Benzothiazines in synthesis: Studies directed toward the synthesis of erogorgiaene

Article abstract of DOI:10.1021/jo701935s

(Chemical Equation Presented) The use of benzothiazenes for the formal total synthesis of erogorgiaene and stereoselective total syntheses of two diastereomers of this natural product is described. In particular, the stereochemical course of a radical cyc

Full text of DOI:10.1021/jo701935s

Benzothiazines in Synthesis: Studies Directed toward the Synthesis
of Erogorgiaene
Michael Harmata,*,† Xuechuan Hong,† and Peter R. Schreiner‡
Department of Chemistry, UniVersity of Missouri-Columbia, Columbia, Missouri 65211, and Institute of
Organic Chemistry, Justus-Liebig UniVersity, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
harmatam@missouri.edu
ReceiVed September 10, 2007
The use of benzothiazenes for the formal total synthesis of erogorgiaene and stereoselective total syntheses
of two diastereomers of this natural product is described. In particular, the stereochemical course of a
radical cyclization anticipated to give the correct relative stereochemistry for the synthesis of erogorgiaene
is discussed utilizing both experimental and computational data.
Introduction
As part of our program involving the study of the synthesis
and chemistry of benzothiazines, and in conjunction with our
interest in the synthesis of compounds possessing antitubercular
activity, we have been interested in the preparation of a number
of the compounds shown in Figure 1. We recently reported the
synthesis of pseudopteroxazole (2a)3 and formal total syntheses
of (+)-curcuphenol, (+)-curcumene,4 and (+)-erogorgiaene
(1).2e
Our basic approach involves the application of the intramo-
lecular addition of a sulfoximine carbanion to an R,â-unsaturated
ester (Scheme 1).5 As far as we can tell, this reaction is
completely diastereoselective. Enantiomerically pure starting
material is converted to enantiomerically pure product with
complete stereochemical fidelity. Establishing the benzylic
Since the late 1990s, a very large number of structurally
interesting natural products have been discovered from the West
Indian Sea Whip, Pseudopterogorgia elisabethae (Bayer).1 The
evaluation of the pharmacologically active metabolites of this
marine organism revealed a wide variety of promising bioac-
tivities including antitubercular, anticancer, anti-inflammatory,
and antibacterial. Some representatives of these metabolites are
shown in Figure 1. Their unique structures, limited availability
from natural sources, and potential importance in medicinal
chemistry have provided the impetus for the development of
total synthetic routes to these natural products in the recent past.2
Highlighted in red in Figure 1 are the stereochemical and
structural features shared by these compounds. This suggests
that a single strategy to construct this array of stereocenters
might be sufficient for the synthesis of all of the compounds
shown.
(2) (a) Dai, X.; Wan, Z.; Kerr, R. G.; Davies, H. M. L. J. Org. Chem.
2007, 72, 1895. (b) Yadav, J. S.; Basak, A. K.; Srihari, P. Tetrahedron
Lett. 2007, 48, 2841. (c) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am.
Chem. Soc. 2006, 128, 2485. (d) Davies, H. M. L.; Walji, A. M. Angew.
Chem., Int. Ed. 2005, 117, 1761. (e) Harmata, M.; Hong, X. Tetrahedron
Lett. 2005, 46, 3847. (f) Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J.
Am. Chem. Soc. 2004, 126, 96. (g) Davidson, J. P.; Corey, E. J. J. Am.
Chem. Soc. 2003, 125, 13486. (h) Davidson, J. P.; Heckrodt, T. J.; Mulzer,
J. J. Am. Chem. Soc. 2003, 125, 4680. (i) Nicolaou, K. C.; Snyder S. A.
Classics in Total Synthesis II; Wiley-Interscience: Weinheim, Germany,
2003; pp 423-442. (j) Kim, A. I.; Rychnovsky, S. D. Angew. Chem., Int.
Ed. 2003, 42, 1267. (k) Nicolaou, K. C.; Vassilikogiannakis, G.; Magerlein,
W.; Kranich, R. Chem. Eur. J. 2001, 7, 5359-5371. (l) Johnson, T. W.;
Corey, E. J. J. Am. Chem. Soc. 2001, 123, 4475. (m) Corey, E. J.; Lazerwith,
S. E. J. Am. Chem. Soc. 1998, 120, 12777.
† University of Missouri-Columbia.
‡ Justus-Liebig University.
(1) (a) Heckrodt, T. J.; Mulzer, J. Top. Curr. Chem. 2005, 244, 1. (b)
Sanchez, J. A.; Ortega-Barria, E.; Gonzalez, J. J. Nat. Prod. 2004, 67, 1672.
(c) Rodriguez, I. I.; Shi, Y.-P.; Garcia, O. J.; Rodriguez, A. D.; Mayer, A.
M. S. J. Nat. Prod. 2004, 67, 1672. (d) Rodriguez, I. I.; Rodriguez, A. D.
J. Nat. Prod. 2003, 66, 855. (e) Rodriguez, A. D.; Shi, Y.-P. Tetrahedron
2003, 56, 9015. (f) Rodriguez, A. D.; Rodriguez, I. I. Tetrahedron Lett.
2002, 43, 5601. (g) Rodriguez, A. D.; Ramirez, C. J. Nat. Prod. 2001, 64,
100. (h) Rodriguez, A. D.; Ramirez, C.; Shi, Y.-P. J. Org. Chem. 2000, 65,
6682. (i) Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Barnes, C. L. J.
Org. Chem. 2000, 65, 1390. (j) Rodriguez, A. D.; Ramirez, C. Org. Lett.
2000, 2, 507. (k) Ata, A.; Kerr, R. G. Tetrahedron Lett. 2000, 41, 5821. (l)
Rodriguez, A. D.; Ramierz, C.; Rodriguez, I. I.; Gonzalez, E. Org. Lett.
1999, 1, 527. (m) Rodriguez, A. D.; Gonzalez, E.; Huang, S. D. J. Org.
Chem. 1998, 63, 7083.
(3) (a) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581. (b) Harmata,
M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201.
(4) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44,
7261.
(5) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754.
10.1021/jo701935s CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/24/2008
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J. Org. Chem. 2008, 73, 1290-1296

Synthesis of Erogorgiaene
FIGURE 1. Natural products from Pseudopterogorgia elisabethae.
SCHEME 1. Stereoselective Synthesis of Benzothiazines
SCHEME 2. Retrosynthetic Analysis of 1
stereocenter then serves as a basis for studying chemistry that
can establish the remaining stereocenters in various targets,
largely through substrate control of stereoselecitivity.
Erogorgiaene (1), a novel anti-mycobacterial serrulatane
diterpene, was first isolated from the West Indian Sea Whip
Pseudopterogorgia elisabethae and showed activity against
Mycobacterium tuberculosis H37Rv. The promising biological
activity of erogorgiaene has aroused attention due to interest in
the development of new chemotherapeutics for tuberculosis.
Organic chemists have devised several synthetic approaches to
1. The first asymmetric total synthesis of (+)-erogorgiaene was
accomplished in 2004 by Hoveyda and co-workers.2f It utilized
catalytic, asymmetric conjugate addition chemistry to install a
key benzylic stereogenic center. A second synthetic route
involved a carbene insertion and Cope rearrangement strategy
that rapidly established all of the stereocenters of the natural
product and provided a somewhat more efficient route to
erogorgiaene.2d As mentioned above, a formal synthesis of
erogorgiaene was reported from our group using benzothiazine
chemistry.2e
either cis or trans. More subtle is the relationship between the
hydrogen at C-4 and the methyl group at C-11. When erogor-
giaene is drawn as shown in Scheme 2, these two groups are
denoted as being syn. Thus, we would refer to erogorgiaene as
trans/syn.
Our efforts toward realizing the plan depicted in Scheme 2
began with a Horner-Wadsworth-Emmons reaction of com-
mercially available o-bromobenzaldehyde (18). This was then
coupled with (S)-S-methyl-S-phenylsulfoximine using the Buch-
wald-Hartwig reaction as modified by Bolm6 to give the
corresponding sulfoximine in 89% yield. This compound was
treated with an amide base (LDA or LiHMDS) to afford
benzothiazine 17 with complete diastereoselectivity in 85%
yield.4 The aniline 16 was obtained in 65% yield over three
steps by reduction, protection, and reductive desulfurization
(Scheme 3).7
We decided to use our methodology toward the synthesis of
(+)-erogorgiaene and indeed completed a formal total synthesis.
We also pursued a different approach to this compound based
on the retrosynthetic analysis shown in Scheme 2. This effort
ended in the synthesis of two diastereomers of (+)-erogorgiaene.
Results and Discussion
To facilitate our presentation, we use a nomenclature that is
based on the relative stereochemistry of the methyl group at
C-1 and the alkyl chain at C-4 of (+)-erogorgiaene. They are
(6) (a) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419.
(b) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731.
J. Org. Chem, Vol. 73, No. 4, 2008 1291

Harmata et al.
SCHEME 3. Synthesis of Aniline 16
To rationalize the stereochemical outcome of this reaction,
we computed the cyclization paths from radical intermediate
15r (i.e., 15 minus iodine) to the respective cyclic radicals 13ar
and 13br utilizing density functional theory at the B3PW9110
level in conjunction with a cc-pVDZ11 basis set. This approach
has shown to be reasonably accurate for reproducing the heats
of formations of polycyclic hydrocarbons.12 We used the
Gaussian program suite for all computations.13 In agreement
with the experimental findings the formation of 13b is also
preferred computationally (Figure 2, Table 1). The reaction
apparently is kinetically controlled as the radical products have
virtually the same energies. The chairlike transition structures
are markedly different in their orientation of the 1,4 substitu-
ents: while the preferred TS13br places these groups both in
approximately equatorial orientations, the methyl group is axial
in TS13ar. This conformational preference (we also evaluated
other transition state conformations but all of these are higher
in energy) ultimately leads to a sizable energy difference for
the two cyclization paths of 3.5 kcal/mol. Hence, the product
prefence should therefore even be larger for groups larger than
methyl.
SCHEME 4. Intramolecular Radical Cyclization of 15
Though at this stage we did not experimentally know the
stereochemistry of the products, we pushed forward. Installation
of the C-11 stereogenic center was easily accomplished by
alkylation of the lithium enolate of esters 13 with methyl iodide.
The reaction was conducted at -45 °C. Subsequently, reduction
of the corresponding inseparable alkylated esters with lithium
aluminum hydride delivered four alcohols in 86% overall yield
in the ratio of 7.2:1.0:0.6:0.1 (Scheme 5). We could not separate
the alcohols 21a-d but we were able to use HPLC to get two
fractions, each enriched in one component. The first sample
contained 21a and 21b in a ratio of 13:1. The second sample
contained 21c and 21d in a ratio of 11:1. The stereochemistry
of alkylation reaction can be rationalized using a model
introduced by Kocienski to predict the stereochemical outcome
of related enolate alkylations (Figure 3).14 The desired (R)-
stereochemistry is a consequence of alkylation taking place
selectively from the less hindered re-face of the enolates of 13a
and 13b, the favored conformation of which the carbon 11-H
bond resides in the plane of the enolate in order to minimize
A1,3-strain.15
The elaboration of aniline 16 (Scheme 4) into erogorgiaene
started with the construction of the trans ring system. This began
with a Heck coupling reaction of an aromatic diazonium salt
with ethyl acrylate in the presence of Pd(OAc)2 to yield the
ester 19. During the course of the diazotization we utilized
isoamyl nitrite and 2.1 equiv of trifluoroacetic acid (TFA) in
CH2Cl2 to furnish the soluble diazonium trifluoroacetate salt.
In the same pot, a diazotization-Heck reaction was carried out
in ethanol delivering 19 in 62% yield (two steps).8 The benzyl
group of 19 was removed by treatment with BCl3 at -78 °C
for 1 h, then at -20 °C for 12 h to afford alcohol 20 in 93%
yield. The reaction of alcohol 20 with triphenylphosphine,
imidazole, and iodine resulted in the formation of iodide 15 in
quantitative yield.9 The next step was an intramolecular radical
cyclization with carbon-carbon bond formation to give a
tetrahydronaphthalene, which was anticipated to occur with the
desired diastereoselectivity. The radical cyclization reaction was
performed via a standard procedure to give a mixture of the
compounds 13a and 13b in a ratio of 1:7.4 by NMR. At this
stage we did not actually know the stereochemistry of what we
had produced. The assignment, based on later results, is given
here to make the presentation simpler (Scheme 4).
(10) Perdew, J. P.; Wang, Y. Phys. ReV. B 1992, 23, 12947.
(11) Dunning, T. H. J. Chem. Phys. 1989, 90, 1007.
(12) Schreiner, P. R.; Fokin, A. A.; Pascal, R. A.; de Meijere, A. Org.
Lett. 2006, 8, 3635.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision D.02; Gaussian, Inc.: Pittsburgh, PA, 2003.
(14) (a) Chow, R.; Kocienski, P. J.; Kuhl, A.; LeBrazidec, J.-Y.; Muir,
K.; Fish, P. J. Chem. Soc., Perkin Tran. 2001, 1, 2344. (b) Kocienski, P.
J.; Pontiroli, A.; Qun, L. J. Chem. Soc., Perkin Tran. 2001, 1, 2356.
(15) (a) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841. (b) Hoffmann, R.
W. Angew. Chem., Int. Ed. 2000, 39, 2055.
(7) Harmata, M.; Kahraman, M. Synthesis 1994, 142.
(8) Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1999, 1357.
(9) Marshall, J. A.; Cleary, D. G. J. Org. Chem. 1986, 51, 858.
1292 J. Org. Chem., Vol. 73, No. 4, 2008

Synthesis of Erogorgiaene
FIGURE 2. Computed reaction path for the cyclization of radical intermediate 15r to bicyclic radicals 13ar and 13br; relative energies at B3PW91/
cc-pVDZ+ZPVE (in kcal/mol).
TABLE 1. Absolute (in au) and Relative Energies (in kcal/mol) for
the Optimized Radicals and Transition Structures Depicted in
Figure 2
B3PW91/cc-pVDZ
ZPVE
∆H0
0.0
+4.9
+1.4
-26.5
-26.7
15r
772.49987
772.49312
772.49906
772.54767
772.54765
206.7
207.4
207.6
210.2
210.0
TS13ar
TS13br
13ar
13br
FIGURE 3. Rationalization for the stereoselective alkylation of
enolates of 13a and 13b.
SCHEME 5. Alkylation and Reduction of Ester 13
NMR data suggested that the pairs 21a/21b and 21c/21d had
the same stereochemical relationship between carbons 4 and
11 (erogorgiaene numbering) as the chemical shift for the newly
introduced methyl group was approximately the same for each
member of the group. It should be noted that all compounds
have the same configuration at carbon 1. So the pairs 21a/21b
and 21c/21d are either both syn or both anti, as shown in Figure
4. However, at this stage we did not know which set was which.
FIGURE 4. Preliminary structural assignments for the pairs 21a/b
and 21c/d.
Kocienski and co-workers reported the synthesis of com-
pounds 22 and 23 in 2001.14 Compound 22 is cis/syn, and the
methyl group appears at 0.72 ppm in the 1H NMR whereas the
corresponding signal for cis/anti 23 appears at 1.12 ppm (Figure
5). On the basis of these data, we made an initial stereochemical
J. Org. Chem, Vol. 73, No. 4, 2008 1293

Harmata et al.
FIGURE 7. Stereochemical assignments of 21a and 21b.
FIGURE 5. C-11 methyl shifts (erogorgiaene numbering) for two
model compounds.
FIGURE 8. Complete stereochemical assignments of 21a-d.
SCHEME 7. Establishing Stereochemical Relationships
through Oxidation and Epimerization
FIGURE 6. Assignment of C-4/C-11 relative stereochemistry in 21a/b
and 21c/d pairs.
SCHEME 6. Synthesis of an Isomer (26) of Erogorgiaene
stereocontrol in the alkylation was of no practical consequence,
since treatment of the mixture with lithium and ethylamine at
-78 °C resulted in rapid and clean reduction of 25 to produce
1
compound 26 in 61% yield. The H NMR spectroscopic data
for erogorgiaene and compound 24 are very similar with the
exception of the signals for the methyl group on carbon 11.
Erogorgiaene displays a signal at 0.64 ppm, whereas the
compound 24 signal appears at 0.69 ppm. Moreover, 13C NMR
chemical shifts of compound 26 are significantly different from
that of erogorgiaene. On the basis of these data, we assigned
the stereochemistry of compound 26 as cis/syn (erogorgiaene
is trans/syn). We thus also predicted that 21b was trans/syn
(Figure 7).
The configurations of the remaining diastereoisomers were
established completely by a chemical correlation of the two
samples 21a/21b and 21c/21d. Swern oxidation of the mixtures
21a/21b or 21c/21d and then epimerization of the corresponding
aldehydes with 10 equiv of DBU gave mixtures of two
aldehydes for both reactions (Scheme 7). These samples were
1
the essentially the same by H NMR. This suggested that 21a
and 21c were epimeric at carbon 11. Since 21c/21d was enriched
in 21c, and 21a was indeed cis/syn, then 21c had to be cis/anti.
Since we could conclude that 21b was trans/syn, then 21d had
to be trans/anti (Figure 8).
assignment. We assigned the H and the C-11 methyl group as
syn in 21a/b and anti in 21c/d (Figure 6).
To verify this assignment and complete the synthesis, 21a/
21b was treated with DCC-MeI in THF at 37 °C to give iodide
24 in almost quantitative yield (Scheme 6).16 It was anticipated
that the iodide product 24 would be derived from 21a since the
21a/21b mixture was enriched in 21a (13:1).17 Nucleophilic
displacement of the iodide 24 with the lithium derivative 3,3-
dimethylallyl p-tolyl sulfone gave an 87% yield of the alkylation
product 25 as a 2.7:1 mixture of diastereoisomers. The lack of
To further confirm our assignment, the same reaction
sequence for the 21a/21b mixture shown in Scheme 6 was
repeated on the 21c/21d mixture (Scheme 8). Iodination of 21c/
21d with DCC-MeI in THF at 37 °C led to iodide 27 in 97%
yield. The product isolated was derived from 21c since 21c/
21d mixture is enriched in 21c (11:1). Nucleophilic displacement
of the iodide 27 with the lithium derivative 3,3-dimethylallyl
p-tolyl sulfone gave a 90% yield of the alkylation product 28
as a mixture of diastereoisomers. One of the stereoisomers was
crystallized and the X-ray structure of 28a confirmed that the
(16) Scheffold, R.; Saladin, E. Angew. Chem., Int. Ed. 1972, 11, 229.
(17) The amount of material obtained demanded that the product was
derived from the major component of the mixture, 21a.
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Synthesis of Erogorgiaene
SCHEME 8. Synthesis of an Isomer (29) of Erogorgiaene
We required more functional group manipulations and this
situation must be reckoned with as other applications of our
methodology are considered.
In conclusion, we have accomplished a formal synthesis of
the serrulatane diterpene, (+)-erogorgiaene (1), and two of its
diastereoisomers (26 and 29) using our benzothiazine methodol-
ogy as a key step. The antitubercular activity of 26 and 29 differ
dramatically, suggesting a specific interaction based on con-
formation is responsible for the activity. Future studies including
an independent approach to erogorgiaene as well as the synthesis
of pseudopteroxazole and related compounds will be reported
in due course.
Experimental Section
A few representative reactions are listed here. Full experimental
details for all reactions and characterization data for all compounds
can be found in the Supporting Information, which also contains
the xyz coordinates of the structures depicted in Figure 2.
(S,E)-Ethyl 3-(2-(4-(Benzyloxy)butan-2-yl)-5-methylphenyl)-
acrylate (19). The aniline (16) (538 mg, 2 mmol) was dissolved
in 5 mL of CH2Cl2 at room temperature under Argon. Under
vigorous stirring, 323 µL (4.2 mmol) of TFA was then added
dropwise. The mixture was cooled at 0 °C for 10 min, and isoamyl
nitrite (322 µL, 2.4 mmol) was added to the well-stirred reaction
mixture over a period of 10 min dropwise at 0 °C. The reaction
was stirred for 1 h at 0 °C. Then solvent was removed at reduced
pressure under no light. The resulting diazonium trifluoroacetate
was dissolved in 5 mL of ethanol under Ar and with protection
from light. The ethyl acrylate (260 µL, 2.4 mmol) was then added
to the stirred solution, followed by the Pd(OAc)2 catalyst (22.4 mg,
0.1 mmol). After 1 h, the reaction was stopped simply by filtration
through Celite. The filtrate was concentrated in vacuo, the residue
was redissolved in diethyl ether, and the resulting solution was
washed twice with water and brine. After drying over MgSO4
purification of the product by flash chromatography (5% EtOAc/
Hexanes) afforded compound 19 as a colorless oil (439 mg, 62%);
IR 2921, 2855, 1711, 1634, 1311, 1176, 1098 cm-1; 1H NMR (250
MHz, CDCl3) δ 8.14 (d, J ) 15.7 Hz, 1H), 7.33-7.15 (m, 8H),
6.32 (d, J ) 15.7 Hz, 1H), 4.39 (dd, J ) 19.3, 11.9 Hz, 2H), 4.22
(q, J ) 7.2 Hz, 2H), 3.41-3.26 (m, 3H), 2.30 (s, 3H), 1.94-1.86
(m, 2H), 1.29 (t, J ) 7.1 Hz, 3H), 1.21 (d, J ) 6.9 Hz, 3H); 13C
NMR (62.5 MHz, CDCl3) δ 166.8, 143.3, 142.5, 138.4, 135.4,
132.9, 131.0, 128.1, 127.4, 127.3, 127.2, 126.0, 119.8, 72.8, 68.2,
60.2, 37.7, 30.7, 22.2, 20.8, 14.2; HRMS calcd for C23H28O3Na
[M + Na]+ 375.1930, found 375.1929; [R]25D -10.4 (c 1.0, CHCl3).
stereochemistry of 21c was indeed cis/anti.18 Reduction of
compound 28 with lithium and ethylamine at -78 °C resulted
in the formation of compound 29 in 76% yield. This is the cis/
anti diastereoisomer of (+)-erogorgiaene.
At this point, we knew we had prepared two diastereoisomers
of erogorgiaene in enantiomerically pure form. Both of them
were submitted to the Tuberculosis Antimicrobial Acquistion
and Coordinating Facility (TAACF) for biological testing. The
cis/syn diastereomer 26 showed 94% growth inhibition at 12.5
µg/mL, whereas the cis/anti diastereomer 29 showed no
inhibition at all, compared to 96% inhibition for (+)-erogorgi-
aene (against Mycobacterium tuberculosis H37Rv).19 These
results are interesting. They suggest that there is specificity in
activity based on stereochemistry and not something more
general like simple hydrophobicity. The conformation of the
side chain is likely important to activity. Further studies will
be required to provide more support for this idea.
Since our radical cyclization approach to erogorgiaene was
not successful, we explored a new approach to its synthesis.
Aniline 30 was converted to 1-aryl-3,3-diethyltriazene in 90%
yield at 0-5 °C, in an Et2O/THF/CH3CN/H2O solvent system,
in the presence of potassium carbonate. Subsequently, upon
treatment with iodomethane in a sealed tube at 130 °C for 30
min, triazene was smoothly converted to aryl iodide 31 in 80%
yield. Sonogashira coupling reaction of iodide 31 with (trim-
ethylsilyl)acetylene in the presence of PdCl2, PPh3, CuI, and
triethylamine afforded compound 32 in 90% yield. Swern
oxidation of 32 provided aldehyde 33 in 96% yield. Finally,
aldehyde 33 was converted to compound 34 in 98% yield via
a Wittig reaction. Hoveyda and co-workers reported that this
compound could be converted to erogorgiaene in 12 steps. The
proton and carbon NMR data as well as rotation value for
compound 34 matched those reported by Hoveyda.2f We
obtained 34 in 10 steps in an overall yield of 27% (Scheme 9),
while Hoveyda required 6 steps with an overall yield of 48%.
(S,E)-Ethyl 3-(2-(4-Iodobutan-2-yl)-5-methylphenyl)acrylate
(15). Triphenylphosphine (285 mg, 1.09 mmol), imidazole (74 mg,
1.09 mmol), and iodine (275 mg, 1.09 mmol) were successively
added to 20 (151 mg, 0.543 mmol) in a mixture of diethyl ether/
acetonitrile (16 mL/4 mL). The reaction mixture was stirred for 2
h at rt. Diethyl ether (15 mL) was added, and the mixture was
filtered on Celite and washed with diethyl ether (10 mL). The yellow
solution recovered was washed with a saturated sodium thiosulfate
solution (2 × 15 mL) and brine (20 mL), dried over magnesium
sulfate, filtered, and concentrated by rotary evaporation. The crude
oil was purified by flash chromatography on silica gel using 2%
EtOAc/hexanes to yield 15 (210.7 mg, 99%) as a colorless oil. IR
1
2962, 2921, 1711, 1629, 1311, 1176 cm-1; H NMR (300 MHz,
CDCl3) δ 8.13 (d, J ) 15.7 Hz, 1H), 7.34 (s, 1H), 7.16-7.12 (m,
2H), 6.32 (d, J ) 15.7 Hz, 1H), 4.26 (q, J ) 7.2 Hz, 2H), 3.30-
3.25 (m, 1H), 3.10-2.96 (m, 2H), 2.32 (s, 3H), 2.21-2.03(m, 1H),
1.34 (t, J ) 7.1 Hz, 2H), 1.23 (d, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 166.8, 142.2, 141.7, 135.9, 133.1, 131.1, 127.5,
125.9, 120.2, 60.4, 41.5, 35.0, 21.4, 20.8, 14.3, 4.0; HRMS calcd
(18) The amount of material obtained demanded that the product was
derived from the major component of the mixture, 21c.
(19) TAACF, http://www.taacf.org/.
for C16H21IO2Na [M + Na]+ 395.0478, found 395.0504; [R]25
-36.3 (c 3.31, CHCl3).
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J. Org. Chem, Vol. 73, No. 4, 2008 1295

Harmata et al.
SCHEME 9. Formal Synthesis of Erogorgiaene
Ethyl 2-((1S,4S)-4,7-Dimethyl-1,2,3,4-tetrahydronaphthalen-
1-yl)acetate (13b). To a solution of iodide 15 (150 mg, 0.387 mmol)
in benzene (20 mL) was added Bu3SnH (0.167 mL, 0.62 mmol) in
10 mL of benzene and AIBN (0.01 g, 0.058 mmol) in 10 mL of
benzene dropwise via syringe pumps under refluxing. The reaction
was stirred overnight. After the reaction mixture was cooled, a
concentrated KF (3 mL) was added, and then the reaction was
stirred again overnight. The reaction mixture was extracted with
Et2O (3 × 15 mL) and washed with brine. After drying over
MgSO4, the solvent was removed under reduced pressure. The crude
product was subjected to flash chromatography on silica gel (4%
Et2O/Hexanes) to afford a colorless oil, two diastereoisomers in a
ratio of 7.4:1 by NMR (95.1 mg, 96%). Major 13b: IR 2953, 2917,
2859, 1732, 1605, 1164 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.13-
7.11 (m, 1H), 6.98-6.95 (m, 2H), 4.17 (q, J ) 7.2 Hz, 2H), 3.29-
3.26 (m, 1H), 2.83-2.79 (m, 1H), 2.71 (dd, J ) 15.1, 4.7 Hz, 1H),
2.52 (dd, J ) 15.1, 10.5 Hz, 1H), 2.28 (s, 3H), 1.88-1.83 (m,
2H), 1.75-1.70 (m, 1H), 1.56-1.50 (m, 1H), 1.30-1.20 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 172.8, 139.0, 138.9, 135.1, 128.6,
127.7, 127.0, 60.3, 41.9, 35.0, 32.3, 28.2, 26.1, 22.3, 20.9, 14.2;
HRMS calcd for C16H22O2Na [M + Na]+ 269.1512, found
2855, 1499, 1454, 1372 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.04
(s, 1H), 7.01 (d, J ) 7.7 Hz, 1H), 6.92 (d, J ) 7.0 Hz, 1H), 5.18-
5.15 (m, 1H), 2.86-2.84 (m, 1H), 2.80-2.76 (m, 1H), 2.30 (s,
3H), 2.22-2.16 (m, 1H), 2.10-2.04 (m, 2H), 1.85-1.77 (m, 1H),
1.72 (s, 3H), 1.68-1.57 (m, 2H), 1.63 (s, 3H), 1.49-1.21 (m, 3H),
1.22 (d, J ) 7.2 Hz, 3H), 0.69 (d, J ) 6.8 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 140.4, 139.9, 134.7, 131.3, 128.6, 127.8, 126.0,
124.8, 41.1, 35.8, 35.3, 32.5, 29.0, 26.3, 25.8, 23.2, 21.2, 18.0, 17.7,
14.7; HRMS calcd for C20H30 270.2348, found 270.2327; [R]25
D
-18.5 (c 0.5, CHCl3).
(-)-4-(epi)-Erogorgiaene (29). The procedure was similar to
the above yielding a colorless oil (76%). IR: 2962, 2921, 2847,
1499, 1458, 1372 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.04-6.90
(m, 3H), 5.02-4.98 (m, 1H), 2.88-2.83 (m, 1H), 2.67-2.62 (m,
1H), 2.29 (s, 3H), 2.17-2.12 (m, 1H), 2.10-1.91 (m, 1H), 1.88-
1.64 (m, 4H), 1.67 (s, 3H), 1.57 (s, 3H), 1.25-1.09 (m, 3H), 1.22
(d, J ) 7.2 Hz, 3H), 1.03 (d, J ) 6.8 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 140.1, 139.4, 134.5, 131.2, 128.6, 128.3, 126.1,
125.0, 43.6, 35.2, 32.5, 31.6, 29.0, 26.2, 25.7, 23.4, 21.2, 19.6, 18.1,
17.7; HRMS calcd for C20H30 270.2348, found 270.2309; [R]25
-20.0 (c 0.28, CHCl3).
D
269.1524; [R]25 +9.12 (c 1.71, CHCl3).
D
Acknowledgment. This work was generously supported by
the NIH (1R01-AI59000-01A1). The authors thank Prof. Abi-
mael D. Rodriguez for the spectra of authentic erogorgiaene
and Dr. Charles L. Barnes for the X-ray crystal structure
analysis.
(-)-1-(epi)-ent-Erogorgiaene (26). A 50-mL round-bottomed
flask was charged with 0.5 mL of anhydrous THF and sulfone 25
(10 mg, 0.024 mmol). The solution was cooled to -78 °C and
EtNH2 (5 mL) was added. The lithium wire (1.7 mg, 0.24 mmol)
was added and the solution sustained a blue color. The reaction
was stirred for 15 min then quenched by EtOH at -78 °C. The
resulting solution was warmed to room temperature for a while.
Removal the solvents gave the crude residue, which was purified
by column chromatography (pentanes) to afford (-)-1-(epi)-ent-
erogorgiaene 26 as a colorless oil (4.0 mg, 61%). IR 2958, 2921,
Supporting Information Available: Spectroscopic data and
experimental procedures for the reported compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO701935S
1296 J. Org. Chem., Vol. 73, No. 4, 2008