Total synthesis of sarcodictyins A and B

Article abstract of DOI:10.1021/ja981062g

The total synthesis of cytotoxic marine natural products possessing tubulin polymerization and microtubule stabilization properties, sarcodictyins A (7) and B (8), is described. Two related approaches to these target molecules have been developed, both utilizing (+)-carvone (9) as starting material. The first approach involves a stereoselective construction of acetylenic aldehyde 27 (Scheme 2) while the second approach proceeds through a more direct but less selective sequence to the similar intermediate 36 (Scheme 3). Both strategies involve ring closures of the acetylenic aldehyde precursors to 10-membered rings under basic conditions followed by elaboration and selective reduction of the acetylenic linkage to a cis double bond. This promotes bridging to form the required tricyclic skeleton of the sarcodictyins (27 → 37 → 38 → 39 4, Scheme 4 and 37 → 44 → 45 → 46 → 47 → 42, Scheme 5) and (36 → 48 → 45, Scheme 6). Installation of the (E)- N(6')-methylurocanic acid residue was achieved by esterification with mixed anhydride 52, while the C-3 ester moieties were installed by standard deprotection, oxidation, and esterification procedures.

Full text of DOI:10.1021/ja981062g

J. Am. Chem. Soc. 1998, 120, 8661-8673
8661
Total Synthesis of Sarcodictyins A and B
K. C. Nicolaou,* J. Y. Xu, S. Kim, J. Pfefferkorn, T. Ohshima, D. Vourloumis, and
S. Hosokawa
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology, The
Scripps Research Institute, 10550 North Torrey Pines Road La Jolla, California 92037, and Department of
Chemistry and Biochemistry, UniVersity of California, San Diego 9500 Gilman DriVe,
La Jolla, California 92093
ReceiVed March 30, 1998
Abstract: The total synthesis of cytotoxic marine natural products possessing tubulin polymerization and
microtubule stabilization properties, sarcodictyins A (7) and B (8), is described. Two related approaches to
these target molecules have been developed, both utilizing (+)-carvone (9) as starting material. The first
approach involves a stereoselective construction of acetylenic aldehyde 27 (Scheme 2) while the second approach
proceeds through a more direct but less selective sequence to the similar intermediate 36 (Scheme 3). Both
strategies involve ring closures of the acetylenic aldehyde precursors to 10-membered rings under basic
conditions followed by elaboration and selective reduction of the acetylenic linkage to a cis double bond.
This promotes bridging to form the required tricyclic skeleton of the sarcodictyins (27 f 37 f 38 f 39 f
4, Scheme 4 and 37 f 44 f 45 f 46 f 47 f 42, Scheme 5) and (36 f 48 f 45, Scheme 6). Installation
of the (E)-N(6′)-methylurocanic acid residue was achieved by esterification with mixed anhydride 52, while
the C-3 ester moieties were installed by standard deprotection, oxidation, and esterification procedures.
1. Introduction
The success of Taxol (1, Figure 1) in the clinic as an
anticancer agent1 and the emergence of the epothilones (Figure
1) as potential new chemotherapeutic agents2 has elevated
tubulin-binding agents3 to the forefront of chemical and biologi-
cal research.4 Among the most exciting new tubulin polymer-
ization and microtubule stabilizing agents are eleutherobin (4,
Figure 1),5 eleuthosides A and B (5 and 6, Figure 1),6 and
sarcodictyins A and B (7 and 8, Figure 1). The latter
compounds (7 and 8) are rare natural substances originally found
by Pietra and his group in the Mediterranean stoloniferan coral
Sarcodictyon roseum.7 Their potent antitumor properties and
Taxol-like mechanism of action3 were reported in 1997 by an
(1) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem. Int. Ed.
Engl. 1994, 33, 15-44.
(2) (a) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem. Int. Ed. Engl. 1996, 35, 1567-1569. (b)
Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch,
J.; Goetz, M.; Lazarides, E.; Woods, C. M. Cancer Res. 1995, 55, 2325-
2333. (c) Kowalski, R. J.; Giannakakou, P.; Hamel, E. J. Biol. Chem. 1997,
272, 2534-2541. (d) Su, D.-S.; Meng, D.; Bertinato, P.; Balog, A.;
Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, S.;
Horwitz, S. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 757-759. (e) Meng,
D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen, E. J.; Danishefsky, S. J.;
Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. J. Am. Chem. Soc. 1997,
119, 2733-2734. (f) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm, O. M.;
Cordes, M. Angew. Chem. Int. Ed. Engl. 1997, 36, 523-524.
(3) Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665-667.
(4) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem. Int.
Ed., in press.
(5) (a) Fenical, W.-H.; Hensen, P. R.; Lindel, T. US Pat. 5,473,057, Dec.
5, 1995. (b) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza,
A. M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744-
8745. (c) Long, B. H.; Carboni, J. M.; Wasserman, A. J.; Cornell, L. A.;
Casazza, A. M.; Jensen, P. R.; Lindel, T.; Fenical, W.; Fairchild, C. R.
Cancer Res. 1998, 58, 1111-1115.
Figure 1. Molecular structures of paclitaxel (tradename Taxol, 1),
epothilones A (2) and B (3), eleutherobin (4), eleuthosides A (5) and
B (6), and sarcodictyins A (7) and B (8) (Ac ) acetyl, Bz benzoyl).
Upjohn-Pharmacia group.8 As part of our program studying
the chemistry and biology of tubulin-binding agents, we have
pursued and accomplished the total synthesis of paclitaxel
(tradename Taxol, 1),9 epothilones A (2)10 and B (3),10d,11
eleutherobin (4),12 and sarcodictyins A (7)13 and B (8).14 In
this paper, we describe the details of the total synthesis of
sarcodictyins A (7) and B (8).
(8) Ciomei, M.; Albanese, C.; Pastori, W.; Grandi, M.; Pietra, F.;
D’Ambrosio, M.; Guerriero, A.; Battistini, C. Proc. Am. Ass. Canc. Res.
1997, 38, 5 (Abstract 30).
(9) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.;
Guy, R. K.; Claiborne, C. F.; Renaud, J. B.; Couladouros, E. A.; Paulvannan,
K.; Sorensen, E. J. Nature 1994, 367, 630-634.
(6) Ketzinel, S.; Rudi, A.; Schleyer, M.; Benayahu, Y.; Kashman, Y. J.
Nat. Prod. 1996, 59, 873-875.
(7) (a) D’Ambrosio, M.; Guerriero, A.; Pietra, F. HelV. Chim. Acta 1987,
70, 2019-2027. (b) D’Ambrosio, M.; Guerriero, A.; Pietra, R. HelV. Chim.
Acta 1988, 71, 964-976.
S0002-7863(98)01062-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/13/1998

8662 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Nicolaou et al.
Scheme 1. Synthesis of Key Intermediate 14a
Figure 2. Retrosynthetic analysis of the core structure of sarcodictyins
A (7) and B (8).
a Reagents and conditions: a. 1.2 equiv of H2O2, 0.3 equiv of NaOH,
MeOH, 2 h, 0 °C; b. H2, 0.005 equiv of PtO2, EtOH, 12 h, 25 °C, 87%
for two steps; c. 1.4 equiv of LDA, 5.0 equiv of CH2O, THF, -78 f
0 °C, 2 h; d. 1.2 equiv of TBSCl, 4.0 equiv of Et3N, CH2Cl2, 12 h,
53% for two steps; 3. 1.2 equiv of L-selectride, THF, -78 °C, 2 h,
93%; f. 1.2 equiv of MsCl, 2.5 equiv of Et3N, CH2Cl2, 0 °C, 0.5 h; g.
5.0 equiv of sodium naphthalenide, THF, 0 °C, 0.5 h, 85% for two
2. Retrosynthetic Analysis and Strategy
The general structures of sarcodictyins (I, Figure 2) are
characterized by a rigid tricyclic framework from which a
number of appendages branch out. Prominent among these
appendages are the carboxylate group at C-3, the hydroxyl group
at C-4, and the ester group at C-8 carrying the (E)-N(6′)-
methylurocanic acid residue. The bridging oxygen involved in
the lactol functionality at C-4 allows a strategic disconnection
that unravels the [6.2.1]bicyclic structure of I into the 10-
membered ring II. The latter structure is expected to spontane-
n
steps; h. 40 equiv of CH3C(OEt)3, 0.1 equiv of PrCO2H, 170 °C, 72
h, 74%; i. 1.2 equiv of DIBAL, CH2Cl2, -78 °C, 0.5 h, 97%. LDA )
lithium diisopropylamide. TBS ) t-butyldimethylsilyl. MsCl ) meth-
anesulfonyl chloride. DIBAL ) diisobutylaluminum hydride.
(Scheme 1) as a key intermediate required for its construction.
The appeal of (+)-carvone (9) as a starting material for this
synthesis was considerably enhanced by the work of Trost15
who described its conversion to compound 13 (Scheme 1). Thus,
following a modification of the communicated protocols 13 was
prepared as shown in Scheme 1. Epoxidation of (+)-carvone
under basic hydrogen peroxide conditions followed by hydro-
genation of this exocyclic double bond gave 10 in 87% overall
yield. Treatment of 10 with LDA (for abbreviations see legends
in the schemes) followed by quenching with formaldehyde and
silylation of the resulting alcohol furnished silyl ether 11 in 53%
overall yield. Stereoselective L-Selectride reduction of the
ketone functionality in 11 led to 12 (93%). Subsequent
mesylation followed by reduction with sodium naphthalenide
provided allylic alcohol 13 (85% overall). Finally, exposure
of 13 to CH3C(OEt)3 and n-PrCO2H furnished, via Claisen
rearrangement, the expected ethyl ester, which was cleanly
reduced with DIBAL to produce aldehyde 14 (72% yield, two
steps).
ously collapse back into I in the synthetic directions. The ∆5,6
-
cis double bond in II can be derived from the corresponding
acetylene moiety whose disconnection at C4-C5 via a retro
acetylide-aldehyde addition leads to open-chain acetylenic
aldehyde III. Two further disconnections, indicated in structure
III through retro acetylide-ketone addition and Knoevenagel
condensation, furnish intermediate IV whose structure is highly
suggestive of (+)-carvone (9).
This retrosynthetic analysis led to a strategy whose execution
resulted in efficient total synthesis of both sarcodictyins A (7)
and B (8). The sequence can be divided in three subse-
quences: the construction of the key cyclization precursors, the
cyclization and formation of the tricyclic framework, and the
construction of the remaining side chains.
3. Construction of Cyclization Precursors 27 and 36
The stereoselective conversion of 14 to 27 is shown in
Scheme 2. Thus, olefination of aldehyde 14 with trieth-
ylphosphonoacetate proceeded quantitatively in the presence of
NaH to afford ethyl ester 15. DIBAL reduction of 15 gave
allylic alcohol 16 in 91% yield and subsequent Sharpless
asymmetric epoxidation16 (diethyl L-tartrate) furnished epoxide
17 (91% yield). The transformation of epoxide 17 to allylic
alcohol 19 was accomplished via mesylate 18 in 90% overall
yield. Protection of 19 as a PMB-ether [PMBOC(dNH)CCl3,
PPTS, 89% yield based on ca. 50% conversion]17 followed by
The synthetic plan called for the initial construction of
cyclization precursors of general formula (III, Figure 2).
Consideration of protecting groups and possible routes defined
structure 27 (Scheme 2) as a subtarget and compound 14
(10) (a) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K.
C. Angew. Chem. Int. Ed. Engl. 1997, 36, 166-168. (b) Nicolaou, K. C.;
Sarabia, F.; Ninkovic, S.; Yang, Z. Angew. Chem. Int. Ed. Engl. 1997, 36,
525-526. (c) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.;
Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am.
Chem. Soc. 1997, 119, 7960-7973. (d) Nicolaou, K. C.; Ninkovic, S.;
Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M. R. V.; Yang,
Z. J. Am. Chem. Soc. 1997, 119, 7974-7991.
(11) Nicolaou, K. C.; Winssinger, N.; Pastor, J. A.; Ninkovic, S.; Sarabia,
F.; He, Y. Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E.
Nature 1997, 387, 268-272.
(12) Nicolaou, K. C.; van Delft, F.; Ohshima, T.; Vourloumis, D.; Xu,
J.; Hosokawa, S.; Pfefferkorn, J.; Kim, S.; Li, T. Angew. Chem. Int. Ed.
Engl. 1997, 36, 2520-2524.
18
sequential treatment with Hg(OAc)2 and Li2PdCl4-CuCl2
furnished methyl ketone 21 (65% yield). Chelation-controlled
addition of HCtCMgBr (excess)19 to ketone 21, followed by
(15) Trost, B. M.; Tasker, A. S.; Ruther, G.; Brands, A. J. Am. Chem.
Soc. 1991, 113, 670-672.
(16) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976.
(17) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139-4142.
(18) Rodeheaver, G. T.; Hunt, D. F. J. Chem. Soc., Chem. Commun.
1971, 818-819.
(13) Nicolaou, K. C.; Xu, J.-Y.; Kim, S.; Ohshima, T.; Hosokawa, S.;
Pfefferkorn, J. J. Am. Chem. Soc. 1997, 119, 11353-11354.
(14) Nicolaou, K. C.; Kim, A.; Pfefferkorn, J.; Xu, J.-Y.; Ohshima, T.;
Hosokawa, S.; Vourloumis, D.; Li, T. Angew. Chem. Int. Ed. 1998, 37,
1418-1421.

Total Synthesis of Sarcodictyins A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8663
Scheme 2. First Generation Synthesis of
Acetylene-Aldehyde Compound 27a
Figure 3. Synthesis and crystal structure of A providing evidence of
the absolute stereochemistry of advanced intermediate 22. a. 3.0 equiv
of Dess-Martin periodinane, 20 equiv of NaHCO3, CH2Cl2, 0 f 25
°C, 12 h, 70%. D-M [O] ) Dess-Martin oxidation.
121 °C (ether-hexanes)] in 60% yield. The serendipitous
preparation of this crystalline compound allowed the assignment
of relative stereochemistry within 22 and subsequent intermedi-
ates (by X-ray crystallographic analysis) (see ORTEP drawing,
Figure 3).
Controlled oxidation of 22 with 1.5 equiv of Dess-Martin
reagent20 in the presence of pyridine and NaHCO3 led to the
desired aldehyde 23 in good yield. Aldehyde 23 was subjected
to Knoevenagel condensation conditions with ethyl cyanoac-
etate21 in the presence of â-alanine leading, after silylation with
TMSOTf and i-Pr2NEt, to the (E)-R,â-unsaturated cyano ester
25 via 24 (in 71% overall yield). The geometry of the cyano
ester bearing double bond was later confirmed by successful
ring closure to intermediate 37 (vide infra, Scheme 4). A highly
regioselective reduction of the cyano ester moiety of 25 was
effected with DIBAL to afford hydroxy aldehyde 26 in 80%
yield. Finally, protection of the primary alcohol in 26 with
TIPSOTf and i-Pr2NEt gave the targeted protected acetylenic
aldehyde precursor 27 in 91% yield.
A second, less stereoselective but more direct, route to a
cyclization precursor acetylenic aldehyde 36 was also under-
taken,12 as shown in Scheme 3. Thus, aldehyde 1413was reacted
with 1-ethoxyvinyllithium followed by exposure to acid to afford
a 1.25:1 mixture of C-8 epimeric hydroxy ketones 28 in 82%
overall yield. This mixture was then reacted with excess
HCtCMgBr in a stereoselective manner,22 affording a chro-
matographically separable mixture of the two epimeric acety-
lenic diols, 29 (43% yield) along with its C-7,C-8 diastereoi-
somer (33% yield). Removal of the silyl protecting group from
29 was accomplished by exposure to TBAF furnishing, after
flash column chromatography, the pure triol 30 (92%). The
identity of 30 was proven by comparison to an authentic sample
obtained from 22 (whose structure was unambiguously proven
by X-ray analysis as discussed above).13 The conversion of 30
to aldehyde 33 required a sequence defined by intermediates
a Reagents and conditions: a. 1.5 equiv of (EtO)2P(O)CH2CO2Et,
2.0 equiv of NaH, THF, 0 °C for 1 h, then 25 °C for 4 h, 100%; b. 4.0
equiv of DIBAL, CH2Cl2, -78 °C, 2 h, 91%; c. 0.2 equiv of Ti(OiPr)4,
0.24 equiv of diethyl L-tartrate, 2.0 equiv of tBuOOH, 4 Å MS, CH2Cl2,
-20 °C, 8 h, 91%; d. 5.0 equiv of MsCl, 6.0 equiv of Et3N, CH2Cl2,
-20 °C, 1 h; e. 5.0 equiv of sodium naphthalenide, THF, 0 °C, 10
min, 90% for two steps; f. 5.0 equiv of PMBOC(dNH)CCl3, 1.0 equiv
of PPTS, CH2Cl2, 25 °C, 48 h, 89% based on ca. 50% conversion; g.
1.1 equiv of Hg(OAc)2, MeOH, 25 °C, 12 h; then 1.0 equiv of Li2PdCl4,
3.0 equiv of CuCl2, MeOH, 55 °C, 3 h, 65%; h. 15 equiv of
HCtCMgBr (0.5 M in THF), CH2Cl2-THF-(3:1), -78 f 25 °C, 12
h; i. 4.0 equiv of TBAF, THF, 25 °C, 1 h, 72% for two steps, ds ratio
ca. 7:1; j. 1.5 equiv of Dess-Martin periodinane, 20 equiv of pyridine,
20 equiv of NaHCO3, CH2Cl2, 0 f 25 °C, 4 h; k. 30 equiv of
NCCH2COOEt, 4.0 equiv of â-alanine, 95% EtOH, 25 °C, 72 h; l. 5.0
equiv of TMSOTf, 10 equiv of iPr2NEt, CH2Cl2, -78 °C, 10 min, 71%
for three steps; m. 10 equiv of DIBAL, CH2Cl2, -78 °C for 7 h then
i
-40 °C for 1 h, 80%; n. 10 equiv of TIPSOTf, 20 equiv of Pr2NEt,
t
CH2Cl2, -78°C, 1 h, 91%. TBS ) butyldimethylsilyl. DIBAL )
diisobutylaluminum hydride. PMB ) p-methoxybenzyl. PPTS )
pyridinium p-toluenesulfonate. TMS ) trimethylsilyl. TIPS ) triiso-
propylsilyl. Ms ) methanosulfonyl. TBAF ) tetra-n-butylammonium
fluoride. D-M [O] ) Dess-Martin oxidation. Tf ) trifluoromethane-
sulfonate. MS ) molecular sieves. THF ) tetrahydrofuran.
(19) Still, W. C.; McDonald, J. H., III Tetrahedron Lett. 1980, 21, 1031-
1034.
(20) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(21) Anderson, N. H.; Golec, F. A., Jr. Tetrahedron Lett. 1977, 3783-
3787.
(22) Evans, D. A.; Kalder, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001-7031.
desilylation with TBAF gave acetylenic diol 22 as the major
diastereoisomer (72% yield, ca. 7:1 de). Attempted oxidation
of alcohol 22 to aldehyde 23 with excess Dess-Martin reagent20
resulted in the formation of lactone A [(Figure 3), mp 120-

8664 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Nicolaou et al.
Scheme 3. Second Generation Synthesis of
Acetylene-Aldehyde Compound 36a
Scheme 4. First Generation Synthesis of the Sarcodictyin
Tricyclic Core Structure 42
a Reagents and conditions: a. 1.5 equiv of LiHMDS, THF, 25 °C,
10 min; b. 2.5 equiv of Dess-Martin periodinane, 20 equiv of NaHCO3,
CH2Cl2, o f 25 °C, 4.5 h, 85% for two steps; c. 1.0 equiv of PPTS,
MeOH, 25 °C, 30 min, 94%; d. 0.3 equiv of Lindlar’s cat., H2, toluene,
25 °C, 20 min, 75% for 40, plus 15% for 5,6-dihydro analog; e. 1.0
equiv of PPTS, MeOH, 25 °C, 10 min, 100%; f. 10 equiv of Na-liq
NH3, -78 °C; then add 41 in THF-EtOH, 5 min, 95% yield, ca. 2:1
mixture of 42 and 5,6-dihydro analogue 43. THF ) tetrahydrofuran.
LiHMDS ) lithium bis(trimethylsilyl)amide. PPTS ) pyridinium
p-toluenesulfonate. Lindlar’s cat. ) Pd/CaCO3/Pb. D-M [O] ) Dess-
Martin oxidation.
a Reagents and conditions: a. 2.0 equiv of CH2dCH(OEt), 1.8 equiv
of tBuLi (1.7 M in THF), THF, -78 f 0 °C, 1 h; then cool to -78 °C
and add 14 in THF; then slowly warm to -40 °C; b. conc. H2SO4,
Et2O, 25 °C, 2 min, 82% for two steps as a ca. 1.25:1 mixture of
diastereoisomers; c. 5.0 equiv of ethynylmagnesium bromide (0.5 M
in THF), THF, -78 f 20 °C, 14 h, 76%, 29 (43%) plus 7,8-
diastereoisomer (33%); d. 29, 2.0 equiv of TBAF (1.0 M in THF),
THF, 0 f 25 °C, 1 h, 92%; e. 5.0 equiv of TESOTf, 10 equiv of Et3N,
CH2Cl2, 25 °C, 2 h, 100%; f. 0.1 equiv of PPTS, MeOH-CH2Cl2, (3:
1), 25 °C, 45 min, 98%; g. 0.05 equiv of TPAP, 1.5 equiv of NMO,
CH2Cl2, 4 Å MS, 1.5 h, 98%; h. 30 equiv of ethyl cyanoacetate, 4.0
equiv of â-alanine, 95% EtOH, 72 h, 50 °C, 95%; i. 10 equiv of DIBAL,
hexanes -78 °C for 6 h, then -40 °C for 1 h, then -10 °C for 1 h,
4. Cyclization and Formation of Tricyclic Framework
The first approach to sarcodictyins involved key intermediate
27 and had as its initial subtarget tricyclic compound 42 (Scheme
4). The ring closure of 27 was effected by the action of
LiHMDS in THF at 25 °C yielding the expected 10-membered
ring alcohol (mixture of two isomers) whose oxidation with
Dess-Martin reagent20 led to eneynone 37 in 85% overall yield.
The TMS group was then removed from 37 by exposure to
PPTS in MeOH furnishing alcohol 38 in 94% yield. Hydro-
genation of eneynone 38 in the presence of Lindlar’s catalyst
resulted in the formation of tricyclic system 40 (75% yield),
presumably via spontaneous collapse of the initially formed
dienone 39. Quantitative conversion of hemiketal 40 to its
methoxy derivative 41 was effected by exposure to PPTS in
MeOH. Removal of the PMB group from 41 for the purposes
of side-chain attachment was carried out by Na in liquid NH3
(THF-EtOH) and furnished the targeted tricyclic system 42
along with its C-5,C-6 saturated counterpart, compound 43 (95%
combined yield, ca. 2:1 ratio.). A slightly modified sequence
is presented in Scheme 5. Specifically, removal of the PMP-
ether from 37 was accomplished after its treatment with DDQ
in aqueous CH2Cl2 resulting in the formation of ynone hydroxy
44 in 80% yield. Liberation of the propargylic hydroxy moiety
i
90%; j. 5.0 equiv of TIPSOTf, 10 equiv of Pr2NEt, CH2Cl2, -78 °C,
1 h, 93%. THF ) tetrahydrofuran. TBAF ) tetra-n-butylammonium
fluoride. TESOTf ) triethylsilyl trifluoromethanesulfonate. PPTS )
pyridinium p-toluenesulfonate. TPAP ) tetra-n-propylammonium per-
ruthenate. NMO ) 4-methylmorpholine N-oxide. MS ) molecular
sieves. DIBAL ) diisobutylaluminium hydride. TIPSOTf ) triisopro-
pylsilyl trifluoromethanesulfonate.
31 (persilylation with TESOTf-Et3N, 100% yield) and 32
(selective desilylation with PPTS in MeOH, 98% yield), and
oxidation of the latter compound with TPAP-NMO in CH2Cl2
(98% yield).23 The Knoevenagel condensation of 33 with ethyl
cyanoacetate21 proceeded smoothly as described above for 33
furnishing (E)-R,â-unsaturated cyano ester 34 (95% yield) whose
DIBAL reduction gave, regioselectively, hydroxy aldehyde 35
(90% yield). Silylation of 35 with TIPSOTf and i-Pr2NEt finally
led to the desired acetylenic aldehyde precursor 36 in 93% yield.
(23) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13-19.

Total Synthesis of Sarcodictyins A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8665
Scheme 5. Alternative Route to Tricyclic Core 42a
conversion to the key dihydroxy ynone 45 is detailed in Scheme
6. Thus, treatment of 36 with LiHMDS in THF at -20 °C
resulted, as before, in the formation of the 10-membered ring
alcohol 48 (mixture of diastereoisomers) which was immediately
oxidized with Dess-Martin reagent to eneynone 49 (89% yield
for two steps). Selective removal of both TES groups was
achieved by exposure to Et3N‚3HF (78% yield) furnishing diol
45 and setting the stage for selective hydrogenation and internal
cyclization. To this end, the experiments summarized in Table
1 were carried out using acetylenic substrates 37 (Scheme 4),
38 (Scheme 4), and 45 (Scheme 6) and a variety of hydrogena-
tion conditions. The exploration led quickly to the adoption of
the rhodium complex [Rh(nbd)(dppb)]BF4 in acetone solution
as the catalyst of choice (ca. >10:1 ratio in favor of the desired
product 42 which was obtained in 80% yield). With the solution
of the reduction problem at hand, the only remaining task was
the construction of the side chains before the final targets were
reached.
5. Construction of the Side Chain and Completion of the
Synthesis
a Reagents and conditions: a. 2.0 equiv of DDQ, CH2Cl2-H2O (18:
1), 25 °C, 0.5 h, 80%; b. 1.0 equiv of PPTS, MeOH, 25 °C, 1 h, 80%;
c. 0.05 equiv of [Rh(nbd)(dppb)]BF4, H2, acetone, 25 °C, 10 min; d.
0.5 equiv of PPTS, MeOH, 25 °C, 10 min, 80% for two steps. DDQ )
2,3-dichloro-5,6-dicyano-1,4-benzoquinone. PPTS ) pyridinium p-
toluenesulfonate. nbd ) 2,5-norbornadiene. dppb ) 1,4-bis(diphe-
nylphosphino)butane.
For the attachment of the C-8 ester functionality, a mixed
anhydride protocol was adopted.12 To this end, ethyl (E)-N(6′)-
methylurocanate (50, Scheme 7)25 was sequentially converted
to its sodium salt 51 by the action of NaOH (THF-H2O, 100%)
and then to tert-butyl mixed anhydride 52 by treatment with
t-BuCOCl in THF (75% yield). Reaction of 42 with 52 in the
presence of Et3N and DMAP resulted in the formation of ester
53 in 83% yield. For the purposes of completing the side chain
at C-3, a carboxylic acid group was formed at this position as
follows: (i) desilylation with TBAF to afford alcohol 54 in
100% yield; (ii) Dess-Martin oxidation to aldehyde 55; and
(iii) further oxidation of 55 with NaClO2 to furnish 56.
Exposure of carboxylic acid to CH2N2 or CH3CHN2 furnished
methoxysarcodictyin A (57, 88% overall yield from 54) or
methoxysarcodictyin B (58, 86% overall yield from 54).
Finally, sarcodictyins A (7) and B (8) were generated from their
respective methoxy derivatives by treatment with CSA in CH2-
Cl2-H2O (80% yield for 7 and 86% for 8).
Scheme 6. Second Generation Synthesis of Alkynone 45a
To evaluate the importance of the C-5,C-6 double bond of
sarcodictyins for biological activity, C-5,C-6 dihydrosarcodictyin
A (61) was targeted for chemical synthesis. Scheme 8 sum-
marizes an efficient route to 61 from intermediate 45. Thus,
hydrogenation of 45 in the presence of 5% Pd/BaSO4 in EtOAc,
followed by exposure to PPTS in MeOH resulted in the
formation of tricyclic compound 43 (64% overall yield) in which
the C-5,C-6 bond was completely reduced. The construction
of the two side chains proceeded smoothly as described already
for compound 42 (Scheme 5) and via compounds 59 and 60
furnishing the desired dihydrosarcodictyin A (61) in excellent
overall yield (see Scheme 8).
a Reagents and conditions: a. 2.0 equiv of LiHMDS, THF, -20 °C,
20 min; b. 2.0 equiv of Dess-Martin periodinane, 6.0 equiv of
NaHCO3, 6.0 equiv of pyridine, CH2Cl2, 0 °C, 1 h, 89% for two steps;
c. 5.0 equiv of Et3N‚3HF, THF (1:5), 25 °C, 1.5 h, 78%. LiHMDS )
lithium bis(trimethylsilyl)amide. THF ) tetrahydrofuran. D-M [O] )
Dess-Martin oxidation.
6. Conclusion
was performed by the action of PPTS in MeOH furnishing diol
45 in 80% yield. The employment of [Rh(nbd)(dppb)]BF4 as
the hydrogenation catalyst24 proved to be beneficial since
tricyclic alcohol 42 was isolated in 80% yield after the formation
of the methyl ketal functionality (PPTS, MeOH).
The significant extent of reduction of the C-5,C-6 double bond
in our first approach, which was observed in the hydrogenation
of 38 to 40, prompted the second general approach to the
sarcodictyins which involved intermediate 36 (Scheme 6)
carrying different protecting groups for easier removal. Its
In this paper, we detailed two slightly different approaches
to sarcodictyins A (7) and B (8) and C-5,C-6 dihydrosarcodictyin
A (61). Both approaches utilize an intramolecular acetylide-
aldehyde addition to construct a 10-membered ring, whose
elaboration and selective hydrogenation results in the formation
of a transient hydroxy dienone which spontaneously collapses
to the tricyclic ring system of sarcodictyins A and B. Ap-
propriate appendage attachments at C-8 and C-15 then lead to
(25) Viguerie, N. L.; Sergueeva, N.; Damiot, M.; Mawlawi, H.; Riviere,
M.; Lattes, A. Heterocycles 1994, 37, 1561-1576.
(26) Numbering is depicted in Figure 2.
(24) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 2143-
2147.

8666 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Nicolaou et al.
Table 1. Selective Hydrogenation Studies for the Construction of the Sarcodictyin Tricyclic Corea
substrate
conditions
Lindlar’s cat., MeOH
Lindlar’s cat., CH2Cl2
Lindlar’s cat., EtOAc
Lindlar’s cat., toluene; then PPTS, MeOH
Pd/BaSO4, pyridine
products (ratio)
yield (%)
38: R ) PMB, R2 ) H
38: R ) PMB, R2 ) H
38: R ) PMB, R2 ) H
38: R ) PMB, R2 ) H
38: R ) PMB, R2 ) H
45: R ) H, R2 ) H
40:49 (ca. 2:1)
40:49 (ca. 3:1)
40:49 (ca. 3:1)
41:49 (ca. 5:1)
40:49 (ca. 3-5:1)
42:49 (ca. 2-3:1)
42:49 (ca. >10:1)
50 (of 40)
60 (of 40)
60 (of 40)
75 (of 41, two steps)
74 (of 40)
52 (of 42, two steps)
80 (of 42, two steps)
Lindlar’s cat., toluene; then PPTS, MeOH
[Rh(nbd)(dppb)]BF4, acetone; then PPTS, MeOH
45: R ) H, R2 ) H
a Reagents and conditions. a. 1.0 equiv of PPTS, MeOH, 25 °C, 30 min 94%. Lindlar’s cat. ) Pd/CaCO3/Pb. PPTS ) pyridinium p-toluenesulfonate.
nbd ) 2,5-norbornadiene. dppb ) 1,4-bis(diphenylphosphino)butane.
Scheme 7. Total Synthesis of the Sarcodictyins A (7) and B
(8)a
Scheme 8. Synthesis of C5,C6-Dihydrosarcodictyin A (61)a
a Reagents and conditions: a. 1.05 equiv of LiOH‚H2O, THF-H2O,
t
1:1, 25 °C, 12 h, 100%; b. 1.1 equiv BuC(O)Cl, THF, 25 °C, 12 h,
75%; c. 2.0 equiv of 52, 20 equiv of Et3N, 1.0 equiv of DMAP, CH2Cl2,
25 °C, 48 h, 83%; d. 2.0 equiv of TBAF, THF, 25 °C, 2 h, 100%; e.
2.0 equiv of Dess-Martin periodinane, 10 equiv of NaHCO3, CH2Cl2,
25 °C, 0.5 h, 100%; f. 6.0 equiv of NaClO2, 3.0 equiv of NaH2PO4, 50
equiv of 2-methyl-2-butene, THF, tBuOH, H2O, 2 h; g. excess CH2N2,
Et2O, 10 min, 88% for two steps; h. excess CH3CH2N2, Et2O, 0.5 h,
89% for two steps; i. 2.0 equiv of CSA, CH2Cl2-H2O (10:1), 25 °C,
48 h, 80% for 7, 86% for 8. THF ) tetrahydrofuran. DMAP ) 4-(N,N′-
dimethylamino)pyridine. TBAF ) tetra-n-butylammonium fluoride.
D-M [O] ) Dess-Martin oxidation. CSA ) 10-camphorsulfonic acid.
a Reagents and conditions: a. 1.0 equiv of 5% Pd/BaSO4, EtOAc,
25 °C, 1 h; b. 2.0 equiv of PPTS, MeOH, 25 °C, 6 h, 64% for two
steps; c. 5.0 equiv of 52, 20 equiv of Et3N, 2.0 equiv of DMAP, CH2Cl2,
25 °C, 48 h, 83%; d. 2.0 equiv of TBAF, THF, 25 °C, 2 h, 100%; e.
2.5 equiv of Dess-Martin periodinane, 10 equiv of NaHCO3, CH2Cl2,
25 °C, 0.5 h; f. 6.0 equiv of NaClO2, 3.0 equiv of NaH2PO4, 50 equiv
t
of 2-methyl-2-butene, THF, BuOH, H2O; g. excess of CH2N2, Et2O,
88% for three steps. PPTS ) pyridinium p-toluenesulfonate. DMAP
) 4-(N,N′-dimethylamino)pyridine. TBAF ) tetra-n-butylammonium
fluoride. D-M [O] ) Dess-Martin oxidation.
completion of the syntheses. The designed strategy allows for
a solid-phase synthesis, specific analogue construction, and
combinatorial library generation. The solid-phase synthesis of
sarcodictyins A and B and analogues thereof has already been
accomplished and will be reported elsewhere in due course.
These studies should facilitate further investigations of the
chemical biology of sarcodictyins and related compounds. In
the following paper. we describe details of our total syntheses
of eluetherobin and eleuthosides A and B.
7. Experimental Section
General Techniques. All reactions were carried out under an argon
atmosphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Tetrahydrofuran (THF), toluene,
and ethyl ether (ether) were distilled from sodium benzophenone, and
methylene chloride (CH2Cl2) was from calcium hydride. Anhydrous
solvents were also obtained by passing them through commercially
available alumina column. Yields refer to chromatographically and

Total Synthesis of Sarcodictyins A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8667
spectroscopically (1H NMR) homogeneous materials, unless otherwise
stated. Reagents were purchased at highest commercial quality and
used without further purification, unless otherwise stated. Reactions
were monitored by thin-layer chromatography carried out on 0.25 mm
E. Merck silica gel plates (60F-254) using UV light as visualizing agent
and 7% ethanolic phosphomolybdic acid or p-anisaldehyde solution
and heat as developing agents. E. Merck silica gel (60, particle size
0.040-0.063 mm) was used for flash column chromatography.
Preparative thin-layer chromatography (PTLC) separations were carried
out on 0.25, 0.50, or 1 mm E. Merck silica gel plates (60F-254). NMR
spectra were recorded on Brucker DRX-600, AMX-500 or AMX-400
instruments and calibrated using residual undeuterated solvent as an
internal reference. The following abbreviations were used to explain
the multiplicities: s ) singlet, d ) doublet, t ) triplet, q ) quartet,
sept ) septet, m ) multiplet, br ) broad. IR spectra were recorded
on a Perkin-Elmer 1600 series FT-IR spectrometer. Optical rotations
were recorded on a Perkin-Elmer 241 polarimeter. High-resolution
mass spectra (HRMS) were recorded on a VG ZAB-ZSE mass
spectrometer under fast atom bombardment (FAB) conditions with NBA
as the matrix. Melting points (mp) are uncorrected and were recorded
on a Thomas-Hoover Unimelt capillary melting point apparatus. Full
procedures and data for compounds 10-13 can be found in the
Supporting Information accompanying this paper.
the reaction mixture was stirred at the same temperature for 1 h and at
25 °C for 4 h. After the end of the reaction was established by TLC,
the reaction was quenched by the addition of saturated NH4Cl solution
(50 mL), extracted with ether (2 × 100 mL), dried over Na2SO4, and
concentrated. The residue was purified by flash chromatography (silica
gel, 2% EtOAc in hexane) to furnish the R,â-unsaturated ester 15 (2.67
g, 100%) as a colorless oil: Rf ) 0.53 (silica gel, EtOAc-hexane,
1:10); FT-IR (neat) νmax 2956, 1722, 1651, 1465, 1367, 1258, 1159,
1
1078, 841 cm-1; H NMR (250 MHz, CDCl3) δ 7.11-6.97 (m, 1 H,
C-8), 5.78 (dd, J ) 15.2, 6.2 Hz, 1 H, C-7), 5.38-5.30 (br s, 1 H,
C-12), 4.09 (qd, J ) 7.2, 1.6 Hz, 2 H, OCH2CH3), 3.65 (dd, J ) 10.4,
5.7 Hz, 1 H, SiOCHH), 3.55 (dd, J ) 10.4, 5.7 Hz, 1 H, C-2) 2.41-
2.38 (m, 2H), 2.26-2.23 (m, 1 H), 1.87-1.65 (m, 4 H), 1.64 (d, J )
1.4 Hz, 3 H, C-17), 1.51-1.47 (m, 1 H), 1.25 (t, J ) 7.2 Hz, 3 H,
OCH2CH3), 0.84 (d, J ) 6.7 Hz, 3 H, C-19 or C-20), 0.87 (s, 9 H,
Si-tBu), 0.76 (d, J ) 6.7 Hz, 3 H, C-19 or C-20), 0.09 (s, 6 H, SiCH3);
13C NMR (62.5 MHz, CDCl3) δ 166.8, 150.4, 136.0, 122.1, 121.1, 62.2,
60.0, 41.3, 39.3, 36.0, 32.6, 26.7, 25.9, 24.2, 23.0, 21.1, 18.2, 15.7,
14.3, -5.4, -5.5; HRMS (FAB) calcd for C23H42NaO3Si (M + Na+)
417.2801, found 417.2814.
Synthesis of Allylic Alcohol 16 from Ester 15. A 1.0 M CH2Cl2
solution of DIBAL (12.2 mL, 12.20 mmol, 4.0 equiv) was gradually
added to a solution of R,â-unsaturated ethyl ester 15 (1.20 g, 3.05 mmol,
1.0 equiv) in CH2Cl2 (15 mL) at -78 °C, and the reaction was stirred
for 2 h at the same temperature. The reaction mixture was quenched
by addition of saturated NH4Cl solution (30 mL), stirred vigorously at
ambient temperature for 2 h, extracted with CH2Cl2 (3 × 50 mL), dried
over Na2SO4, and concentrated. The residue was purified by flash
chromatography (silica gel, 10% EtOAc in hexane) to provide allylic
alcohol 16 (980 mg, 91%) as a light-yellow oil: Rf ) 0.21 (silica gel,
EtOAc-hexane, 1:10); FT-IR (neat) νmax 3326, 2925, 1464, 1385, 1253,
1106, 1005, 836, 774, 668 cm-1; 1H NMR (250 MHz, CDCl3) δ 5.85-
5.68 (m, 1 H, C-7), 5.67-5.53 (m, 1 H, C-8), 5.35-5.28 (br s, 1 H,
C-12), 4.04 (d, J ) 5.6 Hz, 2 H, CH2OH), 3.66 (dd, J ) 10.2, 6.9 Hz,
1 H, C-2), 3.53 (t, J ) 10.2 Hz, 1 H, C-2), 2.32-2.05 (m, 3 H), 2.00-
1.50 (m, 6 H), 1.64 (d, J ) 1.3 Hz, 3 H, C-17), 0.86 (s, 9 H, Si-tBu),
0.83 (d, J ) 6.8 Hz, 3 H, C-19 or C-20), 0.76 (d, J ) 6.7 Hz, 3 H,
C-19 or C-20), 0.01 (s, 6 H, Si-CH3); 13C NMR (62.5 MHz, CDCl3) δ
136.6, 134.0, 128.9, 121.5, 63.8, 62.2, 41.0, 39.1, 36.3, 32.3, 26.9, 25.9,
24.2, 23.1, 21.1, 18.2, 16.4, -5.4; HRMS (FAB) calcd for C21H40-
NaO3Si (M + Na+) 375.2695, found 375.2704.
Synthesis of Epoxide 17 from Allylic Alcohol 16. To a suspension
of diethyl L-tartrate (0.28 mL, 1.50 mmol, 0.2 equiv) and powdered 4
Å MS (6.8 g) in CH2Cl2 (90 mL) was added titanium(IV) isopropoxide
(0.40 mL, 1.25 mmol, 0.2 equiv) at -20 °C followed by a 5.0 M CH2-
Cl2 solution of tert-butyl hydroperoxide (2.7 mL, 13.5 mmol, 2.0 equiv).
After the mixture was stirred for 40 min at the same temperature, a
solution of allylic alcohol 16 (2.38 g, 6.75 mmol, 1.0 equiv) in CH2Cl2
(5 mL) was added dropwise via cannula. The reaction mixture was
stirred for 8 h at the same temperature, further diluted with CH2Cl2
(150 mL), and quenched by addition of a saturated NaHCO3 solution
(100 mL). The mixture was then filtered through a Celite pad eluting
with CH2Cl2 and the organic phase was separated, washed with water
and brine, dried over Na2SO4, and concentrated. The residue was
purified by flash chromatography (silica gel, 10% EtOAc in hexane)
to furnish epoxy alcohol 17 (2.25 g, 91%) as a colorless oil: Rf ) 0.47
(silica gel, EtOAc-hexane, 1:3); FT-IR (neat) νmax 3442, 2927, 1465,
1387, 1253, 1104, 838, 775, 668 cm-1; 1H NMR (400 MHz, CDCl3) δ
5.34 (br s, 1 H, C-12), 3.84 (br d, J ) 12.4 Hz, 1 H), 3.72 (dd, J )
10.5, 5.1 Hz, 1 H, C-2), 3.60-3.45 (m, 2 H, CHHOH, C-2), 3.07, 3.02
(m, 1 H, C-7), 2.92-2.88 (m, 1 H, C-8), 2.43-2.33 (m, 1 H), 2.20-
1.98 (m, 1 H), 1.95-1.70 (m, 5 H), 1.68 (s, 3 H), 1.56-1.47 (m 1 H),
0.85 (s, 9 H, TBS), 0.84 (d, J ) 6.7 Hz, 3 H, C-19 or C-20), 0.76 (d,
J ) 6.7 Hz, 3 H, C-19 or C-20), 0.10 (s, 6 H, TBS); 13C NMR (100.6
MHz, CDCl3) 136.0, 121.8, 62.6, 62.0, 59.4, 55.9, 40.9, 37.5, 36.1,
31.6, 26.8, 25.9, 24.2, 22.6, 21.0, 18.1, 15.8, -5.3, -5.5; HRMS (FAB)
calcd for C21H40NaO3Si (M + Na+) 391.2644, found 391.2657.
Synthesis of Allylic Alcohol 19 through the Corresponding
Mesylate. To a solution of epoxy alcohol 17 (1.05 g, 2.82 mmol, 1.0
equiv) and triethylamine (2.40 mL, 16.9 mmol, 6.0 equiv) in CH2Cl2
(28 mL) was added dropwise methanesulfonyl chloride (1.4 mL, 18.08
Synthesis of Key Intermediate Aldehyde 14. A mixture of alcohol
13 (1.61 g, 5.42 mmol, 1.0 equiv), triethyl orthoacetate (39.6 mL, 216.8
mmol, 40.0 equiv), and propionic acid (0.04 mL, 0.542 mmol, 0.1 equiv)
was heated at 170 °C for 72 h. The excess triethyl orthoacetate was
removed by vacuum distillation (25 mmHg), and the remaining residue
was purified by flash chromatography (silica gel, 3% EtOAc in hexane)
to produce the expected ethyl ester (1.50 g, 74%) which was used for
the next step without further purification. A 1.0 M CH2Cl2 solution of
DIBAL (4.6 mL, 4.60 mmol, 1.2 equiv) was gradually added to a
solution of the ethyl ester (1.41 g, 3.83 mmol, 1.0 equiv) in CH2Cl2
(19 mL) at -78 °C, and the reaction mixture was stirred for 30 min at
that temperature. Quenching was performed by addition of saturated
NH4Cl solution (20 mL) and stirring for 2 h at ambient temperature.
The organic layer was separated, dried over Na2SO4, and concentrated.
The residue was purified by flash chromatography (silica gel, 5% EtOAc
in hexane) to provide aldehyde 14 (1.20 g, 97%) as a colorless oil.
Data for ethyl ester: Rf ) 0.34 (silica gel, EtOAc-hexane, 1:30); FT-
IR (neat) νmax 2929, 2857, 1738, 1470, 1369, 1255, 1156, 1100, 837,
775 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.38-5.30 (br s, 1 H, C-12),
4.09 (dq, J ) 7.2, 1.6 Hz, 2 H, OCH2CH3), 3.65 (dd, J ) 10.4, 5.7 Hz,
1 H, C-2), 3.55 (dd, J ) 10.4, 5.7 Hz, 1 H, C-2), 2.80-2.70 (m, 1 H,
C-10), 2.55 (dd, J ) 15.2, 6.2 Hz, 1 H, C-9), 2.22 (dd, J ) 15.2, 7.0
Hz, 1 H, C-9), 1.97-1.65 (m, 4 H), 1.62 (d, J ) 1.3 Hz, 3 H, C-17),
1.52-1.37 (m, 1 H), 1.22 (t, J ) 7.2 Hz, 3 H, OCH2CH3), 0.88 (d, J
) 6.7 Hz, 3 H, C-19 or C-20), 0.87 (s, 9 H, Si-tBu), 0.79 (d, J ) 6.7
Hz, 3 H, C-19 or C-20), 0.06 (s, 6 H, SiCH3); 13C NMR (100.6 MHz,
CDCl3) d 173.9, 135.7, 121.9, 62.6, 60.1, 40.6, 36.8, 36.4, 35.0, 26.9,
25.9, 24.2, 22.3, 20.9, 18.2, 16.9, 14.1, -5.5, -5.6; HRMS (FAB) calcd
for C21H41SiO3 (M + H+) 369.2825, found 369.2834(M + H+). For
14: Rf ) 0.32 (silica gel, EtOAc-hexane, 1:30); FT-IR (neat) νmax 2956,
1
2856, 1726, 1467, 1254, 1103, 1079, 838 cm-1; H NMR (400 MHz,
CDCl3) δ 9.74 (t, J ) 2.3 Hz, 1 H, C-8), 5.38 (br s, 1 H, C-12), 3.71
(dd, J ) 10.6, 4.6 Hz, 1 H, C-2), 3.45 (t, J ) 10.6 Hz, 1 H, C-2),
2.85-2.78 (m, 1 H), 2.59 (ddd, J ) 16.5, 7.3, 2.9 Hz, 1 H), 2.24 (ddd,
J ) 16.5, 4.3, 2.0 Hz, 1 H), 1.93-1.70 (m, 4 H), 1.66 (s, 3 H, C-17),
1.48-1.40 (m, 1 H, C-14), 0.87 (d, J ) 6.5 Hz, 3 H, C-19 or C-20),
0.86 (s, 9 H), 0.77 (d, J ) 6.8 Hz, 3 H, C-19 or C-20), 0.01 (s, 6 H);
13C NMR (100.6 MHz, CDCl3) δ 203.6, 136.3, 122.3, 62.1, 44.3, 41.0,
35.8, 34.9, 26.5, 25.8, 24.1, 22.2, 21.1, 18.2, 15.5, -5.5, -5.6; HRMS
(FAB) calcd for C19H36 NaO2Si (M + Na+) 347.2382, found 347.2372.
Synthesis of r,â-Unsaturated Ester 15. To a THF (30 mL)
suspension of sodium hydride (60% w/w in mineral oil, 542 mg, 13.55
mmol, 2.0 equiv) was gradually added a solution of triethyl phospho-
noacetate (2.7 mL, 13.55 mmol, 2.0 equiv) in THF (10 mL) via cannula
at 0 °C. After the addition was complete, the reaction mixture was
stirred at 25 °C for 30 min before being cooled back down to 0 °C. A
solution of aldehyde 14 (2.20 g, 6.78 mmol, 1.0 equiv) in THF (15
mL) was slowly added to the reaction mixture via cannula at 0 °C, and

8668 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Nicolaou et al.
mmol, 4.9 equiv) at -20 °C. After 1 h (TLC monitoring), the reaction
was quenched by addition of saturated NH4Cl solution (20 mL),
extracted with CH2Cl2 (2 × 50 mL), dried over Na2SO4, and
concentrated. The residue was filtered through a short silica gel pad
eluting with CH2Cl2, concentrated, and used immediately for the next
step without further purification. A solution of the mesylate in THF
(28 mL) was added via cannula to a 0.3 M THF solution of sodium
naphthalenide (4.7 mL, 14.1 mmol, 5.0 equiv), generated in the same
way described for the synthesis of allylic alcohol 13, at 0 °C. After
10 min, the reaction was quenched by addition of saturated NH4Cl
solution (50 mL), extracted with ether (2 × 50 mL), washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by flash
chromatography (silica gel, 5% EtOAc in hexane) to produce allylic
alcohol 19 (895 mg, 90%) as a colorless oil: Rf ) 0.34 (silica gel,
EtOAc-hexane, 1:10); FT-IR (neat) νmax 3420, 2955, 1464, 1387, 1254,
1073, 837, 775 cm-1; 1H NMR (250 MHz, CDCl3) δ 5.98-5.80 (m, 1
H, CHdCH2), 5.30-5.20 (m, 2 H, C-12, CHdCHH), 5.08 (dd, J )
10.4, 1.6 Hz, 1 H, CHdCHH), 4.37-4.26 (br s, 1 H, OH), 3.75 (dd,
J ) 10.9, 5.4 Hz, 1 H, C-2), 3.60 (t, J ) 10.9 Hz, 1 H, C-2), 2.43-
2.33 (m, 1 H), 1.97-1.60 (m, 6 H), 1.62 (s, 3 H, C-17), 1.60-1.40
(m, 2 H), 0.89 (s, 9 H, Si-tBu), 0.86 (d, J ) 6.7 Hz, 3 H, C-19 or
C-20), 0.78 (d, J ) 6.7 Hz, 3 H, C-19 or C-20), 0.07 (s, 6 H, Si-CH3);
13C NMR (62.5 MHz, CDCl3) δ 141.8, 137.5, 120.9, 113.6, 71.1, 63.1,
41.4, 37.0, 34.1, 26.9, 25.9, 24.2, 22.7, 21.0, 18.2, 16.2, -5.2, -5.4;
HRMS (FAB) calcd for C21H41O2Si (M + H+) 353.2876, found
353.2866.
J ) 6.7 Hz, 3 H, C-19 or C-20), 0.79 (d, J ) 6.7 Hz, 3 H, C-19 or
C-20), 0.03 (s, 6 H, Si-CH3); 13C NMR (62.5 MHz, CDCl3) δ 212.3,
159.3, 136.8, 130.0, 129.5, 121.3, 113.8, 84.8, 72.7, 62.2, 55.3, 41.1,
36.6, 34.9, 32.6, 27.0, 26.1, 25.1, 24.3, 22.4, 21.1, 18.5, 17.0, -5.0,
-5.2; HRMS (FAB) calcd for C29H48CSO4Si (M + Cs+) 621.2376,
found 621.2404.
Synthesis of Propargylic Alcohol 22. To a stirring solution of
methyl ketone 21 (180 mg, 0.369 mmol, 1.0 equiv) in CH2Cl2-THF
(3:1, 20 mL) at -78 °C was added ethynylmagnesium bromide (0.5
M in THF, 11.8 mL, 5.40 mmol, 14.6 equiv) via syringe over 15 min.
The reaction was stirred for 6 h at that temperature after which it was
allowed to warm to 25 °C. The reaction was quenched with saturated
NH4Cl solution (10 mL). The aqueous layer was separated and
extracted with ether (3 × 20 mL), and the combined organic phase
was dried over Na2SO4 and concentrated. The residue was taken up
in THF (2 mL) and treated with 1.0 M THF solution of TBAF (1.47
mL, 1.47 mmol, 4.0 equiv) at 25 °C. After 2 h (TLC monitoring), the
reaction was quenched with water and extracted with ethyl acetate (3
× 20 mL). The combined organic phase was dried over Na2SO4 and
concentrated. The residue was purified by flash chromatography (silica
gel, 50% EtOAc in hexane) to afford diol 22 (106 mg, 72%, two steps)
as a colorless oil. Rf ) 0.24 (silica gel, EtOAc-hexane, 1:1); FT-IR
(neat) νmax 3305, 2958, 1614,ied by flash chromatography (silica gel,
6% EtOAc, hexane) to afford 25 (0.12 g, 71%, three steps): Rf - 0.27
(silica gel, EtOAc-hexane, 1:3); FT-IR (neat) νmax 2959, 2231, 1730,
1614, 1513, 1248, 1078, 1022, 842 cm-1; 1H NMR (600 MHz, CDCl3)
δ 7.83 (d, J ) 11.8 Hz, 1 H, C-2), 7.19 (d, J ) 8.6 Hz, 2 H, ArH),
6.85 (d, J ) 8.6 Hz, 2 H, ArH), 5.33 (s, 1 H, C-12), 4.81 (d, J ) 11.3
Hz, 1 H, OCHHAr), 4.47 (d, J ) 11.3 Hz, 1 H, OCHHAr), 4.30 (q, J
) 7.2 Hz, 2 H, OCH2CH3), 3.80 (s, 3 H, OCH3), 3.16 (d, J ) 9.8 Hz);
13C NMR (62.5 MHz, CDCl3) δ 158.8, 137.5, 130.4, 129.1, 120.3,
113.3, 86.5, 83.2, 73.4, 72.3, 71.2, 61.7, 54.9, 40.8, 36.1, 34.7, 31.5,
26.6, 25.7, 23.9, 22.5, 20.8, 16.2.
Synthesis of PMB-ether 20. To a solution of allylic alcohol 19
(445 mg, 1.57 mmol, 1.0 equiv) and p-methoxybenzyl 2,2,2-trichlo-
roacetimidate (2.22 g, 7.85 mmol, 5.0 equiv) in CH2Cl2 (8 mL) was
added pyridinium p-toluenesulfonate (395 mg, 0.31 mmol, 0.2 equiv)
at 25 °C. The reaction mixture was stirred for 48 h at the same
temperature, and after the end of the reaction was established by TLC,
the reaction was quenched by addition of saturated NaHCO3 solution
(10 mL). The organic phase was separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL). The combined organic extracts
were dried over Na2SO4 and concentrated. The residue was purified
by flash chromatography (silica gel, EtOAc-pentane, 1:99) to produce
PMB-ether 20 (240 mg, 89% based on 50% conversion) as a light
yellow oil: Rf ) 0.61 (silica gel, EtOAc-hexane, 1:3); FT-IR (neat)
Synthesis of Cyano Ester 25 through an Oxidation-Knoevenagel
Condensation-Protection Sequence. A mixture of NaHCO3 (504
mg, 5.99 mmol, 20.0 equiv), pyridine (0.485 mL, 5.99 mmol, 20.0
equiv), Dess-Martin periodinane (191 mg, 0.449 mmol, 1.5 equiv),
and diol 22 (0.120 g, 0.300 mmol, 1.0 equiv) was stirred at 25 °C for
4 h. To the reaction was then added saturated NaHCO3 solution (15
mL), and the product was extracted with ether (3 × 25 mL). The
combined organic layers were dried over Na2SO4, filtered through Celite
eluting with ether, and concentrated to afford aldehyde 23 that was
used for the next step without futher purification. To a solution of
aldehyde 23 in 95% ethanol (1.8 mL) were added ethyl cyanoacetate
(0.963 mL, 9.00 mmol, 30 equiv) and â-alanine (107 mg, 1.20 mmol,
4.0 equiv). After 72 h at 25 °C, the reaction mixture was filtered
through a pad of silica gel eluting with ether and concentrated to afford
R,â-unsaturated cyano ester 24, which was used for the next step
without further purification. The residue of 24 was dissolved in CH2-
Cl2, and N,N-diisopropylethylamine (0.522 mL, 2.99 mmol, 10 equiv)
was added. The reaction was cooled to -78 °C, and TMSOTf (0.288
mL, 1.49 mmol, 5.0 equiv) was added over 15 min. After 2 h, the
reaction was quenched with excess methanol (10 mL) and concentrated.
The resulting residue was purified by flash chromatography (silica gel,
6% EtOAc, hexane) to afford 25 (0.12 g, 71%, three steps): Rf ) 0.27
(silica gel, EtOAc-hexane, 1:3); FT-IR (neat) νmax 2959, 2231, 1730,
1614, 1513, 1248, 1078, 1022, 842 cm-1; 1H NMR (600 MHz, CDCl3)
δ 7.83 (d, J ) 11.8 Hz, 1 H, C-2), 7.19 (d, J ) 8.6 Hz, 2 H, ArH),
6.85 (d, J ) 8.6 Hz, 2 H, ArH), 5.33 (s, 1 H, C-12), 4.81 (d, J ) 11.3
Hz, 1 H, OCHHAr), 4.47 (d, J ) 11.3 Hz, 1 H, OCHHAr), 4.30 (q, J
) 7.2 Hz, 2 H, OCH2CH3), 3.80 (s, 3 H, OCH3), 3.16 (d, J ) 9.8 Hz,
1 H, C-8), 3.02-2.97 (m, 1 H, C-10), 2.50 (s, 1 H, C-5), 2.10-2.05
(m, 1 H), 1.98-1.82 (m, 3 H), 1.73-1.67 (m, 1 H), 1.63 (d, J ) 1.1
Hz, 3 H, C-17), 1.56-1.45 (m, 2 H), 1.47 (s, 3 H, C-17), 1.36 (t, J )
7.2 Hz), 3 H, OCH2CH3), 0.90 (d, J ) 6.8 Hz, 3 H, C-19 or C-20),
0.76 (d, J ) 6.7 Hz, 3 H, C-19 or C-20), 0.20 (s, 9 H, Si-tBu); 13C
NMR (150 MHz, CDCl3) δ 167.9, 161.0, 159.2, 135.8, 130.5, 129.8,
120.8, 113.8, 113.7, 109.2, 86.2, 83.4, 74.5, 74.3, 73.3, 62.2, 55.1, 44.1,
39.7, 39.0, 32.6, 26.0, 23.9, 21.5, 20.9, 17.0, 14.2 1.8; HRMS (FAB)
1
νmax 2954, 1614, 1514, 1464, 1250, 1080, 837, 775 cm-1; H NMR
(250 MHz, CDCl3) δ 7.25 (d, J ) 11.4 Hz, 2 H, ArH), 6.84 (dd, J )
11.4, 2.8 Hz, 2 H, ArH), 5.85-5.66 (m, 1 H, CHdCH2), 5.30-5.17
(m, 3 H, C-12), 4.49 (d, J ) 11.0 Hz, 1 H, CHH-Ar), 4.28 (d, J )
11.0 Hz, 1 H, CHH-Ar), 4.03-3.90 (m, 1 H, C-8), 3.78 (s, 3 H, OCH3),
3.68-3.47 (m, 2 H, C-2), 2.50-2.40 (m, 1 H, C-10), 2.05-1.75 (m, 3
H), 1.60 (d, J ) 2.4 Hz, 3 H, C-17), 1.65-1.45 (m, 4 H), 0.89 (s, 9 H,
Si-tBu), 0.86 (d, J ) 6.7 Hz, 3 H, C-10 or C-20), 0.82 (d, J ) 6.6 Hz,
3 H, C-19 or C-20), 0.04 (s, 6 H, Si-CH3); 13C NMR (62.5 MHz, CDCl3)
δ 158.9, 139.8, 137.4, 131.0, 129.2, 120.8, 116.6, 113.6, 79.6, 70.1,
62.4, 55.2, 40.7, 36.9, 36.1, 34.6, 27.1, 26.0, 24.2, 22.6, 21.0, 18.3,
17.6, -5.2, -5.3; HRMS (FAB) calcd for C29H48CsO3Si (M + Cs+)
605.2427, found 605.2446.
Synthesis of Methyl Ketone 21. A solution of PMB-ether 20 (135
mg, 0.285 mmol, 1.0 equiv) and mercuric acetate (100 mg, 3.4 mmol,
1.2 equiv) in methanol (2 mL) was stirred at 25 °C for 12 h. The
reaction mixture was then transferred to a solution of LiCl (24.1 mg,
0.568 mmol, 2.0 equiv), PdCl2 (50.5 mg, 0.285 mmol, 1.0 equiv), and
CuCl2 (0.115 mg, 0.855 mmol, 3.0 equiv) in methanol (1 mL) via
cannula and was further stirred at 55 °C for another 3 h. Saturated
NaHCO3 (5 mL) was added, and the product was extracted with ether
(20 × 3 mL). The organic extracts were dried over Na2SO4 and
concentrated. The crude product was purified by flash chromatography
(silica gel, 6% EtOAc in hexane) to furnish methyl ketone 21 (90.5
mg, 65%) as a colorless oil: Rf ) 0.34 (silica gel, EtOAc-hexane,
1:15); FT-IR (neat) νmax 2956, 1714, 1514, 1249, 1081, 836 cm-1; 1H
NMR (250 MHz, CDCl3) δ 7.26 (d, J ) 6.6 Hz, 2 H, ArH), 6.85 (dd,
J ) 6.6, 2.1 Hz, 2 H, ArH), 5.33-5.25 (br s, 1 H, C-12), 4.41 (s, 2 H,
OCH2Ar), 4.04 (dd, J ) 9.7, 3.6 Hz, 1 H, C-8), 3.79 (s, 3 H, OCH3),
3.70 (dd, J ) 9.3, 5.8 Hz, 1 H, C-2), 3.59 (t, J ) 9.3 Hz, 1 H, C-2),
2.53-2.44 (m, 1 H, C-10), 2.13 (s, 3 H, COCH3), 2.00-1.75 (m, 3 H),
1.65 (s, 3 H, C-17), 1.70-1.40 (m, 4 H), 0.89 (s, 9 H, Si-tBu), 0.84 (d,
calcd for C33H47CsNO5Si (M + Cs+) 698.2278, found 698.2289; [R]25
-23.3 (c 2.58, CHCl3).
D

Total Synthesis of Sarcodictyins A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8669
Synthesis of r,â-Unsaturated Aldehyde 27. To a solution of cyano
ester 25 (280 mg, 0.497 mmol, 1.0 equiv) in hexanes (25 mL) at -78
°C was added dropwise a 1.0 M THF solution of DIBAL (5.0 mL, 5.0
mmol, 10.0 equiv). After 7 h at -78 °C and 1 h at -40 °C, EtOAc (5
mL) was added, and the reaction mixture was warmed to 25 °C.
Addition of water (30 mL) and stirring for 1 h at ambient temperature
completed the workup procedure. The reaction mixture was extracted
with ether (3 × 50 mL), dried over Na2SO4, and concentrated. The
product was purified by flash chromatography (silica gel, 10% EtOAc
in hexane) to afford alcohol 26 (210 mg, 80%). To a solution of 26
(50.0 mg, 0.0949 mmol, 1.0 equiv) in CH2Cl2 (0.95 mL) was added
N,N-diisopropylethylamine (0.33 mL, 1.90 mmol, 20.0 equiv), and the
resulting mixture was cooled to -78 °C, after which TIPSOTf (0.26
mL, 0.95 mmol, 10.0 equiv) was added dropwise. After 1 h (TLC
monitoring), the reaction was quenched by the addition of MeOH (0.2
mL). After 10 min, aqueous saturated NH4Cl solution (5 mL) was
added, and the mixture was warmed to 25 °C, extracted with ether (10
mL), and concentrated. The residue was purified by flash chromatog-
raphy (silica gel, 2% EtOAc in hexane) to furnish TIPS ether 27 (58.8
mg, 91%) as a colorless oil: Rf ) 0.33 (silica gel, EtOAc-hexane,
1:10); FT-IR (neat) νmax 3470, 3300, 2957, 2360, 2337, 1672, 1613,
3 H, C-19 or C-20), 0.81 (d, J ) 7.0 Hz, 3 H, C-19 or C-20), 0.05 (s,
6 H, Si-CH3); 13C NMR (125.7 MHz, CDCl3) δ 136.5, 121.2, 86.4,
74.6, 72.4, 70.9, 62.5, 40.5, 35.8, 35.0, 30.6, 26.8, 25.8, 24.0, 23.7,
22.2, 20.9, 18.7, 17.0, -5.4, -5.5.
Synthesis of Triol 30. To a solution of diol 29 (0.63 g, 1.59 mmol,
1.0 equiv) in THF (16 mL) at 0 °C was added TBAF (1.0M in THF,
3.18 mL, 3.18 mmol, 2.0 equiv), and the reaction mixture was allowed
to warm to 25 °C over 1 h. After the end of the reaction was established
by TLC, the reaction was quenched by addition of saturated NH4Cl
(50 mL) and extracted with ether (3 × 100 mL). The combined organic
extracts were concentrated, and the residue was purified by filtration
through silica gel to furnish triol 30 (0.45 g, 100%) as a light yellow
oil: Rf ) 0.12 (silica gel, Et2O-hexane, 3:1); FT-IR (neat) νmax 3385,
1
2958, 1448, 1368, 1078, 946 cm-1; H NMR (500 MHz, CDCl3) δ
5.38 (br s, 1 H, C-12), 3.83 (dd, J ) 10.0, 2.5 Hz, 1 H, C-2), 3.81 (dd,
J ) 10.0, 5.5 Hz, 1 H, C-2), 3.73 (dd, J ) 11.0, 8.5 Hz, 1 H, C-8),
2.50 (s, 1 H, C-5), 2.49 (br s, 1 H), 2.01-1.92 (m, 3 H), 1.89-1.81
(m, 3 H), 1.80-1.71 (m, 1 H), 1.72 (d, J ) 1.5 Hz, 3 H, C-17), 1.65-
1.56 (m, 3 H), 1.48 (s, 3 H, C-16), 0.92 (d, J ) 6.5 Hz, 3 H, C-19 or
C-20), 0.83 (d, J ) 6.5 Hz, 3 H, C-19 or C-20); 13C NMR (125.7 MHz,
CDCl3) δ 136.5, 121.3, 86.2, 74.9, 72.9, 71.0, 62.2, 40.4, 36.1, 35.3,
31.2, 26.9, 24.2, 23.5, 22.3, 20.9, 16.7; HRMS (FAB) calcd for C17H28-
1
1513, 1418, 1370, 1302, 1250 cm-1; H NMR (500 MHz, CDCl3) δ
NaO3 (M + Na+) 303.1936, found 303.1944; [R]25 +43.5 (c 0.2,
10.10 (s, 1 H, CHO), 7.20 (d, J ) 8.5 Hz, 2 H, ArH), 7.00 (d, J )
11.5 Hz, 1 H, C-2), 6.81 (d, J ) 8.5 Hz, 2 H, ArH), 5.34 (s, 1 H,
C-12), 4.86 (d, J ) 11.0 Hz, 1 H, OCHHAr), 4.47 (d, J ) 14.0 Hz, 1
H, C-15), 4.38 (d, J ) 11.0 Hz, 1 H, OCHHAr), 4.33 (d, J ) 14.0 Hz,
1 H, C-15), 3.48 (s, 3 H, OCH3), 3.45-3.36 (m, 1 H, C-10), 3.36 (d,
J ) 10.0 Hz, 1 H, C-8), 2.44 (s, 1 H, C-5), 2.25-2.17 (m, 1 H), 2.02-
1.94 (m, 1 H), 1.92-1.78 (m, 2 H), 1.72-1.62 (m, 1 H), 1.61 (s, 3 H,
C-17), 1.60-1.50 (m, 3 H), 1.43 (s, 3 H, C-16), 1.15-1.05 (m, 3 H,
TIPS), 1.04 (d, J ) 7.8 Hz, 18 H, TIPS), 0.90 (d, J ) 6.8 Hz, 3 H,
C-19 or C-20), 0.72 (d, J ) 6.6 Hz, 3 H, C-19 or C-20), 0.18 (s, 9 H,
Si-CH3); 13C NMR (125 MHz, CDCl3) δ 190.2, 159.0, 152.8, 138.3,
136.0, 131.2, 129.4, 120.8, 113.6, 86.6, 84.3, 74.7, 74.6, 73.5, 60.0,
55.2, 42.5, 38.1, 36.6, 31.7, 28.5, 25.5, 23.9, 21.8, 20.9, 18.0, 17.7,
12.0, 2.0; HRMS (FAB) calcd for C40H66CsNO5Si (M + Cs+) 815.3503,
D
CHCl3).
Synthesis of Trisilyl Ether 31. To a solution of triol 30 (0.45 g,
1.59 mmol, 1.0 equiv) in CH2Cl2 (16 mL) was added triethylamine
(2.3 mL, 16.5 mmol, 10.3 equiv), and the solution was chilled to 0 °C.
TESOTf (2.10 g, 8.00 mmol, 5.0 equiv) was then added, and the
reaction mixture was allowed to warm to 25 °C. After the disappear-
ance of the starting triol was established by TLC, the reaction was
quenched by addition of saturated NH4Cl (50 mL) and extracted with
CH2Cl2 (3 × 100 mL). The organic extracts were combined, dried
over MgSO4, and concentrated. The residue was purified by filtration
through silica gel (25% Et2O in hexane) to produce trisilyl ether 31
(0.99 g, 100%) as a light yellow oil: Rf ) 0.62 (silica gel, Et2O-
hexane, 1:9); FT-IR (neat) νmax 3308, 2956, 2876, 1459, 1414, 1378,
found 815.3538; [R]25 -10.1 (c 0.98, CHCl3).
1
1239, 1115, 1006 cm-1; H NMR (500 MHz, CDCl3) δ 5.30 (br s, 1
D
H, C-12), 3.77 (d, J ) 10.0, 7.5 Hz, 1 H, C-2), 3.60 (dd, J ) 10.0, 7.5
Hz, 1 H, C-2), 2.43 (s, 1 H, C-5), 2.34 (br s, 1 H), 1.97-1.75 (m, 6
H), 1.67 (s, 3 H, C-17), 1.64-1.57 (m, 1 H), 1.39 (s, 3 H, C-16), 1.00-
0.94 (m, 27 H, Si-CH2CH3), 0.91 (d, J ) 7.0 Hz, 3 H, C-19 or C-20),
0.85 (d, J ) 7.0 Hz, 3 H, C-19 or C-20), 0.81-0.57 (m, 18 H, Si-
CH2CH3); 13C NMR (125.7 MHz, CDCl3) δ 137.8, 120.7, 87.2, 78.1,
73.9, 61.6, 42.7, 36.6, 35.1, 34.9, 29.9, 27.2, 25.3, 23.9, 22.0, 21.5,
17.1, 7.1, 6.9, 6.8, 6.0, 5.6, 4.3; HRMS (FAB) calcd for C35H70CsO3-
Si3 (M + Cs+) 755.3687, found 755.3710; [R]25D +19.0 (c 0.8, CHCl3).
Selective Deprotection of the Primary Hydroxide to Produce
Alcohol 32. To a solution of trisilyl ether 31 (1.48 g, 2.37 mmol, 1.0
equiv) in 3:1 MeOH/CH2Cl2 (20 mL) was added a catalytic amount of
PPTS (45 mg, 0.24 mmol, 0.1 equiv). After its completion (TLC
monitoring), the reaction mixture was worked up by addition of
saturated NaHCO3 (50 mL) and extraction with ether (3 × 150 mL).
The combined organic extracts were dried over MgSO4 and concen-
trated. The residue was purified by filtration through silica gel eluting
with ether to provide alcohol 32 (1.18 g, 98%) as a colorless oil: Rf )
0.12 (silica gel, Et2O-hexane, 1:9); FT-IR (neat) νmax 3490, 3308, 2955,
2876, 1459, 1414, 1378, 1238, 1109, 1072, 1004 cm-1; 1H NMR (500
MHz, CDCl3) δ 5.33 (br s, 1 H, C-12), 3.79 (dd, J ) 9.5, 1.5 Hz, 1 H),
3.79-3.74 (m, 1 H), 3.70 (dd, J ) 11.0, 4.5 Hz, 1 H, C-2), 2.46 (s, 1
H, C-5), 2.35 (br s, 1 H), 2.04 (ddd, J ) 15.0, 9.0, 1.5 Hz, 1 H), 1.97-
1.72 (m, 5 H), 1.69 (d, J ) 1.5 Hz, 3 H, C-17), 1.69-1.52 (m, 2 H),
1.46 (s, 3 H, C-16), 0.97 (t, J ) 7.5 Hz, 18 H, Si-CH2CH3), 0.92 (d,
J ) 6.5 Hz, 3 H), 0.83 (d, J ) 6.5 Hz, 3 H), 0.80-0.65 (m, 12 H,
Si-CH2CH3); 13C NMR (125.7 MHz, CDCl3) δ 137.4, 120.7, 86.4, 78.0,
74.0, 73.4, 62.5, 41.2, 36.9, 35.2, 33.9, 26.9, 26.4, 23.9, 22.3, 21.3,
17.1, 7.0, 6.9, 6.7, 6.3, 5.9, 5.6; HRMS (FAB) calcd for C29H56CsO3-
Si2 (M + Cs+) 641.2822, found 641.2852; [R]25D +20.4 (c 2.0, CHCl3).
Synthesis of Aldehyde 33. To a solution of alcohol 32 (1.24 g,
2.43 mmol, 1.0 equiv) and powdered activated 4 Å MS (0.5 g) in CH2-
Cl2 (16 mL) was added NMO (0.43 g, 3.64 mmol, 1.5 equiv), and the
reaction mixture was stirred for 10 min. TPAP (0.043 g, 0.181 mmol,
Synthesis of Diastereoisomeric Diols 29. To a solution of ethyl
vinyl ether (1.16 g, 16.0 mmol, 2.0 equiv) in THF (70.0 mL) at -78
°C was added 1.7 M t-BuLi in hexanes (8.5 mL, 14.4 mmol, 1.8 equiv),
and the solution was warmed to 0 °C. The reaction was followed by
the color change from yellow to colorless. The resulting vinyl anion
solution was then cooled to -78 °C, and a solution of aldehyde 14
(2.60 g, 8.02 mmol, 1.0 equiv) in THF (25 mL) was added dropwise,
after which the reaction mixture was stirred for an additional 30 min
at -78 °C. The reaction was quenched by addition of saturated NH4-
Cl solution (40 mL) and extracted with ether (3 × 150 mL). The
combined organic extracts were dried over MgSO4 and concentrated.
The crude product was then dissolved in ether and treated with
concentrated H2SO4 in a separatory funnel while shaking vigorously.
The progress of the hydrolysis was followed by TLC, and upon
completion, the ether solution was washed with water (20 mL) and
saturated NaHCO3 solution (20 mL), dried over MgSO4, and concen-
trated. The residue was purified by flash chromatography (silica gel,
10% to 15% Et2O in hexane) to produce hydroxy ketones 28 as an
inseparable mixture of stereoisomers (ca. 1.25:1 by NMR). To a
solution of mixture 28 in THF (78 mL) at -78 °C was added
ethynylmagnesium bromide (0.5 M in THF, 70.8 mL, 35.0 mmol, 4.4
equiv), and the solution was stirred at -78 °C for 6 h and then was
allowed to slowly warm to -10 °C. The reaction was quenched by
addition of saturated NH4Cl solution (50 mL) and extracted with ether
(3 × 100 mL). The combined organic extracts were dried over MgSO4
and concentrated, and the resulting residue was purified by flash
chromatography (silica gel, 10% to 25% Et2O in hexane) to afford the
desired isomer 29 (1.39 g, 44%) along with its C-7, C-8 stereoisomer
1
(1.04 g, 33%). For 29: Rf ) 0.40 (silica gel, Et2O-hexane, 1:3); H
NMR (500 MHz, CDCl3) δ 5.32 (br s, 1 H, C-12), 3.84-3.79 (m, 1 H,
C-2), 3.72-3.67 (m, 1 H, C-2), 3.64 (dd, J ) 10.5, 9.5 Hz, 1 H, C-8),
3.02 (d, J ) 4.0 Hz, 1 H), 2.95 (br s, 1 H), 2.48-2.43 (m, 1 H), 2.43
(s, 1 H, C-5), 1.98-1.70 (m, 5 H), 1.68 (s, 3 H, C-17), 1.63-1.44 (m,
2 H), 1.42 (s, 3 H, C-16), 0.88 (s, 9 H, Si-tBu), 0.88 (d, J ) 7.5 Hz,

8670 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Nicolaou et al.
2361, 1675, 1462, 1381, 1239, 1167, 1117, 1007, 882, 819, 741 cm-1
0.07 equiv) was then added, and the reaction mixture was stirred at 25
°C for 30 min. The heterogeneous solution was then filtered through
a short pad of silica gel and washed with CH2Cl2. After concentration,
aldehyde 33 (1.20 g, 98%) was obtained as a colorless oil: Rf ) 0.42
(silica gel, Et2O-hexane, 1:9); FT-IR (neat) νmax 3309, 2955, 2876,
1719, 1458, 1414, 1378, 1238, 1073, 1004 cm-1; 1H NMR (500 MHz,
CDCl3) δ 9.86 (d, J ) 6.7 Hz, 1 H, C-2), 5.37 (br s, 1 H, C-12), 3.41
(d, J ) 12.0 Hz, 1 H, C-8), 2.47-2.42 (m, 1 H), 2.43 (s, 1 H, C-5),
2.36-2.29 (m, 2 H), 2.09-1.97 (m 2 H), 1.86-1.67 (m, 2 H), 1.69 (d,
J ) 1.7 Hz, 3 H, C-17), 1.57-1.52 (m, 1 H), 1.39 (s, 3 H, C-16),
1.00-0.85 (m, 24 H), 0.80-0.59 (m, 12 H); 13C NMR (125.7 MHz,
CDCl3) δ 207.8, 136.2, 121.2, 86.4, 78.7, 74.2, 72.9, 53.5, 37.2, 35.5,
33.9, 28.7, 25.8, 25.7, 23.6, 21.6, 21.1, 16.1, 7.0, 6.8, 6.4, 6.0, 5.6;
HRMS (FAB) calcd for C29H54NaO3Si2 (M + Na+) 529.3509, found
;
1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1 H, C-4), 6.98 (d, J ) 11.6
Hz, 1 H, C-2), 5.37 (br s, 1 H, C-12), 4.52 (dd, J ) 14.0, 1.2 Hz, 1 H,
C-15), 4.21 (dd, J ) 14.0, 1.6 Hz, 1 H, C-15), 3.53 (d, J ) 9.3 Hz, 1
H, C-8), 3.45-3.38 (m, 1 H, C-1), 2.39 (s, 1 H, C-5), 2.28-2.23 (m,
1 H), 2.04-1.92 (m, 2 H), 1.90-1.82 (m, 1 H), 1.78-1.70 (m, 1 H),
1.65-1.54 (m, 1 H), 1.67 (d, J ) 1.2 Hz, 3 H, C-17), 1.45-1.38 (m,
1 H), 1.33 (s, 3 H, C-16), 1.03-1.00 (m, 24 H, TIPS, C19 or C20),
0.93-0.87 (m, 21 H, Si-CH2CH3 and C19 or C20), 0.72-0.50 (m, 12
H); 13C NMR (100.6 MHz, CDCl3) δ 190.1, 153.0, 138.4, 136.5, 120.8,
86.9, 78.6, 74.6, 72.8, 60.5, 40.8, 39.2, 37.2, 33.9, 29.7, 28.4, 25.0,
23.7, 21.9, 21.2, 18.0, 16.7, 11.9, 7.1, 6.1, 5.9, 5.6; HRMS (FAB) calcd
for C41H78NaO4Si3 (M + Na+) 741.5105, found 741.5136; [R]25D +33.7
(c 1.4, CHCl3).
529.3487; [R]25 +18.5 (c 0.65, CHCl3).
D
Synthesis of Alkynone 37 by Intramolecular Acetylide Addition
to Aldehyde 27. A solution of LiHMDS (1.0M in THF, 0.037 mL,
0.037 mmol, 1.5 equiv) was added dropwise to a solution of aldehyde
27 (17.0 mg, 0.025 mmol, 1.0 equiv) in THF (1.2 mL) at 25 °C. After
10 min (TLC monitoring), the reaction mixture was quenched by the
addition of aqueous saturated NH4Cl solution (5 mL), extracted with
ether (2 × 10 mL), dried over Na2SO4, and concentrated. The residue
was redissolved in CH2Cl2 (1.0 mL) and NaHCO3 (41.8 mg, 0.497
mmol, 20 equiv) was added to the solution at 0 °C. After 40 min,
Dess-Martin periodinane (10.6 mg, 0.025 mmol, 1.0 equiv) was added
to the reaction mixture at the same temperature, and the solution was
warmed to 25 °C. After 4 h of stirring at ambient temperature, the
reaction was diluted with ether (5 mL) and quenched by the consecutive
addition of saturated aqueous NaHCO3 solution (5 mL) and sodium
thiosulfate pentahydrate (Na2S2O3‚5H2O, 65 mg, 0.261 mmol, 10.4
equiv). The resulting solution was extracted with ether (2 × 10 mL),
and the combined organic extracts were dried over Na2SO4 and
concentrated. The crude product was purified by flash chromatography
(silica gel, 1% EtOAc in hexane) to provide enyneone 37 (14.4 mg,
85%, two steps) as a colorless oil: Rf ) 0.46 (silica gel, EtOAc-
hexane, 1:10); FT-IR (neat) νmax 2961, 2361, 2197, 1650, 1611, 1512,
Formation of r,â-unsaturated Cyano Ester 34. A solution of
aldehyde 33 (1.14 g, 2.25 mmol, 1.0 equiv), ethyl cyanoacetate (7.63
g, 67.0 mmol, 30 equiv), and â-alanine (0.080 g, 9.00 mmol, 4.0 equiv)
in EtOH (15 mL) was stirred at 50 °C for 72 h. The reaction mixture
was then concentrated and purified by filtration through a short pad of
silica gel eluting with 10% Et2O in hexanes to produce cyano ester 34
(1.28 g, 95%) as a colorless oil: Rf ) 0.40 (silica gel, Et2O-hexane,
1:9); FT-IR (neat) νmax 3308, 2958, 2878, 2201, 1735, 1619, 1461,
1370, 1249, 1117, 1008 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.88 (d,
J ) 12.0 Hz, 1 H, C-2), 5.39 (br s, 1 H, C-12), 4.36-4.26 (m, 2 H,
OCH2CH3), 3.34 (d, J ) 9.5 Hz, 1 H, C-8), 3.06 (dd, J ) 7.0, 5.0 Hz,
1 H, C-1), 2.47 (s, 1 H, C-5), 2.28-2.23 (m, 1 H), 2.13 (dd, J ) 15.0,
9.0 Hz, 1 H, C-13), 1.99-1.74 (m, 5 H), 1.69 (s, 3 H, C-17), 1.38 (s,
3 H, C-16), 1.35 (t, J ) 7.0 Hz, 3 H, OCH2CH3), 1.00-0.91 (m, 6 H,
C-19 and C-20), 0.99 (t, J ) 8.0 Hz, 9 H, SiCH2CH3), 0.94 (t, J ) 7.5
Hz, 9 H), 0.81-0.58 (m, 12 H); 13C NMR (125.7 MHz, CDCl3) δ 168.3,
160.9, 136.2, 120.9, 113.8, 109.0, 86.4, 78.9, 74.2, 72.7, 62.2, 44.8,
40.1, 38.5, 34.3, 31.4, 30.2, 29.6, 25.8, 23.7, 21.6, 21.1, 15.9, 14.1,
7.1, 7.0, 6.1, 5.6; HRMS (FAB) calcd for C34H59CsNO4Si2 (M + Cs+)
734.3037, found 734.3063; [R]25 +46.4 (c 1.2, CHCl3).
D
1461, 1384, 1461, 1384, 1248, 1175, 1095, 1035, 841, 760, 685 cm-1
;
Synthesis of Hydroxy Aldehyde 35. To a solution of cyanoester
34 (101 mg, 0.168 mmol, 1.0 equiv) in hexanes (8.4 mL) at -78 °C
was added DIBAL (1.0M in toluene, 1.7 mL, 1.70 mmol, 10.0 equiv).
The reaction mixture was stirred for 6 h at -78 °C and then slowly
warmed to -10 °C for 2 h. The reaction was then quenched with
ethyl acetate (0.2 mL), saturated NH4Cl (10 mL) solution was added,
and the reaction was stirred for 2 h, after which it was filtered through
a short Celite pad eluting with ether and extracted with ethyl acetate
(3 × 10 mL). The combined organic extracts were concentrated and
purified by flash chromatography (silica gel, 10% Et2O in hexanes) to
produce hydroxyaldehyde 35 (79.8 mg, 90%) as a light yellow oil: Rf
) 0.42 (silica gel, Et2O-hexane, 1:1); FT-IR (neat) νmax 3447, 3307,
2957, 2877, 1677, 1459, 1414, 1380, 1239, 1117, 1008 cm-1; 1H NMR
(500 MHz, CDCl3) δ 10.18 (s, 1 H, C-4), 6.89 (d, J ) 12.0 Hz, 1 H,
C-2), 5.39 (br s, 1 H, C-12), 4.35 (dd, J ) 13.0, 5.0 Hz, 1 H, C-15),
4.17 (dd, J ) 13.0, 7.0 Hz, 1 H, C-15), 3.47 (d, J ) 10.0 Hz, 1 H,
C-8), 3.37-3.29 (m, 1 H, C-1), 2.49 (s, 1 H, C-5), 2.23-2.12 (m, 3
H), 2.01-1.68 (m, 4 H), 1.68 (d, J ) 1.0 Hz, 3 H, C-17), 1.58 (s, 1
H), 1.37 (s, 3 H, C-16), 0.98-0.88 (m, 6 H, C-19 and C-20), 0.97 (t,
J ) 8.0 Hz, 9 H, SiCH2CH3), 0.89 (t, J ) 8.0 Hz, 9 H, SiCH2CH3),
0.81-0.62 (m, 12 H, SiCH2CH3); 13C NMR (125.7 MHz, CDCl3) δ
191.2. 154.8, 138.1, 136.6, 120.9, 86.8, 79.3, 74.5, 72.9, 62.8, 40.9,
38.4, 38.3, 34.2, 29.7, 28.5, 25.6, 23.5, 21.7, 21.1, 15.4, 7.1, 7.0, 6.0,
5.6; HRMS (FAB) calcd for C32H58O4Si2 (M + Cs+) 695.2928, found
1H NMR (400 MHz, CDCl3) δ 7.25 (d, J ) 8.3 Hz, 2 H, Ar-H), 6.84
(d, J ) 8.3 Hz, 2 H, Ar-H), 6.27 (d, J ) 12.0 Hz, 1 H, C-2), 5.33 (br
s, 1 H, C-12), 4.80 (d, J ) 12.0 Hz, 1 H OCHH-Ar), 4.65 (d, J ) 12.0
Hz, 1 H, OCHH-Ar), 4.34 (d, J ) 14.2 Hz, 1 H, C-15), 4.30 (d, J )
14.2 Hz, 1 H, C-15), 3.78 (s, 3 H, OCH3), 3.39 (d, J ) 2.8 Hz, 1 H,
C-8), 3.36 (d, J ) 12.0 Hz, 1 H, C-1), 2.18-2.05 (m, 1 H), 1.98-1.80
(m, 2 H), 1.67 (s, 3 H, C-17), 1.62-1.53 (m, 1 H), 1.45 (s, 3 H, C-16),
1.20-1.10 (m, 1 H, C-14), 1.08-0.94 (m, 21 H, TIPS), 0.81 (d, J )
6.4 Hz, 3 H, C-19 or C-20), 0.64 (d, J ) 6.5 Hz, 3 H, C-19 or C-20),
0.24 (s, 9 H, Si-CH3); 13C NMR (100.6 MHz, CDCl3) δ 181.2, 159.2,
142.0, 139.5, 133.6, 130.9, 129.7, 121.4, 113.7, 103.2, 88.6, 87.2, 73.7,
73.5, 63.5, 55.2, 44.8, 38.3, 37.8, 33.4, 29.6, 25.7, 21.9, 21.9, 21.5,
20.3, 17.9, 11.9, 1.7; HRMS (FAB) calcd for C40H64CsO5Si2 (M +
Cs+) 813.3347, found 813.3314; [R]25 +22.7 (c 1.8, CHCl3).
D
Synthesis of Propargylic Alcohol 38. To a solution trimethylsilyl
ether 37 (3.2 mg, 0.0047 mmol, 1.0 equiv) in MeOH (1 mL) was added,
at 25 °C, PPTS (1.18 mg, 0.0047 mmol, 1.0 equiv), and the reaction
mixture was allowed to stir at ambient temperature for 30 min. The
reaction was quenched by addition of saturated NaHCO3 solution (1
mL) and extracted with ether (2 × 10 mL). The combined organic
extracts were dried over Na2SO4 and concentrated. The crude product
was purified by flash chromatography (silica gel, 15% EtOAc in hexane)
to provide alcohol 38 (2.7 mg, 94%) as a colorless oil: Rf ) 0.45 (silica
gel, EtOAc-hexane, 1:3); 1H NMR (600 MHz, CDCl3) δ 7.22 (d, J )
6.7 Hz, 2 H, ArH), 6.85 (dd, J ) 6.7, 2.3 Hz, 2 H, ArH), 6.28 (d, J )
11.7 Hz, 1 H, C-2), 5.39 (s, 1 H, C-12), 4.70 (d, J ) 11.6 Hz, 1 H,
OCHHAr), 4.59 (d, J ) 11.6 Hz, 1 H, OCHHAr), 4.34 (s, 2 H, C-15),
3.78 (s, 3 H, OCH3), 3.52 (s, 1 H, C-8), 3.44 (d, J ) 11.6 Hz, 1 H,
C-1), 2.48 (br s, 1 H, OH), 2.22-2.10 (m, 2 H), 2.01 (d, J ) 14.1 Hz,
1 H), 1.92 (d, J ) 18.3 Hz, 1 H), 1.72 (s, 3 H, C-17), 1.70-1.66 (m,
1 H), 1.47 (s, 3 H, C-16), 1.40-1.30 (m, 2 H), 1.10-1.02 (m, 21 H,
TIPS), 0.85 (d, J ) 6.7 Hz, 3 H, C-19 or C-20), 0.74 (d, J ) 6.7 Hz,
3 H, C-19 or C-20); 13C NMR (150 MHz, CDCl3) δ 181.0, 159.5, 142.7,
139.3, 133.1, 129.8, 129.5, 122.0, 114.0, 102.2, 87.6, 86.1, 72.5, 71.7,
63.5, 55.3, 45.1, 38.7, 37.8, 32.6, 29.7, 25.7, 21.9, 21.5, 21.4, 20.5,
695.2951; [R]25 +66.0 (c 3.0 CHCl3).
D
Synthesis of Trisilyl Ether 36. To a solution of hydroxy aldehyde
35 (930.0 mg, 1.65 mmol, 1.0 equiv) and iPr2NEt (2.8 mL, 16.07 mmol,
9.7 equiv) in CH2Cl2 (8 mL) at -78 °C was added TIPSOTf (2.2 mL,
8.25 mmol, 5.0 equiv), and the solution was stirred at that temperature
for 1 h. The reaction mixture was quenched by addition of MeOH
(0.5 mL) followed by addition of saturated NH4Cl (10 mL). The
mixture was then extracted with ether (10 mL), and the organic extracts
were combined, dried over Na2SO4, and concentrated. The resulting
residue was purified by flash chromatography (silica gel, 2% EtOAc-
hexane) to furnish trisilyl ether 36 (1.10 g, 93%) as a light yellow oil:
Rf ) 0.33 (silica gel, hexane); FT-IR (neat) νmax 3309, 2957, 2872,

Total Synthesis of Sarcodictyins A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8671
17.9, 11.9; HRMS (FAB) calcd for C37H56CsO5Si (M + Cs+) 741.2951,
by addition of saturated NaHCO3 (10 mL), extracted with ether (3 ×
10 mL), dried over Na2SO4, and concentrated to a crude residue. To
a solution of this residue in MeOH (6 mL) was added PPTS (6.9 mg,
0.027 mmol, 0.5 equiv) at 25 °C. After 10 min, the reaction was
quenched by addition of saturated NaHCO3, (10 mL), extracted with
ether (3 × 20 mL), dried over Na2SO4 and concentrated. The residue
was purified by flash chromatography (silica gel, 15% EtOAc in hexane)
to produce methyl ketal 42 (22.2 mg, 80%, two steps) as a colorless
oil: Rf ) 0.43 (silica gel, EtOAc-hexane, 1:3); FT-IR (neat) νmax 3456,
found 741.2979; [R]25 +39.3 (c 0.68, CHCl3).
D
Synthesis of the Basic Tricyclic Core 40. To a solution of alkynone
38 (6.2 mg, 0.0135 mmol, 1.0 equiv) in toluene (1 mL) was added 5%
Pd on CaSO4 treated with Pb (Lindlar catalyst, 14.0 mg, 0.00675 mmol,
0.5 equiv) at 25 °C under argon. This suspension was then stirred
under a H2 atmosphere (1 atm) at the same temperature for 20 min,
and the reaction mixture was filtered through Celite and concentrated.
The crude residue was purified by flash chromatography (silica gel,
10% EtOAc-hexanes) to produce hemiketal 40 (6.2 mg, 75%) as a
colorless oil, along with its 5,6-dihydro analogue (1.5 mg, 15%): Rf )
0.55 (silica gel, EtOAc-hexane, 1:3); FT-IR (neat) νmax 3418, 2866,
1
2940 2866, 1466, 1366, 1047, 881 cm-1; H NMR (500 MHz, C6D6)
δ 6.03 (d, J ) 5.8 Hz, 1 H, C-5 or C-6), 5.95 (d, J ) 9.5 Hz, 1 H,
C-2), 5.92 (d, J ) 5.8 Hz, 1 H, C-5 or C-6), 5.37 (br s, 1 H, C-12),
4.43 (d, J ) 14.0 Hz, 1 H, C-5), 4.41 (d, J ) 14.0 Hz, 1 H, C-5),
4.20-4.10 (m, 1 H, C-8), 3.53 (d, J ) 7.0 Hz, 1 H, C-1), 3.16 (s, 3 H,
OCH3), 2.53 (br d, J ) 18.5 Hz, 1 H, C-13), 2.34 (br d, J ) 10.5 Hz,
1 H, C-10), 2.04 (d, J ) 18.5 Hz, 1 H, C-13), 1.75-1.66 (m, 1 H),
1.63 (s, 3 H, C-17), 1.60-1.53 (m, 2 H), 1.52 (s, 3 H, C-16), 1.36-
1.28 (m, 1 H), 1.25-1.18 (m, 1 H), 1.15-1.05 (m, 21 H, TIPS), 0.96
(d, J ) 6.5 Hz, 3 H, C-19 or C-20), 0.93 (d, J ) 6.5 Hz, 3 H, C-19 or
C-20); 13C NMR (125 MHz, C6D6) δ 137.3, 134.6, 134.5, 130.1, 129.5,
121.9, 116.2, 91.6, 80.8, 65.2, 49.4, 43.2, 39.6, 35.0, 33.8, 29.6, 25.3,
24.9, 22.6, 22.4, 20.7, 18.3, 12.4; HRMS (FAB) calcd for C30H52NaO4-
Si (M + Na+) 527.3532, found 527.3548; [R]25D +75.7 (c 2.3, benzene).
1
1615, 1515, 1463, 1248, 1017 cm-1; H NMR (600 MHz, CDCl3) δ
7.24 (d, J ) 8.5 Hz, 2 H, ArH), 6.85 (dd, J ) 8.5, 2.3 Hz, 2 H, ArH),
6.04 (s, 2 H, C-5, C-6), 5.40 (d, J ) 9.3 Hz, 1 H, C-2), 5.25 (s, 1 H,
C-12), 4.89 (s, 1 H, OH), 4.56 (d, J ) 11.3 Hz, 1 H, C-15), 4.37 (d,
J ) 11.3 Hz, 1 H, OCHH-Ar), 4.36 (d, J ) 11.6 Hz, 1 H, C-15), 4.05
(d, J ) 11.6 Hz, 1 H, C-15), 3.95-3.90 (m, 1 H, C-1), 3.78 (s, 3 H,
OCH3), 3.31 (d, J ) 7.1 Hz, 1 H, CHCdC), 2.27 (br d, J ) 16.4 Hz,
1 H), 2.16 (br d, J ) 11.5 Hz, 1 H), 1.98 (br d, J ) 17.9 Hz, 1 H),
1.74 (d, J ) 13.9 Hz, 1 H), 1.57 (s, 3 H, CdCCH3), 1.54 (s, 3 H,
OCCH3), 1.48-1.40 (m, 1 H), 1.28-1.20 (m, 2 H), 1.15-1.05 (m, 3
H, Si-CH(CH3)2), 1.03 (d, J ) 6.4 Hz, 18 H, Si-CH(CH3)2), 0.91 (d, J
) 6.7 Hz, 3 H, C-19 or C-20), 0.87 (d, J ) 6.7 Hz, 3 H, C-19 or
C-20); 13C NMR (150 MHz, CDCl3) δ 159.4, 136.2, 134.6, 133.9, 133.4,
131.2, 130.3, 129.8, 121.5, 113.8, 112.2, 91.4, 86.6, 71.3, 68.3, 55.3,
42.0, 39.2, 33.7, 29.5, 29.0, 25.8, 24.4, 22.2, 22.1, 20.3, 17.8, 11.6;
HRMS (FAB) calcd for C37H58CsO5Si (M + Cs+) 743.3108, found
Synthesis of 5,6-Dihydro Analogue 43 from Hydroxy Alkynone
45. To a solution of ketone 45 (4.5 mg, 0.0092 mmol, 1.0 equiv) in
ethyl acetate (0.5 mL) was added 5% Pd on BaSO4 (19.6 mg, 0.0092
mmol, 1.0 equiv). This suspension was stirred under a hydrogen
atmosphere (1 atm) at 25 °C for 1 h. The reaction mixture was then
filtered through Celite and concentrated by evaporation. To a solution
of the crude residue in MeOH (0.5 mL) was added PPTS (4.6 mg,
0.018 mmol, 2.0 equiv), and the mixture was stirred for 6 h at 25 °C.
A saturated solution of NaHCO3 (5 mL) was added, and the reaction
mixture was extracted with ether (3 × 10 mL), dried over Na2SO4,
and concentrated. The crude residue was purified by flash chroma-
tography (silica gel, 15% EtOAC-hexane) to provide 5,6-dihydro
methyl ketal analogue 43 (3.0 mg, 64%, two steps): Rf ) 0.50 (silica
gel, EtOAc-hexane, 1:3); FT-IR (neat) νmax 3422, 2961, 2865, 2361,
1464, 1383, 1122, 1047, 882, 684 cm-1; 1H NMR (400 MHz, C6D6) δ
6.05 (d, J ) 9.7 Hz, 1 H, C-2), 5.41 (br s, 1 H, C-12), 4.31 (dd, J )
13.7, 1.0 Hz, 1 H, C-15), 4.26 (dd, J ) 13.7, 1.5 Hz, 1 H, C-15),
4.16-4.12 (m, 1 H, C-1), 3.38 (d, J ) 16 Hz, 1 H, C-8), 3.23 (s, 3 H,
OCH3), 2.63-2.52 (m, 1 H), 2.41-2.26 (m, 3 H), 2.19-2.11 (m, 2H),
1.85-1.79 (m, 1 H), 1.70-1.58 (m, 3 H), 1.66 (s, 3 H, C-17), 1.45 (s,
3 H, C-16), 1.35-1.30 (m, 2 H), 1.15-1.01 (m, 21 H, TIPS), 1.01 (d,
J ) 6.6 Hz, 3 H, C-19 or C-20), 0.96 (d, J ) 6.4 Hz, 3 H, C-19 or
C-20); 13C NMR (100.6 MHz, C6D6) δ 137.7, 134.5, 130.3, 121.9,
112.9, 87.4, 80.2, 64.7, 49.8, 43.8, 39.7, 38.9, 35.4, 33.8, 29.6, 29.3,
28.9, 25.1, 22.6, 22.3, 20.8, 18.3, 12.3; HRMS (FAB) calcd for C30H54-
743.3132; [R]25 +38.1 (c 0.28, CHCl3).
D
Synthesis of Methyl Ketal 41. To a solution of hemiketal 40 (4.0
mg, 0.0066 mmol, 1.0 equiv) in MeOH (0.5 mL) was added PPTS
(1.65 mg, 0.0066 mmol, 1.0 equiv). After 10 min, the reaction was
quenched by addition of saturated NaHCO3 solution (5 mL). The
biphasic system was then extracted with CH2Cl2,(3 × 10 mL), and the
organic extracts were combined, dried over Na2SO4, and concentrated.
The product was purified by flash chromatography (silica gel, 5%
EtOAc in hexane) to furnish ketal 41 (4.5 mg, 100%) as a light yellow
oil: Rf ) 0.68 (silica gel, EtOAc-hexane, 1:3); FT-IR (neat) νmax 2957,
2866, 1614, 1514, 1463, 1250, 1064 cm-1; 1H NMR (600 MHz, CDCl3)
δ 7.24 (d, J ) 8.5 Hz, 2 H, ArH), 6.86 (d, J ) 8.5 Hz, 2 H, ArH), 6.06
(d, J ) 5.8 Hz, 1 H, C-5 or C-6), 5.91 (d, J ) 5.8 Hz, 1 H, C-5 or
C-6), 5.65 (d, J ) 9.5 Hz, 1 H, C-2), 5.22 (s, 1 H, C-12), 4.57 (d, J )
11.4 Hz, 1 H, OCHHAr), 4.36 (d, J ) 11.4 Hz, 1 H, OCHHAr), 4.17
(d, J ) 13.5 Hz, 1 H, C-15), 4.12 (d, J ) 13.5 Hz, 1 H, CHHOSi),
3.83-3.80 (m, 1 H, C-8), 3.79 (s, 3 H, ArOCH3), 3.28 (d, J ) 7.0 Hz,
1 H, C-1), 3.15 (s, 3 H, OCH3), 2.34 (br d, J ) 19.4 Hz, 1 H), 2.14 (br
d, J ) 8.6 Hz, 1 H), 1.95 (br d, J ) 17.9 Hz, 1 H), 1.73 (d, J ) 14.9
Hz, 1 H), 1.56 (s, 3 H, C-17), 1.45 (s, 3 H, C-16), 1.38-1.30 (m, 1 H),
1.25-1.17 (m, 2 H), 1.07-1.00 (m, 3 H, Si-CH(CH3)2), 1.01 (d, J )
6.4 Hz, 18 H, Si-tBu), 0.90 (d, J ) 6.7 Hz, 3 H, C-19 or C-20), 0.85
(d, J ) 6.7 Hz, 3 H, C-19 or C-20); 13C NMR (150 MHz, CDCl3) δ
159.4, 136.5, 135.1, 134.3, 130.3, 129.9, 129.7, 128.5, 121.5, 115.7,
113.8, 91.0, 86.7, 71.1, 64.7, 55.2, 49.4, 42.3, 39.3, 33.2, 29.3, 29.1,
24.6, 24.5, 22.1, 20.4, 17.9, 11.8; HRMS (FAB) calcd for C38H60CsO5-
Si (M + Cs+) 757.3264, found 757.3294; [R]25D +43.9 (c 0.20, CHCl3).
Synthesis of Alcohol 42 from PMB-ether 41. A solution of ether
41 (5.0 mg, 0.0080 mmol, 1.0 equiv) in THF (1 mL) and EtOH (2
drops) was added to liquid NH3 (2 mL) at -78 °C. Sodium (1.8 mg,
0.078 mmol, 9.8 equiv) was then added, and the reaction was stirred
at -78 °C for 20 min. After the end of the deprotection was established
by TLC, the reaction was quenched by addition of solid NH4Cl (50
mg), warmed to ambient temperature to evaporate the NH3, extracted
with ether (3 × 10 mL), dried with Na2SO4, concentrated, and purified
by flash chromatography (silica gel, 15% EtOAc in hexane) to provide
alcohol 42 along with its 5,6-dihydro analogue 43 as an inseparable
mixture (ca. 2:1, 3.8 mg, 95%).
NaO4Si (M + Na+) 529.3689, found 529.3708; [R]25 +32.6 (c 0.83,
D
1,4-dioxane).
Synthesis of Bicyclic Alcohol 44. To a solution of PMB-ether 37
(31.0 mg, 0.045 mmol, 1.0 equiv) in CH2Cl2 (4.6 mL) and H2O (0.3
mL) was added DDQ (21.0 mg, 0.091 mmol, 2.0 equiv), and the
reaction was stirred at 25 °C for 30 min. After the disappearance of
starting ether was established by TLC, the reaction was quenched by
addition of saturated NaHCO3 (3 mL), extracted with ether (3 × 10
mL), and dried over Na2SO4. The crude residue was purified by flash
chromatography (silica gel, EtOAc-hexane, 1:99) to yield alcohol 44
(20.4 mg, 80%) as a colorless oil: Rf ) 0.57 (silica gel, EtOAc-hexane,
1:10); FT-IR (neat) νmax 3490, 2959, 2866, 2197, 1651, 1464, 1384,
1252, 1122, 1095, 1021, 864, 843 cm-1; 1H NMR (400 MHz, CDCl3)
δ 6.32 (d, J ) 12.0 Hz, 1 H, C-2), 5.41 (br s, 1 H, C-12), 4.37 (s, 2 H,
C-15), 3.66 (d, J ) 2.9 Hz, 1 H, C-8), 3.49 (d, J ) 12.0 Hz, 1 H, C-1),
2.57 (br s, 1 H, OH), 2.41 (br d, J ) 11.0 Hz, 1 H, C-10), 2.22 (br d,
J ) 17.0 Hz, 1 H, C-13), 1.89 (br d, J ) 17.0 Hz, 1 H, C-13), 1.86
(dd, J ) 14.4, 4.1 Hz, 1 H), 1.71 (s, 3 H, C-17), 1.62-1.52 (m, 3 H),
1.37 (s, 3 H, C-16), 1.11-1.02 (m, 21 H, TIPS), 0.92 (d, J ) 6.1 Hz,
3 H, C-19 or C-20), 0.91 (d, J ) 6.2 Hz, 3 H, C-19 or C-20), 0.24 (s,
9 H, TMS); 13C NMR (100.6 MHz, CDCl3) δ 181.2, 142.5, 139.3,
133.6, 121.7, 102.4, 89.2, 81.8, 72.2, 63.7, 45.0, 38.8, 32.0, 29.8, 25.9,
Synthesis of Alcohol 42 from Hydroxy Alkynone 45. To a solution
of R,â-alkynone 45 (26.8 mg, 0.055 mmol, 1.0 equiv) in acetone (3
mL) was added [Rh(nbd)(dppb)]BF4 (1.9 mg, 0.0027 mmol, 0.05 equiv)
at 25 °C under argon. The reaction flask was then evacuated and treated
with hydrogen gas (1 atm). After 10 min, the reaction was quenched

8672 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Nicolaou et al.
21.8, 21.6, 20.8, 20.2, 17.9, 11.9, 1.5; HRMS (FAB) calcd for C32H56-
(s, 9 H, Me); 13C NMR (100.6 MHz, CDCl3) δ 174.2, 163.2, 139.4,
139.1, 138.0, 125.0, 114.6, 39.9, 33.8, 26.6, 26.6, 26.6.
CsO4Si2 (M + Cs+) 693.2772, found 693.2745; [R]25 +45.2 (c 0.44,
D
CHCl3).
Synthesis of 53 by Attachment of the Aromatic Side Chain. A
mixture of alcohol 42 (61.0 mg, 0.120 mmol, 1.0 equiv), DMAP (14.7
mg, 0.120 mmol, 1.0 equiv), triethylamine (0.3 mL, 2.15 mmol, 17.9
equiv), and mixed anhydride 52 (6.0 mL of 0.2 M solution in CH2Cl2,
1.22 mmol, 10.0 equiv) was stirred at 25 °C for 22 h. The reaction
mixture was then concentrated and purified by flash chromatography
(silica gel, 10:10:1, EtOAc-CH2Cl2-MeOH) to yield ester 53 (75.0
mg, 98%): Rf ) 0.42 (silica gel, 10:10:1, EtOAc-CH2Cl2-MeOH);
FT-IR (neat) νmax 2940, 2864, 1704, 1639, 1465, 1384, 1269, 1154,
1060, 994 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.51 (d, J ) 15.6 Hz,
1 H, C-3′), 7.48 (s, 1 H, C-5′), 7.07 (s, 1 H, C-7′), 6.56 (d, J ) 15.6
Hz, 1 H, C-2′), 6.10 (d, J ) 5.8 Hz, 1 H, C-5 or C-6), 6.02 (d, J ) 5.8
Hz, 1 H, C-5 or C-6), 5.70 (d, J ) 9.6 Hz, 1 H, C-2), 5.20 (br s, 1 H,
C-12), 4.80 (d, J ) 7.2 Hz, 1 H, C-8), 4.20 (d, J ) 13.2 Hz, 1 H, C-8),
4.12 (d, J ) 13.2 Hz, 1 H, C-15), 3.95-3.92 (m, 1 H, C-1), 3.69 (s, 3
H, C-9′), 3.19 (s, 3 H, OCH3), 2.58 (br d, J ) 10.0 Hz, 1 H, C-10),
2.33 (br d, J ) 18.5 Hz, 1 H, C-13), 1.95 (br d, J ) 18.5 Hz, 1 H,
C-13), 1.57-1.53 (m, 2 H, C-9), 1.52-1.49 (m, 1 H, C-18), 1.47 (s, 3
H, C-17 Hz), 1.42 (s, 3 H, C-16), 1.25-1.18 (m, 1 H, C-14), 1.08-
1.00 (m, 21 H), 0.97 (d, J ) 6.6 Hz, 3 H, C-19 or C-20), 0.90 (d, J )
6.4 Hz, 3 H, C-19 or C-20); 13C NMR (150 MHz, CDCl3) δ 166.3,
139.1, 136.1, 136.0, 134.1, 134.0, 130.6, 130.4, 122.6, 121.1, 116.2,
116.0, 89.8, 81.6, 64.9, 49.6, 42.6, 38.7, 33.6, 31.5, 29.1, 24.7, 24.4,
22.2, 22.0, 20.6, 18.0, 12.0; HRMS (FAB) calcd for C37H58CsN2O5Si
Synthesis of Alkynone 49. To a solution of aldehyde 36 (243.0
mg, 0.338 mmol, 1.0 equiv) in THF (17 mL) was added dropwise a
1.0 M THF solution of LiHMDS (0.68 mL, 0.68 mmol, 2.0 equiv) at
-20 °C. The reaction mixture was stirred for 20 min at that
temperature, and the reaction was then quenched with saturated NH4-
Cl solution (30 mL), extracted with ether (2 × 50 mL), dried over
Na2SO4, and concentrated to a crude residue. A solution of this residue
in CH2Cl2 (9 mL) was added to a solution of NaHCO3 (170.0 mg, 2.0
mmol, 5.9 equiv), pyridine (0.16 mL, 2.0 mmol, 5.9 equiv), and Dess-
Martin reagent (286.0 mg, 0.67 mmol, 2.0 equiv) in CH2Cl2 (9 mL) at
0 °C. The reaction was stirred for 1 h at the same temperature and
then quenched by consecutive addition of saturated NaHCO3 (20 mL)
and Na2S2O3‚5H2O (1.17 g, 4.7 mmol, 13.9 equiv). The resulting
solution was stirred for an additional 30 min, extracted with ether (2
× 50 mL), dried over Na2SO4, and concentrated. This crude residue
was then purified by flash chromatography (silica gel, 0.5% EtOAc in
hexane) to produce bicyclic alkynone 49 (216 mg, 89%, two steps) as
a light yellow oil: Rf ) 0.74 (silica gel, EtOAc-hexane, 1:10); FT-IR
(neat) νmax 2957, 2362, 1652, 1460, 1383, 1212, 1114, 1004, 883, 732,
684 cm-1; H NMR (400 MHz, CDCl3) δ 6.33 (d, J ) 11.8 Hz, 1 H,
1
C-2), 5.39 (br s, 1 H, C-12), 4.38 (d, J ) 14.2 Hz, 1 H, C-15), 4.32 (d,
J ) 14.2 Hz, 1 H, C-15), 3.71 (s, 1 H, C-1), 3.55 (d, J ) 11.8 Hz, 1H,
C-8), 2.36 (br d, J ) 8.8 Hz, 1 H, C-10), 2.20 (br d, J ) 18.0 Hz, 1
H, C-13), 1.98 (br d, J ) 18.0 Hz, 1 H, C-13), 1.80-1.70 (m, 3 H),
1.67 (s, 3 H, C-17), 1.57-1.50 (m, 1 H), 1.36 (s, 3 H, C-16), 1.07-
0.90 (m, 45 H), 0.77-0.53 (m, 12 H); 13C NMR (100.6 MHz, CDCl3)
δ 181.2, 141.9, 139.7, 133.8, 121.8, 103.8, 87.7, 83.3, 72.5, 63.4, 44.8,
38.9, 38.0, 36.0, 30.0, 25.9, 21.9, 21.5, 21.2, 20.2, 17.9, 11.9, 7.0, 6.9,
5.8, 5.2; HRMS (FAB) calcd for C41H76CsO4Si3 (M + Cs+) 849.4106,
(M + Cs+) 771.3169, found 771.3191; [R]25 +5.6 (c 1.6, CHCl3).
D
Synthesis of Alcohol 54. To a solution of silyl ether 53 (75.0 mg,
0.117 mmol, 1.0 equiv) in THF (2 mL) was added 1.0 M TBAF in
THF (0.22 mL, 0.22 mmol, 1.9 equiv), and the reaction was stirred for
1 h at 25 °C. After completion (thin-layer chromatography monitoring),
the reaction mixture was concentrated and purified by flash chroma-
tography (silica gel, 10:10:1, EtOAc-CH2Cl2-MeOH) to provide
alcohol 54 (50.0 mg, 89%): Rf ) 0.23 (silica gel, 10:10:1, EtOAc-
CH2Cl2-MeOH); FT-IR (neat) νmax 3380, 2961, 2361, 1700, 1636,
1450, 1382, 1269, 1156, 1036, 731 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.51 (d, J ) 15.6 Hz, 1 H, C-3′), 7.42 (s, 1 H, C-5′), 7.06 (s, 1 H,
C-7′), 6.54 (d, J ) 15.6 Hz, 1 H, C-2′), 6.20 (d, J ) 6.0 Hz, 1 H, C-5
or C-6), 6.01 (d, J ) 5.9 Hz, 1 H, C-5 or C-6), 5.53 (d, J ) 9.6 Hz,
1 H, C-2), 5.24 (br s, 1 H, C-12), 4.79 (d, J ) 7.2 Hz, C-8), 4.13 (d,
J ) 12.0 Hz, 1 H, C-15), 3.94-3.85 (m, 2 H, C-15, C-1), 3.68 (s, 3 H,
N-CH3), 3.21 (s, 3 H, OCH3), 2.67 (br d, J ) 8.6 Hz, 1 H, C-10),
2.57 (br s, 1 H, OH), 2.30 (br d, J ) 10.0 Hz, 1 H, C-13), 1.97 (br d,
J ) 18.0 Hz, 1 H, C-13), 1.65-1.50 (m, 3 H, C-9, C-18), 1.57 (s, 3 H,
C-17), 1.49 (s, 3 H, C-16), 1.28-1.25 (m, 1 H, C-14), 0.96 (d, J ) 6.6
found 849.4139; [R]25 +50.3 (c 3.87, CHCl3).
D
Synthesis of Diol 45. To a solution of trisilyl ether 49 (200 mg,
0.28 mmol, 1.0 equiv) in THF (1 mL) was added Et3N‚3HF (0.23 mL,
1.40 mmol, 5.0 equiv) at 25 °C. After 1.5 h, the reaction was cooled
to 0 °C, quenched by addition of NaHCO3 (10 mL), extracted with
ether (3 × 10 mL), dried over Na2SO4, and concentrated. The residue
was purified by flash chromatography (silica gel, 25% EtOAc in hexane)
to produce diol 45 (107 mg, 78%) as a colorless oil: Rf ) 0.26 (silica
gel, EtOAc-hexane, 1:3); FT-IR (neat) νmax 3411, 2941, 2867, 2202,
1650, 1465, 1385, 1207, 1089, 1018, 883, 757, 685 cm-1; H NMR
1
(400 MHz, CDCl3) δ 6.32 (d, J ) 12.0 Hz, 1 H, C-2), 5.40 (br s, 1 H,
C-12), 4.35 (s, 2 H, C-15), 3.75 (s, 1 H, C-1), 3.47 (d, J ) 12.0 Hz, 1
H, C-8), 2.47 (s, 1 H), 2.42 (br d, J ) 11.5 Hz, 1 H), 2.38 (s, 1 H),
2.23-2.17 (m, 1 H), 1.98 (d, J ) 18.4 Hz, 1 H), 1.88 (dd, J ) 14.6,
4.2 Hz, 1 H), 1.70 (s, 3 H, C-17), 1.64 (t, J ) 13.1 Hz, 1 H), 1.56-
1.49 (m, 2 H), 1.43 (s, 3 H, C-16), 1.09-1.03 (m, 3 H), 1.01 (d, J )
6.5 Hz, 18 H), 0.90 (d, J ) 6.9 Hz, 3 H, C-19 or C-20), 0.89 (d, J )
6.9 Hz, 3 H, C-19 or C-20); 13C NMR (100.6 MHz, CDCl3) δ 181.4,
142.6, 139.5, 133.4, 121.8, 102.5, 87.8, 80.6, 71.2, 63.7, 45.0, 38.8,
38.3, 33.0, 29.8, 25.9, 21.8, 21.6, 20.4, 19.8, 17.9, 11.9; HRMS (FAB)
Hz, 3 H, C-19 or C-20), 0.90 (d, J ) 6.4 Hz, 3 H, C-19 or C-20); 13
C
NMR (125 MHz, CDCl3) δ 166.6, 139.2, 138.4, 136.8, 136.4, 135.6,
135.0, 134.0, 129.16, 122.7, 121.4, 117.0, 115.8, 90.3, 81.4, 67.3, 49.6,
42.0, 38.7, 33.9, 33.6, 31.5, 29.0, 24.3, 22.2, 22.1, 20.5; HRMS (FAB)
calcd for C28H38NaN2O5 (M + Na+) 505.2678, found 505.2661; [R]25
-44.7 (c 0.49, CHCl3).
D
Synthesis of Aldehyde 55. To a solution of allylic alcohol 54 (50
mg, 0.104 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added NaHCO3
(88.0 mg, 0.595 mmol, 10.0 equiv) and Dess-Martin reagent (84.8
mg, 0.20 mmol, 2.0 equiv), and the reaction was stirred for 30 min at
ambient temperature, after which 2-propanol (0.1 mL) was added
followed by ethyl acetate (10 mL). The precipitate was filtered off,
and the filtrate was concentrated and purified by flash chromatography
(silica gel, 10:10:1, EtOAc-CH2Cl2-MeOH) to yield aldehyde 55 (49.5
mg, 100%): Rf ) 0.43 (silica gel, 10:10:1, EtOAc-CH2Cl2-MeOH);
FT-IR (neat) νmax 2961, 1694, 1636, 1269, 1156, 1051 cm-1; 1H NMR
(500 MHz, CDCl3) δ 9.28 (s, 1 H, C-15), 7.53 (d, J ) 15.6 Hz, 1 H,
C-3′), 7.47 (s, 1 H, C-5′), 7.09 (s, 1 H, C-7′), 6.56 (d, J ) 15.6 Hz, 1
H, C-2′), 6.48 (d, J ) 9.9 Hz, 1 H, C-2), 6.30 (d, J ) 5.9 Hz, 1 H, C-5
or C-6), 6.19 (d, J ) 5.9 Hz, 1 H, C-5 or C-6), 5.34 (br s, 1 H, C-12),
4.80 (d, J ) 7.4 Hz, 1 H, C-8), 4.30-4.28 (m, 1 H, C-1), 3.70 (s, 3 H,
C-9′), 3.25 (s, 3 H, OCH3), 2.77 (br d, J ) 9.4 Hz, 1 H, C-10), 2.41
(br d, J ) 18.8 Hz, 1 H, C-13), 2.10 (br d, J ) 18.8 Hz, 1 H, C-13),
1.67-1.56 (m, 3 H, C-9, C-18), 1.53 (s, 3 H, C-17), 1.46 (s, 3 H,
C-16), 1.38-1.36 (m, 1 H, C-14), 1.01 (d, J ) 6.6 Hz, 3 H, C-19 or
C-20), 0.96 (d, J ) 6.4 Hz, 3 H, C-19 or C-20); 13C NMR (125 MHz,
calcd for C29H48CsO4Si (M + Cs+) 621.2376, found 621.2345; [R]25
+30.2 (c 1.49, CHCl3).
D
Synthesis of Mixed Anhydride of the Aromatic Side Chain 52.
To a solution of ethyl ester 50 (750 mg, 4.16 mmol, 1.0 equiv) in (1:1)
THF-water (32.0 mL) at 25 °C was added LiOH‚H2O (192 mg, 4.57
mmol, 1.1 equiv), and the resulting reaction mixture was stirred at the
same temperature for 12 h. The solvent was removed under reduced
pressure, and the solid was azeotroped with benzene (5 mL × 5) and
finally dried under high vacuum. The acid salt 51 was used without
further purification. To a solution of 51 in THF (40 mL) at 25 °C was
added Piv-Cl (0.54 mL, 4.58 mmol, 1.1 equiv), and the reaction mixture
was stirred at the same temperature for 12 h. Once complete by TLC,
the reaction mixture was filtered, and the filtrate was concentrated under
reduced pressure and dried under high vacuum to give anhydride 52
(698 mg, 75%). The anhydride was stored as a 0.2 M solution in CH2-
Cl2 and used in this form for the esterification: 1H NMR (400 MHz,
CDCl3) δ 7.61 (d, J ) 19.4 Hz, 1 H, C-2′), 7.46 (s, 1 H, C-5′), 7.14 (s,
1 H, C-7′), 6.58 (d, J ) 19.3 Hz, 1 H, C-3′), 3.73 (s, 3 H, C-9′), 1.27

Total Synthesis of Sarcodictyins A and B
J. Am. Chem. Soc., Vol. 120, No. 34, 1998 8673
CDCl3) δ 193.9, 166.7, 159.4, 142.0, 139.3, 138.3, 136.5, 135.6, 134.1,
129.7, 122.8, 121.5, 115.8, 114.5, 89.4, 81.2, 50.2, 41.4, 39.0, 35.6,
33.6, 31.6, 28.9, 24.3, 24.3, 22.1, 22.0, 20.5; HRMS (FAB) calcd for
C28H37N2O5 (M + H+) 481.2702, found 481.2714; [R]25D +72.7 (c 0.4,
CHCl3).
1 H, C-5), 6.17 (d, J ) 5.9 Hz, 1 H, C-6), 5.28 (br s, 1 H, C-12), 4.79
(d, J ) 7.4 Hz, 1 H, C-14, C-8), 4.15 (q, J ) 7.6 Hz, 2 H, OCH2CH3),
4,14-4.11 (m, 1 H, C-1), 3.69 (s, 3 H, C-9′), 3.23 (s, 3 H, OCH3),
2.67 (br d, J ) 8.1 Hz, 1 H, C-10), 2.37 (br d, J ) 17.4 Hz, 1 H,
C-13), 2.03 (br d, J ) 17.4 Hz, 1 H, C-13), 1.63 (d, J ) 15.0 Hz, 1 H,
C-9), 1.62-1.60 (m, 2 H, C-9, C-18), 1.51 (s, 3 H, C-17), 1.44 (s, 3
H, C-16), 1.36-1.30 (m, 1 H, C-14), 1.26 (t, J ) 7.6 Hz, 3 H,
OCH2CH3, 0.97 (d, J ) 6.6 Hz, 3 H, C-19 or C-20), 0.93 (d, J ) 6.4
Hz, 3 H, C-19 or C-20); 13C NMR (125 MHz, CDCl3) δ 166.8, 166.7,
146.1, 139.2, 138.4, 136.4, 134.8, 134.0, 132.3, 131.1, 122.7, 121.4,
115.9, 115.6, 89.53, 81.43, 60.6, 50.1, 41.7, 38.8, 34.7, 33.6, 31.5, 28.9,
24.4, 24.3, 22.2, 22.0, 20.5, 14.1; HRMS (FAB) calcd for C30H40CsN2O6
Synthesis of Methyl Ester 57 with the Intermediacy of Acid 56.
To a solution of aldehyde 55 (14.0 mg, 0.0291 mmol, 1.0 equiv) in
tBuOH-H2O (5:1, 1.2 mL total) were added 2.0 M 2-methyl-2-butene
in THF (1 mL, 2.0 mmol, 68.7 equiv), NaH2PO4 (10.5 mg, 0.087 mmol,
2.9 equiv), and NaClO2 (15.7 mg, 0.174 mmol, 6.0 equiv) at 0 °C.
The reaction was stirred at the same temperature for 2 h, after which
an ether solution of CH2N2 (excess) was added and the reaction was
stirred for an additional 10 min at 25 °C. The excess CH2N2 was
removed by an argon stream, the reaction was extracted with ethyl
acetate (3 × 15 mL), dried over Na2SO4, and concentrated. The crude
residue was purified by flash chromatography (silica gel, 10:10:1
EtOAc-CH2Cl2-MeOH) to furnish methyl ester 57 (13.1 mg, 88%,
two steps): Rf ) 0.42 (silica gel, 10:10:1 EtOAc-CH2Cl2-MeOH);
FT-IR (neat) νmax 3410, 2960, 1711, 1637, 1435, 1384, 1269, 1155,
1048, 732 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J ) 15.6 Hz,
1 H, C-3′), 7.44 (s, 1 H, C-5′), 7.07 (s, 1 H, C-7′), 6.72 (d, J ) 9.9 Hz,
1 H, C-2), 6.55 (d, J ) 15.6 Hz, 1 H, C-2′), 6.48 (d, J ) 5.9 Hz, 1 H,
C-5), 6.17 (d, J ) 5.9 Hz, 1 H, C-6), 5.28 (br s, 1 H, C-12), 4.78 (d,
J ) 7.4 Hz, 1 H, C-8), 4.15-4.12 (m, 1 H, C-1), 3.70 (s, 3 H, OCH3),
3.69 (s, 3 H, C-9′), 3.22 (s, 3 H, OCH3), 2.67 (br d, J ) 10.8 Hz, 1 H,
C-10), 2.38 (br d, J ) 16.4 Hz, 1 H, C-13), 2.03 (br d, J ) 16.4 Hz,
1 H, C-13), 1.66-1.53 (m, 3 H, C-9, C-18), 1.51 (s, 3 H, C-17), 1.44
(s, 3 H, C-16), 1.37-1.28 (m, 1 H, C-14), 0.97 (d, J ) 6.6 Hz, 3 H,
C-19 or C-20), 0.92 (d, J ) 6.4 Hz, 3 H, C-19 or C-20); 13C NMR
(125 MHz, CDCl3) δ 167.1, 166.7, 146.4, 139.2, 138.4, 136.4, 134.9,
134.0, 132.0, 131.0, 122.7, 121.4, 115.9, 115.5, 89.6, 81.4, 51.8, 50.2,
41.7, 38.7, 34.7, 33.6, 31.5, 28.9, 24.4, 24.3, 22.2, 22.0, 20.5; HRMS
(FAB) calcd for C29H38CsN2O6 (M + Cs+) 643.1784, found 643.1762;
(M + Cs+) 657.1941, found 657.1959; [R]25 -12.0 (c 0.4, CHCl3).
D
Completion of the Synthesis of Sarcodictyin B (8). To a solution
of ethyl ester 58 (3.5 mg, 0.0067 mmol, 1.0 equiv) in 10:1 CH2Cl2-
H2O (1.1 mL) was added CSA (10.0 mg, 0.043 mmol, 6.4 equiv). The
reaction was then stirred at 25 °C for 24 h, after which triethylamine
was added and the reaction mixture was concentrated. The crude
mixture was purified by flash chromatography (silica gel, 10:10:1
EtOAc-CH2Cl2-MeOH) to yield sarcodictyin B (8) (3.0 mg, 86%)
as a white solid: Rf ) 0.32 (silica gel, 10:10:1 EtOAc-CH2Cl2-
MeOH); FT-IR (neat) νmax 3348, 2926, 2855, 1708, 1637, 1458, 1383,
1299, 1271, 1244, 1156, 1051; 1H NMR (500 MHz, CDCl3) δ 7.52 (d,
J ) 15.6 Hz, 1 H, C-3′), 7.44 (s, 1 H, C-5′), 7.08 (s, 1 H, C-7′), 6.81
(d, J ) 9.8 Hz, 1 H, C-2), 6.55 (d, J ) 15.5 Hz, 1 H, C-2′), 6.32 (d,
J ) 5.8 Hz, 1 H, C-5 or C-6), 6.09 (d, J ) 5.8 Hz, 1 H, C-5 or C-6),
5.30 (br s, 1 H, C-12), 4.80 (d, J ) 7.4 Hz, 1 H, C-8), 4.24-4.15 (m,
3 H, C-1 and OCH2CH3), 4.04 (s, 1 H, OH), 3.69 (s, 3 H, N-CH3),
2.71 (br d, J ) 11.7 Hz, 1 H, C-10), 2.37 (br d, J ) 11.0 Hz, 1 H,
C-13), 2.05 (br d, J ) 11.3 Hz, 1 H, C-13), 1.65 (d, J ) 14.7 Hz, 1 H,
C-9), 1.64-1.55 (m, 2 H, C-9, C-18), 1.52 (s, 3 H, C-17), 1.49 (s, 3
H, C-16), 1.28 (t, J ) 7.0 Hz, 3 H, OCH2CH3), 1.23-1.21 (m, 1 H,
C-14), 0.98 (d, J ) 6.6 Hz, 3 H, C-19 or C-20), 0.93 (d, J ) 6.4 Hz,
3 H, C-19 or C-20); 13C NMR (125 MHz, CDCl3) δ 167.8, 166.7, 147.0,
139.2, 138.4, 136.5, 134.1, 133.2, 132.8, 131.9, 122.7, 121.4, 115.9,
111.0, 90.9, 81.1, 61.1, 41.8, 39.1, 35.0, 33.6, 31.8, 28.9, 25.6, 24.4,
22.2, 22.1, 20.5, 14.1; HRMS (FAB) calcd for C29H38CsN2O6 (M +
[R]25 -44.7 (c 0.5, CHCl3).
D
Completion of the Synthesis for Sarcodictyin A (7). To a solution
of methyl ester 57 (6.0 mg, 0.0117 mmol, 1.0 equiv) in 10:1 CH2Cl2-
H2O (1.1 mL) was added CSA (10 mg, 0.043 mmol, 6.4 equiv) and
the reaction was stirred at 25 °C for 16 h, after which triethylamine
was added and the reaction mixture was concentrated. The crude
mixture was purified by flash chromatography (silica gel, 10:10:1,
EtOAc-CH2Cl2-MeOH) to yield sarcodictyin A (7) (4.6 mg, 79%)
as a white solid: Rf ) 0.32 (silica gel, 10:10:1, EtOAc-CH2Cl2-
MeOH); FT-IR (neat) νmax 2958, 2361, 1711, 1636, 1244, 1153, 1050
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J ) 16.0 Hz, 1 H, C-3′),
7.43 (s, 1 H, C-5′), 7.07 (s, 1 H, C-7′), 6.80 (d, J ) 15.6 Hz, 1 H,
C-5′), 6.33 (d, J ) 5.6 Hz, 1 H, C-5 or C-6), 6.09 (d, J ) 5.6 Hz, 1 H,
C-5 or C-6), 5.30 (br s, 1 H, C-12), 4.79 (d, J ) 7.3 Hz, 1 H, C-8),
4.20-4.17 (m, 1 H, C-1), 4.03 (s, 1 H, OH), 3.74 (s, 3 H, OCH3), 3.68
(s, 3 H, OCH3), 2.71 (d, J ) 9.9 Hz, 1 H, C-10), 2.37 (br d, J ) 16.4
Hz, 1 H, C-13), 2.05 (br d, J ) 17.2 Hz, 1 H, C-13), 1.68-1.55 (m, 3
H, C-9, C-18), 1.52 (s, 3 H, C-17), 1.48 (s, 3 H, C-16), 1.35-1.30 (m,
1 H, C-14), 0.98 (d, J ) 6.7 Hz, 3 H, C-19 or C-20), 0.92 (d, J ) 6.4
Hz, 3 H, C-19 or C-20); 13C NMR (125 MHz, CDCl3) δ 168.1, 166.7,
147.2, 139.2, 138.4, 136.5, 134.1, 133.3, 132.8, 131.8, 122.7, 121.4,
115.8, 110.9, 90.8, 81.0, 52.1, 41.8, 39.0, 35.0, 33.6, 31.8, 28.9, 25.6,
24.4, 22.2, 22.0, 20.5; HRMS (FAB) calcd for C28H36CsN2O6 (M +
Cs+) 643.1784, found 643.1804; [R]25 -4.0 (c 0.15, EtOH).
D
Synthesis of C5,C6-Saturated Analogue 61. Analogue 61 was
synthesized by the same reaction sequence followed for the two natural
products (53, 54, 55, 56, 57, 58) from alcohol 43: Rf ) 0.32 (silica
gel, 10:10:1, EtOAc-CH2Cl2-MeOH); FT-IR (neat) νmax 2959, 1711,
1
1638, 1451, 1247, 1159, 1043 cm-1; H NMR (500 MHz, CDCl3) δ
7.52 (d, J ) 15.6 Hz, 1 H), 7.45 (s, 1 H), 7.07 (s, 1 H), 6.77 (d, J )
10.2 Hz, 1 H), 6.51 (d, J ) 5.6 Hz, 1 H), 5.34 (br s, 1 H, C-12), 4.64
(d, J ) 8.0 Hz, 1 H, C-8), 4.11 (m, 1 H, C-1), 3.70 (s, 3 H, CO2Me),
3.69 (s, 3 H, N-Me), 3.20 (s, 3 H, OMe), 2.62-2.53 (m, 2 H, C-10,
C-5 or C-6), 2.49 (m, 1 H, C-5 or C-6), 2.35 (br dd, J ) 16.5, 2.0 Hz,
1 H, C-13), 2.20 (m, 1 H, C-5 or C-6), 2.06 (br dd, J ) 18.7, 2.0 Hz,
1 H, C-13), 1.82-1.75 (m, 2 H, C-5 or C-6, C-9), 1.56 (s, 3 H, Me),
1.55-1.46 (m, 1 H, C-9), 1.35 (s, 3 H, Me), 20 (m, 1 H, C-14), 0.95
(d, J ) 6.6 Hz, 3 H, C-19 or C-20), 0.92 (d, J ) 6.4 Hz, 3 H, C-19 or
C-20); 13C NMR (125 MHz, CDCl3) δ 167.5, 166.8, 148.0, 139.1, 138.4,
136.1, 133.9, 132.7, 122.6, 121.6, 116.3, 112.0, 85.4, 80.9, 51.8, 50.4,
42.4, 39.5, 37.9, 34.9, 33.6, 32.1, 30.6, 28.6, 28.1, 24.1, 22.1, 22.1,
20.6; HRMS (FAB) calcd for C29H40CsN2O6 (M + Cs+) 645.1941,
Cs+) 629.1628, found 629.1648; [R]25 -19.1 (c 0.11, EtOH).
D
found 645.1962; [ga]25 +41.7 (c 0.2, CHCl3).
D
Synthesis of Ethyl Ester 58. To a solution of aldehyde 55 (27.8
t
mg, 0.058 mmol, 1.0 equiv) in BuOH-H2O (5:1, 1.2 mL total) were
Acknowledgment. This work was supported by The Skaggs
Institute for Chemical Biology, the National Institutes of Health
USA, Novartis and CaP CURE, and by fellowships from
Novartis (to D.V.), the Japanese Society for the Promotion of
Science for Young Scientists (to S.H.), and the Department of
Defense, USA (to J.P.)
added 2.0 M 2-methyl-2-butene in THF (1 mL, 2.0 mmol, 34.4 equiv),
NaH2PO4 (20.9 mg, 0.174 mmol, 3.0 equiv) and NaClO2 (31.5 mg,
0.340 mmol, 2.9 equiv) at 0 °C. The reaction was stirred at the same
temperature for 2 h, after which an ether solution of excess CH3CHN2
was added and the reaction was stirred for an additional 10 min at 25
°C. The excess CH3CHN2 was removed by an argon stream, and the
reaction mixture was extracted with ether (2 × 15 mL), dried over
Na2SO4, and concentrated. The crude residue was purified by flash
chromatography (silica gel, 10:10:1 EtOAc-CH2Cl2-MeOH) to yield
ethyl ester 58 (27.0 mg, 89%, two steps); Rf ) 0.41 (silica gel, 10:10:1
EtOAc-CH2Cl2-MeOH); FT-IR (neat) νmax 2963, 1708, 1636, 1269,
Supporting Information Available: Selected physical data
for intermediates 10-13 (5 pages, print/PDF). See any current
masthead page for ordering information and Web access
instructions.
1
1154, 1048 cm-1; H NMR (500 MHz, CDCl3) δ 7.52 (d, J ) 15.6
Hz, 1 H, C-3′), 7.44 (s, 1 H, C-5′), 7.08 (s, 1 H, C-7′), 6.72 (d, J ) 9.8
Hz, 1 H, C-2), 6.56 (d, J ) 15.6 Hz, 1 H, C-2′), 6.49 (d, J ) 5.9 Hz,
JA981062G