Total synthesis of berkeleyamide a and its 10-epi isomer

Article abstract of DOI:10.1002/ejoc.201000914

A short and efficient synthesis of the novel cytotoxic natural product berkeleyamide A, isolated from a deep-water Penicillium rubrum, has been accomplished. L-Leucinol was used as the only chiral starting material. A diastereoselective aldol condensation

Full text of DOI:10.1002/ejoc.201000914

FULL PAPER
DOI: 10.1002/ejoc.201000914
Total Synthesis of Berkeleyamide A and its 10-epi Isomer
Narayan S. Chakor,*[a] Sabrina Dallavalle,[a] Leonardo Scaglioni,[a] and Lucio Merlini[a]
Keywords: Natural products / Total synthesis / Diastereoselectivity / Aldol reactions
A short and efficient synthesis of the novel cytotoxic natural
product berkeleyamide A, isolated from a deep-water Peni-
as the only chiral starting material. A diastereoselective aldol
condensation is the key step in the synthesis.
cillium rubrum, has been accomplished. L-Leucinol was used
Stierle et al.[2] assigned the absolute configuration at C10
as (10S) by using Mosher’s method, whereas the relative
configuration at the chiral lactam ring was established by
1D NOE difference spectroscopy, H11 and H14 showing a
trans relationship. However, uncertainty remained over the
absolute configuration of the C11 and C14 stereogenic cen-
ters.
Introduction
The Berkeley Pit lake system near Butte, Montana, is
part of the largest EPA superfund site in North America.
The Pit is filled to a depth of about 274 meters with heavily
acidic and metal-laden water. New fungal and bacterial spe-
cies have been found to have adapted to the extreme and
harsh conditions inside the pit. Stierle and co-workers iden-
tified more than 100 types of microbes in the lake that man-
age to survive in the unique, noxious ecosystem.[1] One of
the first microbes to be studied was isolated from a water
sample taken from a depth of 270 meters and identified as
Penicillium rubrum Stoll. The organic extracts of this fungus
contained several novel bioactive compounds, among which
were berkeleyamide A–D. Berkeleyamide A (1a) was shown
to exhibit activity against caspase 1 and MMP-3 in the low
to submicromolar range (IC50 = 0.33 µ).[2]
Consequently, we initially focused on the synthesis of a
diastereomer arbitrarily chosen with the (S) configuration
at C14, by assuming the natural -configuration in the bio-
synthetic pathway. Thus, -leucine was envisaged as the
starting material for the construction of the lactam ring. At
the beginning of this year, when this work was already at
an advanced stage, two total syntheses, different from ours,
appeared in the literature; the first by Brimble’s[3] group and
the second by Avery et al.[4] Moreover, Brimble’s group con-
firmed the absolute stereochemistry of 1a as (10S,11R,14S).
Our retrosynthetic approach was envisioned to proceed
through a Grignard reaction between a magnesium benzyl
halide and aldehyde 2. The key step involved a diastereo-
selective aldol condensation for the assembly of a protected
3-hydroxypropanal and lactam 3 fragments. As the syn/anti
outcome is controlled by the enolate geometry and as the
lithium enolate of lactam 3 must have an E geometry,
stereoselective formation of the anti aldol products should
be favored. Moreover, the preferred formation of (10R,11R)
diastereomer 1b should be expected as a consequence of
diastereofacial selection. Therefore, inversion at C10 was
planned as the last step (Scheme 1).
Results and Discussion
As a part of a research program aimed at studying new
natural compounds endowed with potential antitumor ac-
tivity, we developed a stereoselective synthesis of 1a, which
may, in principle, have value in the preparation of other
berkeleyamides as well as its analogues.
Pyrrolidinone 7 was obtained from commercially avail-
able -leucinol (4) that was converted into compound 6 by
using a literature method.[5] Conversion of leucinol into its
bis-toluene-p-sulfonate 5 followed by heating under reflux
in THF with an excess amount of potassium tert-butoxide
and diethyl malonate gave 3-ethoxycarbonylpyrrolidinone
6. Finally, Krapcho decarbethoxylation gave tosyl-protected
pyrrolidinone 7 in 85% yield (Scheme 2).
[a] Dipartimento di Scienze Molecolari Agroalimentari, Università
di Milano,
Via Celoria 2, 20133 Milano, Italy
Fax: +39-02-50316801
With lactam 7 in hand, attention was focused on the key
aldol condensation. Conversion of 1,3-propanediol (8) to
aldehyde 9 proceeded easily in two steps by monoprotection
E-mail: nschakor@gmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000914.
View this journal online at
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N. S. Chakor, S. Dallavalle, L. Scaglioni, L. Merlini
FULL PAPER
Scheme 3.
Scheme 1. Retrosynthetic approach to 10-epi-berkeleyamide A (1b).
Scheme 2.
with PMBCl,[6] followed by oxidation with IBX. Addition
of aldehyde 9 to the lithium enolate of lactam 7 delivered a
major product with only a minor amount of another dia-
stereomer (19:1dr). As diastereomers 10 were hardly sepa-
rable, the mixture was treated with TBSOTf to obtain the
corresponding less-polar OTBS-protected derivatives 11a/b,
which were separated by column chromatography to give
11a as the major product (Ͼ95%, Scheme 3). The C11–C14
relative configuration in 11a was determined by TROESY
measurements.
The 10,11 diastereoselection is controlled by the enolate
geometry and can be predicted on the basis of the six-mem-
bered cyclic Zimmerman–Traxler-type transition state.
Thus, as the lithium enolate of lactam 7 must have E geom-
etry, stereoselective formation of the anti aldol products
should be favored. The diastereofacial selection, and there-
Scheme 4. Possible transition-state models for aldol addition.
fore the relation between the new centers and that at C14, 14 with benzylmagnesium bromide disappointingly resulted
can be explained on the basis of a preferred Si-face attack in a complex mixture of products, whereas a 2–3-fold excess
by the enolate, due to the presence of the bulky isobutyl of the benzylmagnesium chloride in THF gave expected
group on the lactam ring. (Scheme 4).
product 15, although in low yield. Oxidation of the second-
Attention was then focused on the incorporation of the ary alcohol with IBX and removal of the silyl protecting
benzyl moiety. As we opted to proceed through a Grignard group with TBAF furnished (10R,11R,14S)-berkeleyamide
condensation, removal of the tosyl and PBM protecting (1b, Scheme 5). The structure and stereochemistry of this
groups from 11a was followed by oxidation of primary compound were confirmed by NMR experiments. The
alcohol 13 with IBX to give 14. Various attempts to react C11–C14 relative configuration in 1b was determined by
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Total Synthesis of Berkeleyamide A and its 10-epi Isomer
Scheme 5.
TROESY measurements. A NOE correlation between H11 TROESY measurements confirmed the 11–14 trans-rela-
and H15 and the absence of NOE between H11 and H14 tionship, the absolute stereochemistry of 21 must be
clearly established the H11–H14 anti stereochemistry. The (10R,11R,14S).
spectroscopic data completely matched those reported by
Once aldol reaction product 21 was obtained, we had
to set the S configuration at C10. Disappointingly, all the
Brimble et al.[3]
Due to the difficulties encountered during Grignard con- attempts made to invert the C10 configuration, either
densation, the synthetic pathway was reevaluated. We envi- through Mitsunobu,[8] Cainelli,[9] or Mukaiyama[10] reac-
sioned that the key aldol reaction could be postponed to tions, failed, giving very rapidly the elimination product.
a later stage, using an aldehyde-bearing fragment already Thus, compound 21 was oxidized with DMSO and TFAA
containing the ketone functionality, masked by an appro- to the corresponding ketone. Gratifyingly, reduction with
priate protecting group. Accordingly, 2-benzyl-1,3-dithiane sodium borohydride gave a single diastereomer, different
(17)[7] was treated with commercially available 2-bromo-1,1- from 21, whose stereochemistry at C10 predictably had to
diethoxyethane by using nBuLi in THF to give acetal 19, be S, in agreement with Felkin–Anh conformational model
which was subsequently deprotected to obtain 2-(2-benzyl- of the transition state. The difference in magnitude of the
1,3-dithian-2-yl)acetaldehyde (20). Aldol condensation be- observed vicinal J10,11 coupling constants (6.5 Hz in 21,
tween this aldehyde and lactam 5 proceeded as expected to 3.2 Hz in 23, see the Supporting Information) also sup-
give as a major product alcohol 21 (19:1dr, Scheme 6). The ported inversion at C10. Deprotection of the keto group
stereochemical outcome of the reaction can again be ration- with iodine/NaHCO3 followed by removal of the tosyl
alized by using a six-membered Zimmermann–Traxler group with Na/naphthalene, afforded the natural com-
chair-like transition state, as described previously for com- pound (10S,11R,14S)-berkeleyamide A (1a, Scheme 6). The
pound 10a, whereas the facial selectivity can be explained spectroscopic data of the obtained compound completely
as directed by the bulky group on the lactam ring. As matched those reported for the natural product. This new
Scheme 6.
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N. S. Chakor, S. Dallavalle, L. Scaglioni, L. Merlini
FULL PAPER
[1-Hydroxy-3-(4-methoxybenzyloxy)propyl]-5-isobutyl-1-(toluene-4-
sulfonyl)pyrrolidin-2-one (10b): To a stirred solution of pyrrolidin-
one 7 (2.0 g, 6.76 mmol) in THF (40 mL) was added LiHMDS (1 
in THF, 8.12 mmol, 8.15 mL) at –78 °C. The reaction mixture was
stirred for 45 min, then aldehyde 9 (1.32 g, 6.76 mmol) in THF
(16 mL) was added dropwise at –78 °C. The resulting reaction mix-
ture was stirred for 3 h. Saturated aqueous NH4Cl (150 mL) was
added, and the aqueous phase was extracted with diethyl ether
(3ϫ120 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash col-
umn chromatography (EtOAc/hexane, 28:72) to afford a mixture of
isomers 10a (Ͻ95%)/10b (Ͻ5%) as an oil (2.68 g, 81%). Rf = 0.48
(EtOAc/hexane, 40:60). 1H NMR (300 MHz, CDCl3): δ = 7.90 (m,
2 H, o-H Ts), 7.29 (m, 2 H, m-H Ts), 7.20 (m, 2 H, Ph-H), 6.86
(m, 2 H, Ph-H), 4.32 (m, 2 H, Ph-CH2), 4.25 (m, 1 H, 5-H), 4.09
(m, 1 H, 4Ј-H), 3.80 (s, 3 H, Ph-OMe), 3.42 (m, 2 H, 6Ј-H), 2.75
(m, 1 H, 3-H), 2.41 (s, 3 H, Ph-CH3), 2.28 (m, 1 H, 4-CH), 1.36–
1.89 (m, 7 H, 4-H, 6-H, 7-H,5Ј-H), 0.97 (d, J = 6.6 Hz, 3 H, 8-
CH3), 0.93 (d, J = 6.6 Hz, 3 H, 9-CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 175.8, 159.3, 145.3, 136.0, 130.4, 129.8, 129.5, 129.3,
128.6, 114.0, 113.8, 73.06, 70.3, 66.8, 57.4, 55.4, 43.1, 33.9, 27.5,
25.7, 23.8, 21.9, 21.3 ppm.
sequence was shorter and simpler than the previous one
and allowed the desired compound to be obtained through
a convergent rather than sequential approach, giving the
flexibility to develop various analogues of the natural prod-
uct.
Conclusions
In conclusion, a short and efficient synthesis of the natu-
ral compound (–)-berkeleyamide A was designed and car-
ried out. Crucial step for our strategy was a stereoselective
aldol condensation applied for the installation of the side
chain on the lactam moiety. Compared to those previously
reported,[3,4] our synthesis appears to be shorter, requiring
only a total of 10 steps from commercially available -leuci-
nol (4) and 2-benzyl-1,3-dithiane (17) in 16% overall yield.
The synthetic sequence requires cheap and simple reagents
and -leucinol as the only chiral reactant. Moreover, it is
scalable and amenable to the preparation of analogues that
may be of interest for structure–activity relationship studies,
due to the biological activity of these compounds.
(3R,5S,1ЈR)-3-[1Ј-(tert-Butyldimethylsilanyloxy)-3Ј-(4-methoxybenz-
yloxy)propyl]-5-isobutyl-1-(toluene-4-sulfonyl)pyrrolidin-2-one (11a):
To an ice-cold stirred solution of 10a + 10b (2.3 g, 4.69 mmol) in
CH2Cl2 (40 mL) was added 2,6-lutidine (1.09 mL, 9.39 mmol) and
TBSOTf (1.29 mL, 5.6 mmol) at 0 °C. The resulting mixture was
stirred for 1 h at 0 °C, then water (30 mL) was added. The aqueous
layer was extracted with CH2Cl2 (3ϫ20 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), and concen-
trated under reduced pressure. The crude mixture of diastereomers
was separated by flash column chromatography (EtOAc/hexane,
18: 82) to obtain 11a as a viscous oil (2.68 g, 95%). [α]2D5 = +30.8
(c = 0.12, MeOH). Rf = 0.59 (EtOAc/hexane, 25:75). 1H NMR
(300 MHz, CDCl3): δ = 7.91 (m, 2 H, o-H Ts), 7.29 (m, 2 H, m-H
Ts), 7.21 (m, 2 H, Ph-H), 6.86 (m, 2 H, Ph-H), 4.32 (m, 3 H, Ph-
CH2, 5-H), 4.05 (m, 2 H, 4Ј-H), 3.80 (s, 3 H, Ph-OCH3), 3.41 (t, J
= 6.3 Hz, 2 H, 6Ј-H), 2.82 (ddd, J = 3.9, 5.1, 8.9 Hz, 1 H, 3-H),
2.39 (s, 3 H, Ph-CH3), 2.15 (m, 1 H, 4-H), 1.60–1.94 (m, 5 H), 1.42
(m, 1 H, 7-H), 1.00 (d, J = 6.6 Hz, 3 H, CH3), 0.96 (d, J = 6.6 Hz,
3 H, CH3), 0.76 (s, 9 H, SiCMe3), 0.02 (s, 6 H, SiMe) ppm. 13C
NMR (75 MHz, CDCl3): δ = 172.7, 159.1, 144.8, 136.2, 130.5,
129.4, 129.3, 128.4, 113.7, 72.3, 68.6, 66.6, 57.1, 55.3, 46.1, 43.8,
32.9, 26.1, 25.7, 25.5, 23.8, 21.7, 21.4, 17.9, –6.11, –6.12 ppm.
C32H49NO6SSi (603.89): calcd. C 63.64, H 8.18, N 2.32; found C
63.71, H 8.22, N 2.21.
Experimental Section
General Information: All reagents and solvents were reagent grade
or were purified by standard methods before use. Melting points
were determined in open capillaries. NMR spectra were recorded
at 300 or 600 MHz. Mass spectra were recorded with a Fourier
transform ion cyclotron resonance (FT-ICR) mass spectrometer.
Solvents were routinely distilled prior to use; anhydrous tetra-
hydrofuran (THF) and ether (Et2O) were obtained by distillation
from sodium–benzophenone ketyl; dry dichloromethane was ob-
tained by distillation from phosphorus pentoxide. All reactions re-
quiring anhydrous conditions were performed under a positive ni-
trogen flow, and all glassware were oven dried and/or flame dried.
Isolation and purification of the compounds were performed by
flash column chromatography on silica gel 60 (230–400 mesh). An-
alytical thin-layer chromatography (TLC) was conducted on Fluka
TLC plates (silica gel 60 F254, aluminum foil).
(5S)-5-Isobutyl-1-(toluene-4-sulfonyl)pyrrolidin-2-one (7): To
a
stirred solution of pyrrolidinone 6[4] (3 g, 8.16 mmol, 0.40 mL) in
DMSO (32 mL) was added LiCl (1.38 g, 32.6 mmol) and water
(0.4 mL). The reaction mixture was heated at 170 °C for 10 h, then
cooled to room temperature. Saturated aqueous NH4Cl (150 mL)
was added, and the mixture was then extracted with diethyl ether
(3ϫ150 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash col-
umn chromatography (EtOAc/hexane, 2:8) to afford 7 (2.07 g, 85%)
as a white crystalline solid; m.p. 111 °C. [α]2D0 = +64 (c = 0.22,
CHCl3). Rf = 0.6 (EtOAc/hexane, 35:65). 1H NMR (300 MHz,
CDCl3): δ = 7.89 (m, 2 H, o-H Ts), 7.28 (m, 2 H, m-H Ts), 4.38
(m, J = 9.4 Hz, 1 H, 5-CH), 2.50 (m, 1 H, 3-CH), 2.38 (s, 3 H, Ph-
CH3), 2.26 (m, 1 H, 3-H), 2.10 (m, 1 H, 4-H), 1.82 (m, 2 H, 4-H,
6-H), 1.65 (m, 1 H, 7-H), 1.47 (m, 1 H, 6-H), 0.97 (d, J = 6.6 Hz, 3
H, CH3), 0.93 (d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 173.5, 144.9, 136.2, 129.5, 128.3, 59.2, 43.2, 30.5, 25.4,
23.9, 21.7, 21.3 ppm. C15H21NO3S (295.40): calcd. C 60.99, H 7.17,
N 4.74; found C 61.08, H 7.10, N 4.63.
(3R,5S,1ЈR)-3-[1Ј-(tert-Butyldimethylsilanyloxy)-3Ј-(4-methoxybenz-
yloxy)propyl]-5-isobutylpyrrolidin-2-one (12): To a solution of naph-
thalene (1.52 g, 11.92 mmol) in dry THF (32 mL) was added Na
(0.274 g, 11.92 mmol), and the mixture was sonicated until a deep-
green solution of sodium naphthalenide was obtained (10–15 min).
The solution was further stirred for 2 h at room temperature then
it was dropped into a solution of 11a (1.2 g, 1.98 mmol) in THF
(60 mL) at –78 °C until the green color persisted. The resulting
reaction mixture was stirred at –78 °C for 3 h, then quenched with
saturated aqueous NH4Cl and extracted with EtOAc (3ϫ50 mL).
The combined organic layers were dried (Na2SO4) and concen-
trated. The crude product was purified by flash column chromatog-
raphy (EtOAc/hexane, 40:60) to afford 12 (0.866 g, 97%) as a color-
less oil. [α]2D5 = –4.4 (c = 0.09, MeOH). Rf = 0.48 (EtOAc/hexane,
1
1:1). H NMR (300 MHz, CDCl3): δ = 7.24 (m, 2 H, Ph-H), 6.86
(3R,5S,1ЈR)-3-[1Ј-Hydroxy-3Ј-(4-methoxybenzyloxy)propyl]-5-iso- (m, 2 H, Ph-H), 5.76 (br. s, 1 H, NH), 4.40 (m, 2 H, Ph-CH2), 4.18
butyl-1-(toluene-4-sulfonyl)pyrrolidin-2-one (10a) and (3S,5S,1ЈS)-3- (m, 1 H, 4Ј-H), 3.79 (s, 3 H, Ph-OCH3), 3.40–3.70 (m, 3 H, 6Ј-H,
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Total Synthesis of Berkeleyamide A and its 10-epi Isomer
5-H), 2.70 (m, 1 H, 3-H), 2.30 (m, 1 H, 4-H), 1.50–1.95 (m, 4 H,
SiCMe3), –0.04 (s, 3 H, SiMe), –0.06 (s, 3 H, SiMe) ppm. 13C NMR
4-H, 5Ј-H, 7-H), 1.23–1.40 (m, 2 H, 6-H), 0.91 (d, J = 6.2 Hz, 6 (75 MHz, CDCl3): δ = 177.8, 138.8, 129.5, 128.5, 126.3, 71.8, 69.5,
H, 2 CH3), 0.86 (s, 9 H, SiCMe3), 0.05 (s, 6 H, SiMe) ppm. 13C
NMR (75 MHz, CDCl3): δ = 177.0, 158.7, 130.63, 129.3, 113.7,
72.5, 69.8, 67.2, 55.4, 51.3, 46.8, 46.5, 32.9, 29.5, 25.9, 25.7, 25.4,
23.0, 22.8, 22.5, 18.0, –6.1, –6.2 ppm. C25H43NO4Si (449.70): calcd.
C 66.77, H 9.64, N 3.11; found C 66.89, H 9.72, N 3.02.
51.7, 46.7, 45.9, 45.3, 40.3, 31.0, 29.8, 25.8, 25.4, 22.9, 22.5, 18.0,
–4.5, –4.6 ppm. C24H41NO3Si (419.67): calcd. C 68.69, H 9.85, N
3.34; found C 68.79, H 9.74, N 3.21.
(3R,5S,1ЈR)-3-[1Ј-(tert-Butyldimethylsilanyloxy)-3Ј-oxo-4-phenylbut-
yl]-5-isobutylpyrrolidin-2-one (16): To a solution of 15 (0.400 g,
0.953 mmol) in DMSO (6 mL) was added IBX (0.66 g, 2.38 mmol)
under an atmosphere of N2, and the resulting mixture was stirred
for 16 h at room temperature. Then the solution was quenched by
adding H2O (2.5 mL) and stirred for 10 min. The suspension was
filtered through a Celite pad and washed with diethyl ether. The
filtrate was extracted with Et2O (3ϫ25 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated. The crude
product was purified by flash chromatography (EtOAc/hexane,
25:75) to afford compound 16 (0.302 g, 76%) as a yellow oil. [α]2D5
= –31.2 (c = 0.1, CHCl3). Rf = 0.69 (EtOAc/hexane, 1:1). 1H NMR
(300 MHz, CDCl3): δ = 7.14–7.36 (m, 5 H, Ph-H), 5.63 (br. s, 1 H,
(3R,5S,1ЈR)-3-[1Ј-(tert-Butyldimethylsilanyloxy)-3Ј-hydroxypropyl]-
5-isobutylpyrrolidin-2-one (13): To a solution of 12 (0.866 g,
1.78 mmol) in a mixture of CH2Cl2 (56 mL) and H2O (2.4 mL)
was added DDQ (0.525 g, 2.31 mmol) portionwise. After stirring
vigorously at room temperature for 3 h, the mixture was hydrolyzed
with saturated NaHCO3 and extracted with Et2O (3ϫ40 mL). The
combined organic layers were washed with brine, dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash
chromatography (EtOAc/hexane, 75:25) to give the title compound
(1.41 g, 93%) as a colorless oil. [α]2D5 = –5.0 (c = 0.10, MeOH). Rf
= 0.23 (EtOAc/hexane, 75:25). 1H NMR (300 MHz, CDCl3): δ =
5.98 (br. s, 1 H, NH), 4.19 (m, 1 H, 4Ј-H), 3.70 (m, 3 H, 6Ј-H, 5- NH), 4.39 (m, 1 H, 10-H), 3.73 (s, 2 H, 7-H), 3.63 (m, 1 H, 14-H),
H), 2.87 (m, 1 H, 3-H), 2.28 (m, 1 H, 4-H), 1.83 (m, 2 H, 4-H), 3.24 (dd, J = 17.2, 6.90 Hz, 1 H, 9-H), 2.65 (dd, J = 17.2, 6.02 Hz,
1.61 (m, 1 H, 7-H), 1.14–1.53 (m, 2 H, 5Ј-H), 0.92 (d, J = 6.6 Hz, 1 H, 9-H), 2.17 (m, 1 H, 19-H), 1.80 (m, 1 H, 19-H), 1.59 (m, 1 H,
6 H, CH3), 0.88 (s, 9 H, SiCMe3), 0.09 (s, 6 H, SiMe) ppm. 13C
NMR (75 MHz, CDCl3): δ = 178.0, 71.0, 59.7, 51.9, 46.7, 35.8,
29.7, 26.0, 25.7, 25.3, 22.8, 22.6, 18.0 ppm. C17H35NO3Si (329.55):
calcd. C 61.96, H 10.70, N 4.25; found C 62.12, H 10.60, N 4.17.
16-H), 1.18–1.43 (m, 3 H, 15-H), 0.90 (d, J = 6.6 Hz, 6 H, CH3),
0.83 (s, 9 H, SiCMe3), 0.05 (s, 3 H, SiMe), 0.03 (s, 3 H, SiMe) ppm.
13C NMR (75 MHz, CDCl3): δ = 206.9, 177.1, 134.1, 129.6, 128.7,
127.1, 69.5, 51.4, 50.8, 46.6, 46.4, 45.3, 31.4, 29.8, 25.9, 25.8, 25.5,
25.4, 23.0, 22.4, 18.0 ppm. C24H39NO3Si (417.66): calcd. C 69.02,
H 9.41, N 3.35; found C 69.11, H 9.33, N 3.24.
(3R,3ЈR,5ЈR)-3-(tert-Butyldimethylsilanyloxy)-3-(5Ј-isobutyl-2Ј-oxo-
pyrrolidin-3Ј-yl)propionaldehyde (14): To a solution of 13 (0.50 g,
1.50 mmol) in DMSO (5 mL) was added IBX (0.531 g, 1.89 mmol)
under an atmosphere of N2, and the resulting mixture was stirred
for 6 h at room temperature. The reaction mixture was quenched
by adding H2O (2 mL) and then it was stirred for 10 min. The
suspension was filtered through a Celite pad and washed with di-
ethyl ether. The filtrate was extracted with diethyl ether
(3ϫ25 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. The crude product was purified by flash
chromatography (EtOAc/hexane, 6:4) to afford aldehyde 14 (0.45 g,
91%) as a colorless oil. [α]2D5 = –6.4 (c = 0.12, CHCl3). Rf = 0.46
2-Benzyl-2-(2,2-diethoxyethyl)-1,3-dithiane (19): nBuLi (2.7  in
heptane, 3.64 mL, 9.89 mmol) was added dropwise to a solution of
17 (2.08 g, 9.89 mmol) in THF (45 mL) stirred at –78 °C under an
argon atmosphere. After completion of the addition, the bath tem-
perature was raised to –25 °C and kept for 3–4 h before cooling
again to –78 °C. Freshly distilled 18 (1.48 mL, 9.89 mmol) was
added dropwise to the above solution. The bath temperature was
allowed to raise slowly to 0 °C. When TLC showed completion of
the reaction, the reaction mixture was poured into ice water and
extracted with diethyl ether. The ethereal phase was separated,
washed with water and brine, dried (Na2SO4), filtered, and concen-
1
(EtOAc/hexane, 75:25). H NMR (300 MHz, CDCl3): δ = 9.73 (s,
1 H, CHO), 6.61 (br. s, 1 H, NH), 4.58 (m, 1 H, 4Ј-H), 3.62 (m, 1 trated. The crude product was purified by flash chromatography
H,5-H), 2.87 (dd, J = 16.2, 5.1 Hz, 1 H, 3-H), 2.74 (m, 1 H, 5Ј-H), (EtOAc/hexane, 4:96) to afford the title compound (2.52 g, 78%)
2.56 (dd, J = 16.2, 7.4 Hz, 1 H, 5Ј-H), 2.22 (m, 1 H, 4-H), 1.77 (m, as a colorless oil. Rf = 0.38 (EtOAc/hexane, 8:92). 1H NMR
1 H, 4-H), 1.60 (m, 1 H, 7-H), 1.38 (m, 1 H, 6-H), 1.29 (m, 1 H,
6-H), 0.89 (d, J = 6.9 Hz, 6 H CH3), 0.84 (s, 9 H, SiCMe3), 0.07
(s, 3 H, SiMe), 0.05 (s, 3 H, SiMe) ppm. 13C NMR (75 MHz,
CDCl3): δ = 201.1, 176.7, 67.8, 51.2, 47.5, 46.6, 46.1, 29.7, 25.7,
(300 MHz, CDCl3): δ = 7.43 (m, 2 H, Ph-H), 7.27 (m, 2 H, Ph-H),
4.87 (t, J = 4.8 Hz, 1 H, CH), 3.68 (q, J = 6.7 Hz, 2 H, CH2), 3.60
(q, J = 6.7 Hz, 2 H, CH2), 3.27 (s, 2 H, CH2), 2.69–2.98 (m, 4 H,
CH2), 2.24 (d, J = 4.8 Hz, 2 H), 1.82–2.08 (m, 2 H, CH2), 1.24 (t,
22.9, 22.3, 17.9 ppm. C17H33NO3Si (327.53): calcd. C 62.34, H J = 6.7 Hz, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
10.16, N 4.28; found C 62.18, H 10.01, N 4.20.
131.6, 131.2, 128.2, 127.7, 127.5, 126.9, 101.5, 61.7, 49.3, 46.4, 45.2,
40.2, 26.4, 24.6, 24.9, 24.4, 15.5 ppm. C17H26O2S2 (326.52): calcd.
C 62.53, H 8.03; found C 62.62, H 8.12.
(3R,5S,1ЈR)-3-[1Ј-(tert-Butyldimethylsilanyloxy)-3Ј-hydroxy-4Ј-phen-
ylbutyl]-5-isobutylpyrrolidin-2-one (15): To a stirred solution of al-
dehyde 14 (0.400 g, 1.22 mmol) in THF (15 mL) was added
PhCH2MgCl (2.0  in THF, 1.82 mL, 3.66 mmol) dropwise at 0 °C.
The resulting reaction mixture was stirred for 3 h at 0 °C. The reac-
tion was quenched with saturated aqueous NH4Cl and extracted
with EtOAc (3ϫ30 mL). The organic layers were combined, dried
(Na2SO4), filtered, and concentrated. The crude product was puri-
fied by flash column chromatography (EtOAc/hexane, 4:6 to 8:2)
2-(2-Benzyl-1,3-dithian-2-yl)acetaldehyde (20): A solution of 19
(1.35 g, 4.13 mmol) and pTsOH (157 mg, 0.82 mmol) in acetone/
water (10:1, 23 mL) was heated to reflux with stirring until TLC
showed completion of the reaction. The solvent was removed by
rotary evaporation. The residue was extracted with diethyl ether
and washed with saturated aqueous NaHCO3, water, and brine.
The organic layer was dried (Na2SO4), filtered, and concentrated.
to afford 15 (0.210 g, 41%) as a yellow oil. Rf = 0.34 (EtOAc/hex- The crude product was purified by flash chromatography (EtOAc/
1
ane, 75:25). H NMR (300 MHz, CDCl3): δ = 7.13–7.40 (m, 5 H, hexane, 8:92) to afford 20 (1.18 g, 97%) as a colorless oil. Rf = 0.52
1
Ph-H), 5.78 (br. s, 1 H, NH), 4.07 (m, 1 H, 8-H), 3.84 (m, 1 H, 10- (EtOAc/hexane, 2:8). H NMR (300 MHz, CDCl3): δ = 9.71 (br. s,
H), 3.67 (m, 1 H, 14-H), 2.86 (m, 2 H, 7-H), 2.67 (dd, J = 6.6,
13.3 Hz, 11-H), 2.18 (m, 1 H, 19-H), 1.20–1.90 (m, 6 H, 9-H, 19-
1 H, CHO), 7.30 (m, 5 H, Ph-H), 3.34 (s, 2 H, CH2), 2.90 (m, 4 H,
CH2), 2.79 (s, 2 H, CH2), 2.01 (m, 2 H, CH2) ppm. 13C NMR
H, 15-H, 16-H), 0.89 (d, J = 6.6 Hz, 6 H, CH3), 0.83 (s, 9 H, (75 MHz, CDCl3): δ = 199.8, 134.7, 131.2, 128.2, 127.6, 49.4, 46.4,
Eur. J. Org. Chem. 2010, 6217–6223
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6221

N. S. Chakor, S. Dallavalle, L. Scaglioni, L. Merlini
FULL PAPER
26.5, 24.5 ppm. C13H16OS2C (252.40): Calcd. C 61.86, H 6.39;
found C 61.94, H 6.45.
3.2, 8.4, 11.0 Hz, 1 H, 14-H), 3.33 (d, J = 14 Hz, 1 H, 7-H), 3.22
(d, J = 14 Hz, 1 H, 7-H), 3.01 (s, 1 H, OH), 2.95 (m, 1 H, SCHH),
2.80–2.90 (m, 3 H, SCH2CHHS), 2.57 (ddd, J = 3.2, 8.4, 11.3 Hz,
1 H, 11-H), 2.45 (s, 3 H, Ph-CH3), 2.37 (ddd, J = 8.4, 12.1, 8.4 Hz,
1 H, 19-H), 2.14 (dd, J = 9.7, 5.1 Hz, 1 H, 9-H), 2.05 (m, 2 H,
CH2CH2S), 1.90 (ddd, J = 4.0, 11.0, 13.0 Hz, 1 H, 15-H), 1.83 (m,
1 H, 19-H), 1.79 (dd, J = 1.7, 15.1 Hz, 1 H, 9-H), 1.69 (m, 1 H,
16-H), 1.47 (m, 1 H, 15-H), 1.05 (d, J = 6.6 Hz, 3 H, CH3), 0.99
(d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
173.4, 144.9, 136.1, 135.1, 131.2, 130.0, 129.5, 128.5, 128.0, 127.2,
66.5, 57.3, 52.4, 47.8, 45.9, 43.9, 41.4, 26.8, 26.4, 25.6, 24.6, 24.1,
23.9, 21.8, 21.4 ppm. C28H37NO4S3 (547.80): calcd. C 61.39, H
6.81, N 2.56; found C 61.48, H 6.90, N 2.48.
(3R,5S,1ЈR)-3-[2Ј-(2-Benzyl-1,3-dithian-2-yl)-1Ј-hydroxyethyl]-5-iso-
butyl-1-(toluene-4-sulfonyl)pyrrolidin-2-one (21): To a stirred solu-
tion of pyrrolidinone 7 (1.33 g, 3.79 mmol) in THF (32 mL) was
added LiHMDS (1  in THF, 0.761 g, 6.0 mL, 4.55 mmol) at
–78 °C, and the solution was stirred for 45 min. Aldehyde 20
(0.950 g, 3.71 mmol) in THF (16 mL) was added dropwise at
–78 °C, and the reaction mixture was stirred for 3 h. After addition
of saturated aqueous NH4Cl (130 mL), the aqueous phase was ex-
tracted with diethyl ether (3ϫ100 mL). The combined organic lay-
ers were dried (Na2SO4), filtered, and concentrated. The residue
was purified by flash column chromatography (EtOAc/hexane,
18:82) to afford 21 as an oil (1.85 g, 75%). [α]2D5 = +35.0 (c = 0.09,
(3R,5S,1ЈS)-3-(1Ј-Hydroxy-3Ј-oxo-4Ј-phenylbutyl)-5-isobutyl-1-
MeOH). Rf = 0.57 (EtOAc/hexane, 25:75). 1H NMR (600 MHz, (toluene-4-sulfonyl)pyrrolidin-2-one (24): Iodine (183 mg, 0.721
CDCl3): δ = 7.94 (m, 2 H, o-H Ts), 7.37 (m, 2 H, Ph-H), 7.34 (m, mmol) was added to a mixture of 23 (120 mg, 0.219 mmol) and
2 H, m-H Ts), 7.24–7.31 (m, 3 H, Ph-H), 4.37 (dddd, J = 1.1, 3.1, NaHCO3 (123 g, 1.46 mmol) in acetone (1.20 mL) and water
8.1, 11 Hz, 1 H, 14-H), 4.25 (ddd, J = 1.6, 6.5, 9.5 Hz, 1 H, 10-H), (0.12 mL), and the solution was stirred at 0 °C until TLC showed
3.93 (br. s, 1 H, OH), 3.41 (d, J = 13.8 Hz, 1 H, 7-H), 3.18 (d, J = completion of the reaction. The excess amount of iodine was de-
13.8 Hz, 1 H, 7-H), 2.80 (m, 4 H, SCH2CHHS), 2.68 (ddd, J = 6.5,
8.5, 11.4 Hz, 1 H, 11-H), 2.45 (s, 3 H, Ph-CH3), 2.24 (dd, J = 9.5,
stroyed with aqueous Na2S2O3; the mixture was diluted with di-
ethyl ether and washed first with aqueous Na2S2O3 until the iodine
15.2 Hz, 1 H, 19-H), 1.84–2.05 (m, 5 H, 19-H, CH2CH2S), 1.77 color completely vanished and then with brine. The organic layer
(dd, J = 1.6, 15.2 Hz, 1 H, 9-H), 1.67 (m, 1 H, 16-H), 1.48 (ddd, J
= 4.0, 11.0, 15.2 Hz, 1 H, 15-H), 1.02 (d, J = 6.6 Hz, 3 H, CH3),
was dried (Na2SO4), filtered, and concentrated. The crude product
was purified by flash chromatography (EtOAc/hexane, 32:68) to
0.98 (d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): afford 24 as a colorless solid (87 mg, 87%). M.p. 95 °C. [α]2D5
=
δ = 174.6, 145.2, 136.0, 135.8, 131.6, 129.6, 128.5, 127.8, 127.0,
69.7, 57.2, 52.6, 46.5, 45.8, 43.4, 41.5, 27.8, 26.7, 26.5, 25.6, 24.7,
23.9, 21.8, 21.3 ppm. HRMS (ESI+): calcd. for C28H37NO4S3Na
570.17769; found 570.17887.
+22.7 (c = 0.11, MeOH). Rf = 0.23 (EtOAc/hexane, 3:7). 1H NMR
(300 MHz, CDCl3): δ = 7.89 (m, 2 H, o-H Ts), 7.31 (m, 2 H, m-H
Ts), 7.16 (m, 2 H, Ph-H), 4.19–4.41 (m, 2 H, 10-H, 14-H), 3.68 (s,
2 H, 7-H), 2.85 (m, 1 H, 9-H), 2.62 (m, 2 H, 9-H), 2.42 (s, 3 H,
Ph-CH3), 2.12 (m, 1 H, 19-H), 1.83 (m, 1 H, 19-H), 1.64 (br. s, 1
H), 1.42 (m, 1 H), 0.99 (d, J = 6.5 Hz, 3 H, CH3), 0.94 (d, J =
6.5 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 208.3,
173.2, 145.0, 136.0, 133.4, 129.5, 129.4, 128.9, 128.3, 127.3, 66.1,
57.1, 50.6, 45.9, 43.4, 25.9, 25.5, 23.8, 21.7, 21.2 ppm. HRMS
(ESI+): calcd. for C25H31NO5SNa 480.18151; found 480.18172.
(3R,5S)-3-[2Ј-(2-Benzyl-1,3-dithian-2-yl)acetyl]-5-isobutyl-1-(toluene-
4-sulfonyl)pyrrolidin-2-one (22): To a solution of dimethyl sulfoxide
(0.30 mL, 4.36 mmol) in CH2C12 (10 mL) at –78 °C was added tri-
fluoroacetic anhydride (0.40 mL, 2.94 mmol), and the mixture was
stirred for 10 min. Alcohol 21 (400 mg, 0.731 mmol) in CH2C12
(5 mL) was added, and the solution was stirred for 30 min at
–78 °C. After addition of triethylamine (1.62 mL, 15.97 mmol), the
mixture was warmed to room temperature over 1 h. The solution
was diluted with CH2Cl2 (50 mL), washed with 5% HCl and water
(2ϫ), dried (Na2SO4), filtered, and concentrated. The crude prod-
uct was purified by flash chromatography (EtOAc/hexane, 15:85)
Berkeleyamide A (1a): To a solution of naphthalene (144 mg,
1.12 mmol) in dry THF (1.7 mL) was added Na (25 mg,
1.12 mmol) in small pieces. The mixture was stirred for 2 h at room
temperature, and then it was added to a solution of 24 (43 mg,
0.093 mmol) in THF (2.2 mL) at –78 °C until the green color per-
sisted. The resulting reaction mixture was stirred at –78 °C for
to give the title compound as a yellow oil (370 mg, 93%). [α]2D5
=
+20.0 (c = 0.11, MeOH). Rf = 0.71 (EtOAc/hexane, 3:7). 1H NMR 30 min, then quenched with saturated aqueous NH4Cl and ex-
(300 MHz, [D6]DMSO): δ = 7.85 (m, 2 H, o-H Ts), 7.44 (m, 2 H, tracted with EtOAc (3ϫ15 mL). The combined organic layers were
Ph-H), 7.05–7.25 (m, 5 H, Ph-H), 4.27–4.48 (m, 2 H, 11-H, 14-H), dried (Na2SO4) and concentrated. The crude product was purified
3.34 (s, 4 H), 2.55–3.00 (m, 4 H, CH2), 2.39 (s, 3 H, Ph-CH3), 2.00– by flash column chromatography (EtOAc/hexane, 9:1) to afford 1a
2.35 (m, 2 H, CH2), 1.50–195 (m, 5 H), 0.96 (d, J = 6.06 Hz, 3 H,
CH3) 0.92 (d, J = 6.06 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 201.0, 174.1, 145.2, 135.5, 135.9, 135.8, 131.1,
130.2, 130.1, 128.5, 128.4, 128.3, 60.2, 59.3, 50.3, 43.3, 30.4, 26.0,
25.8, 25.2, 24.9, 24.1, 23.8, 21.7 ppm. C28H35NO4S3 (545.78): calcd.
C 61.62, H 6.46, N 2.57; found C 61.55, H 6.54, N 2.68.
(24 mg, 85%) as a viscous liquid. [α]2D5 = –39.7 (c = 0.11,
MeOH).[11] Rf = 0.33 (EtOAc/hexane, 9:1). 1H NMR (300 MHz,
CDCl3): δ = 7.09–7.38 (m, 5 H, Ph-H), 5.83 (br. s, 1 H, NH), 4.37
(m, 1 H, 10-H), 3.74 (s, 2 H, 7-H), 3.64 (m, 1 H, 14-H), 2.85 (dd,
J = 3.2, 17.4 Hz, 1 H, 9-H), 2.70 (dd, J = 8.8, 17.4 Hz, 1 H, 9-H),
2.46 (m, 1 H, 11-H), 2.31 (m, 1 H, 19-H), 1.72 (m, 1 H, 19-H), 1.58
(m, 1 H, 16-H), 1.42 (m, 1 H, 15-H), 1.28 (m, 1 H, 15-H), 0.91 (d,
J = 6.6 Hz, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
208.7, 177.7, 133.7, 129.6, 128.8, 127.2, 66.7, 51.0, 50.8, 46.5, 46.1,
45.7, 28.6, 25.3, 23.0, 22.4 ppm. HRMS (ESI+): calcd. for
C18H25NO3Na 326.17266; found 326.17239.
(3R,5S,1ЈS)-3-[2Ј-(2-Benzyl-1,3-dithian-2-yl)-1Ј-hydroxyethyl]-5-iso-
butyl-1-(toluene-4-sulfonyl)pyrrolidin-2-one (23): To a solution of 22
(150 mg, 0.275 mmol) in THF/water (4:1, 15 mL) was added
NaBH4 (31 mg, 0.825 mmol) at 0 °C whilst stirring. After 30 min,
AcOEt (30 mL) was added. The organic layer was washed with
0.1  HCl, dried (Na2SO4), and concentrated. The crude residue
was purified by flash chromatography (EtOAc/hexane, 2:8) to give
23 as a yellow oil (127 mg, 85%). [α]2D5 = +40.0 (c = 0.09, MeOH).
(3R,5S,1ЈR)-3-(1Ј-Hydroxy-3Ј-oxo-4Ј-phenylbutyl)-5-isobutylpyrrol-
idin-2-one [10-epi-berkeleyamide A (1b)]: To a solution of 16
(0.250 g, 0.59 mmol) in THF (20 mL) was added TBAF (1.0  in
THF, 0.89 mL, 0.90 mmol) at 0 °C. The mixture was stirred for 1 h
1
Rf = 0.54 (EtOAc/hexane, 30:70). H NMR (600 MHz, CDCl3): δ
= 7.96 (m, 2 H, Ph-H), 7.34 (m, 2 H, Ph-H), 7.27–7.32 (m, 5 H, and then quenched with saturated aqueous NH4Cl. The organic
Ph-H), 4.58 (ddd, J = 1.7, 3.2, 9.7 Hz, 1 H, 10-H), 4.40 (ddd, J = layer was separated, and the aqueous layer was extracted with
6222
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6217–6223

Total Synthesis of Berkeleyamide A and its 10-epi Isomer
EtOAc (3ϫ20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. The crude product was puri-
fied by flash chromatography (EtOAc/hexane, 7:3) to afford 1b
(127 mg, 70%) as a pale-yellow solid. M.p. 50–51 °C. [α]2D5 = –7.2
(c = 0.13, MeOH).[3] Rf = 0.53 (EtOAc/hexane, 8:2). 1H NMR
(300 MHz, CDCl3): δ = 7.17–7.37 (m, 5 H, Ph-H), 5.95 (s, 1 H,
NH), 4.50 (s, 1 H, OH), 4.19 (m, 1 H, 10-H), 3.79 (s, 2 H, 7-H),
3.65 (m, 1 H, 14-H), 2.83 (dd, J = 16.1, 8.3 Hz, 1 H, 9-H), 2.64
(dd, J = 16.1, 3.2 Hz, 1 H, 9-H), 2.48 (q, J = 8.2 Hz, 1 H, 11-H),
2.02 (dt, J = 12.6, 8.2 Hz, 1 H, 19-H), 1.80 (ddd, J = 12.6, 9.2,
3.2 Hz, 1 H, 19-H), 1.58 (m, 1 H, 16-H), 1.38 (m, 1 H, 15-H), 1.26
(m, 1 H, 15-H), 0.91 (d, J = 6.6 Hz, 6 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 208.0, 178.8, 133.9, 129.7, 128.8, 127.2, 69.9,
51.2, 51.0, 46.5, 45.8, 45.7, 44.0, 30.7, 25.3, 23.0, 22.8, 22.2 ppm.
HRMS (ESI+): calcd. for C18H25NO3Na 326.17266; found
326.17242.
[1]
[2]
[3]
[4]
[5]
[6]
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A. A. Stierle, D. B. Stierle, B. J. Patacini, J. Nat. Prod. 2008,
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A. P. Craven, H. J. Dyke, E. J. Thomas, Tetrahedron 1989, 45,
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[7] A. S. Anderson, J. Hwang, M. M. Greenberg, J. Org. Chem.
2000, 65, 4648–4654.
[8] O. Mitsunobu, Synthesis 1981, 1–28.
[9] G. Cainelli, F. Manescalchi, G. Martelli, M. Panunzio, L.
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[10] H. Nagao, M. Michida, T. Mukaiyama, Synth. Commun. 2008,
38, 3208–3214.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for compounds 1a,
1b, 7, 10–16, and 19–24.
[11] [α]D for the natural product[2] is –1.0 (c = 0.017, MeOH), in
ref.[3] it is –15.5 (c = 0.11, MeOH), and in ref.[4] it is –34.2 (c
= 0.48, MeOH) and –31.1 (c = 0.11, MeOH).
Received: June 25, 2010
Acknowledgments
This work was supported by the University of Milano (FIRST
funds)
Published Online: September 23, 2010
Eur. J. Org. Chem. 2010, 6217–6223
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6223