Asymmetric synthesis of the ABC-ring system of the antitumor antibiotic MPC1001

Article abstract of DOI:10.1021/jo802344t

trans-4-Hydroxy-L-proline was converted into a tricyclic compound representing three contiguous rings of the anticancer antibiotic MPC1001. The tricyclic model contains the dihydrooxepin and diketopiperazine subunits, as well as one of the sulfur atoms of the natural product. The diketopiperazine unit was formed by a new method that involves cyclization of an enolate onto the carbonyl of a phenyl carbamate, and the dihydrooxepin ring was generated by using an acid-induced cyclization of an alcohol onto the β-carbon of a vinylogous amide.

Full text of DOI:10.1021/jo802344t

Asymmetric Synthesis of the ABC-Ring System of the Antitumor
Antibiotic MPC1001
Jianbiao Peng and Derrick L. J. Clive*
Chemistry Department, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.cliVe@ualberta.ca
ReceiVed October 19, 2008
trans-4-Hydroxy-L-proline was converted into a tricyclic compound representing three contiguous rings
of the anticancer antibiotic MPC1001. The tricyclic model contains the dihydrooxepin and diketopiperazine
subunits, as well as one of the sulfur atoms of the natural product. The diketopiperazine unit was formed
by a new method that involves cyclization of an enolate onto the carbonyl of a phenyl carbamate, and
the dihydrooxepin ring was generated by using an acid-induced cyclization of an alcohol onto the ꢀ-carbon
of a vinylogous amide.
Introduction
values for MPC1001, adriamycin, mitomycin C, and etoposide
being 9.3, 20, 25, and 400 nmol/L, respectively.1a,b No member
of the dihydrooxepin dithiodiketopiperazine family of natural
products has been synthesized, and there is little published
information about the pharmacophore(s) responsible for the
biological activity.1c
MPC1001 (1)1 is a member of a group of naturally occurring
dithiodiketopiperazines that incorporate a dihydrooxepin unit.2-8
Several of these dihydrooxepins have significant biological
properties,9 and MPC1001 itself shows very strong in vitro
activity against the DU145 prostate cancer cell line, with IC50
(1) Isolation and structure of MPC1001: (a) Tsumagari, N.; Nakai, R.;
Onodera, H.; Hasegawa, A.; Rahayu, E. S.; Ando, K.; Yamashita, Y. J. Antibiot.
2004, 57, 532–534. (b) Onodera, H.; Hasegawa, A.; Tsumagari, N.; Nakai, R.;
Ogawa, T.; Kanda, Y. Org. Lett. 2004, 6, 4101–4104. (c) Herath, K. B.;
Jayasuriya, H.; Ondeyka, J. G.; Polishook, J. D.; Bills, G. F.; Dombrowski, A. W.;
Cabello, A.; Vicario, P. P.; Zweerink, H.; Guan, Z.; Singh, S. B. J. Antibiot.
2005, 58, 686–694.
(2) Seya, H.; Nozawa, K.; Nakajima, S.; Kawai, K.; Udagawa, S. J. Chem.
Soc., Perkin Trans. 1 1986, 109–116.
(3) (a) Ooike, M.; Nozawa, K.; Kawai, K.-I. Phytochemistry 1997, 46, 123–
126. (b) Seya, H.; Nozawa, K.; Udagawa, S.; Nakajima, S.; Kawai, K. Chem.
Pharm. Bull. 1986, 34, 2411–2416.
(4) (a) Nagarajan, R.; Neuss, N.; Marsh, M. M. J. Am. Chem. Soc. 1968, 90,
6518–6519. (b) Murdock, K. C. J. Med. Chem. 1974, 17, 827–835, and references
quoted therein.
(5) (a) Nagarajan, R.; Huckstep, L. L.; Lively, D. H.; DeLong, D. C.; Marsh,
M. M.; Neuss, N. J. Am. Chem. Soc. 1968, 90, 2980–2982. (b) Moncrief, J. W.
J. Am. Chem. Soc. 1968, 90, 6517–6518. (c) Cosulich, D. B.; Nelson, N. R.;
van den Hende, J. H. J. Am. Chem. Soc. 1968, 90, 6519–6521.
(6) Hegde, V. R.; Dai, P.; Patel, M.; Das, P. R.; Puar, M. S. Tetrahedron
Lett. 1997, 38, 911–914.
(7) For related compounds in which the disulfide bridge has been cleaved,
see: (a) Chinworrungsee, M.; Kittakoop, P.; Saenboonrueng, J.; Kongsaeree, P.;
Thebtaranonth, Y. J. Nat. Prod. 2006, 69, 1404–1410. (b) Kirby, G. W.; Robins,
D. J.; Stark, W. M. J. Chem. Res., Synop. 1986, 302–303.
(8) (a) Kawahara, N.; Nakajima, S.; Yamazaki, M.; Kawai, K. Chem. Pharm.
Bull. 1989, 37, 2592–2595. (b) Kawahara, N.; Nozawa, K.; Yamazaki, M.;
Nakajima, S.; Kawai, K. Chem. Pharm. Bull. 1990, 38, 73–78. (c) Kawahara,
N.; Nozawa, K.; Yamazaki, M.; Nakajima, S.; Kawai, K. Heterocycles 1990,
30, 507–515.
In an earlier publication,10 we reported a method for
constructing the dihydrooxepin subunit; here, we describe the
formation of the more advanced tricyclic model 2 by applying
our dihydrooxepin synthesis to a suitable diketopiperazine which
was itself formed by a new method.
(9) Chemokine receptor antagonist activity, ref 1c; antiviral activity, refs 4b
and 5c; antibacterial activity, refs 1a, 3b, and 7; antifungal activity, ref 2;
inhibition of epidermal growth factor, ref 6; inhibition of compound 48/80-
induced histamine release, ref 8; antimalarial activity, ref 7; anticancer properties,
ref 1.
(10) Peng, J.; Clive, D. L. J. Org. Lett. 2007, 9, 2939–2941.
10.1021/jo802344t CCC: $40.75
Published on Web 12/09/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 513–519 513

Peng and Clive
SCHEME 1. Initial Model Study
SCHEME 4. Preparation of Carbamate Unit
SCHEME 5. Formation of Diketopiperazine Unita
SCHEME 2. Synthetic Plana
a Pg, Pg′, Pg′′ ) protecting groups.
SCHEME 3. Preparation of Amino Acid Ester 12
a Si* ) t-BuPh2Si.
phenyl carbamate (14). The corresponding acid chloride 15 was
then used to acylate the nitrogen of the hydroxyproline ester
12 (12 f 16, Scheme 5). The newly attached pendant in 16
would eventually be used to construct the diketopiperazine
substructure by intramolecular attack of an enolate on the phenyl
carbamate carbonyl. To prepare for that key step, several minor
modifications were made to the functional groups of 16. First,
the hydroxy group was oxidized under Swern conditions and
the resulting ketone was temporarily protected as a dimethyl
ketal (16 f 17 f 18). At this point, the ester group was reduced
using NaBH4 in the presence of CaCl2,12 and the resulting
hydroxy ketal 19 was hydrolyzed with hydrochloric acid (19
f 20). Finally, protection of the hydroxy group as a t-BuPh2Si
ether gave the substrate 21 for the intended cyclization. In the
event, this ring closure required extensive exploratory work,
but was eventually achieved in good yield (90%) by treatment
of 21 with NaH in hot (70 °C) THF. The product (22) was
obtained initially as a single compound, but it quite rapidly
changed to a mixture of tautomers. In the sequence leading to
22, the phenyl carbamate unit serves both as a nitrogen
protecting group and later as a source of two of the permanent
structural atoms; the cyclization 21 f 22 represents a new
method for generating the diketopiperazine ring system.13 The
choice of a bulky protecting group for the C(4) hydroxy in 20
was based on our expectation that its size would direct
sulfenylation of 22 at C(8a) in the correct stereochemical sense.
For the sulfenylation step, we examined a number of reagents
and conditions but eventually settled on the use of 23, which
Results and Discussion
In our initial studies,10 we had converted the aldehyde 3 into
the epimeric bicyclic dihydrooxepins 4 (Scheme 1). Based on
that experience, we then sought to make a tricyclic model that
incorporated the diketopiperazine ring, and our approach is
summarized in Scheme 2. The presence of the additional ring
and stereocenter at C(8a) introduces a number of complications;
in particular, in constructing intermediate 5, a method was
required to control the stereochemistry at C(8a), and this was
done by a proper choice of stereochemistry at C(5), as described
below.
Our starting point was trans-4-hydroxy-L-proline (10). This
was converted (Scheme 3) by a literature method11 into cis-4-
hydroxy-D-proline hydrochloride (11) which was esterified in
a standard way (11 f 12). The other required component (see
15) was made (Scheme 4) from N-methylglycine (13) via the
(11) (a) Baker, G. L.; Fritschel, S. J.; Stille, J. R.; Stille, J. K. J. Org. Chem.
1981, 46, 2954–2960. (b) Heindl, C.; Hu¨bner, H.; Gmeiner, P. Tetrahedron:
Asymmetry 2003, 14, 3141–3152. (c) Marusawa, H.; Setoi, H.; Sawada, A.;
Kuroda, A.; Seki, J.; Motoyama, Y.; Tanaka, H. Bioorg. Med. Chem. 2002, 10,
1399–1415.
(12) Konradi, A. W.; Kemp, S. J.; Pedersen, S. F. J. Am. Chem. Soc. 1994,
116, 1316–1323.
(13) For recent advances in the synthesis of diketopiperazines, see: Dinsmore,
C. J.; Beshore, D. C. Tetrahedron 2002, 58, 3297–3312.
514 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of the ABC-Ring System of MPC1001
SCHEME 6. Preparation of Reagent 23
SCHEME 8. Side-Chain Homologationa
SCHEME 7. Aldehyde Epimerizationa
a Stereochemical assignment at C(8) is arbitrary.
was made as summarized in Scheme 6.14,15 With this reagent
we could isolate the protected sulfide 24 in 55% yield. A small
amount (13%) of the C(8a) epimeric sulfide was also isolated.
When we had protected the C(4) hydroxy of 20 as a t-BuMe2Si
or i-Pr3Si ether, the stereoselectivity of corresponding sulfeny-
lations was similar. At this stage (compound 24) we were able
to confirm the indicated C(8a)-stereochemistry by X-ray crystal-
lographic analysis (see Figure 1 in the Supporting Information
for ORTEP diagram).
The C(5) substituent in 24, having served as a stereochemical
directing group for introduction of the sulfur unit, now had to
be modified by stereochemical inversion at C(5) and then
homologation. To this end, the ketone carbonyl was reduced
(Scheme 7, 24 f 25) and the resulting alcohol [for which we
show an arbitrary C(8) stereochemistry] was protected in the
form of the THP ethers 26. Use of the THP group introduced
an inconvenient degree of complexity in the NMR spectra of
the next few intermediates because of the additional asymmetric
center of the THP unit, but this form of protection was necessary
because attempts to ketalize the carbonyl group of 24 were
unsuccessful and the use of 2-methoxypropene to protect alcohol
25 gave a ketal that was insufficiently stable for convenient
handling. Desilylation of 26, followed by Swern oxidation, led
to aldehyde 28. At this point, base treatment (catalytic DBU)
effected the desired C(5) epimerization and, although it was
necessary to recycle recovered aldehyde 28, the desired product
(29) could be isolated in acceptable yield (75%).
a Si* ) t-BuMe2Si.
the presence of L-ephedrine.16-18 The epimeric alcohols 31 were
then masked as their MEM ethers 32sthis protecting group was
used because of its satisfactory performance in our model
study.10 While the epimeric alcohols 31 were chromatographi-
cally inseparable, the derived MEM ethers 32 could be separated
easily, and for the present exploration we used the major (1.3:
1) epimer. Its C(4)-stereochemistry was later established as S
(see structure 33) on the basis of 1H NMR measurements made
on the final model (2).20
From 32, the required homologation was easily achieved.
Reaction with PhSeCl (32 f 33) simultaneously served to
produce an aldehyde and to install a PhSe group that would
later be used to generate an olefinic bond. Reduction of the
newly formed aldehyde (33 f 34) was achieved with Zn-
(16) (a) Miyaura, N.; Maeda, K.; Suginome, H. J. Org. Chem. 1982, 47,
2117–2120. (b) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170–
173.
(17) Chaloner, P. A; Langadianou, E.; Perera, S. A. R. J. Chem. Soc., Perkin
Trans. 1 1991, 2731–2735.
(18) (a) Use of Z-1-bromo-2-ethoxyethene/t-BuLi, which had been successful
in our model study (ref 10), gave a complex mixture. We also tried a zinc-ate
complex (cf. ref 19), but this reaction was too slow at-78 °C to be useful and
gave a poor yield at a higher temperature. For related observations, see: (b)
Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2149–2152.
(19) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.; Brenner, S. E.;
Clarke, M. O.; Horan, J. C.; Kan, C.; Lacote, E.; Lippa, B.; Nell, P. G.; Turner,
T. M. J. Am. Chem. Soc. 2002, 124, 13648–13649.
The inverted C(5) chain was now homologated (Scheme 8,
29f30) by reaction with the (ethoxyvinyl)zinc reagent 30 in
(20) The 1H NMR spectrum of 2 clearly indicated the C(4) stereochemistry
because 3JC(4)H-C(5)H is 8.0 Hz, which corresponds closely to the value (7.7 Hz)
in the natural product (ref 1b). The corresponding coupling constants for the
two epimers of 4 are <3 and 7.8 Hz for cis and trans C(4) and C(5) hydrogens,
respectively.
(14) For related reagents, see, for example: Marigo, M.; Wabnitz, T. C.;
Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794–797.
(15) Schwan, A. L.; Brillon, D.; Dufault, R. Can. J. Chem. 1994, 72, 325–
333.
J. Org. Chem. Vol. 74, No. 2, 2009 515

Peng and Clive
SCHEME 9. Formation of Tricyclic Model
H), 2.60-2.80 (m, 1 H), 3.05 (s, 1 H), 3.18-3.22 (m, 2 H),
3.40-3.3.52 (m, 2 H), 3.58-4.00 (m, 2 H), 4.00-4.15 (m, 2.5 H),
4.30-4.42 (m, 0.5 H), 4.65-4.75 (m, 1 H), 7.05-7.15 (m, 2 H),
7.16-7.24 (m, 1 H), 7.30-7.40 (m, 2 H); 13C NMR (125 MHz,
CDCl3) δ 36.5, 29.3, 51.8, 53.1, 56.0, 64.1, 121.7, 125.5, 129.3,
151.2, 155.8, 167.3, 208.7; exact mass (electrospray) m/z calcd for
C15H18N2NaO5 (M + Na) 329.1108, found 329.1106.
(6R)-6-[[(tert-Butyldimethylsilyl)oxy]methyl]tetrahydro-2-me-
thylpyrrolo[1,2-a]pyrazine-1,4,8(8aH)-trione (22). NaH (60% in
mineral oil, 610 mg, 15.20 mmol) was added to a stirred solution
of ketone 21 (4.03 g, 7.42 mmol) in THF (75 mL) (Ar atmosphere).
The reaction flask was lowered into a preheated oil bath (70 °C).
After 15 min, TLC analysis (silica gel, EtOAc) showed all starting
material had been consumed. The reaction mixture was then cooled
to 0 °C, quenched with pH 7.0 buffer, and extracted with EtOAc.
The combined organic extracts were washed with brine, dried
(Na2SO4), and evaporated. Flash chromatography of the residue over
silica gel, using 1:4 EtOAc-hexane to 1:20 MeOH-CH2Cl2, gave
22 (2.34 g, 90%) as a blue, foamy solid. The material was not stable
and was used within a few hours in the next step without
characterization.
21
(BH4)2 in very high yield (98%), and the THP ether group
was then removed (aqueous AcOH). At this point, the primary
hydroxy of 35 was protected (t-BuMe2SiCl) in order to allow
selective oxidation of the remaining secondary hydroxysa
process readily effected with the Dess-Martin reagent (35 f
36 f 37). We had initially protected the primary hydroxy of
35 as an acetate, but the subsequent oxidation proceeded poorly
(under Swern conditions); moreover, hydrolysis of the resulting
keto acetate was also low-yielding. The t-BuMe2Si group
masking the primary hydroxy of 37 was removable (74%) by
treatment with aqueous AcOH without disturbing either the
sulfur protecting group or the MEM ether (37 f 38).
The hydroxy ketone 38 is a key intermediate, as it is correctly
constituted for elaboration of the dihydrooxepin ring by the
procedure we had developed in our earlier10 model study.
Guided by that work, we treated 38 with both Bredereck’s
reagent and dimethylformamide dimethyl acetal (Scheme 9).
In each case, the required vinylogous amides 39 were formed
(as a single geometrical isomer of unestablished stereochem-
istry), but on the basis of one experiment with Bredereck’s
reagent, the dimethylformide acetal appeared to be more efficient
(70% yield corrected for recovered 38). When the vinylogous
amides were exposed to the action of CF3CO2H in warm PhMe
(50 °C), ring closure occurred and the C(3) epimeric phenyl
selenides 40 were isolated in 77% yield. Finally, oxidation of
the selenium led to the desired dihydrooxepin 2 (39%),
representing the ABC ring system of MPC1001. As compound
2 contains only one sulfur group, it also resembles the naturally
occurring MPC1001 analog MPC1001F.1b
(6R,8aR)-6-[[(tert-Butyldimethylsilyl)oxy]methyl]tetrahydro-
2-methyl-8a-[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-
1,4,8(8aH)-trione (24). DBU (0.10 mL, 0.62 mmol) was added to
a stirred and cooled (0 °C) solution of ketone 22 (2.78 g, 6.18 mmol)
and 1-[[2-(trimethylsilyl)ethyl]thio]pyrrolidine-2,5-dione (23) in
CH2Cl2 (50 mL). Stirring was continued for 8 h, at which stage
TLC analysis (silica, 1:15 MeOH-CH2Cl2) showed no 22 remained.
Evaporation of the solvent and flash chromatography of the residue
over silica gel, using 1:10 EtOAc-hexane to 1:6 EtOAc-hexane,
gave 24 (2.29 g, 55%) as a solid: mp 112-114 °C; [R]D ) -38.2
(CH2Cl2, c 0.44); FTIR (CH2Cl2, cast film microscope) 3072, 2953,
1
2859, 1765, 1688, 1473, 1427, 1409, 1397 cm-1; H NMR (500
MHz, CDCl3) δ 0.03 (s, 9 H), 0.69-0.73 (m, 2 H), 0.97 (s, 9 H),
2.60 (dd, J ) 18.0, 2.8 Hz, 1 H), 2.77-2.86 (m, 2 H), 3.00 (s, 3
H), 3.36 (dd, J ) 18.0, 9.0 Hz, 1 H), 3.55 (dd, J ) 10.6, 1.7 Hz,
1 H), 3.75 (d, J ) 17.0 Hz, 1 H), 4.25 (dd, J ) 10.6, 2.9 Hz, 1 H),
4.34 (apparent d, J ) 9.6 Hz, 1 H), 4.39 (d, J ) 16.9 Hz, 1 H),
7.34-7.45 (m, 6 H), 7.50-7.59 (m, 4 H); 13C NMR (125 MHz,
CDCl3) δ -1.7, 15.6, 19.0, 26.6, 27.1, 33.7, 36.1, 52.5, 53.2, 62.4,
62.5, 127.7, 127.8, 129.8, 129.9, 132.62, 132.64, 135.5, 135.6,
160.8, 165.4, 194.5; exact mass (electrospray) m/z calcd for
C30H42N2NaO4SSi2 (M + Na) 605.2296, found 605.2300.
(6R,8S,8aR)-6-[[(tert-Butyldimethylsilyl)oxy]methyl]hexahydro-
8-hydroxy-2-methyl-8a-[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-
a]pyrazine-1,4-dione (25). NaBH4 (370 mg, 9.74 mmol) was added
portionwise to a stirred and cooled (0 °C) solution of ketone 24
(5.66 g, 9.74 mmol) in MeOH (60 mL) and THF (20 mL). The
mixture was stirred for 45 min and then quenched with saturated
aqueous NH4Cl and extract with EtOAc. The combined organic
extracts were washed with brine, dried (Na2SO4), and evaporated.
Flash chromatography of the residue over silica gel, using 1:4
Experimental Section
Phenyl [2-[(2R)-2-(2-Hydroxymethyl)-4-oxopyrrolidin-1-yl]-
2-oxoethyl]methylcarbamate (20). Anhydrous CaCl2 (4.84 g, 43.61
mmol) was added to a stirred and cooled (0 °C) solution of methyl
ester 18 (15.70 g, 39.65 mmol) in a mixture of THF (50 mL) and
EtOH (50 mL), and then NaBH4 (3.40 g, 87.22 mmol) was added
in one portion. Stirring was continued for 3 h, the mixture was
acidified with hydrochloric acid (1 M), and stirring was continued
overnight. The solution was diluted with EtOAc, and the aqueous
layer was extracted with EtOAc. The combined organic extracts
were washed with brine, dried (Na2SO4), and evaporated. Flash
chromatography of the residue over silica gel, using EtOAc-MeOH
mixtures from pure EtOAc to 1:20 MeOH-EtOAc, gave 20 (8.45
g, 70%) as a solid: mp 65-67 °C; [R]D ) -13.6 (CH2Cl2, c 1.30);
FTIR (CH2Cl2, cast film microscope) 3438, 2936, 1763, 1722, 1657,
1456, 1340 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.28-2.32 (m, 1
EtOAc-hexane, gave 25 (5.66 g, 100%) as a semisolid: [R]D
)
-21.1 (CH2Cl2, c 0.73); FTIR (CH2Cl2, cast film microscope) 3436,
1
3071, 2931, 2858, 1680, 1472, 1428 cm-1; H NMR (400 MHz,
CDCl3) δ 0.03 (s, 9 H), 0.68-0.89 (m, 2 H), 1.03 (s, 9 H), 2.27
(ddd, J ) 12.4, 7.0, 0.9 Hz, 1 H), 2.40 (apparent q, J ) 9.5 Hz, 1
H), 2.63 (ddd, J ) 12.2, 11.5, 5.4 Hz, 1 H), 2.86-2.95 (m, 2 H),
3.02 (s, 3 H), 3.64 (dd, J ) 10.4, 5.1 Hz, 1 H), 3.70 (d, J ) 17.0
Hz, 1 H), 4.07 (apparent d, J ) 10.0 Hz, 1 H), 4.12 (dd, J ) 10.4,
3.9 Hz, 1 H), 4.36 (d, J ) 17.1 Hz, 1 H), 4.95 (ddd, J ) 11.0, 7.0,
4.1 Hz, 1 H), 7.35-7.47 (m, 6 H), 7.55-7.63 (m, 4 H); 13C NMR
(125 MHz, CDCl3) δ -1.8, 17.0, 19.1, 26.6, 26.7, 31.7, 33.1, 53.6,
55.3, 62.5, 72.3, 74.1, 127.6, 127.7, 129.6, 129.7, 132.7, 133.0,
135.4, 135.5, 164.6, 166.2; exact mass (electrospray) m/z calcd for
C30H44N2NaO4SSi2 (M + Na) 607.2453, found 607.2457.
(6R,8S,8aR)-6-[[(tert-Butyldimethylsilyl)oxy]methyl]hexahydro-
2-methyl-8-[(tetrahydro-2H-pyran-2-yl)oxy]-8a-[[2-(trimethyl-
silyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-1,4-dione (26). TsOH·H2O
(21) Uemura, S.; Ohe, K. J. Chem. Soc., Perkin Trans. 1 1990, 907–910.
516 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of the ABC-Ring System of MPC1001
(16 mg, 0.082 mmol) was added to a stirred solution of alcohol 25
(2.40 g, 4.11 mmol) and 2,3-dihydropyran (1.10 mL, 12.33 mmol)
in CH2Cl2. After 30 min, powered K2CO3 was added, and stirring
was continued for 2 h. The mixture was filtered through Celite,
using CH2Cl2 as a rinse. Evaporation of the filtrate and flash
chromatographyoftheresidueoversilicagel,using1:4EtOAc-hexane,
gave 26 (2.48 g, 92%) as an oil: [R]D ) -17.8 (CH2Cl2, c 0.47);
FTIR (CH2Cl2, cast film microscope) 3072, 2951, 2858, 1681, 1427
cm-1; 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9 H), 0.60-0.81 (m,
2 H), 1.02 (s, 9 H), 1.51-1.90 (m, 6 H), 2.24-2.40 (m, 1 H),
2.49-2.79 (m, 2 H), 3.02 (s, 3 H), 2.96-3.16 (m, 1 H), 3.44-3.55
(m, 2 H), 3.69 (d, J ) 16.7 Hz, 1 H), 3.90-3.98 (m, 1 H),
4.00-4.15 (m, 2 H), 4.46 (d, J ) 16.8 Hz, 0.5 H), 4.49 (d, J )
16.8 Hz, 0.5 H), 4.95-5.16 (m, 2 H), 7.33-7.44 (m, 6 H),
7.57-7.65 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ -1.84, -1.81,
16.9, 17.0, 18.2, 20.0, 25.2, 25.4, 26.52, 26.54, 26.8, 27.0, 29.5,
30.1, 30.5, 32.4, 33.4, 33.6, 53.5, 53.6, 55.1, 55.6, 60.7, 62.6, 62.7,
63.1, 71.0, 71.1, 74.7, 79.8, 94.3, 100.5, 127.55, 127.59, 129.5,
129.6, 132.7, 133.0, 135.48, 135.52, 165.0, 165.2, 165.3, 165.5;
exact mass (electrospray) m/z calcd for C35H52N2NaO5SSi2 (M +
Na) 691.3028, found 691.3034.
164.3, 164.5, 164.8, 164.9, 196.98, 197.05; exact mass (electro-
spray) m/z calcd for C19H32N2NaO5SSi (M + Na) 451.1693, found
451.1697.
(6S,8S,8aR)-6-[(2E)-3-Ethoxy-1-hydroxy-2-propenyl)]hexahy-
dro-2-methyl-8-[(tetrahydro-2H-pyran-2-yl)oxy]-8a-[[2-(trime-
thylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-1,4-dione (31). BH3 ·
SMe2 (10.0 M, 10.0 µL, 0.10 mmol) was added dropwise to a stirred
and cooled (0 °C) solution of ethyl ethynyl ether (40% w/v in
hexanes, 72.0 µL, 0.30 mmol) in PhMe (1.0 mL). After the addition,
the cold bath was removed, and stirring was continued for 5.5 h.
The mixture was recooled to 0 °C and Me2Zn (2.0 M in PhMe,
0.19 mL, 0.38 mmol) was added. Stirring was continued for 30
min, and then a solution of aldehyde 29 (64.0 mg, 0.15 mmol) in
PhMe (1.2 mL) was added to the resulting zinc reagent.
A solution of L-ephedrine (180 mg, 1.09 mmol) in dry PhMe (6
mL) was prepared during the above operations, an aliquot [58 µL,
corresponding to 0.01 mmol L-ephedrine] was added dropwise to
the reaction mixture, and stirring was continued for 30 min at 0 °C
and for 40 h at room temperature. The mixture was quenched with
saturated aqueous NaHCO3 and extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried (Na2SO4),
and evaporated. Flash chromatography of the residue over silica
gel, using 1:60 MeOH-CH2Cl2 to 1:40 MeOH-CH2Cl2, gave
alcohols 31 (67.3 mg, 90%) as an oil: FTIR (CH2Cl2, cast film
(6R,8S,8aR)-Octahydro-2-methyl-1,4-dioxo-8-[(tetrahydro-
2H-pyran-2-yl)oxy]-8a-[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-
a]pyrazine-6-carbaldehyde (28). DMSO (0.63 mL, 8.72 mmol)
was added at a fast dropwise rate to a stirred and cooled (-78 °C)
solution of (COCl)2 (0.40 mL, 4.36 mmol) in CH2Cl2 (20 mL).
After the addition, stirring was continued for 15 min and then a
solution of alcohol 27 (1.25 g. 2.91 mmol) and pyridine (0.35 mL,
4.36 mmol) in CH2Cl2 (10 mL) was added. Stirring at -78 °C was
continued for 40 min and then Et3N (1.21 mL, 8.72 mmol) was
added dropwise. The cold bath was left in place but not recharged
and stirring was continued for 4 h, by which time the mixture had
reached ca. -30 °C. The mixture was diluted with CH2Cl2 and
saturated aqueous NaHCO3 was added. The organic layer was
separated and washed with brine, dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel, using 1:1
EtOAc-hexane to pure EtOAc and finally 1:4 acetone-EtOAc, gave
aldehyde 28 (1.11 g, 90%) as an oil: [R]D ) -34.6 (CH2Cl2, c
0.49); FTIR (CH2Cl2, cast film microscope) 2950, 1737, 1678, 1418
1
microscope) 3363, 2950, 1674, 1422, 1401 cm-1; H NMR (400
MHz, CDCl3) δ 0.00 (s, 9 H), 0.62-0.80 (m, 2 H), 1.29 (apparent
t, J ) 7.1 Hz, 3 H), 1.52-1.88 (m, 6 H), 2.06-2.80 (m, 3 H),
2.95-3.16 (m, 4 H), 3.52-3.60 (m, 1 H), 3.72-4.02 (m, 6 H),
4.10-4.31 (m, 1 H), 4.40-4.75 (m, 2 H), 4.88-4.92 (m, 0.3 H),
5.05-5.15 (m, 0.7 H), 5.60 (d, J ) 17.0 Hz, 0.3 H), 6.51-6.59
(m, 0.7 H); 13C NMR (100 MHz, CDCl3) δ -1.84, -1.82, 0.92,
14.6, 16.3, 16.5, 16.7, 18.0, 19.3, 19.4, 25.2, 25.3, 25.5, 26.8, 27.0,
27.2, 27.3, 28.5, 30.0, 30.06, 30.10, 30.19, 30.24, 32.6, 33.51, 33.62,
33.69, 33.81, 52.8, 53.0, 61.00, 61.07, 62.48, 62.51, 62.8, 63.1,
63.3, 63.8, 64.3, 64.76, 64.79, 67.9, 70.49, 70.54, 70.95, 71.15,
74.2, 74.9, 76.1, 76.2, 79.2, 79.8, 94.46, 94.48, 100.1, 100.3, 102.3,
102.4, 149.97, 150.04, 164.14, 164.72, 164.79, 165.25, 166.37,
166.48, 166.89, 167.05; exact mass (electrospray) m/z calcd for
C23H40N2NaO6SSi (M + Na) 523.6629, found 523.6628.
(6S,8S,8aR)-6-[3-Ethoxy-1-[(2-methoxyethoxy)methoxy]-2-
propenyl]hexahydro-2-methyl-8-[(tetrahydro-2H-pyran-2-yl)oxy]-
8a-[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-1,4-di-
one (32). MEM-Cl (1.19 mL, 10.44 mmol) was added to a stirred
solution of alcohols 31 (1.74 g, 3.48 mmol), i-Pr2NEt (3.03 mL,
17.41 mmol), and Bu4NI (1.28 g, 3.48 mmol) in THF (40 mL).
The mixture was refluxed for 24 h and cooled to (0 °C). Saturated
aqueous NaHCO3 was added, and the mixture was extracted with
EtOAc. The combined organic extracts were washed with brine,
dried (Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel, using 3:1 EtOAc-hexane to pure EtOAc,
gave the major isomer 32 (more polar, 0.79 g, 39%) and the minor
isomer 32 (less polar, 0.63 g, 31%) as oils.
The less polar isomer had: FTIR (CH2Cl2, cast film microscope)
2949, 1738, 1679, 1597, 1556 cm-1; 1H NMR (400 MHz, CDCl3)
δ -0.02 (s, 9 H), 0.60-0.80 (m, 2 H), 1.24 (apparent t, J ) 7.1
Hz, 3 H), 1.42-1.88 (m, 6 H), 2.20-2.38 (m, 1.5 H), 2.46-2.68
(m, 1.5 H), 2.88-3.08 (m, 4 H), 3.30-3.40 (m, 3 H), 3.42-3.64
(m, 5 H), 3.68-3.90 (m, 5 H), 4.22-4.60 (m, 3 H), 4.72-4.80
(m, 2 H), 4.86-5.10 (m, 2 H), 6.49 (dd, J ) 12.6, 2.9 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ -1.76, -1.74, 14.6, 16.6, 16.7,
18.8, 19.3, 25.36, 25.42, 26.9, 27.0, 30.1, 30.3, 33.9, 53.39, 53.41,
58.93, 58.94, 59.5, 60.2, 61.0, 62.4, 65.16, 65.22, 66.7, 66.8, 67.4,
70.4, 70.6, 71.65, 71.72, 71.82, 71.91, 75.2, 80.0, 91.77, 91.86,
92.3, 94.5, 95.6, 99.5, 99.6, 99.9, 151.38, 151.42, 164.3, 164.5;
exact mass (electrospray) m/z calcd for C27H48N2NaO8SSi (M +
Na) 611.2793, found 611.2794.
1
cm-1; H NMR (400 MHz, CDCl3) δ -0.03 (s, 9 H), 0.62-0.81
(m, 2 H), 1.45-1.90 (m, 6 H), 2.25-2.44 (m, 1.5 H), 2.58-2.80
(m, 1.5 H), 2.98-3.18 (m, 4 H), 3.50-3.62 (m, 1 H), 3.80-3.88
(m, 1.5 H), 4.20-4.28 (m, 0.5 H), 4.40-4.64 (m, 3 H), 4.83
(apparent s, 0.5 H), 5.05 (apparent s, 0.5 H), 9.46-9.52 (m, 1 H);
13C NMR (100 MHz, CDCl3) δ -1.87, -1.85, 16.6, 16.8, 18.0,
19.3, 25.1, 25.2, 26.7, 26.9, 29.0, 29.9, 30.2, 33.7, 33.9, 45.7, 52.9,
59.9, 60.4, 61.0, 62.7, 70.3, 74.2, 78.8, 94.6, 100.1, 164.3, 164.82,
164.84, 165.1, 195.5, 195.7; exact mass (electrospray) m/z calcd
for C19H32N2NaO5SSi (M + Na) 451.1693, found 451.1699.
(6S,8S,8aR)-Octahydro-2-methyl-1,4-dioxo-8-[(tetrahydro-
2H-pyran-2-yl)oxy]-8a-[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-
a]pyrazine-6-carbaldehyde (29). DBU (50 µL, 0.32 mmol) was
added to a stirred solution of aldehyde 28 (2.70 g, 6.31 mmol) in
THF (50 mL). Stirring was continued for 1 h, and then the solvent
was evaporated. Flash chromatography of the residue over silica
gel, using 1:3 EtOAc-CH2Cl2 to 1:10 acetone-EtOAc, gave 29
(1.41 g) and recovered 28 (0.97 g). The recovered aldehyde was
subjected twice more to the above conditions to provide the
epimerized aldehyde 29 (2.02 g, 75% in all) as an oil: [R]D ) -68.0
(CH2Cl2, c 0.17); FTIR (CH2Cl2, cast film microscope) 2950, 1737,
1
1678, 1418 cm-1; H NMR (400 MHz, CDCl3) δ 0.01 (s, 9 H),
0.68-0.81 (m, 2 H), 1.55-1.88 (m, 6 H), 2.05-2.38 (m, 1 H),
2.52-2.80 (m, 2 H), 3.00-3.20 (m, 4 H), 3.55-3.62 (m, 1 H),
3.80-3.88 (m, 2 H), 4.19-4.30 (m, 1 H), 4.48-4.60 (m, 1.5 H),
4.70-4.75 (m, 0.5 H), 4.90 (apparent s, 0.5 H), 5.14 (s, 0.5 H),
9.48-9.52 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ -1.78, -1.77,
16.6, 16.7, 18.1, 19.1, 25.28, 25.33, 26.8, 27.1, 29.2, 30.0, 30.1,
33.9, 34.0, 52.8, 60.3, 60.8, 61.2, 62.4, 70.2, 75.7, 80.3, 94.8, 99.9,
The more polar isomer had: FTIR (CH2Cl2, cast film microscope)
2949, 2882, 1679, 1419, 1400 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.00 (s, 9 H), 0.60-0.80 (m, 2 H), 1.27 (t, J ) 7.0 Hz, 3 H),
J. Org. Chem. Vol. 74, No. 2, 2009 517

Peng and Clive
1.48-1.88 (m, 6 H), 2.25-2.70 (m, 3 H), 2.90-3.04 (m, 4 H),
3.40 (s, 3 H), 3.52-3.65 (m, 5 H), 3.70-3.84 (m, 2 H), 5.85-3.96
(m, 2 H), 4.00-4.09 (m, 1 H), 4.20-4.30 (m, 1.5 H), 4.58-4.65
(m, 1.5 H), 4.70-4.82 (m, 2 H), 4.90-5.15 (m, 2 H), 6.40 (d, J )
12.5 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ -1.76, 15.0, 16.5,
16.7, 18.0, 19.2, 25.35, 25.41, 26.8, 26.9, 27.0, 29.5, 30.1, 30.3,
33.7, 33.9, 53.3, 53.4, 57.7, 58.3, 59.0, 61.0, 62.3, 64.4, 64.5, 66.8,
66.9, 71.6, 71.7, 71.8, 72.8, 75.2, 76.7, 77.1, 77.4, 80.0, 92.4, 92.5,
94.6, 97.0, 97.1, 99.8, 151.6, 151.7, 164.3, 164.5; exact mass
(electrospray) m/z calcd for C27H48N2NaO8SSi (M + Na) 611.2793,
found 611.2793. This major and more polar isomer was used for
the following steps.
as an oil: FTIR (CH2Cl2, cast film) 3451, 2950, 2890, 1661, 1400
1
cm-1; H NMR (400 MHz, CDCl3) δ -0.02 (s, 9 H), 0.52-0.80
(m, 2 H), 2.20-2.35 (m, 2 H), 2.55-2.66 (m, 1 H), 2.70-2.82
(m, 1 H), 2.97 (s, 3 H), 3.20-3.40 (m, 4 H), 3.40-3.52 (m, 3 H),
3.55-3.62 (m, 2 H), 3.62-3.72 (m, 2 H), 3.75-3.88 (m, 2 H),
4.19-4.25 (m, 1 H), 4.30-4.45 (m, 2 H), 4.50-4.70 (m, 2 H),
4.75-4.80 (m, 1 H), 7.18-7.25 (m, 3 H), 7.55-7.76 (m, 2 H);
13C NMR (100 MHz, CDCl3) δ -1.92, -1.86, 16.1, 16.2, 25.4,
25.8, 30.7, 31.0, 33.40, 33.44, 46.8, 48.5, 53.1, 57.2, 58.4, 58.8,
62.8, 63.3, 67.7, 68.1, 71.4, 71.6, 73.3, 75.2, 75.4, 76.8, 77.1, 77.4,
78.5, 82.2, 96.4, 97.5, 127.4, 127.8, 128.0, 129.0, 129.1, 134.0,
134.9, 163.6, 163.7, 166.1; exact mass (electrospray) m/z calcd for
C26H42N2NaO7S80SeSi (M + Na) 657.1539, found 657.1539.
(6S,8S,8aR)-6-[3-(tert-Butyldimethylsilyl)oxy]-1-[(2-methoxye-
thoxy)methoxy]-2-(phenylseleno)propyl]hexahydro-8-hydroxy-
2-methyl-8a-[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-
1,4-dione (36). t-BuMe2SiCl (88 mg, 0.58 mmol) was added to a
stirred solution of diols 35 (245 mg, 0.39 mmol), imidazole (53
mg, 0.78 mmol), and DMAP (3 mg) in CH2Cl2 (5 mL). Stirring
was continued for 48 h, and then water was added. The mixture
was extracted with EtOAc, and the combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated. Flash chro-
matography of the residue over silica gel, using 1:3 EtOAc-hexane
to EtOAc, gave protected alcohols 36 (240 mg, 83%) as an oil:
FTIR (CH2Cl2, cast film) 3448, 2953, 2929, 2886, 2857, 1770, 1681,
(3R)-3-[(2-Methoxyethoxy)methoxy]-3-[(6S,8S,8aR)-octahydro-
2-methyl-1,4-dioxo-8-[(tetrahydro-2H-pyran-2-yl)oxy]-8a-[[2-
(trimethylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazin-6-yl]-2-(phe-
nylseleno)propionaldehyde (33). PhSeCl (153 mg, 0.80 mmol)
in EtOAc (0.5 mL) was added over 4 min to a stirred biphasic
mixture of the more polar ethyl vinyl ether 32 (0.47 g, 0.80 mmol),
NaHCO3 (200 mg, 2.40 mmol), EtOAc (6 mL), and water (3 mL).
Stirring was continued for 40 min, and the mixture was extracted
with EtOAc. The combined organic extracts were dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica
gel using EtOAc gave aldehydes 33 (450 mg, 79%) as an oil: FTIR
1
(CH2Cl2, cast film microscope) 2926, 1677, 1401 cm-1; H NMR
(400 MHz, CDCl3) δ -0.00 (s, 9 H), 0.60-0.80 (m, 2 H),
1.42-1.88 (m, 6 H), 2.20-2.80 (m, 3 H), 2.92-3.16 (m, 4 H),
3.28-3.40 (m, 3 H), 3.40-3.88 (m, 9 H), 4.26-4.50 (m, 2 H),
4.60-5.00 (m, 3 H), 5.00-5.18 (m, 1 H), 7.22-7.20 (m, 3 H),
7.52-7.64 (m, 2 H), 9.30-9.48 (m, 1 H); 13C NMR (100 MHz,
CDCl3) δ -1.82, -1.82, 16.6, 18.7, 19.6, 25.2, 27.1, 30.1, 33.7,
53.2, 53.4, 57.5, 58.0, 58.9, 61.0, 62.4, 67.8, 71.3, 71.6, 72.5, 75.0,
79.7, 79.9, 94.4, 97.6, 99.9, 125.2, 128.6, 129.4, 131.4, 135.0, 135.6,
165.1, 191.4; exact mass (electrospray) m/z calcd for
C31H48N2NaO8S80SeSi (M + Na) 739.1958, found 739.1958.
(6S,8S,8aR)-Hexahydro-6-[(1R)-3-hydroxy-1-[(2-methoxy-
ethoxy)methoxy]-2-(phenylseleno)propyl]-2-methyl-8-[(tetrahy-
dro-2H-pyran-2-yl)oxy]-8a-[[2-(trimethylsilyl)ethyl]thio]pyrro-
lo[1,2-a]pyrazine-1,4-dione (34). Zn(BH4)2 (0.16 M in Et2O, 5.8
mL, 0.91 mmol) was added dropwise to a stirred and cooled (-78
°C) solution of aldehydes 33 (0.44 g, 0.61 mmol) in THF (5 mL).
Stirring was continued for 4 h. Then the mixture was quenched
with saturated aqueous NH4Cl, and the mixture was extracted with
EtOAc. The combined organic extracts were dried (Na2SO4) and
evaporated. Flash chromatography of the residue over silica gel,
using 1:20 MeOH-EtOAc, gave the primary alcohols 34 (0.43 g,
98%) as an oil: FTIR (CH2Cl2, cast film microscope) 3124, 3044,
2947, 2700, 1673, 1437, 1418 cm-1; 1H NMR (400 MHz, CDCl3)
δ -0.03 (s, 9 H), 0.52-0.70 (m, 2 H), 1.42-1.82 (m, 6 H),
2.20-2.40 (m, 1.5 H), 2.50-2.60 (m, 1.5 H), 2.92-3.02 (m, 4 H),
3.05-4.20 (m, 1 H), 3.30-3.40 (m, 3 H), 3.43-3.60 (m, 4 H),
3.60-3.75 (m, 3 H), 3.78-3.83 (m, 3 H), 4.18-4.28 (m, 0.5 H),
4.32-4.50 (m, 2 H), 4.57-4.70 (m, 2 H), 4.72-4.88 (m, 2 H),
5.00-5.08 (m, 0.5 H), 7.18-7.28 (m, 3 H), 7.62-7.68 (m, 2 H);
13C NMR (100 MHz, CDCl3) δ -1.79, -1.74, 16.4, 16.6, 18.5,
19.1, 25.35, 25.40, 26.9, 27.0, 28.9, 30.2, 31.5, 33.8, 34.0, 45.8,
48.4, 53.2, 53.3, 57.0, 58.5, 59.0, 59.4, 62.2, 63.8, 67.8, 68.1, 71.6,
75.6, 77.2, 78.0, 80.6, 94.9, 96.5, 96.8, 99.9, 127.4, 127.6, 128.9,
129.0, 129.2, 134.3, 135.4, 164.4, 164.6; exact mass (electrospray)
m/z calcd for C31H50N2NaO8S80SeSi (M + Na) 741.2115, found
741.2115.
1
1472, 1398 cm-1; H NMR (400 MHz, CDCl3) δ 0.00-0.02 (m,
15 H), 0.65-0.80 (m, 2 H), 0.82-0.86 (m, 9 H), 1.60 (br s, 1 H),
2.30-2.40 (m, 2 H), 2.65-2.82 (m, 2 H), 3.00-3.02 (m, 3 H),
3.38-3.42 (m, 4 H), 3.52-3.60 (m, 2 H), 3.70-3.80 (m, 4 H),
3.88 (t, J ) 10.2 Hz, 1 H), 4.20-4.42 (m, 2 H), 4.58-4.78 (m, 2
H), 4.82 (AB q, J ) 16.8 Hz, ∆νAB ) 23.5 Hz, 2 H), 7.22-7.30
(m, 3 H), 7.60-7.62 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ
-5.4, -1.8, 16.3, 16.5, 25.2, 25.5, 25.92, 25.93, 30.5, 31.8, 33.5,
48.9, 49.1, 53.3, 57.6, 57.9, 58.9, 62.7, 64.1, 68.1, 68.2, 71.8, 73.4,
74.0, 75.7, 76.1, 79.8, 84.2, 97.4, 97.6, 127.2, 127.6, 129.0, 129.1,
129.6, 129.9, 133.7, 134.5, 162.9, 166.6; exact mass (electrospray)
m/z calcd for C32H56N2NaO7S80SeSi2 (M + Na) 771.2404, found
771.2404.
(6S,8aR)-6-[3-[(tert-Butyldimethylsilyl)oxy]-1-[(2-methoxye-
thoxy)methoxy]-2-(phenylseleno)propyl]tetrahydro-2-methyl-8a-
[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-1,4,8(8aH)-
trione (37). Dess-Martin periodinane (169 mg, 0.40 mmol) was
added to a stirred solution of secondary alcohols 36 (199 mg, 0.27
mmol) in CH2Cl2 (6.7 mL). Stirring was continued for 5 h, and
then saturated aqueous NaHCO3 was added. The mixture was
extracted with EtOAc, and the combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated. Flash chro-
matography of the residue over silica gel, using 1:4 EtOAc-hexane
to 2:1 EtOAc-hexane, gave ketones 37 (189 mg, 95%) as an oil:
FTIR (CH2Cl2, cast film) 2953, 2929, 2886, 2857, 1771, 1690, 1397
cm-1 1H NMR (400 MHz, CDCl3) δ 0.00-0.05 (m, 15 H),
;
0.62-0.70 (m, 2 H), 0.80-0.92 (m, 9 H), 2.72-2.85 (m, 2 H),
3.00-3.10 (m, 5 H), 3.36-3.44 (m, 4 H), 3.57 (t, J ) 5.0 Hz, 2
H), 3.68-3.82 (m, 4 H), 3.92 (t, J ) 10.1 Hz, 1 H), 4.39 (dd, J )
6.9, 1.2 Hz, 1 H), 4.43 (d, J ) 15.7 Hz, 1 H), 4.83 (AB q, J ) 7.1
Hz, ∆νAB ) 36.1 Hz, 2 H), 4.98-5.04 (m, 1 H), 7.20-7.28 (m, 3
H), 7.55-7.60 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ -5.4,
-1.72, -1.69, 16.0, 16.1, 25.8, 25.9, 27.0, 27.1, 34.4, 39.4, 49.1,
49.3, 52.8, 52.9, 54.1, 54.7, 59.0, 62.9, 63.7, 63.9, 64.4, 68.2, 68.3,
71.6, 71.7, 78.9, 81.7, 96.9, 97.4, 127.3, 129.0, 129.1, 129.6, 133.7,
134.4, 160.6, 160.7, 164.3, 164.4, 199.0, 199.6; exact mass
(electrospray) m/z calcd for C32H54N2NaO7S80SeSi2 (M + Na)
769.2248, found 769.2247.
(6S,8S,8aR)-Hexahydro-8-hydroxy-6-[(1R)-3-hydroxy-1-[(2-
methoxyethoxy)methoxy]-2-(phenylseleno)propyl]-2-methyl-8a-
[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-1,4-dione (35).
A solution of the primary alcohols 34 (336 mg, 0.47 mmol) in
AcOH (4 mL) and water (1 mL) was stirred for 40 h. The mixture
was diluted with EtOAc and water and then basified with solid
NaHCO3. The organic layer was separated, washed with brine, dried
(Na2SO4), and evaporated. Flash chromatography of the residue over
silica gel, using 1:20 MeOH-EtOAc, gave diols 35 (245 mg, 83%)
(6S,8aR)-Tetrahydro-6-[3-hydroxy-1-[(2-methoxy-
ethoxy)methoxy]-2-(phenylseleno)propyl]-2-methyl-8a-[[2-(tri-
methylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-1,4,8-trione (38).
A solution of the silyl-protected alcohols 37 (19.8 mg, 0.027 mmol)
in AcOH (0.4 mL), water (0.13 mL), and THF (0.13 mL) was stirred
for 2 days, and then saturated aqueous NaHCO3 was added. The
518 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of the ABC-Ring System of MPC1001
mixture was extracted with EtOAc, and the combined organic
extracts were washed with brine, dried (Na2SO4), and evaporated.
Flash chromatography of the residue over silica gel, using 1:1
EtOAc-hexane, gave primary alcohols 38 (12.4 mg, 74%) as an
oil: FTIR (CH2Cl2, cast film microscope) 3465, 2951, 2928, 2893,
1769, 1682, 1478, 1340 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.02
(s, 9 H), 0.63-0.73 (m, 2 H), 2.60-2.88 (m, 3 H), 3.00-3.04 (m,
4 H), 3.40 (s, 3 H), 3.41-3.48 (m, 1 H), 3.50-3.62 (m, 3 H),
3.70-3.92 (m, 4 H), 4.34 (d, J ) 7.4 Hz, 1 H), 4.40-4.50 (m, 1
H), 4.85 (AB q, J ) 6.8 Hz, ∆νAB ) 50.7 Hz, 2 H), 5.14 (apparent
0.02-0.10 (m, 9 H), 0.72-0.88 (m, 2 H), 2.96-3.08 (m, 5 H),
3.40 (s, 2.1 H), 3.42 (s, 0.9 H), 3.55-3.65 (m, 2 H), 3.68-3.75
(m, 2 H), 3.82-3.90 (m, 1 H), 4.06-4.10 (m, 0.3 H), 4.10 (AB q,
J ) 15.8 Hz, ∆νAB ) 237.7 Hz, 2 H), 4.14 (dd, J ) 13.5, 4.0 Hz,
0.7 H), 4.30 (dd, J ) 10.0, 4.0 Hz, 0.7 H), 4.49 (dd, J ) 9.6, 6.6
Hz, 0.3 H), 4.88 (AB q, J ) 7.0 Hz, ∆νAB ) 24.6 Hz, 2 H), 4.96
(d, J ) 7.4 Hz, 0.3 H), 5.00 (d, J ) 13.3 Hz, 0.7 H), 5.65 (dd, J
) 10.2, 1.7 Hz, 0.7 H), 5.69 (dd, J ) 9.4, 1.7 Hz, 0.3 H), 7.25-7.40
(m, 3 H), 7.47 (d, J ) 1.7 Hz, 0.3 H), 7.50 (d, J ) 1.7 Hz, 0.7 H),
7.63-7.67 (m, 0.6 H), 7.68-7.72 (m, 1.4 H); 13C NMR (100 MHz,
CDCl3) δ -1.7, 15.8, 27.2, 34.2, 47.0, 48.7, 52.3, 52.4, 55.1, 56.1,
59.0, 63.2, 67.7, 68.6, 68.9, 71.6, 71.7, 80.4, 83.2, 106.8, 109.0,
127.5, 127.6, 128.3, 128.7, 129.3, 129.4, 135.0, 136.0, 157.4, 157.7,
160.5, 163.2, 163.6, 185.9; exact mass (electrospray) m/z calcd for
C27H38N2NaO7S80SeSi (M + Na) 665.1226, found 665.1228.
(5aS,6S,11aR)-2,3,5a,6-Tetrahydro-6-[(2-methoxyethoxy)me-
thoxy]-2-methyl-11a-[[2-(trimethylsilyl)ethyl]thio]oxepino[3′,4′:
4,5]pyrrolo[1,2-a]pyrazine-1,4,11(11aH)-trione (2). NaIO4 (0.10
M in H2O, 0.14 mL, 0.014 mmol) was added dropwise to a stirred
and cooled (0 °C) solution of selenides 40 (9.0 mg, 0.014 mmol)
in a mixture of THF (0.3 mL) and water (0.2 mL). The cold bath
was removed after 30 min, and stirring was continued overnight.
The mixture was then diluted with CH2Cl2 and basified with
saturated aqueous NaHCO3. The organic phase was washed with
brine, dried (Mg2SO4), and evaporated. Flash chromatography of
the residue over silica gel, using 1:1 EtOAc-hexane to 8:3
EtOAc-hexane, and finally pure EtOAc, gave the dihydrooxepin
2 (2.6 mg, 39%) as an oil: FTIR (CH2Cl2, microscope) 2917, 1731,
t, J ) 7.4 Hz, 1 H), 7.20-7.30 (m, 3 H), 7.52-7.63 (m, 2 H); 13
C
NMR (100 MHz, CDCl3) δ -1.73, -1.71, 16.0, 16.2, 27.2, 27.3,
34.3, 38.1, 38.9, 48.0, 49.8, 52.7, 52.8, 54.7, 55.2, 58.96, 58.99,
62.4, 62.88, 62.94, 63.7, 68.0, 68.8, 71.5, 71.7, 78.6, 82.8, 96.7,
97.5, 127.6, 128.3, 129.0, 129.2, 129.3, 134.0, 135.4, 160.3, 160.6,
164.4, 165.3, 198.6, 199.2; exact mass (electrospray) m/z calcd for
C26H40N2NaO7S80SeSi (M + Na) 655.1383, found 655.1374.
(6S,8aR)-7-[(Dimethylamino)methylene]tetrahydro-6-[3-hy-
droxy-1-[(2-methoxyethoxy)methoxy]-2-(phenylseleno)propyl]-
2-methyl-8a-[[2-(trimethylsilyl)ethyl]thio]pyrrolo[1,2-a]pyrazine-
1,4,8-trione (39). A solution of ketones 38 (20.0 mg, 0.032 mmol)
and N,N-dimethylformamide dimethyl acetal (9.8 µL, 0.073 mmol)
in THF (0.8 mL) was refluxed for 44 h (Ar atmosphere). Eva-
poration of the solvent and flash chromatography of the residue
over silica gel, using pure EtOAc to 1:20 MeOH-EtOAc, and
finally 1:10 MeOH-CH2Cl2, gave recovered ketones 38 (3.0 mg)
and vinylogous amides 39 (13.0 mg, 70% corrected for recovered
starting material) as a yellow oil: FTIR (CH2Cl2, cast film
1
1692, 1621 cm-1; H NMR (400 MHz, CDCl3) δ 0.02 (s, 9 H),
1
microscope) 3384, 2919, 1671, 1591 cm-1; H NMR (400 MHz,
0.65-0.75 (m, 2 H), 2.80-2.90 (m, 2 H), 3.04 (s, 3 H), 3.40 (s, 3
H), 3.55-3.60 (m, 2 H), 3.70-3.78 (m, 2 H), 4.08 (AB q, J )
16.0 Hz, ∆νAB ) 228.9 Hz, 2 H), 4.49 (ddd, J ) 8.0, 2.2, 2.2 Hz,
1 H), 4.90 (AB q, J ) 7.2 Hz, ∆νAB ) 38.3 Hz, 2 H), 5.02 (dd, J
) 8.0, 2.2 Hz, 1 H), 5.22 (dd, J ) 8.3, 2.0 Hz, 1 H), 6.36 (dd, J
) 8.4, 2.3 Hz, 1 H), 7.62 (d, J ) 2.2 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ -1.7, 15.6, 26.9, 29.7, 34.2, 52.4, 57.6, 59.1, 67.5,
71.6, 76.4, 95.7, 110.1, 112.2, 138.4, 151.4, 160.3, 163.3, 185.4;
exact mass (electrospray) m/z calcd for C21H32N2NaO7SSi (M +
Na) 507.1592, found 507.1593.
CDCl3) δ 0.02 (s, 9 H), 0.60-0.80 (m, 2 H), 1.80-1.90 (m, 1 H),
2.71-2.82 (m, 1 H), 2.90-3.05 (m, 4 H), 3.10 (s, 2 H), 3.15 (s, 4
H), 3.30-3.42 (m, 5 H), 3.51-3.61 (m, 2 H), 3.62-3.80 (m, 5 H),
3.82-4.98 (m, 2 H), 4.35 (apparent s, 0.5 H), 4.45-4.60 (m, 0.5
H), 4.70-4.85 (m, 1.5 H), 5.10-5.18 (m, 0.5 H), 5.35 (s, 0.7 H),
5.75 (s, 0.3 H), 7.20-7.30 (m, 3 H), 7.52-7.88 (m, 2 H); 13C NMR
(100 MHz, CDCl3) δ -1.6, 16.8, 25.6, 26.8, 27.0, 27.2, 34.4, 49.4,
49.6, 52.8, 52.9, 59.0, 59.4, 60.0, 61.9, 62.1, 64.2, 67.9, 68.0, 68.6,
71.6, 71.69, 71.74, 77.4, 83.3, 95.6, 95.7, 97.9, 98.2, 127.1, 127.9,
128.2, 129.0, 129.1, 129.6, 133.6, 135.1, 147.7, 150.4, 162.2, 164.9,
166.0; exact mass (electrospray) m/z calcd for C29H45N3NaO7S80SeSi
(M + Na) 710.1805, found 710.1804.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial support
and Dr. R. MacDonald for the X-ray analysis.
(5aS,6S,11aR)-2,3,5a,6,7,8-Hexahydro-6-[(2-methoxyethoxy)-
methoxy]-2-methyl-7-(phenylseleno)-11a-[[2-(trimethylsilyl)eth-
yl]thio]oxepino[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,4,11(11aH)-tri-
one (40). CF3CO2H (2.2 µL, 0.029 mmol) was added to a stirred
solution of vinylogous amides 39 (18.0 mg, 0.026 mmol) in PhMe
(1.5 mL) and the mixture was heated and stirred for 50 h at 50 °C.
Evaporation of the solvent and flash chromatography of the residue
over silica gel, using 1:1 EtOAc-hexane to pure EtOAc, and then
1:20 MeOH-EtOAc, gave the recovered amides 39 (3.0 mg) and
cyclized products 40 (10.8 mg, 77% corrected for recovered starting
material) as an oil: FTIR (CH2Cl2, microscope) 3057, 2925, 1731,
Supporting Information Available: Experimental proce-
dures for 11, 12, 14–18, 21, 23, and 27 X-ray structure data for
24, and spectral data, as well as copies of NMR spectra, for all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org. The X-ray data has been
deposited with the Cambridge Crystallographic Data Centre and
assigned the registry no. 699177.
1
1692, 1621, 1462, 1400 cm-1; H NMR (400 MHz, CDCl3) δ
JO802344T
J. Org. Chem. Vol. 74, No. 2, 2009 519