Enantioselective total synthesis and stereochemical revision of communiols E and F

Article abstract of DOI:10.1021/jo0608927

The enantioselective total synthesis of candidate structures for communiols E and F, novel bicyclic polyketides of fungal origin, was accomplished using a Lewis acid-mediated ring closure reaction of an allylsilane intermediate as the key step. Comparison

Full text of DOI:10.1021/jo0608927

Enantioselective Total Synthesis and
Stereochemical Revision of Communiols E and F
Masaru Enomoto and Shigefumi Kuwahara*
Laboratory of Applied Bioorganic Chemistry,
Graduate School of Agricultural Science, Tohoku UniVersity,
Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
skuwahar@biochem.tohoku.ac.jp
ReceiVed April 28, 2006
FIGURE 1. Newly proposed stereochemistry for communiols E and
F (1a and 2a, respectively) and their original stereochemistry (1b and
2b, respectively).
The enantioselective total synthesis of candidate structures
for communiols E and F, novel bicyclic polyketides of fungal
origin, was accomplished using a Lewis acid-mediated ring
closure reaction of an allylsilane intermediate as the key step.
Comparison of the spectral data of the synthetic materials
with those of natural communiols E and F, coupled with bio-
synthetic considerations, led to the conclusion that the stereo-
chemistry of communiols E and F should be (2S,5S,7R,
8S,11R)- and (5S,7R,8S,11R)-forms, respectively.
FIGURE 2. Revised stereochemistry for communiols A-D and H.
of communiols E and F should be the same as that of communiol
A, which in turn was unambiguously determined to be S by the
modified Mosher method.4 Our previous synthetic studies on
optically active forms of communiols A-D and H, however,
enabled us to conclude that the relative stereochemical assign-
ment between the C7 and C8 positions by Gloer et al. was
incorrect, and that the stereochemistry of communiols A-D and
H should all be altered as shown in Figure 2.5,6 This stereo-
chemical revision led us to suppose that the genuine stereo-
chemistry for communiols E and F should also be altered to
structures 1a (ent-8-epi-1b) and 2a (ent-8-epi-2b), respectively.
In this note, we describe the enantioselective total synthesis of
1a and 2a, which culminated in the stereochemical revison of
communiols E and F.
Our retrosynthetic analysis of 1a and 2a is shown in Scheme
1. For the construction of the 2-oxabicyclo[3.3.0]octane frame-
work incorporated in 1a and 2a, we planned to utilize a Lewis
acid-mediated cyclization of 4 containing a lactol functionality
as the electrophilic site and an allylsilane moiety as the
nucleophilic site. The bicyclic product 3 would be convertible
into either 1a or 2a via oxidative cleavage of the double bond.
The lactol 4 would be readily obtainable from 5 through
diastereoselective trans alkylation and subsequent reduction of
the lactone group.
In the course of screening for bioactive metabolites from
coprophilous (dung-colonizing) fungi, Gloer and co-workers
isolated novel bicyclic polyketides, communiols E and F, along
with biosynthetically related monocyclic polyketides (communi-
ols G and H) from the culture broth of the horse dung-inhabiting
fungus Podospora communis, and proposed their structures as
1
1b and 2b, respectively (Figure 1). Their stereochemical
assignment for communiols E and F was based mainly on the
following three grounds: (1) strong NOESY correlations
between 2-H and 7-H, and 5-H and 11-H to support the relative
stereochemical assignment among the stereogenic centers on
the bicyclic system, (2) the similarity of the 7-H-8-H vicinal
coupling constant (J ) 3.6 Hz) to that observed for analogous
polyketides (communiols A-D)2 of the same microbial origin
to rationalize the threo stereochemistry between the C7 and C8
positions (the C7-C8 threo relative stereochemistry of com-
muniols A-D had previously been deduced on the basis of
Born’s empirical rule),2,3 and (3) the biogenetically acceptable
presumption that the absolute configuration at the C8-position
(1) Che, Y.; Araujo, A. R.; Gloer, J. B.; Scott, J. A.; Malloch, D. J. Nat.
Prod. 2005, 68, 435-438.
(2) Che, Y.; Gloer, J. B.; Scott, J. A.; Malloch, D. Tetrahedron Lett.
2004, 45, 6891-6894.
(3) (a) Born, L.; Lieb, F.; Lorentzen, J. P.; Moeschler, H.; Nonfon, M.;
So¨llner, R.; Wendisch, D. Planta Med. 1990, 56, 312-316. (b) Cha´vez, D.
C.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1998, 61, 419-421. (c) Fujimoto,
Y.; Murasaki, C.; Shimada, H.; Nishioka, S.; Kakinuma, K.; Singh, S.;
Singh, M.; Gupta, Y. K.; Sahai, M. Chem. Pharm. Bull. 1994, 42, 1175-
1184.
(4) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(5) (a) Kuwahara, S.; Enomoto, M. Tetrahedron Lett. 2005, 46, 6297-
6300. (b) Enomoto, M.; Nakahata, T.; Kuwahara, S. Tetrahedron 2006,
62, 1102-1109.
(6) For the synthesis of ent-communiols A-C which led to the same
stereochemical revision as our studies, see the following: Murga, J.; Falomir,
E.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2005, 46, 8199-8202.
10.1021/jo0608927 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/07/2006
J. Org. Chem. 2006, 71, 6287-6290
6287

SCHEME 1. Retrosynthetic Analysis of 1a and 2a
SCHEME 3. Preferential Formation of 11
5-H and 11-H. This desirable diastereoselectivity could be
explained by considering the thermodynamic stability of two
types of transition states, TS-A and TS-B, leading to 11 and
2-epi-11, respectively (Scheme 3). The reaction must have taken
place mainly through the less sterically demanding transition
state TS-A rather than TS-B wherein severe steric repulsion
between the side-chain moiety and the ring portion was
anticipated, giving the desired product 11 preferentially. The
double bond of 11 was cleaved by the Lemieux-Johnson
reaction, and the resulting aldehyde 12 was reduced to alcohol
13. The C2-epimer of 13 originating from the incomplete
stereoselectivity in the formation of 11 (6.4:1, as mentioned
above) was readily removed at this stage by SiO2 chromatog-
raphy. Finally, removal of the silyl protecting group of 13 with
aq HF furnished the target bicyclic diol 1a. Direct comparison
SCHEME 2. Synthesis of Communiol E (1a)
1
of the H and 13C NMR spectra of 1a with those of natural
communiol E indicated them to be identical, which enabled us
to confirm that the relative stereochemistry of communiol E
should be represented by structure 1a. Quite curiously, however,
the specific rotation value of 1a ([R]22D -8.3 (c 0.12, CH2Cl2))
was far different from that reported for natural communiol E
([R]D +129 (c 0.075, CH2Cl2)).1 Although this discrepancy
prevented us from straightforwardly assigning the absolute
stereochemistry of communiol E, the fact that structurally related
metabolites of the same microbial origin (communiols A-D
and H, see Figure 2) all had (S)-absolute configuration in
common at the side chain asymmetric center (C8-position in
1a)1,2,5,6 strongly supported the stereochemical assignment of
communiol E as 1a, including its absolute configuration.
The candidate structure for communiol F (2a), which corre-
sponds to 2,3-dehydrocommuniol E, was synthesized as shown
in Scheme 4. The aldehydic intermediate 12 used for the
synthesis of 1a was subjected to R-selenylation with PhSeNEt2,11
and the resulting R-selenoaldehyde 14 was treated in situ with
aq NaIO4 to give R,â-unsaturated aldehyde 15. Reduction of
15 to allylic alcohol 16 with DIBAL and subsequent deprotec-
tion of its TBDPS-protecting group afforded the target com-
As shown in Scheme 2, our synthesis of the newly proposed
candidate structure for communiol E (1a) began with a four-
step inversion of the stereochemistry at the chiral center on the
side chain of known lactone 6 to afford its epimer 7. The starting
lactone 6, in turn, was prepared in enantiomerically pure form
from ethyl (E)-4-heptenoate according to our previously reported
three-step procedure consisting of the Sharpless asymmetric
dihydroxylation, acid-catalyzed lactonization, and protection
followed by recrystallization.5b The trans-selective alkylation
of 7 with known silylated iodoalkene 87 gave a 15.2:1 mixture
of 9 and its C5-epimer in 44% yield along with recovered
starting lactone 7 (16%).8,9 After isolation of 9 by repeated silica
gel column chromatography (39% isolated yield), the lactone
was reduced with DIBAL to lactol 10, which was then exposed
to BF3‚OEt2 in CH2Cl2 to induce the formation of the bicyclic
ring system in an intramolecular manner.10 Fortunately, the
C2-vinyl substituent of the cyclization product 11 preferred the
desired exo orientation (11/2-epi-11 ) 6.4:1), as determined
by observation of NOE correlations between 2-H and 7-H, and
1
pound 2a. The H and 13C NMR spectral data of 2a were
identical with those of natural communiol F. In this case also,
(9) The modest chemical yield of this conversion is ascribable, in
part, to the formation of a conjugated diene through â-elimination of 8,
in which the lithium enolate generated from 7 functioned as a base. Attempts
to improve the yield of this step by using a zinc enolate of 7 (to reduce
the basicity of the nucleophile) or a more reactive alkylating agent
[TMSCH2CHdCH(CH2)2OTf] were unsuccessful. For successful applica-
tion of these methodologies, see the following: (a) Kuwahara, S.; Hamade,
S.; Leal, W. S.; Ishikawa, J.; Kadama, O. Tetrahedron 2000, 56, 8111-
8117. (b) Uenishi, J.; Tatsumi, Y.; Kobayashi, N.; Yonemitsu, O. Tetra-
hedron Lett. 1995, 36, 5909-5912.
(10) (a) Schmitt, A.; Reiâig, H.-U. Eur. J. Org, Chem. 2000, 3893-
3901. (b) Lee, T. V.; Roden, F. S.; Yeoh, H. T-L. Tetrahedron Lett. 1990,
31, 2063-2066.
(11) (a) Jefson, M.; Meinwald, J. Tetrahedron Lett. 1981, 22, 3561-
3564. (b) Keck, G. E.; Cressman, E. N. K.; Enholm, E. J. J. Org. Chem.
1989, 54, 4345-4349.
(7) (a) Schinzer, D.; Allagiannis, C.; Wichmann, S. Tetrahedron 1988,
44, 3851-3868. (b) Frank, K. E.; Aube´, J. J. Org. Chem. 2000, 65, 655-
666.
(8) For examples of the trans-selective alkylation of γ-substituted-γ-
butyrolactones, see the following: (a) Sells, T. B.; Nair, V. Tetrahedron
1994, 50, 117-138. (b) Davidson, A. H.; Moloney, B. A. J. Chem. Soc.,
Chem. Commun. 1989, 445-446.
6288 J. Org. Chem., Vol. 71, No. 16, 2006

SCHEME 4. Synthesis of Commuiol F (2a)
°C. After 10 min, the reaction was quenched with saturated aq
Rochelle’s salt, and the mixture was stirred for 1 h at room
temperature before being extracted with EtOAc. The extract was
washed with brine, dried (Na2SO4), and concentrated in vacuo to
give 10 (49.6 mg) as a colorless oil, which was then dissolved in
CH2Cl2 (1 mL). To the solution was added BF3‚OEt2 (12 µL, 97
µmol) at -78 °C, and the resulting mixture was gradually warmed
to -15 °C over a period of 45 min before being quenched with a
suspension of NaHCO3 in MeOH. The reaction mixture was filtered
through a pad of Celite, and the filter cake was washed with EtOAc.
The combined filtrate and washings were concentrated in vacuo,
and the residue was chromatographed over SiO2 (hexane/EtOAc,
10:1) to give 31.5 mg (90% from 9) of a 6.4:1 mixture of 11 and
its epimer as a colorless oil: [R]22 -35.4 (c 1.28, CHCl3). IR
D
(film) νmax: 3070 (m), 1640 (w), 1110 (s), 700 (s). 1H NMR (300
MHz, CDCl3): δ 0.78 (3H, t, J ) 7.5 Hz), 1.05 (9H, s), 1.22-
1.51 (4H, m), 1.56 (1H, ddd, J ) 12.1, 5.5, 2.2 Hz), 1.74-1.91
(2H, m), 1.93 (1H, dt, J ) 12.4, 8.7 Hz), 2.42-2.63 (2H, m), 3.76
(1H, dt, J ) 5.4, 5.1 Hz), 3.94 (1H, ddd, J ) 9.0, 5.1, 4.5 Hz),
4.11 (1H, dd, J ) 6.9, 3.8 Hz), 4.96 (1H, d, J ) 10.4 Hz), 5.01
(1H, d, J ) 18.3 Hz), 5.78 (1H, ddd, J ) 18.3, 10.4, 6.9 Hz), 7.33-
7.43 (6H, m), 7.67-7.73 (4H, m). 13C NMR (75 MHz, CDCl3) δ
9.2, 19.4, 26.8, 27.0 (3C), 30.8, 31.6, 34.4, 42.2, 50.4, 75.5, 80.6,
89.5, 113.8, 127.40 (2C), 127.43 (2C), 129.46, 129.47, 134.4, 134.8,
136.1 (2C), 136.2 (2C), 140.4. HRMS (FAB): m/z calcd for
C28H38O2SiNa ([M + Na]+), 457.2539; found, 457.2540.
however, the specific rotation of 2a ([R]22 +21 (c 0.21,
D
CH2Cl2)) disagreed with that of natural communiol F ([R]D
+137 (c 0.058, CH2Cl2)).1 Despite this disagreement, the same
argument on biogenetic similarity as described for communiol
E led us to the conclusion that the stereochemistry of communiol
F should also be revised to 2a.
In summary, on the basis of our previous synthetic studies
on communiols A-D and H, which culminated in their
stereochemical revision, we proposed the most probable ster-
eochemistry for communiols E and F, and synthesized the
candidate structures (1a and 2a). The complete agreement of
1a and 2a with natural communiols E and F, respectively, in
1H and 13C NMR, coupled with the fact that structurally related
communiols A-D and H isolated from the same microbial
origin have (S)-absolute configuration in common at the side
chain asymmetric center, strongly suggested that the originally
proposed structures for cummuniols E and F (1b and 2b,
respectively) should be revised to 1a and 2a, respectively.
(S)-1-[(2R,3aS,6S,6aR)-6-Hydroxymethylhexahydrocyclopenta-
[b]furan-2-yl]-1-propanol (1a). To a stirred solution of 13 (5.7
mg 13 µmol) in CH3CN (0.175 mL) was added 40% aq HF (75
µL) at 0 °C. After 8.5 h, the reaction was quenched with saturated
aq NaHCO3, and the mixture was extracted with EtOAc. The extract
was dried (MgSO4) and concentrated in vacuo. The residue was
chromatographed over SiO2 (EtOAc only) to give 2.4 mg (92%)
of 1a as a colorless oil: [R]22 -8.3 (c 0.12, CH2Cl2). IR (film)
D
ν
max: 3410 (s), 2940 (vs), 2875 (s), 1455 (m), 1045 (m). 1H NMR
(300 MHz, CDCl3): δ 0.99 (3H, t, J ) 7.4 Hz), 1.20-1.39 (2H,
m), 1.42 (2H, qui, J ) 7.3 Hz), 1.52 (1H, br dd, J ) 12.6, 5.6 Hz),
1.58 (1H, br s, OH), 1.78-1.88 (1H, m), 1.89-2.00 (2H, m), 2.02-
2.11 (1H, m), 2.10 (1H, br s, OH), 2.69 (1H, qui, J ) 7.4 Hz),
3.56-3.70 (2H, m), 3.72-3.81 (1H, m), 3.93 (1H, ddd, J ) 9.9,
5.4, 3.4 Hz), 4.34 (1H, dd, J ) 7.2, 4.2 Hz). 13C NMR (75 MHz,
CDCl3): δ 10.5, 25.8, 28.5, 31.2, 31.8, 43.0, 49.9, 65.2, 72.8, 80.9,
88.1. HRMS (FAB): m/z calcd for C11H21O3 ([M + H]+), 201.1491;
found, 201.1493.
Experimental Section
(2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-2-[(Z)-5-trimethyl-
silyl-3-pentenyl]-4-heptanolide (9). To a stirred solution of LDA
[prepared by treating a solution of iPr2NH (22 µL, 0.16 mmol) and
HMPA (50 µL) in THF (0.50 mL) with nBuLi (1.6 M in hexane,
90 µL, 0.14 mmol) at -10 °C] was added a solution of 7 (50.2
mg, 0.131 mmol) in THF (0.50 mL) at -65 °C. After 15 min, a
solution of 8 (70.4 mg, 0.262 mmol) in THF (0.30 mL) was added,
and the resulting mixture was stirred for 1 h at -78 °C. The reaction
was quenched with saturated aq NH4Cl, and the mixture was
extracted with Et2O. The extract was successively washed with
water and brine, dried (MgSO4), and concentrated in vacuo. The
residue was chromatographed over SiO2 (hexane/EtOAc, 50:1-4:
1) to give a 15.2:1 mixture of 9 and its cis isomer (31.8 mg, 44%)
along with recovered starting lactone 7 (16%). Repeated SiO2
column chromatography (hexane/EtOAc, 40:1) of the mixture
(2R,3aS,6aR)-2-[(S)-1-(tert-Butyldiphenylsilyloxy)propyl]-3,-
3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-6-carbaldehyde (15).
To a stirred and ice-cooled solution of 12 (10.2 mg, 23.4 µmol) in
THF (0.25 mL) was added a solution of PhSeNEt2 [prepared by
treating a solution of PhSeCl (9.0 mg, 47 µmol) in hexane (0.25
mL) with Et2NH (10 µL, 94 µmol) at 0 °C for 15 min], and the
mixture was stirred at room temperature for 4 h until compound
12 was completely consumed (TLC analysis). Water (0.2 mL) and
NaIO4 (22.5 mg, 0.105 mmol) were then added, and the resulting
mixture was stirred at room temperature for 7 h, during which time
10.4 mg (49 µmol) and 20.0 mg (94 µmol) of additional NaIO4
were added to bring the oxidative elimination to completion. The
reaction was quenched with saturated aq Na2S2O3 and extracted
with EtOAc. The extract was dried (Na2SO4) and concentrated in
vacuo. The residue was chromatographed over SiO2 (hexane/EtOAc,
afforded 26.5 mg (39%) of pure 9 as a colorless oil: [R]22 -19
D
(c 0.27, CHCl3). IR (film) νmax: 3020 (w), 1770 (s), 1110 (s), 700
1
(vs). H NMR (300 MHz, CDCl3): δ 0.01 (9H, s), 0.68 (3H, t, J
) 7.4 Hz), 1.03 (9H, s), 1.36-1.52 (5H, m), 1.80-1.93 (2H, m),
2.02-2.13 (2H, m), 2.47 (1H, ddd, J ) 12.6, 9.3, 4.1 Hz), 2.54-
2.61 (1H, m), 3.81-3.89 (1H, m), 4.45 (1H, dt, J ) 8.2, 4.1 Hz),
5.21 (1H, dt, J ) 10.7, 7.4 Hz), 5.45 (1H, dt, J ) 10.7, 8.8 Hz),
7.35-7.47 (6H, m), 7.64-7.70 (4H, m). 13C NMR (75 MHz,
CDCl3): δ -1.8 (3C), 9.1, 18.6, 19.4, 24.7, 26.2, 27.0 (3C), 28.0,
31.4, 39.0, 74.9, 79.1, 125.6, 127.0, 127.5 (2C), 127.7 (2C), 129.7,
129.9, 132.8, 134.2, 135.8 (2C), 136.0 (2C), 179.6. HRMS (FAB):
m/z calcd for C31H47O3Si2 ([M + H]+), 523.3064; found, 523.3068.
(2R,3aS,6S,6aR)-2-[(S)-1-(tert-Butyldiphenylsilyloxy)propyl]-
5-vinylhexahydrocyclopenta[b]furan (11). To a stirred solution
of 9 (42.3 mg, 81 µmol) in CH2Cl2 (1 mL) was added dropwise a
solution of DIBAL (0.94 M in hexane, 95 µL, 89 µmol) at -78
7:1) to give 7.8 mg (76%) of 15 as a colorless oil: [R]22 -31 (c
D
0.17, CHCl3). IR (film) νmax: 3070 (w), 3050 (w), 1690 (s), 1110
(m), 740 (m). 1H NMR (300 MHz, CDCl3): δ 0.75 (3H, t, J ) 7.5
Hz), 1.05 (9H, s), 1.35-1.62 (3H, m), 2.00 (1H, dt, J ) 12.5, 9.1
Hz), 2.31 (1H, dm, J ) 19.8 Hz), 2.80 (1H, ddd, J ) 19.8, 8.5, 2.6
Hz), 2.88-2.99 (1H, m), 3.73 (1H, dt, J ) 9.5, 5.1 Hz), 3.79 (1H,
q, J ) 5.1 Hz), 5.18 (1H, dd, J ) 7.1, 1.7 Hz), 6.89 (1H, t, J ) 2.6
Hz), 7.32-7.44 (6H, m), 7.66-7.74 (4H, m), 9.78 (1H, s). 13C NMR
(300 MHz, CDCl3): δ 9.3, 19.6, 27.1 (3C), 27.2, 35.4, 40.1, 40.3,
J. Org. Chem, Vol. 71, No. 16, 2006 6289

75.2, 79.5, 84.1, 127.4 (4C), 129.4 (2C), 134.1, 134.6, 136.06 (2C),
136.14 (2C), 145.4, 153.2, 189.1. HRMS (FAB): m/z calcd for
C27H34O3SiNa ([M + Na]+), 457.2175; found, 457.2181.
5.80 (1H, s). 13C NMR (75 MHz, CDCl3): δ 10.2, 26.0, 33.1, 39.3,
39.7, 60.9, 72.4, 79.4, 89.2, 130.5, 141.1; HRMS (FAB): m/z calcd
for C11H19O3 ([M + H]+), 199.1334; found, 199.1336.
(S)-1-[(2R,3aS,6aR)-6-Hydroxymethyl-3,3a,4,6a-tetrahydro-
2H-cyclopenta[b]furan-2-yl]-1-propanol (2a). To a stirred solution
16 (9.7 mg 0.022 mmol) in CH3CN (0.37 mL) was added 40% aq
HF (0.17 mL) at 0 °C. After 10 h, the reaction was quenched with
saturated aq NaHCO3 and extracted with EtOAc. The extract was
dried (MgSO4) and concentrated in vacuo. The residue was
chromatographed over SiO2 (EtOAc only) to give 4.1 mg (93%)
Acknowledgment. This work was financially supported, in
part, by a Grant-in-Aid for Scientific Research (B) from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan (Grant No. 16380075). We also thank Ms. Yamada
(Tohoku University) for measuring the NMR and mass spectra.
of 2a as a colorless oil: [R]22 +21 (c 0.21, CH2Cl2). IR (film)
D
Supporting Information Available: Experimental procedures
for compounds 7, 12, 13, and 16, and 1H and 13C NMR spectra for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
ν
max: 3735 (s), 3400 (br s), 1700 (w), 1505 (m), 1035 (m). H
NMR (300 MHz, CDCl3): δ 0.98 (3H, t, J ) 7.4 Hz), 1.42 (2H,
qui, J ) 7.1 Hz), 1.51 (1H, ddd, J ) 12.6, 5.0, 1.5 Hz), 2.04 (1H,
dt, J ) 12.6, 9.6 Hz), 2.15 (1H, br d, 17.7 Hz), 1.95-2.26 (2H, br,
OH), 2.67 (1H, br dd, J ) 17.7, 8.6 Hz), 2.94-3.06 (1H, m), 3.71-
3.80 (2H, m), 4.21-4.34 (2H, m), 5.16 (1H, br d, J ) 7.3 Hz),
JO0608927
6290 J. Org. Chem., Vol. 71, No. 16, 2006