An aldol approach to the synthesis of the anti-tubercular agent erogorgiaene

Article abstract of DOI:10.1016/j.tetlet.2007.02.103

A total synthesis of erogorgiaene is described in 16 steps. The synthesis relies upon a highly diastereoselective intramolecular Friedel-Crafts reaction of an oxetane derived via an asymmetric syn aldol coupling.

Full text of DOI:10.1016/j.tetlet.2007.02.103

Tetrahedron Letters 48 (2007) 2841–2843
An aldol approach to the synthesis of the anti-tubercular
agent erogorgiaeneI
J. S. Yadav,* A. K. Basak and P. Srihari
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 18 January 2007; revised 16 February 2007; accepted 22 February 2007
Available online 25 February 2007
Abstract—A total synthesis of erogorgiaene is described in 16 steps. The synthesis relies upon a highly diastereoselective intra-
molecular Friedel–Crafts reaction of an oxetane derived via an asymmetric syn aldol coupling.
Ó 2007 Published by Elsevier Ltd.
Erogorgiaene, isolated1 along with other diterpenes
from the West Indian sea whip Pseudopterogorgia elisa-
bethae, displays promising anti-mycobacterial activity.
Biological evaluation has revealed that it can inhibit
96% of Mycobacterium tuberculosis H37Rv growth at
12.5 lg/mL, making it an interesting lead in the synthe-
sis of new anti-tubercular agents. Although erogorgi-
aene is not complex, the major challenge associated
with its synthesis is control of the three stereocentres.
Stereocontrol has been challenging due to the lack of
functional groups near to the stereogenic centres
(Fig. 1).
strategy to establish all of the stereocentres of the natu-
ral product. Harmata and Hong2c carried out a stereo-
selective intramolecular Michael addition of a chiral
sulfoximine carbanion to an a,b-unsaturated ester to
accomplish a formal synthesis. As part of our ongoing
research programme of synthesizing biologically active
natural products,3 we herein report a total synthesis of
erogorgiaene which relies upon an unprecedented,
highly diastereoselective intramolecular Friedel–Crafts
reaction of an oxetane derived via a non-Evans syn aldol
coupling.
The retrosynthesis of erogorgiaene is depicted in Figure
2. The synthesis began with introduction of the stereo-
genic centre at the benzylic position4 using Evans’ dia-
stereoselective alkylation protocol. The lithiated Evans
auxiliary 25a underwent coupling with readily available
acid 1 under mixed anhydride conditions5b furnishing
imide 3 in good yield (82%). Alkylation of the lithium
enolate of 3, generated by treatment with LDA in
So far, two total syntheses and one formal synthesis of
erogorgiaene have been reported. The first, by Hoveyda
and co-workers,2a utilized catalytic asymmetric conju-
gate addition chemistry to install both the methyl stereo-
genic centres. The second, by Davies et al.,2b made use
of an elegant carbene insertion/Cope rearrangement
O
OH
N
H
H
H
H
H
O
OH
pseudopteroxazole
erogorgiaene
7-hydroxy
erogorgiaene
S
O
O
Figure 1. Diterpenes isolated from Pseudopterogorgia elisabethae.
+
N
O
H
q IICT Communication No. 070211.
Bn
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail: yadavpub@iict.res.in
Figure 2. Retrosynthetic analysis of erogorgiaene.
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.02.103

2842
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 2841–2843
THF at ꢀ78 °C, with MeI afforded 4 with high diastereo-
selectivity6 (>99%). The auxiliary in 4 was eliminated
by reduction with NaBH4 in THF/H2O to give alcohol
5.7 Swern oxidation8 of 5 and subsequent Wittig olefin-
ation led to the unsaturated ester 6 in good yield (86%).
Reduction of the double bond with Pd/C, H2 followed
by treatment with DIBAL-H resulted in aldehyde 7 in
78% yield (Scheme 1).
O
S
OH
i
O
N
O
H
9
Bn
7
OTBS
O
S
iii
ii
N
O
10
Bn
Aldehyde 7 underwent smooth aldol coupling with the
titanium enolate of 89 under Crimmins protocol10 with
high diastereoselectivity (49:1 dr) and yield (93%). The
free hydroxy group in 9 was protected as its TBS ether
with TBSOTf and 2,6-lutidine. Removal of the auxiliary
in 10 by reduction9 with NaBH4 led to the correspond-
ing alcohol, which was then tosylated with tosyl chloride
and triethylamine in DCM. Tosylate 11 was first treated
with a catalytic amount of PTSA in MeOH to deprotect
the TBS ether and then with NaH in THF leading to
oxetane 12 in excellent yield. The crucial intramolecular
Friedel–Crafts reaction of oxetane 12 was carried out
following the protocol11a generally employed for epox-
ides. As anticipated, the reaction proceeded smoothly,
at ambient temperature, resulting in a single diastereo-
mer11b 13 (Scheme 2).
OTBS
iv
OTs
O
11
12
O
S
v
N
O
H
OH
Bn
13
8
Scheme 2. Reagents and conditions: (i) 8, TiCl4, iPr2NEt, ꢀ78 °C,
1.5 h, 93%; (ii) TBSOTf, 2,6-lutidine, DCM, 0 °C, 30 min, 97%; (iii) (a)
NaBH4, MeOH, rt, 12 h, 78%; (b) TsCl, Et3N, DCM, rt, 3 h, 97%; (iv)
PTSA, MeOH then NaH, THF, rt, 12 h, 93%; (v) BF3ÆOEt2, DCM,
ꢀ78 °C to rt, 3 h, 81%.
At this stage all the stereogenic centres had been intro-
duced. The next step was to attach the prenyl moiety
to alcohol 13. Alcohol 13 was converted to the corre-
sponding iodide and then treated with prenyl magne-
sium bromide12 following the conditions described in
the literature.13 Unfortunately, no reaction occurred.
The corresponding bromide and tosylate also failed to
undergo reaction with the prenyl Grignard. Hence, we
oxidized alcohol 13 under Swern conditions8 and subse-
quently carried out a Wittig olefination to obtain unsat-
urated ester 14.
i
H
MgBr
H
I
OH
ii
16
13
H
iv
iii
erogorgiaene
H
H
H
Saturation of the double bond with Pd/C, H2 and then
reduction of the ester with DIBAL-H furnished alde-
hyde 15 in 82% yield. The aldehyde was then treated
with isopropyltriphenylphosphorane in THF to give
erogorgiaene in 80% yield (Scheme 3). The synthetic
CO2Et
O
14
15
Scheme 3. Reagents and conditions: (i) Ph3P, I2, ImH, toluene, rt, 1 h,
84%; (ii) (a) (COCl)2, DMSO, Et3N, DCM, ꢀ78 °C; (b)
Ph3PCHCO2Et, rt, 12 h, 84%; (iii) (a) Pd/C, H2, EtOAc; (b) DIBAL-
H, DCM, ꢀ78 °C, 30 min, 82%; (iv) Me2CHPPh3þIꢀ, n-BuLi, THF,
0 °C, 3 h, 80%.
O
O
ii
i
O
N
O
OH
O
compound14 was found to be identical with the natural
compound based on comparison of 1H NMR, 13C
NMR and MS spectra and optical rotation.1
1
3
Bn
O
iv
iii
N
O
OH
In summary, we have accomplished a linear synthesis of
erogorgiaene in an efficient and highly stereocontrolled
fashion requiring 16 steps with an overall yield of
8.2%. The strategy is quite versatile and can be applied
to the synthesis of all the possible stereoisomers of
erogorgiaene.
5
Bn
4
O
O
Li
v
N
O
CO2Et
H
Bn
7
2
6
Scheme 1. Reagents and conditions: (i) PivCl, Et3N, THF, 2, ꢀ20 °C
to rt, 4 h, 82%; (ii) LDA, MeI, ꢀ78 °C to ꢀ30 °C, 3 h, 56%; (iii)
NaBH4, THF/H2O, rt, 12 h, 95%; (iv) (a) (COCl)2, DMSO, Et3N,
DCM, ꢀ78 °C; (b) Ph3PCHCO2Et, rt, 12 h, 86%; (v) (a) Pd/C, H2,
EtOAc; (b) DIBAL-H, DCM, ꢀ78 °C, 30 min, 78%.
Acknowledgement
A.K.B. thanks UGC, New Delhi, for the award of a
fellowship.

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 2841–2843
2843
11. (a) Muhlthau, F.; Bach, T. Synthesis 2005, 3428; (b)
¨
Supplementary data
Lindstro¨m, U. M.; Somfai, P. Synthesis 1997, 109.
12. Lipshutz, B. H.; Hackmann, C. J. Org. Chem. 1994, 59,
7437.
13. (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135;
(b) Derguini, F.; Lorne, R. B.; Lisrtumelle, G. Tetrahedron
Experimental details, spectral data and copies of 1H
NMR and 13C NMR spectra of selected compounds
are available in the supplementary data. Supplementary
data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2007.02.103.
`
Lett. 1977, 13, 1181; (c) Derguini, F.; Besseiere, Y.;
Lisrtumelle, G. Synth. Commun. 1981, 11, 859.
25
14. Data for compound 9: Oil, ½aꢁD +75.6 (c 1.1, CHCl3); IR
(KBr, neat) m 3451, 2925, 2868, 1694, 1453, 1370, 1190,
956, 747 cmꢀ1; 1H NMR (CDCl3, 300 MHz) d 1.12 (d, 3H,
J = 6.8 Hz), 1.24 (d, 3H, J = 6.8 Hz), 1.41–1.64 (m, 2H),
1.73–1.89 (m, 1H), 2.25 (s, 3H), 2.47 (d, 1H, J = 3.0 Hz),
2.58–2.69 (m, 2H), 3.21 (dd, 1H, J = 3.0, 12.8 Hz), 3.89–
4.01 (m, 1H), 4.30–4.31 (m, 2H), 4.45–4.75 (m, 1H), 4.82–
4.94 (m, 1H), 7.01–7.05 (m, 4H), 7.16–7.35 (m, 5H);
13C NMR (CDCl3, 75 MHz) d 10.23, 20.79, 22.68,
32.19, 34.43, 37.58, 39.47, 41.93, 59.88, 70.06, 71.78,
126.70, 127.32, 128.90, 128.96, 129.25, 135.11, 135.18,
144.06, 177.89, 185.05; MS–ESIMS m/z 448 (M+Na);+
HRMS calcd for C25H31NO3NaS: 448.1922, found
448.1933.
References and notes
1. Rodriguez, A. D.; Ramirez, C. J. Nat. Prod. 2001, 64, 101.
2. (a) Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J. Am.
Chem. Soc. 2004, 126, 96; (b) Davies, H. M. L.; Walji, A.
M. Angew. Chem., Int. Ed. 2005, 117, 1761; (c) Harmata,
M.; Hong, X. Tetrahedron Lett. 2005, 46, 3847.
3. For recent work see: (a) Yadav, J. S.; Pratap, I.; Tadi, B.
P. Tetrahedron Lett. 2006, 47, 3773; (b) Yadav, J. S.;
Srinivas, R.; Sathaiah, K. Tetrahedron Lett. 2006, 47,
1603; (c) Yadav, J. S.; Raju, A. K.; Rao, P. P.; Rajaiah, G.
Tetrahedron: Asymmetry 2005, 16, 3283; (d) Yadav, J. S.;
Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005, 46,
2133.
4. For recent references on creating stereogenic centres at
benzylic positions, see: (a) Harmata, M.; Hong, X.;
Barnes, C. L. Tetrahedron Lett. 2003, 44, 7261; (b) Kim,
S.-G.; Kim, J.; Jung, H. Tetrahedron Lett. 2005, 46,
2437; (c) Lu, J.; Xie, X.; Chen, B.; She, X.; Pan, X.
Tetrahedron: Asymmetry 2005, 16, 1435, and references
cited therein.
5. (a) Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc. 2003,
125, 4680; (b) Prasad, M.; Kim, H.-Y.; Har, D.; Repic, O.;
Blacklock, T. J. Tetrahedron Lett. 1998, 39, 9369.
6. (a) Tredwell, M.; Tenza, K.; Pacheco, M. C.; Gouverneur,
V. Org. Lett. 2005, 7, 4495; (b) Heemstra, J. M.; Kerrigan,
S. A.; Doerge, D. R.; Helferich, W. G.; Boulanger, W. A.
Org. Lett. 2006, 8, 5441.
7. Prasad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron
Lett. 1998, 39, 7076.
8. (a) Omura, K.; Swern, D. Tetrahedron Lett. 1978, 34,
1651; (b) Mancuso, A. J.; Brownfain, D. S.; Swern, D. J.
Org. Chem. 1978, 43, 2480–2482.
25
Compound 12: colourless liquid, ½aꢁD +40.4 (c 3.8,
CHCl3); IR (KBr, neat) m 2960, 2927, 2865, 1513, 1456,
1
1380, 937, 816 cmꢀ1; H NMR (CDCl3, 300 MHz) d 1.07
(d, 3H, J = 7.5 Hz), 1.23 (d, 3H, J = 7.5 Hz), 1.28–1.40
(m, 2H), 1.54–1.70 (m, 2H), 2.31 (s, 3H), 2.48–2.69 (m,
1H), 2.81–2.99 (m, 1H), 3.97 (t, 1H, J = 6.0 Hz), 4.62–4.72
(m, 2H), 7.00 (d, 2H, J = 9.0 Hz), 7.04 (d, 2H, J = 9.0 Hz);
13C NMR (CDCl3, 75 MHz) d 13.1, 20.9, 22.5, 30.1, 31.9,
33.4, 39.7, 75.5, 85.1, 126.8, 129.0, 135.2, 144.3; MS–
ESIMS m/z 241 (M+Na);+ HRMS calcd for C15H22ONa:
241.1568 found 241.1560.
27
Erogorgiaene: colourless liquid, ½aꢁD +23.2 (c 0.75,
25
25
CHCl3); Ref. 1 ½aꢁD +24.4 (c 3.2, CHCl3), Ref. 2b ½aꢁD
20
+21.4 (c 0.14, CHCl3), Ref. 2a ½aꢁD +40.6 (c 0.14 CHCl3);
1H NMR (CDCl3, 400 MHz) d 0.63 (d, 3H, J = 6.6 Hz),
1.26 (d, 3H, J = 7.3 Hz), 1.30–1.38 (m, 2H), 1.39–1.48 (m,
1H), 1.49–1.56 (m, 1H), 1.62 (br s, 3H), 1.70 (br s, 3H),
1.76–1.83 (m, 1H), 1.87–1.93 (m, 1H), 1.99–2.14 (m,3H),
2.28 (s, 3H), 2.64–2.77 (m, 1H), 2.82–2.88 (m, 1H), 5.12
(br t, 1H, J = 6.6 Hz), 6.86 (d, 1H, J = 8.0 Hz), 6.94 (s,
1H), 7.06 (d, 1H, J = 8.0 Hz); 13C NMR (CDCl3,
75 MHz) d 14.5, 17.7, 21.1, 21.5, 21.8, 25.7, 26.3, 31.8,
32.8, 35.2, 37.0, 41.5, 124.9, 126.0, 126.4, 128.1, 131.2,
134.7, 139.9, 140.4; MS–LCMS m/z 270 (M+). The
spectroscopic data are consistent with previously reported
data.1,2a,b
9. (a) Delaunay, D.; Toupet, L.; Corre, M. L. J. Org. Chem.
1995, 60, 6604; (b) Crimmins, M. T.; Choudhary, K. Org.
Lett. 2000, 2, 775.
10. Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem.
Soc. 1997, 119, 7883.