Syntheses of epi-aigialomycin D and deoxy-aigialomycin C via a diastereoselective ring closing metathesis macrocyclization protocol

Article abstract of DOI:10.1016/j.tetlet.2007.11.038

Syntheses of epi-aigialomycin D and deoxy-aigialomycin C are described via a remote stereocontrolled RCM macrocyclization.

Full text of DOI:10.1016/j.tetlet.2007.11.038

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 390–393
Syntheses of epi-aigialomycin D and deoxy-aigialomycin C via a
diastereoselective ring closing metathesis macrocyclization protocol
Naval Bajwa and Michael P. Jennings*
Department of Chemistry, 250 Hackberry Lane, The University of Alabama, Tuscaloosa, AL 35487-0336, United States
Received 5 October 2007; accepted 5 November 2007
Available online 26 November 2007
Abstract—Syntheses of epi-aigialomycin D and deoxy-aigialomycin C are described via a remote stereocontrolled RCM
macrocyclization.
Ó 2007 Elsevier Ltd. All rights reserved.
First isolated and disclosed in 2002 by Isaka and
co-workers, aigialomycin D (1) was shown to exhibit
modest anti-malarial activities (IC50: 6.6 lg/ml) against
Plasmodium falciparum K1, as well as, cytotoxicity
towards the KB and Vero cancer cell lines at 3.0 and
1.8 lg/ml (IC50), respectively.1 In addition, aigialomycin
D has recently been shown to bind to HSP90, but does
not function as an indiscriminate ATP antagonist. Also,
Winssinger has demonstrated that 1 is a selective kinase
inhibitor for CDK1/cyclin and CDK/5p25 (5.7–
5.8 lM).2 From this data, it can be inferred that aigialo-
mycin D and other resorcinol based natural products
show promise as a valuable class of compounds for
chemical genetics (Fig. 1).
macrocycle at the C70–C80 linkage and a very elegant
late stage Diels–Alder reaction for the construction of
the aromatic core.4 A second synthesis was reported
by She and Pan in which they employed a Julia-Kocien-
ski olefination reaction for the construction of both dou-
ble bonds and a Yamaguchi macrolactonization finished
the targeted compound 1.5 Most recently, a macrocyclic
RCM strategy at the C70–C80, similar to the Danishef-
sky effort, was recently utilized by Winssinger for the
completion of 1 and structurally related analogues via
both solution and solid phase protocols.2
Our synthetic blueprint of 1 was envisioned to feature a
highly chemoselective RCM protocol for the completion
of the 14-membered macrocycle as shown in Figure 2.
While RCM had been utilized by both Danishefsky
and Winssinger for the C70–C80 olefin formation, our
approach to 1 relied on a disconnection at the C10–C20
Based on the biological data of aigialomycin D and
other structurally similar resorcinol natural products,
it is not surprising that there has been great interest in
these compounds.3 The first total synthesis of 1 was
reported by the Danishefsky group in 2004 and utilized
a ring-closing metathesis (RCM) reaction to forge the
alkynyl addition
esterification
OH
O
O
O
O
HO
OH
O
OH O
O
O
8'
5
O
O
1'
7'
HO
BnO
BnO
8'
8'
1'
7'
7'
3
2'
HO
MeO
O
O
OH
O
2'
1
7
OH
RCM
OH
OH
aigialomycin C (2)
aigialomycin D (1) OH
OH
O
O
OTBS
Figure 1. Structures of aigialomycin D (1) and aigialomycin C (2).
+
O
H
4
6
OMOM
OTf
*
Corresponding author. Tel.: +1 205 348 0351; fax: +1 205 348
9104; e-mail: jenningm@bama.ua.edu
Figure 2. Retrosynthetic analysis of 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.038

N. Bajwa, M. P. Jennings / Tetrahedron Letters 49 (2008) 390–393
391
O
O
O
O
TBSO
11
OTBS
a) Pd(dppf)Cl2
a)
n
BuLi
O
O
K+
-
7
F3B
BnO
OTf
BnO
6
OH
OMOM
4
3
Scheme 1. Synthesis of intermediate 3: Reagents and conditions: (a)
potassium vinyl trifluoroborate (1.1 equiv), Et3N (1.3 equiv),
Pd(dppf)Cl2 (10 mol %), EtOH, 80 °C, 16 h, 77%.
b) Red-Al
TBSO
TBSO
TBSO
8'
c) TPAP-NMO
8'
styrene linkage, which would require a highly chemo-
selective macrocyclization versus a six-membered ring
formation, vide infra.
7'
7'
OH
OMOM
O
13
OMOM
12
Our synthetic outline to 1 required the synthesis of the
substituted styrene 3 as highlighted in Scheme 1. Hence,
a subsequent Suzuki–Miyaura coupling of the aryl
triflate 46 with potassium vinyl trifluoroborate and
Pd(dppf)Cl2 utilizing Molander’s procedure7 readily
provided substituted styrene 3 in 77% yield.8
d) Red-Al
HO
8'
7'
8'
7'
e) HCl
f) DMP, PPTS
OH
OMOM
O
O
With the aromatic segment readily in hand and in gram
quantities, we next focused our effort on the completion
of the aliphatic portion of 1 as delineated in Schemes 2,
3. Thus, treatment of the previously reported TBDPS
protected glycidol derivative 8 with allyl magnesium
bromide and 2 mol % of dilithio-tetrachlorocuprate
readily provided the olefinic alcohol intermediate 9 in
87% yield.9 Protection of the free hydroxyl group resi-
dent in 9 with MOMCl and Hunig’s base furnished
the protected olefinic diol 10 in 93% yield and sub
sequent selective removal of the silyl ether with TBAF
afforded the free primary alcohol which was further oxi-
dized with TPAP-NMO to furnish the MOM protected
chiral a-hydroxy aldehyde 7 in 71% yield over two steps
from 10.10
14
5
Scheme 3. Synthesis of intermediate 5: Reagents and conditions: (a)
nBuLi (1.1 equiv), 7
6
(1.0 equiv), THF, ꢀ78 °C, 1.5 h, then
(0.7 equiv), THF, ꢀ78 °C, 1.5 h, 71%. (b) Red-Al (3.2 equiv), THF,
0 °C, 48 h, 72%. (c) TPAP (10 mol %), NMO (3.0 equiv), CH2Cl2,
0 °C, 1.5 h, 92%. (d) Red-Al (1.2 equiv), toluene, 0 °C, 0.5 h, 84%. (e)
HCl (two drops concd), MeOH, 50 °C, 0.5 h, 100%. (f) DMP
(25 equiv), PPTS (2 mol %), CH2Cl2, rt, 5.0 h, 62%.
nucleophilic addition to 6 might display modest selectiv-
ity for the anti-Cram product due to the ability of the
MOM group to undergo chelation controlled additions.
Somewhat surprisingly, the addition of 6 to 7 gave rise
to a 2:1 diastereomeric ratio (dr) favoring the Cram
product 11.12 Ensuing diastereoselective reduction of
the acetylene moiety of 11 was accomplished upon the
addition of Red-Al via chelation-hydroalumination to
selectively (P15:1, E:Z) afford the allylic alcohol 12 in
72% yield, while maintaining the 2:1 dr at the hydroxyl
group. With the olefin geometry set, attention was
turned to final induction of the required diol stereo-
chemistry of 5. Thus, oxidation of the allylic alcohol res-
ident in 12 with TPAP-NMO readily removed the
redundant 2:1 dr at C60 and provided the a,b-unsatu-
rated ketone 1313 in 92% yield which set the stage for
a chelation controlled reduction in anticipation of form-
ing the cis-diol 14.
With 7 in hand, we next focused our attention on the
completion of 5 via an alkynyl addition to the aldehyde
moiety. With this in mind, treatment of the known TBS
protected propargylic alcohol 611 with nBuLi provided
the lithium alkynyl nucleophile which smoothly under-
went addition to the aldehyde moiety of 7 to afford 11
which represented the entire carbon framework of the
aliphatic portion of 1. We initially surmised that the
a) Li2CuCl4
OTBDPS
OTBDPS
O
allylMgBr
OH
8
9
Both lithium and sodium borohydrides failed to exhibit
selectivity as the product alcohol was isolated in good
yields (80–88%). Unfortunately and contrary to Burke’s
report, LiBH4 appeared not to undergo a chelation con-
trolled addition as a modest amount of the Cram alco-
hol was isolated (2:1).14 Attempted reduction of 13
with LAH in THF (0 °C) provided the desired alcohol
14 in very high yield. However, the selectivity for the
LAH reduction just simply replicated the dr from
the addition of 6 to 7. With the LAH result in hand, it
appeared that aluminum ‘ate’ based reducing reagents
b) MOMCl, DIPEA
O
c) TBAF
d) TPAP-NMO
OTBDPS
OMOM
H
7
10
OMOM
Scheme 2. Synthesis of intermediate 7: Reagents and conditions: (a)
Li2CuCl4 (2 mol %), allylMgBr (1.2 equiv), THF, ꢀ30 °C, 0.25 h, 87%.
(b) MOMCl (2.0 equiv), DIPEA (1.5 equiv), CH2Cl2, rt, 8 h, 93%. (c)
TBAF (1.5 equiv), THF, rt, 16 h, 96%. (d) TPAP (10 mol %), NMO
(3.0 equiv), CH2Cl2, 0°C, 1.5 h, 74%.

392
N. Bajwa, M. P. Jennings / Tetrahedron Letters 49 (2008) 390–393
H
H
OH
O
OH
O
O
O
O
O
a) NaH
O
a) BBr3
HO
3
O
O
O
+
5
BnO
1'
BnO
BnO
6'
O
15
16
OH
O
O
18
epi-
1
O
O
O
OH
OH
O
OH O
N
N
5.58 ppm
5.68 ppm
H
H
OH
b) 17
6:1 ratio of 15:16
Cl
Cl
O
O
Ru
Ph
17
H
H
OH
PCy3
1
HO
HO
epi-
1
OH
O
OH
O
3.40 ppm
3.81 ppm
H
H
OH
3.62 ppm
aigialomycin D
OH
O
4.35 ppm
O
+
8'
C6'-epi aigialomycin D
1'
7'
+
BnO
BnO
2'
19
Scheme 5. Synthesis of epi-aigialomycin D: Reagents and conditions:
(a) BBr3 (4.0 equiv), CH2Cl2, ꢀ78 °C, 1.0 h, 74%.
O
18
O
Scheme 4. Synthesis of intermediate 18: Reagents and conditions: (a)
NaH (1.2 equiv), 5 (1.3 equiv), THF/DMF 1:1, rt, 5 h, 78%. (b) 17
(5 mol %), CH2Cl2, 50 °C, 16 h, 13% of 18 and 84% of 19.
furnished the macrocycle epi-1 in a respectable 74%
yield, as shown in Scheme 5. Unfortunately, the spectral
data (1H NMR, 360 MHz; 13C NMR, 90 MHz) were
not in agreement with the natural sample 1.1 As delin-
1
eated in Scheme 5, close investigation of the H NMR
showed a propensity for a chelation controlled reduction
of ketone 13. Based on this observation, we decided to
investigate Red-Al as a chelating reagent for the reduc-
tion of 13 to 14. Much to our delight, treatment of 13
with Red-Al in toluene at 0 °C readily afforded alcohol
of epi-1 and 1 coupled with the comparison of the struc-
tural data of aigialomycin C suggested that the synthe-
sized compound was that of epi-C06 aigialomycin D.1,16
The methine proton of C06 possessed a dramatic upfield
shift of 3.81 ppm versus that of 4.35 ppm in 1. In
addition, both protons a- to the C06 methine displayed
a upfield shift with respect to that of 1.
1
14 with a satisfactory level of dr (6:1 by H NMR of
the crude product) in a very acceptable 84% yield. With
14 in hand, only a couple of protecting group removals
and a selective reprotection of the 1,2-diol subunit as the
acetonide was left to complete the aliphatic portion of 1.
Hence, treatment of the protected triol 14 with concd
HCl in refluxing methanol readily cleaved both the silyl
ether, as well as the MOM protecting group to provide
the triol intermediate. Ensuing acetal formation of the
cis-diol functionality to afford the acetonide protected
compound 5 was accomplished via 2,2-dimethoxypro-
pane and PPTS as the acid catalyst in a 62% yield over
two steps from 15. The absolute configuration of the cis-
diol moiety was unequivocally defined as illustrated in
Scheme 3 via NOE enhancements between the C50 and
C60 hydrogen atoms.
Thus, it appeared that the stereochemistry resident at C60
influenced macrocyclization by means of a classical res-
olution of the two diastereomers (15 and 16) by Grubbs’
catalyst 17. The initial insertion of 17 must have taken
place at the more accessible terminal alkene moiety of
15 and 16 followed either by six- or 14-membered ring
formation via RCM. The formation of the cis-acetonide
protected cyclohexene diol appeared to be favored over
H
O
O
O
O
O
O
a) NaH, 12
O
O
8'
With the two subunits readily in our hands, we proceeded
to couple advanced intermediates 3 and 5 as described in
Scheme 4. Thus, deprotonation of 5 with NaH in 1:1
THF/DMF at 0 °C proceeded to provide the alkoxide
anion which was then esterified with the aromatic com-
pound 3 to afford the macrocyclic precursors 15 and 16
as an inseparable 6:1 ratio of diastereomers.
MeO
MeO
2/1:cis/trans
ratio at C6'
6'
MeO
MeO
20
O
19
O
b) 17
OH
OH
O
c) HCl
O
8'
8'
7'
1'
1'
7'
With the two subunits coupled, the stage was finally set
for our proposed macrocyclization via a chemoselective
RCM reaction. Much to our surprise, treatment of 15
and 16 with Grubbs’ 2nd generation catalyst (17)15 in
refluxing CH2Cl2 (0.0002 M) led to the formation of a
14-membered macrocycle 18 and the acyclic compound
19 in 13% and 84% yields, respectively. Finally, treat-
ment of 18 with 4 equiv of BBr3 at ꢀ78 °C in CH2Cl2
2'
2'
OH
O
21
deoxy-
2
OH
O
Scheme 6. Synthesis of deoxy-2: Reagents and conditions: (a) NaH
(1.2 equiv), 12 (1.3 equiv), THF/DMF 1:1, rt, 5.0 h, 78%. (b) 17
(5 mol %), CH2Cl2, 50 °C, 16 h, 31%. (c) HCl (two drops concd),
MeOH, rt, 1 h, 69%.

N. Bajwa, M. P. Jennings / Tetrahedron Letters 49 (2008) 390–393
393
202.9, 137.2, 115.9, 96.9, 81.8, 56.1, 29.3, 28.9. IR
(CH2Cl2): 3053, 2986, 2305, 1733, 1422, 1374, 1265,
1046, 895, 735, 705, 421, 410, 404 cmꢀ1. Rf = 0.33, 20%
macrocyclization (also leading to the production of 19).
However, the construction of the trans-substituted six-
membered ring was not readily viable, and RCM of 16
exclusively lead to the desired macrocyclic framework.
24
EtOAc in hexanes. ½aꢁD 23.3° (c 0.012 g/mL, CH2Cl2).
HRMS (EI) calcd for C8H14O3 [MꢀH]+: 157.0865; found,
157.0863.
As shown in Scheme 6, we took advantage of such a
diastereoselective RCM reaction to also synthesize
deoxy-aigialomycin C. As described above, esterification
of 12 (2/1 ratio at C60 ) with styrene 1917 provided 20 in
good yield. A subsequent RCM with 17 furnished the
macrocycle 21 in virtually quantitative yield with respect
to the trans-dioxolane diastereomer. Final deprotection
of the acetonide moiety with HCl provided deoxy-
aigialomycin C 2 in 69% yield.18
11. Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.;
Langenhan, J. M.; Sun, L.; Akhiezer, A.; Liu, J. O. J.
Am. Chem. Soc. 1998, 120, 12237.
12. Mead, K. T. Tetrahedron Lett. 1987, 28, 1019.
13. Data for ketone 13: 1H NMR (360 MHz, CDCl3) d 7.0 (m,
1H), 6.4 (dt, J = 15.7, 1.4 Hz, 1H), 5.8 (m, 1H), 5.1 (m,
2H), 4.7 (dd, J = 15.4, 6.8 Hz, 2H), 4.2 (dd, J = 7.7,
5.5 Hz, 1H), 4.0 (dd, J = 11.8, 5.9 Hz, 1H), 3.4 (s, 3H), 2.3
(m, 2H), 2.2 (m, 2H), 1.8 (m, 2H), 1.2 (d, J = 6.1 Hz, 3H),
0.90 (s, 9H), 0.10 (d, J = 3.9 Hz, 6H). 13C NMR (90 MHz,
CDCl3) d 199.8, 146.1, 137.7, 127.6, 115.8, 96.5, 80.8, 67.8,
56.3, 43.2, 32.0, 30.0, 26.0, 24.1, 18.3, ꢀ4.3, ꢀ4.6. IR
(CH2Cl2): 3054, 2986, 1733, 1422, 1373, 1265, 1046, 895,
In conclusion, the syntheses of epi-aigialomycin D and
deoxy-aigialomycin C have been described via a remote
stereocontrolled RCM macrocyclization. Future work
in this area will focus on the completion of both 1 and
2 by means of site-selective RCM.
24
739, 705 cmꢀ1. Rf = 0.48, 20% EtOAc in hexanes. ½aꢁD
ꢀ3.3° (c 0.046 g/mL, CH2Cl2). HRMS (EI) calcd for
C19H36O4Si [MꢀC4H9]+: 299.1679; found, 299.1681.
14. Burke, S. D.; Deaton, D. N.; Olsen, R. J.; Armistead, D.
M.; Blough, B. E. Tetrahedron Lett. 1987, 28, 3905.
15. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
Acknowledgments
1
16. Data for epi-1: H NMR (360 MHz, acetone-d6) d 11.7 (s,
Support was provided by the University of Alabama
and the NSF (CHE-0115760) for the departmental
NMR facility.
1H), 9.2 (br s, 1H), 7.2 (dt, J = 15.9, 1.8 Hz, 1H), 6.6 (d,
J = 2.5 Hz, 1H), 6.3 (d, J = 2.5 Hz, 1H), 6.2 (dt, J = 15.9,
5.0 Hz, 1H), 6.0 (m, 1H), 5.6 (m, 2H), 4.0 (d, J = 3.0 Hz,
1H), 3.9 (d, J = 3.6 Hz, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 2.5
(m, 4H), 2.2 (m, 1H), 1.6 (m, 1H), 1.4 (d, J = 6.6 Hz, 3H).
13C NMR (90 MHz, acetone-d6) d 171.2, 165.1, 162.3,
143.3, 135.6, 132.4, 129.5, 127.0, 106.7, 103.4, 101.7, 76.8,
72.6, 71.7, 37.0, 30.4, 26.9, 17.8. IR (acetone): 3413, 3003,
References and notes
1. Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kon-
gsaeree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67,
1561.
1714, 1575, 1418, 1361, 1222, 1091, 901, 667 cmꢀ1
Rf = 0.31, 7% MeOH in DCM. ½aꢁD +19.6° (c
0.0056 g/mL, MeOH). HRMS (EI) calcd for C18H22O6
[M]+: 334.1416; found, 334.1410.
.
24
2. Barluenga, S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.;
Winssinger, N. Angew. Chem., Int. Ed. 2006, 45, 3951.
3. (a) Delmotte, P.; Delmotte-Plaquee, J. Nature 1953, 171,
344; (b) Ellestad, G. A.; Lovell, F. M.; Perkinson, N. A.;
Hargreaves, R. T.; McGahren, W. J. J. Org. Chem. 1978,
43, 2339; (c) Ayer, W. A.; Lee, S. P.; Tsuneda, A.;
Hiratsuka, Y. Can. J. Microbiol. 1980, 26, 766; (d) Ayer,
W. A.; Pena-Rodriguez, L. Phytochemistry 1987, 26, 1353;
(e) Sugawara, F.; Kim, K. W.; Kobayashi, K.; Uzawa, J.;
Yoshida, S.; Murofushi, N.; Takahashi, N.; Strobel, G. A.
Phytochemistry 1992, 31, 1987; (f) Sharma, S. V.; Agat-
suma, T.; Nakano, H. Oncogene 1998, 16, 2639.
4. Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413.
5. Lu, J.; Ma, J.; Xie, X.; Chen, B.; She, X.; Pan, X.
Tetrahedron: Asymmetry 2006, 17, 1066.
17. Styrene 19 was synthesized in the same manner as
compound 3. Data for compound 19: 1H NMR
(360 MHz, CDCl3) d 7.7 (dd, J = 17.5, 10.9 Hz, 1H), 6.8
(d, J = 2.0 Hz, 1H), 6.4 (d, J = 2.0 Hz, 1H), 5.7 (d,
J = 17.5 Hz, 1H), 5.4 (d, J = 10.9 Hz, 1H), 3.8 (s, 3H),
1.7 (s, 6H). 13C NMR (90 MHz, CDCl3) d 165.0, 160.2,
158.7, 144.0, 135.5, 117.6, 108.6, 105.1, 103.9, 100.8, 55.7,
25.6. IR (CH2Cl2): 4450, 3065, 2985, 1720, 1427, 1158,
895, 740, 705 cmꢀ1. Rf = 0.64, 50% EtOAc in hexanes.
HRMS (EI) calcd for C13H14O4 [M]+: 234.0892; found,
234.0900.
1
18. Data for deoxy-2: H NMR (360 MHz, CDCl3) d 11.8 (s,
1H), 7.1 (d, J = 15.9 Hz, 1H), 6.6 (d, J = 2.7 Hz, 1H), 6.4
(d, J = 2.7 Hz, 1H), 6.2 (dt, J = 15.9, 5.2 Hz, 1H), 6.0 (m,
1H), 5.6 (m, 2H), 3.9 (t, J = 8.4 Hz, 1H), 3.8 (s, 3H), 3.5
(m, 1H), 3.5 (s, 1H), 2.6 (m, 2H), 2.4 (m, 2H), 2.1 (m, 1H),
2.1 (s, 1H), 1.6 (m, 1H), 1.4 (d, J = 6.6 Hz, 3H). 13C NMR
(90 MHz, CDCl3) d 171.2, 165.2, 163.9, 142.7, 134.1,
132.3, 129.8, 128.6, 106.7, 104.0, 99.8, 73.0, 71.4, 55.4,
37.3, 30.7, 27.0, 18.6. IR (CH2Cl2): 3420, 3000, 1720, 1560,
1216, 1080, 890, 705, 667 cmꢀ1. Rf = 0.31, 50% EtOAc in
6. Dushin, R. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1992,
114, 655.
7. Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107.
8. Bajwa, N.; Jennings, M. P. J. Org. Chem. 2006, 71, 3646.
9. Dixon, D. J.; Ley, S. V.; Reynolds, D. J. Angew. Chem.,
Int. Ed 2000, 39, 3622.
10. Data for aldehyde 7: 1H NMR (360 MHz, CDCl3) d 9.7 (d,
J = 1.8 Hz, 1H), 5.8 (m, 1H), 5.1 (m, 2H), 4.8 (dd,
J = 14.8, 7.0 Hz, 2H), 4.0 (t, J = 5.7 Hz, 1H), 3.5 (s, 3H),
2.2 (m, 2H), 1.8 (m, 2H). 13C NMR (90 MHz, CDCl3) d
24
hexanes. ½aꢁD +25.4° (c 0.054 g/mL, CH2Cl2). HRMS (EI)
calcd for C19H24O6 [M]+: 348.1573; found, 348.1573.