophane natural prod-
ucts and the preparation of the coupling partners required
for the synthesis of polyesters pepluanin A (1) and eupho-
salicin (2) is currently underway in our laboratory.
(13) Experimental Details.
2-[(1S,5R)-5-(tert-Butyldimethylsilyloxy)-3-methylcyclo-
pent-2-enyl]-N,N-dimethylacetamide (11). To a stirred
solution of alcohol 4 (13.9 g, 61.0 mmol) in toluene (30 mL)
N,N-dimethlyacetamide dimethoxy acetal (24.6 g, 183.0
mmol) was added dropwise. The mixture was heated to
reflux for 48 h, during which time the generated MeOH was
allowed to distill out. The volatiles were removed under
reduced pressure and the resulting crude material was
purified by flash chromatography (5:1 hexane–EtOAc) to
give amide 11 (15.5 g, 52.0 mmol, 85% yield) as a clear
yellow oil: Rf = 0.31 (hexane–EtOAc = 2:1); [a]D20 +24.4 (c
1.1, acetone). IR (thin film): n = 3035, 2929, 2856, 1652,
1471, 1397 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.01 (s,
3 H), 0.03 (s, 3 H), 0.86 (s, 9 H), 1.68 (s, 3 H), 2.10–2.25 (m,
2 H), 2.43 (dd, J = 16.0, 6.7 Hz, 1 H), 2.62 (dd, J = 16.0, 6.8
Hz, 1 H), 2.92 (s, 3 H), 2.97 (s, 3 H), 3.09–3.17 (m, 1 H),
4.48–4.54 (m, 1 H), 5.25–5.30 (m, 1 H) ppm. 13C NMR
(100.6 MHz, CDCl3): d = –5.1, –4.7, 17.0, 18.1, 25.8, 32.3,
35.3, 37.1, 45.6, 46.1, 73.6, 127.0, 137.7, 172.8 ppm. MS
(EI, 70eV): m/z (%) = 297 (1) [M+], 240 (42), 72 (100).
HRMS (EI, 70 eV): m/z calcd for C16H31NO2Si [M+]:
297.2124; found: 297.2127.
(3aS,4R,6R,6aR)-4-(tert-Butyldimethylsilyloxy)-6-
hydroxy-6-methyl-hexahydrocyclopenta[b]furan-2-one
(13). To a cool (0 °C), stirred solution of amide 11 (15.0 g,
50.3 mmol) and 18-crown-6 ether (1.0 g, 3.8 mmol) in a
mixture of 1:1:1 CH2Cl2–acetone–H2O (450 mL) was added
NaHCO3 (32.0 g, 381 mmol) portionwise over 20 min. A
solution of oxone (60.0 g, 100 mmol) in H2O (300 mL) was
added dropwise over 1 h. The resulting mixture was allowed
to stir for another 2 h at 0 °C, EtOAc (200 mL) was then
added and the layers were separated. Usual workup and flash
chromatography (2:1 hexane–EtOAc gave lactone 13 (11.5
g, 40.2 mmol, 80% yield) as a clear colorless oil: Rf = 0.17
(hexane–EtOAc = 2:1); [a]D20 –26.6 (c 0.95, acetone). IR
(thin film): n = 3440, 2957, 2931, 1778, 1472 cm–1. 1H NMR
OMOM
OMOM
OR
O
d
b
O
O
MOMO
a
MOMO
N
OR
PMBO
21 R = H
19 R = H
20 R = PMB
c
22 R = TES
OMOM
OMOM
OTES
OTf
OTES
O
e
MOMO
MOMO
PMBO
PMBO
23
3
Scheme 6 Reagents: (a) PMBOC(NH)CCl3, CSA (87%);
(b) pyrrolidine (91%); (c) TESCl, pyridine (88%); (d) MeLi (81%);
(e) KHMDS, PhNTf2 (91%).
Acknowledgment
Financial support by the Austrian Science Foundation (FWF,
project P15929-N03) is gratefully acknowledged. We also thank
Hanspeter Kählig for NMR support.
Synlett 2004, No. 14, 2558–2562 © Thieme Stuttgart · New York

LETTER
Toward the Total Syntheses of Pepluanin A and Euphosalicin
2561
(400 MHz, CDCl3): d = 0.04 (s, 6 H), 0.88 (s, 9 H), 1.40 (s,
2.58 (dd, J = 18.0, 10.1 Hz, 1 H), 2.68 (dd, J = 18.0, 2.8 Hz,
1 H), 3.10–3.25 (m, 1 H), 3.33 (s, 3 H), 3.41 (s, 3 H), 3.86 (d,
J = 5.8 Hz, 1 H), 4.55–4,70 (m, 4 H), 4.97 (dd, J = 7.5, 7.5,
4.3 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): d = 18.4,
29.5, 41.6, 42.7, 55.7, 56.6, 83.7, 85.3, 87.3, 91.4, 98.2,
177.5 ppm. MS (EI, 70eV): m/z (%) = 260 (2) [M+], 240
(25), 215 (74), 198 (100). HRMS (EI, 70 eV): m/z calcd for
C12H20O6 [M+]: 260.1260; found: 260.1264.
3 H), 1.53–1.65 (m, 2 H), 1.97 (dd, J = 13.6, 6.3 Hz, 1 H),
2.44 (dd, J = 18.8, 10.9 Hz, 1 H), 2.98 (dd, J = 18.8, 2.9 Hz,
1 H), 3.09–3.18 (m, 1 H), 4.41 (dd, J = 6.6, 1.5 Hz, 1 H),
4.52–4.59 (m, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3):
d = –5.0, –4.8, 18.0, 23.6, 25.7, 28.0, 41.4, 45.3, 71.1, 78.4,
89.9, 177.6 ppm. MS (EI, 70eV): m/z (%) = 229 (41) [M –
t-Bu]+, 137 (42), 75 (100). HRMS (EI, 70 eV): m/z calcd for
C10H17O4Si [M – t-Bu]+: 229.0896; found: 229.0901.
(3aS,4R,6R,6aR)-4-(tert-Butyldimethylsilyloxy)-6-
(methoxymethoxy)-6-methyl-hexahydrocyclo-
(3R,3aR,4R,5R,6aR)-3-Hydroxy-4,5-bis(methoxy-
methoxy)-5-methyl-hexahydrocyclopenta[b]furan-2-one
(19). To a cold (–78 ºC), stirred solution of lactone 4 (850
mg, 3.27 mmol) in dry THF (40 mL) was added a solution of
KHMDS (0.5 M in toluene, 9.80 mL, 4.90 mmol). The
mixture was stirred for 1 h at –78 ºC and a cold (–78 ºC)
solution of Davis’ reagent [2-benzenesulfonyl-3-(3-nitro-
phenyl)oxaziridine] (1.28 g, 4.90 mmol) in dry THF (5 mL)
was added via a cannula. The mixture was stirred for an
additional 30 min at –78 ºC and a solution of CSA (1.14 g,
4.90 mmol) in dry THF (5 mL) was added via a cannula. The
resulting mixture was allowed to warm to r.t. over 1 h and
sat. aq NH4Cl (15 mL) was added. The layers were separated
and the aqueous layer was extracted with EtOAc (3 × 20
mL). Usual workup including flash chromatography (1:1
hexane–EtOAc) gave alcohol 19 (665 mg, 2.41 mmol, 74%
yield) as a clear colorless oil: Rf = 0.36 (100% EtOAc);
[a]D20 +21.6 (c 1.1, CHCl3). IR (thin film): n = 3385, 2948,
1770, 1640, 1567, 1447 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.33 (s, 3 H), 1.86 (dd, J = 14.5, 5.2 Hz, 1 H), 2.42 (ddd,
J = 14.5, 7.2, 1.3 Hz, 1 H), 2.88 (br s, 1 H), 3.16 (ddd,
J = 7.9, 6.6, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.42 (s, 3 H), 4.08
(dd, J = 6.6, 1.3, 1 H), 4.59 (d, J = 3.3 Hz, 1 H), 4.65–4.72
(m, 4 H), 5.10 (ddd, J = 7.9, 7.2, 5.2 Hz, 1 H) ppm. 13C NMR
(100.6 MHz, CDCl3): d = 18.4, 42.2, 49.7, 55.8, 56.5, 68.9,
82.1, 83.4, 87.0, 91.4, 97.9, 177.6 ppm. MS (EI, 70eV):
m/z (%) = 276 (2) [M+], 231 (25), 214 (51), 77 (100). HRMS
(EI, 70 eV): m/z calcd for C12H20O7 [M+]: 276.1209; found:
276.1217.
penta[b]furan-2-one (14). To a cool (0 °C), stirred solution
of alcohol 13 (11.2 g, 39.3 mmol) and i-Pr2NEt (25.2 g, 194
mmol) in dry CH2Cl2 (100 mL) was added MOMCl (9.5 g,
118 mmol) dropwise over 15 min. The resulting mixture was
allowed to warm to r.t. and stirred for 48 h. Sat. aq NaHCO3
(25 mL) was added and usual workup including flash
chromatography (3:1 hexane–EtOAc) gave MOM ether 14
(10.5 g, 31.8 mmol, 81% yield) as a clear colorless oil:
Rf = 0.39 (2:1 hexane–EtOAc); [a]D20 –21.3 (c 1.2, acetone).
IR (thin film): n = 2957, 2823, 1789, 1471 cm–1. 1H NMR
(400 MHz, CDCl3): d = 0.05 (s, 6 H), 0.88 (s, 9 H), 1.37 (s,
3 H), 1.50 (dd, J = 13.9, 9.3 Hz, 1 H), 2.18 (dd, J = 13.9, 6.4
Hz, 1 H), 2.45 (dd, J = 18.7, 10.9 Hz, 1 H), 2.98 (dd,
J = 18.7, 2.9 Hz, 1 H), 3.05–3.08 (m, 1 H), 3.37 (s, 3 H), 4.50
(ddd, J = 9.3, 8.3, 6.4 Hz, 1 H), 4.58 (dd, J = 6.6, 1.5 Hz, 1
H), 4.65–4.70 (m, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3):
d = –5.1, –4.7, 18.0, 18.9, 25.7, 28.0, 41.4, 43.7, 55.7, 71.0,
83.8, 88.5, 91.3, 177.4 ppm. MS (EI, 70eV): m/z (%) = 273
(21) [M – t-Bu]+, 243 (100). HRMS (EI, 70 eV): m/z calcd
for C12H21O5Si [M – t-Bu]+: 273.1158; found: 273.1161.
(3aS,4R,5R,6aR)-4-Hydroxy-5-(methoxymethoxy)-5-
methyl-hexahydrocyclopenta[b]furan-2-one (16). To a
stirred solution of silyl ether 14 (9.50 g, 28.8 mmol) in dry
THF (40 mL) was added a solution of TBAF (1 M in THF,
43.2 mL, 43.2 mmol). The mixture was stirred at r.t. for 18
h. The solvent was removed under reduced pressure and the
resulting crude material was subjected to flash
(3R,3aR,4R,5R,6aR)-3-(4-Methoxybenzyloxy)-4,5-
bis(methoxymethoxy)-5-methyl-hexahydrocyclo-
penta[b]furan-2-one (20). To a stirred solution of alcohol
19 (505 mg, 1.83 mmol) in dry CH2Cl2 (25 mL) was added
PMBOC(=N)CCl3 (780 mg, 2.74 mmol) and CSA (42 mg,
0.18 mmol). The resulting mixture was stirred for 18 h at r.t.
Sat. aq NaHCO3 (10 mL) was then added and the resulting
layers were separated. Usual workup including flash
chromatography (2:1 hexane–EtOAc) gave PMB ether 20
(630 mg, 1.59 mmol, 87% yield) as a clear colorless oil:
Rf = 0.16 (2:1 hexane–EtOAc); [a]20D +48.6 (c 1.1, CHCl3).
IR (thin film): n = 3277, 2948, 1769, 1731, 1613, 1586, 1447
cm–1. 1H NMR (400 MHz, CDCl3): d = 1.32 (s, 3 H), 1.90
(dd, J = 14.9, 4.3 Hz, 1 H), 2.44 (ddd, J = 14.9, 7.3, 1.2 Hz,
1 H), 3.12 (ddd, J = 7.4, 5.9, 1.5 Hz, 1 H), 3.30 (s, 3 H), 3.32
(s, 3 H), 3.80 (s, 3 H), 3.97 (d, J = 6.3 Hz, 1 H), 4.20 (d,
J = 1.5 Hz, 1 H), 4.40–4.80 (m, 6 H), 5.10 (ddd, J = 7.4, 7.4,
4.2 Hz, 1 H), 6.9 (d, J = 8.6 Hz, 2 H), 7.30 (d, J = 8.6 Hz, 2
H) ppm. 13C NMR (100.6 MHz, CDCl3): d = 18.2, 42.4, 49.5,
55.3, 55.8, 56.6, 71.7, 74.4, 82.9, 84.3, 87.4, 91.4, 98.0,
113.9, 129.2, 130.1, 159.5, 175.0 ppm. MS (EI, 70eV):
m/z (%) = 396 (1) [M+], 275 (3), 137 (24), 121 (100). HRMS
(EI, 70 eV): m/z calcd for C20H28O8 [M+]: 396.1786; found:
396.1775.
chromatography (1:1 hexane–EtOAc) to give alcohol 16
(5.47 g, 25.3 mmol, 88% yield) as a clear colorless oil:
Rf = 0.3 (100% EtOAc); [a]D20 –15.1 (c 1.2, CHCl3). IR (thin
film): n = 3443, 2940, 2825, 1769, 1644, 1454 cm–1. 1H
NMR (400 MHz, CDCl3): d = 1.35 (s, 3 H), 2.03 (dd,
J = 14.8, 3.5 Hz, 1 H), 2.39 (dd, J = 14.8, 6.8 Hz, 1 H), 2.56
(dd, J = 18.4, 11.1 Hz, 1 H), 2.60 (br s, 1 H), 2.81 (dd,
J = 18.4, 2.8 Hz, 1 H), 3.18–3.26 (m, 1 H), 3.38 (s, 3 H), 3.97
(dd, J = 6.5, 2.6 Hz, 1 H), 4.63 (d, J = 7.6 Hz, 1 H), 4.75 (d,
J = 7.6 Hz, 1 H), 4.99 (ddd, J = 7.5, 6.8, 3.5 Hz, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3): d = 17.8, 28.7, 41.3, 42.4,
55.8, 77.9, 83.2, 86.7, 91.3, 177.9 ppm. MS (EI, 70eV):
m/z (%) = 216 (1) [M+], 171 (46), 153 (65), 57 (100). HRMS
(EI, 70 eV): m/z calcd for C10H16O5 [M+]: 216.0998; found:
216.0993.
(3aR,4R,5R,6aR)-4,5-Bis(methoxymethoxy)-5-methyl-
hexahydrocyclopenta[b]furan-2-one (4). To a cool (0 °C),
stirred solution of alcohol 16 (950 mg, 4.40 mmol) and i-
Pr2NEt (2.84 g, 22.00 mmol) in dry CH2Cl2 (20 mL) was
added MOMCl (1.06 g, 13.20 mmol) dropwise over 15 min.
NaI (20 mg, 0.13 mmol) was added and the resulting mixture
was heated to reflux for 18 h. The mixture was allowed to
cool to r.t., sat. aq NaHCO3 (10 mL) was added. Usual
workup and flash chromatography (1:1 hexane–EtOAc)
gave MOM ether 4 (984 mg, 3.79 mmol, 86% yield) as a
clear colorless oil: Rf = 0.38 (100% EtOAc); [a]D20 +28.5 (c
1.1, CHCl3). IR (thin film): n = 2947, 2896, 1772, 1451 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.36 (s, 3 H), 1.93 (dd,
J = 14.8, 4.2 Hz, 1 H), 2.44 (ddd, J = 14.8, 7.2, 1.3 Hz, 1 H),
(R)-2-(4-Methoxybenzyloxy)-2-[(1R,2R,3R,5R)-5-
hydroxy-2,3-bis(methoxymethoxy)-3-methylcyclo-
pentyl]-1-(pyrrolidin-1-yl)ethanone (21). To a stirred
solution of lactone 20 (504 mg, 1.27 mmol) in dry toluene
(5 mL) was added pyrrolidine (524 mL, 6.40 mmol). The
resulting mixture was heated to reflux for 18 h. The mixture
Synlett 2004, No. 14, 2558–2562 © Thieme Stuttgart · New York

2562
M. W. Gilbert et al.
LETTER
was allowed to cool to r.t. and the volatiles were removed
under reduced pressure. The resulting crude material was
subjected to flash chromatography (EtOAc) to give amide 21
(541 mg, 1.16 mmol, 91% yield) with traces amount of
1.240 mmol) dropwise over 30 min. The mixture was stirred
for an additional 15 min at 0 ºC and sat. aq NH4Cl (5 mL)
was added. The aqueous layer was extracted with EtOAc (3
× 10 mL). Usual workup and flash chromato-graphy (5:1
hexane–EtOAc) gave methyl ketone 23 (265 mg, 0.503
mmol, 81% yield) as a clear colorless oil: Rf = 0.42 (2:1
hexane–EtOAc); [a]D20 –5.5 (c 1.7, CHCl3). IR (thin film):
n = 2955, 2878, 1715, 1613, 1586, 1515, 1458 cm–1. 1H NMR
(400 MHz, CDCl3): d = 0.58 (q, J = 8.0 Hz, 6 H), 0.95 (t,
J = 8.0 Hz, 9 H), 1.34 (s, 3 H), 1.82 (dd, J = 13.6, 7.6 Hz, 1
H), 2.20–2.29 (m, 4 H), 3.00 (m, 1 H), 3.33 (s, 3 H), 3.35 (s,
3 H), 3.80 (s, 3 H), 3.98 (d, J = 5.8 Hz, 1 H), 4.18 (d, J = 7.8
Hz, 1 H), 4.38 (ddd, J = 7.6, 7.5, 7.3 Hz, 1 H), 4.42 (s, 2 H),
4.52–4.72 (m, 4 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.6
Hz, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3): d = 4.8, 6.7,
20.0, 26.9, 47.0, 49.0, 55.2, 55.4, 56.3, 70.8, 71.1, 81.4, 85.1,
86.0, 91.5, 97.8, 113.8, 129.5, 130.1, 159.2, 210.0 ppm. MS
(EI, 70eV): m/z (%) = 497 (0.5) [M – MeO]+, 465 (1), 390
(3), 121 (100). HRMS (EI, 70 eV): m/z calcd for C25H41O8Si
[M – MeO]+: 497.2571; found: 497.2559.
20
pyrrolidine as a clear orange oil: Rf = 0.9 (EtOAc); [a]D
–13.3 (c 1.0, CHCl3). IR (thin film): n = 3450, 2957, 2882,
1774, 1631, 1514, 1449 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.44 (s, 3 H), 1.72–1.95 (m, 5 H), 2.44 (dd, J = 14.6, 7.1
Hz, 1 H), 2.77 (m, 1 H), 3.31 (s, 3 H), 3.32–3.38 (m, 1 H),
3.40 (s, 3 H), 3.45–3.60 (m, 4 H), 3.79 (s, 3 H), 4.03 (d,
J = 3.8 Hz, 1 H), 4.12–4.20 (m, 1 H), 4.40 (d, J = 10.9 Hz, 1
H), 4.48 (d, J = 10.9 Hz, 1 H), 4.53 (d, J = 11.1 Hz, 1 H),
4.62 and 4.69 (m, 3 H), 4.76 (d, J = 6.6 Hz, 1 H), 6.86 (br d,
J = 8.8 Hz, 2 H), 7.24 (br d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3): d = 21.0, 23.9, 26.8, 46.7, 46.9, 48.2,
50.0, 55.7, 55.9, 57.0, 71.2, 72.9, 76.9, 86.8, 86.9, 91.9, 99.0,
114.2, 129.7, 130.0, 159.7, 171.2 ppm. MS (EI, 70eV):
m/z (%) = 422 (1) [M – MOM]+, 210 (13), 137 (27), 121
(100). HRMS (EI, 70 eV): m/z calcd for C22H32O7N [M –
MOM]+: 422.2179; found: 422.2191.
(R)-2-[(1R,2R,3R,5R)-2,3-Bis(methoxymethoxy)-3-
methyl-5-(triethylsilyloxy)cyclopentyl]-2-(4-methoxy-
benzyloxy)-1-(pyrrolidin-1-yl)ethanone (22). To a stirred
solution of alcohol 21 (392 mg, 0.84 mmol) in dry CH2Cl2
(10 mL) was added pyridine (200 mL, 2.5 mmol). TESCl
(212 mL, 1.26 mmol) was added and the resulting mixture
was stirred at r.t. for 1 h. Sat. aq NH4Cl (5 mL) was added.
Usual workup including flash chromatography (2:1 hexane–
EtOAc) gave TES ether 22 (430 mg, 0.74 mmol, 88% yield)
as a clear colorless oil: Rf = 0.21 (hexane–EtOAc = 2:1);
[a]D20 –34.0 (c 0.6, CHCl3). IR (thin film): n = 3854, 3822,
1646, 1613, 1586, 1441 cm–1. 1H NMR (400 MHz, CDCl3):
d = 0.51 (q, J = 7.9 Hz, 6 H), 0.91 (t, J = 7.9 Hz, 9 H), 1.40
(s, 3 H), 1.73 (dd, J = 13.8, 5.4 Hz, 1 H), 1.75–1.95 (m, 4 H),
2.38 (dd, J = 13.8, 6.8 Hz, 1 H), 3.28–3.35 (m, 1 H), 3.38 (s,
3 H), 3.39 (s, 3 H), 3.40–3.55 (m, 3 H), 3.58–3.68 (m, 1 H),
3.78 (s, 3 H), 3.85 (d, J = 4.3 Hz, 1 H), 4.29 (d, J = 10.8 Hz,
1 H), 4.49 (d, J = 10.8 Hz, 1 H), 4.51–4.58 (m, 1 H), 4.61–
4.72 (m, 4 H), 4.83 (d, J = 6.3 Hz, 1 H), 6.84 (d, J = 8.7 Hz,
2 H), 7.20 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR (100.6 MHz,
CDCl3): d = 4.8, 6.8, 19.7, 24.2, 26.1, 45.3, 45.5, 45.8, 47.6,
55.2, 55.7, 56.4, 66.6, 72.6, 73.7, 85.2, 86.3, 91.4, 98.44,
113.6, 129.3, 130.9, 158.9, 168.3 ppm. MS (EI, 70eV):
m/z (%) = 582 (2) [M+], 552 (9) [M – Et]+, 324 (34), 121
(100). HRMS (EI, 70 eV): m/z calcd for C28H46O8NSi
[M – Et]+: 552.2883; found: 552. 2881.
(R)-1-[(1S,2R,3R,5R)-2,3-Bis(methoxymethoxy)-3-
methyl-5-(triethylsilyloxy)cyclopentyl]-1-(4-methoxy-
benzyloxy)prop-2-en-2-yl Trifluoro-methanesulfonate
(3). To a cold (–78 ºC), stirred solution of methyl ketone 23
(201 mg, 0.381 mmol) in dry THF (10 mL) was added a
solution of KHMDS (0.5 M in toluene, 0.84 mL, 0.42
mmol). The mixture was stirred for 1 h at –78 ºC and a cold
(–78 ºC) solution of PhNTf2 (204 mg, 0.57 mmol) in dry
THF (1 mL) was added via a cannula. The mixture was
stirred for an additional 10 min at –78 ºC and then allowed
to warm to r.t. over 1 h. Sat. aq NH4Cl (5 mL) was added and
the resulting layers were separated. Usual workup and flash
chromatography (50:10:1 hexane–EtOAc–Et3N) gave
vinyltriflate 3 (229 mg, 0.348 mmol, 91% yield) as a clear
colorless oil: Rf = 0.55 (2:1 hexane–EtOAc); [a]D20 –3.3 (c
0.9, CHCl3). IR (thin film): n = 2956, 1664, 1613, 1515,
1443, 1417 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.56 (q,
J = 7.9 Hz, 6 H), 0.96 (t, J = 7.9 Hz, 9 H), 1.39 (s, 3 H), 1.77
(dd, J = 14.2, 4.2 Hz, 1 H), 2.39 (dd, J = 14.2, 6.4 Hz, 1 H),
2.71–2.78 (m, 1 H), 3.31 (s, 3 H), 3.38 (s, 3 H), 3.79 (s, 3 H),
3.89 (d, J = 4.5 Hz, 1 H), 4.18 (d, J = 10.1 Hz, 1 H), 4.32 (d,
J = 10.4 Hz, 1 H), 4.37 (ddd, J = 6.9, 6.4, 4.2 Hz, 1 H), 4.59–
4.71 (m, 5 H), 5.24 (d, J = 3.4 Hz, 1 H), 5.39 (d, J = 3.4 Hz,
1 H), 6.86 (br d, J = 8.6 Hz, 2 H), 7.28 (br d, J = 8.6 Hz, 2 H)
ppm. 13C NMR (100.6 MHz, CDCl3): d = 4.9, 6.8, 20.0, 48.3,
48.5, 55.2, 55.5, 56.3, 69.9, 71.6, 76.6, 85.9, 86.7, 91.4, 98.9,
108.5, 113.7, 118.4 (q, CF3), 129.5, 129.9, 152.7, 159.1 ppm.
MS (EI, 70eV): m/z (%) = 613 (1) [M – MOM]+, 283 (3),
181 (5), 135 (8), 121 (100). HRMS (EI, 70 eV): m/z calcd for
C26H40O9F3SSi [M – MOM]+: 613.2114; found: 613.2097.
(R)-1-[(1R,2R,3R,5R)-2,3-Bis(methoxymethoxy)-3-
methyl-5-(triethylsilyloxy)cyclopentyl]-1-(4-methoxy-
benzyloxy)propan-2-one (23). To a cool (0 ºC), stirred
solution of amide 22 (362 mg, 0.623 mmol) in dry THF (10
mL) was added a solution of MeLi (1.6 M in Et2O, 0.780 mL,
Synlett 2004, No. 14, 2558–2562 © Thieme Stuttgart · New York