Total synthesis of the ansamycin antibiotic (+)-thiazinotrienomycin E

Article abstract of DOI:10.1021/jo991958j

The first total synthesis of (+)-thiazinotrienomycin E (1), member of a novel class of cytotoxic ansamycin antibiotics, has been achieved. Key features of the synthetic strategy include (a) the efficient construction of sulfone 7 incorporating TBS protection of the aniline, (b) an improved synthesis of allyl chloride (-)-6, the advanced intermediate employed in our trienomycins A and F total syntheses, (c) application of the Kocienski modified Julia protocol to elaborate the E,E,E-triene subunit in a stereo- controlled fashion, (d) an efficient union of sulfone 7 with advanced iodide 62, and (e) Mukaiyama macrolactamization to access the thiazinotrienomycin macrocyclic ring.

Full text of DOI:10.1021/jo991958j

3738
J . Org. Chem. 2000, 65, 3738-3753
Tota l Syn th esis of th e An sa m ycin An tibiotic
(+)-Th ia zin otr ien om ycin E
Amos B. Smith, III* and Zehong Wan
Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure
of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Received December 23, 1999
The first total synthesis of (+)-thiazinotrienomycin E (1), member of a novel class of cytotoxic
ansamycin antibiotics, has been achieved. Key features of the synthetic strategy include (a) the
efficient construction of sulfone 7 incorporating TBS protection of the aniline, (b) an improved
synthesis of allyl chloride (-)-6, the advanced intermediate employed in our trienomycins A and F
total syntheses, (c) application of the Kocienski modified J ulia protocol to elaborate the E,E,E-
triene subunit in a stereo-controlled fashion, (d) an efficient union of sulfone 7 with advanced iodide
62, and (e) Mukaiyama macrolactamization to access the thiazinotrienomycin macrocyclic ring.
In 1995, Hosokawa and co-workers reported the isola-
tion and planar structures of the (+)-thiazinotrieno-
mycins (A-E, Figure 1),1 novel ansamycin antibiotics
produced by Streptomyces sp. MJ 672-m3, displaying
significant in vitro cytotoxicity against human cancer cell
lines derived from the cervix, stomach, colon, and breast.1,2
Our interest in the chemistry and biology of the ansa-
mycin antibiotics, particularly the structurally similar
trienomycins,3 led us to consider the synthesis of thia-
zinotrienomycin E. As a prelude to this venture, we, in
collaboration with Hosokawa and co-workers,4 assigned
the complete relative and absolute stereochemistries of
(+)-thiazinotrienomycin E (1) exploiting both degradation
and chemical correlation. In this, a full account, we
describe the first total synthesis of (+)-thiazinotrieno-
mycin E.5 We anticipate that our synthetic strategy will
not only provide access to other members of the thiazino-
trienomycin family but also to potentially bioactive
analogues.
Syn th etic An a lysis. From the retrosynthetic perspec-
tive, we envisioned installation of the C(29-38) side
chain late in the synthesis (Scheme 1), thereby permit-
ting construction of thiazinotrienomycins C, D, and E
F igu r e 1. Planar structures of the (+)-thiazinotrienomycins
A-E.
(1) Hosokawa, N.; Naganawa, H.; Inuma, H.; Hamada, M.; Takeuchi,
T.; Kanbe, T.; Hori, M. J . Antibiot. 1995, 48, 471-478.
(2) Hosokawa, N.; Yamamoto, S.; Uehara, Y.; Hori, M.; Tsuchiya,
K. S. J . Antibiot. 1999, 52, 485-490. Hosokawa, N.; Inuma, H.;
Takeuchi, T.; Sato, S.; Yamori, T.; Tsuchiya, K. S.; Hori, M. J . Antibiot.
2000, 53, 306-308.
from a common advanced intermediate (e.g., 2). A similar
tactic was employed to good advantage in our trienomycin
syntheses. Further disconnections of 2 led to aniline 3,
acetylenic acid 4, and phosphonate 5. Assembly of the
requisite macrocyclic lactam would entail coupling of 3
with 4 to furnish the amide, followed by Horner-
Emmons union with 5 and macrocyclization exploiting
Stille cross-coupling reaction. Alternatively, the last two
operations could be reversed. Advanced aniline 3 in turn
was envisioned to derive via alkylation of allyl chloride
(-)-6 with sulfone 7, the former prepared during our
earlier trienomycin syntheses.3
Allyl Ch lor id e (-)-6: An Im p r oved Syn th esis. We
are pleased to report here a significant improvement in
the construction of allyl chloride (-)-6 (Scheme 2),
begining with known homoallyl alcohol (+)-8,6 prepared
in three steps from 3-buten-1-ol. Protection as the tri-
(3) Smith, A. B., III; Wood, J . L.; Wong, W.; Gould, A. E.; Rizzo, C.
J .; Barbosa, J .; Komiyama, K.; Oh mura, S. J . Am. Chem. Soc. 1996,
118, 8308-8315. Smith, A. B., III; Barbosa, J .; Wong, W.; Wood, J . L.
J . Am. Chem. Soc. 1996, 118, 8316-8328. Smith, A. B., III; Barbosa,
J .; Wong, W.; Wood, J . L. J . Am. Chem. Soc. 1995, 117, 10777-10778.
Smith, A. B., III; Wood, J . L.; Gould, A. E.; Oh mura, S.; Komiyama, K.
Tetrahedron Lett. 1991, 32, 1627-1630. Smith, A. B., III; Wood, J . L.;
Oh mura, S. Tetrahedron Lett. 1991, 32, 841-842. Smith, A. B., III;
Wood, J . L.; Wong, W.; Gould, A. E.; Rizzo, C. J .; Funayama, S.; Oh mura,
S. J . Am. Chem. Soc. 1990, 112, 7425-7426. For other synthetic
approaches to the trienomycins and related mycotrienins, see: Masse,
C. E.; Yang, M.; Solomon, J .; Panek, J . S. J . Am. Chem. Soc. 1998,
120, 4123-4134. Yadav, J . S.; Praveen Kumar, T. K.; Maniyan, P. P.
Tetrahedron Lett. 1993, 34, 2965-2968. Fu¨rstner, A.; Baumgartner,
J . Tetrahedron 1993, 49, 8541-8560. Schoning, K. U.; Hayashi, R. K.;
Powell, D. R.; Kirschning, A. Tetrahedron: Asymmetry 1999, 10, 817-
820. Schoning, K. U.; Wittenberg, R.; Kirschning, A. Synlett 1999,
1624-1626.
(4) Smith, A. B., III; Barbosa, J .; Hosokawa, N.; Naganawa, H.;
Takeuchi, T. Tetrahedron Lett. 1998, 39, 2891-2894.
(5) Preliminary communication: Smith, A. B., III; Wan, Z. Org. Lett.
1999, 1, 1491-1494.
(6) Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T.
K.; Minowa, N.; Koide, K. Chem. Eur. J . 1995, 1, 318-333.
10.1021/jo991958j CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/11/2000

Total Synthesis of (+)-Thiazinotrienomycin E
J . Org. Chem., Vol. 65, No. 12, 2000 3739
Sch em e 1
Sch em e 2
compared to our previous route of 16 steps and 24%
overall yield.
Con str u ction of Su lfon e 7. Our point of departure
for sulfone 7 was commercially available 2-fluoro-6-meth-
oxybenzonitrile (16, Scheme 3). Reduction with diiso-
butylaluminum hydride (DIBAL) and oxidation (KMnO4)
of the resultant aldehyde provided known acid 17.10
Esterification with methanol followed by bisnitration
with nitronium tetrafluroborate (NO2BF4)11 furnished 18.
Displacement of the fluorine with the lithium salt of
methyl thioglycolate12 to provide phenylthioether 19
followed by tin(II)-mediated reduction of the nitro groups
with concomitant cyclization13 then led to benzolactam
20 albeit in modest yield. Other reduction protocols such
as hetero- or homogeneous hydrogenation14,15 did not
improve the yield. Protection of the aniline as benzyloxy
carbamate (Cbz) and reduction of the benzoate with super
hydride produced benzyl alcohol 21. Initially, this reduc-
tion was also troublesome due to the unexpected ease
with which the amide functionality was reduced over the
ester (Scheme 4). This difficulty was eliminated by using
a combination of super hydride and 15-crown-5 ether.
Although the mechanistic details of this reduction remain
unknown, we speculate that the amide is first converted
to the lithium enolate via the basic combination of super
hydride and 15-c-5, thereby rendering the amide carbonyl
unreactive. Completion of sulfone 7 entailed tosylation
methylsilyl ether followed by reductive ozonolysis to
furnish aldehyde (+)-9 and then addition of the vinyl
anion derived from vinyl iodide 10,7 the latter available
in two steps from 2-butyn-1-ol, afforded a mixture of
alcohols (11; ca. 2:1). After removal of the TMS group,
selective oxidation of the allylic hydroxyl with manga-
nese(IV) oxide provided ketone (+)-12. Completion of
(-)-6 entailed directed reduction8 of the â-hydroxyl
ketone with tetramethylammonium triacetoxyborohy-
dride (95% de), generation of the 1,3-acetonide, selective
removal of the primary BPS moiety in the presence of
the primary TBS,9 and conversion of the resultant allylic
hydroxyl to the corresponding chloride. Allyl chloride (-)-
6, identical in all respects to that prepared previously,
was thus available in nine steps and 48% overall yield,
(10) Horne, S.; Rodrigo, R. J . Org. Chem. 1990, 55, 4520-4522.
(11) Olah, G. A.; Kuhn, S. J .; Flood, S. H. J . Am. Chem. Soc. 1961,
83, 4571-4580.
(12) Teulade, J . C.; Grassy, G.; Escale, R.; Chapat, J . P. J . Org.
Chem. 1981, 46, 1026-1030.
(7) Takemoto, T.; Sdeoka, M.; Sasai, H.; Shibasaki, M. J . Am. Chem.
Soc. 1993, 115, 8477-8478.
(13) Kelly, T. R.; Kim, M. H.; Gurtis, A. D. M. J . Org. Chem. 1993,
58, 5855-5857.
(8) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560-3578.
(14) Sleath, P. R.; Noar, J . B.; Eberlein, G. A.; Bruice, T. C. J . Am.
Chem. Soc. 1985, 107, 3328-3338.
(9) To the best of our knowledge, this is the first example of such
selectivity.
(15) Entwistle, I. D. Tetrahedron Lett. 1979, 20, 555-558.

3740 J . Org. Chem., Vol. 65, No. 12, 2000
Smith and Wan
Sch em e 3
Sch em e 4
sodium amalgam, followed by treatment with silica gel
in chloroform to remove the silyl group then furnished
aniline (-)-3 in 38% yield for the three steps. The acid
chloride derived from acid (+)-4 was next added to
produce amide (+)-35 in 80% overall yield.
of 21 (Scheme 3), displacement with sodium benzene-
sulfinate, removal of methyl and Cbz groups,16 and TBS
protection of both the amine and hydroxyl groups.
Acid (+)-4 a n d P h osp h on a te 5. The synthesis of acid
(+)-4 began with (+)-26,17 readily prepared from pro-
pargyl alcohol in two steps (Scheme 5). Methylation of
the hydroxyl provided (+)-27; selectivity vis-a`-vis the
hydroxyl and alkyne was 10:1. Ozonolysis of the terminal
alkene in the presence of the alkyne,18 followed by
reduction with triphenyl phosphine and oxidation with
pyridinium dichromate (PDC) completed the synthesis
of acid (+)-4.
Phosphonate 5 was readily prepared from known
alcohol 29,19 the latter available from propargyl alcohol
in one step (Scheme 6). Three steps were required:
bromination, displacement of bromide with the sodium
salt of diethyl phosphite, and titration with iodine; the
overall yield was 78%.
Con str u ction of th e Ma cr ocyclic La cta m . We
turned next to the union of the four fragments (Scheme
7). Allyl chloride (-)-6 was first converted to the iodide
(32) by treatment with sodium iodide in the presence of
2,6-di-tert-butyl-4-methylpyridine. Without isolation, the
iodide was added to the anion derived from sulfone 7
(NaHMDS, THF, -78 °C); a diastereomeric mixture
resulted. Reductive removal of the sulfone moiety with
Sch em e 5
With union of three of the key components complete,
palladium(0)-promoted hydrostannylation20 afforded the
trans-vinylstannane, accompanied by a small amount of
the internal vinylstannane (ca. 4:1). Without purification,
removal of the phenolic TBS moiety with TBAF at 0 °C
furnished phenol (+)-36 in 59% yield (two steps). It was
at this stage that the desired trans-vinylstannane could
be separated from the internal vinylstannane. Treatment
of (+)-36 with TBAF at room temperature, oxidation of
the resultant alcohol to the aldehyde employing the
Parikh-Doering protocol,21 and reprotection of the phenol
led to aldehyde (+)-38. Intermolecular Horner-Emmons
Sch em e 6
(16) Combes, S.; Finet, J .-P. Synth. Commun. 1997, 27, 3769-3778.
(17) Smith, A. B., III; Ott, G. R. J . Am. Chem. Soc. 1996, 118,
13095-13096.
(18) Chen, S.-Y.; J oullie´, M. M. Synth. Commun. 1984, 14, 591-
597.
(19) J ung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851-
3854.

Total Synthesis of (+)-Thiazinotrienomycin E
J . Org. Chem., Vol. 65, No. 12, 2000 3741
Sch em e 7
A Secon d Gen er a tion Str a tegy. Our inability to
install the E,E,E-triene with simultaneous macrocycliza-
tion via an intramolecular Stille reaction led us to
consider a second generation strategy for macrocyclic
lactam assembly, which called for alkylation of sulfone
7 with triene 40 followed by a Mukaiyama macrolactam-
ization (Scheme 8).24 Advanced triene 40 in turn was
envisioned to derive from aldehyde 41 and phosphonate
42.
Sch em e 8
Con str u ction of Ald eh yd e (+)-41 a n d P h osp h on -
a te (+)-42. Aldehyde (+)-41 was prepared from allylic
alcohol (-)-15 in three steps (Scheme 9): pivalation
(PivCl) of the hydroxyl, removal of the TBS group
(TBAF), and Parikh-Doering oxidation.
Sch em e 9
reaction of (+)-38 with phosphonate 5 then afforded a
1:1 mixture of olefins 39 in modest yield. Unfortunately,
all attempts at this point to effect macrocyclization,
employing a variety of Stille22 protocols, led only to rapid
decomposition of the olefins.23
Construction of phosphonate (+)-42 began with radical-
promoted (AIBN) hydrostannylation of alkyne (+)-28
(Scheme 10); trans-vinylstannane (+)-44 was obtained,
(20) Zhang, H. X.; Guibe, F.; Balavoine, G. J . Org. Chem. 1990, 55,
1857-1867.
(21) Parikh, J . R.; Doering, W. von E. J . Am. Chem. Soc. 1967, 89,
5505-5507.
(22) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813-
817.

3742 J . Org. Chem., Vol. 65, No. 12, 2000
Smith and Wan
contaminated with ca. 6% of the cis isomer.25 Separation
of the isomers via flash chromatography, followed by
treatment with iodine, afforded alcohol (+)-45. Prepara-
tion of (+)-42 was then completed via a palladium-
catalyzed Stille cross-coupling reaction with 31, followed
by TBS protection of the primary hydroxyl.
Scheme 12). J ulia olefination26 of sulfone 53 with alde-
hyde 54 appeared to be the obvious choice.
Sch em e 12
Sch em e 10
Hor n er -Em m on s Con str u ction of th e Tr ien e.
With both aldehyde (+)-41 and phosphonate (+)-42 in
hand, Horner-Emmons reaction (Scheme 11) led to an
inseparable mixture of trienes 50 in at best modest yield
(25-30%). A variety of bases, solvents, and reaction
temperatures did not improve either the selectivity or
yield. The lack of selectivity can be rationalized as
depicted in Scheme 11. Treatment of (+)-42 with
NaHMDS produces anion 47, which can either react with
(+)-41 to give the desired all-trans triene 48 or isomerize
to a mixture of anions 49, which in turn would afford a
mixture of olefins. Presumably, isomerization (k1) is
faster than olefination (k2).
Toward this end, construction of aldehyde (-)-54
(Scheme 13) entailed protection of alcohol (+)-44 as the
TBS ether followed in turn by treatment with iodine,
Stille cross-coupling with vinylstannane 29 and Swern27
oxidation of the derived alcohol led to aldehyde (-)-54
in 83% overall yield for the four steps.
Sch em e 11
Sch em e 13
Synthesis of the requisite sulfone (+)-53 began with
alcohol (+)-56 (Scheme 14). Mitsunobu reaction28 with
(23) For an example of macrocyclization employing Stille coupling,
see: Smith, A. B., III; Condon, S. M.; McCauley, J . A.; Leazer, J . L.,
J r.; Leahy, J . W.; Maleczka, R. E., J r. J . Am. Chem. Soc. 1997, 119,
947-973.
(24) For an example of Mukaiyama macrolactamization of a free
aniline, see: Roush, W. R.; Coffey, D. S.; Madar, D. J . J . Am. Chem.
Soc. 1997, 119, 11331-11332.
(25) Interestingly, the aldehyde was also reduced under these
conditions.
J u lia Olefin a tion : An Alter n a te Ap p r oa ch to
Tr ien e 40. To avoid anion isomerization, we considered
reversal of the coupling functionality (e.g., 51 and 52;

Total Synthesis of (+)-Thiazinotrienomycin E
J . Org. Chem., Vol. 65, No. 12, 2000 3743
Sch em e 14
Sch em e 15
2-mercaptobenzothiazole (57) followed by oxidation with
hydrogen peroxide and ammonium heptamolybdate tet-
rahydrate [(NH4)6Mo7O24‚4H2O] furnished sulfone (+)-
53 in 85% yield (two steps). J ulia coupling then afforded
triene 58, with the newly formed C(8,9) olefin obtained
as a cis/trans mixture (ca. 1:1.5). Importantly no isomer-
ization at either the C(4,5) or C(6,7) olefins was observed.
Th e Kocien sk i-J u lia P r otocol: Con str u ction of
th e All-Tr a n s Tr ien e. In 1998, Kocienski29 and co-
workers introduced an important modification of the
J ulia olefination reaction, leading to high trans selectiv-
ity. The protocol calls for the construction of the 1-phenyl-
1H-tetrazole-5-yl sulfone. Toward this end, Mitsunobu
reaction of (+)-56 with 1-phenyl-1H-tetrazole-5-thiol (59)
followed by oxidation of the resultant sulfide furnished
(+)-60 (Scheme 15). Addition of aldehyde (-)-54 to the
derived anion provided triene (+)-48; importantly, the
newly formed C(8,9) olefin was predominantly trans (ca.
10:1). In addition, no isomerization at C(4,5) or C(6,7)
was observed. Reductive removal of the pivaloate moi-
ety30 and halogenation of the resultant allylic alcohol
completed the construction of (+)-40.
aniline moiety furnished (+)-64. Treatment with allyl
chloroformate (AllocCl) followed by selective removal of
the phenolic TBS with HOAc-TBAF and reprotection of
the resultant phenol with chloromethyl methyl ether
(MOMCl)31 then afforded MOM ether (+)-65. After
unmasking of the primary alcohol, a two-step oxidation
protocol (Parikh-Doering and NaClO232) led to acid (+)-
(30) This strategy should give us the option to oxidize the C(1)
alcohol to acid before coupling with sulfone 7. This route although more
convergent, is highly risky. To this end, (-)-61 was converted to iv as
outlined below. Unfortunately, coupling with 7 proved impossible; only
recovery of sulfone 7 was observed. We reasoned that initial depro-
tonation of C(2) in iv by the sulfone anion leads to elimination of C(3)
methoxy followed by decomposition. To avoid this problem, we intro-
duced the carboxylic acid functionality after union with sulfone 7.
With the E,E,E-triene available, we proceeded with the
alkylation of sulfone 7. The allyl chloride moiety in (+)-
40 was first converted to the corresponding iodide (62,
Scheme 16). Addition to the anion derived from 7 (1.05
equiv) then afforded a diastereomeric mixture (ca. 2:1)
of sulfones 63. Although the iodide was completely
consumed, approximately 30% of sulfone 7 was recovered
(e.g., 95% based on the conversion of 7). Attempts to
improve the conversion of this coupling procedure went
unrewarded. Notwithstanding this event, we turned to
functional group manipulation in anticipation of macro-
lactamization.
Reductive desulfonylation of 63 followed by treatment
with silica gel in chloroform to liberate selectively the
(26) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175-1178.
(27) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-185.
(28) Mitsunobu, O. Synthesis 1981, 1-28.
(29) Blakemore, P. R.; Cole, W. J .; Kocienski, P. J .; Morley, A. Synlett
1998, 1, 26-28. For recent applications of this reaction in synthesis,
see: Blakemore, P. R.; Kocienski, P. J .; Morley, A.; Muir, K. J . Chem.
Soc., Perkin Trans. 1 1999, 955-968. Williams, D. R.; Brooks, D. A.;
Berliner, M. A. J . Am. Chem. Soc. 1999, 121, 4924-4925. Williams,
D. R. Clark, M. P. Tetrahedron Lett. 1999, 40, 2291-2294. Metternich,
R.; Denni, D.; Thai, B.; Sedrani, R. J . Org. Chem. 1999, 64, 9632-
9639.
(31) Protecting group exchange proved very important for the
macrolactamization step: unpublished result of Z.W.
(32) Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; Hollis, W. G.,
J r.; O’Mahony, R.; Lever, J . G.; Bankaitis-Davis, D. M. J . Am. Chem.
Soc. 1996, 118, 7513-7528.

3744 J . Org. Chem., Vol. 65, No. 12, 2000
Smith and Wan
Sch em e 16
of (+)-thiazinotrienomycin E (1) was removal of the
acetonide, installation of the acylated amino acid side
chain, and final deprotection (Scheme 17). To this end,
treatment of (+)-68 with acidic methanol and the sym-
metrical anhydride derived from FMOC-D-alanine led to
an inseparable mixture of monoacylated products in a
ratio of 2:1 favoring acylation at C(11). A small amount
(<7%) of bis-acylated material was also observed. Libera-
tion of the primary amine by exposure of the mixture to
diethylamine in THF, followed by BOP-mediated coupling
with cyclohexanecarboxylic acid, removal of the MOM
group, and separation (HPLC) furnished (+)-thiazino-
trienomycin E (1), identical in all respects with the
natural material (1H and 13C NMR, HRMS, optical
rotation, and TLC in three solvent systems).
Sch em e 17
Su m m a r y. The first total synthesis of (+)-thiazino-
trienomycin E (1) has been achieved. Importantly, the
synthesis confirms the previously reported relative and
absolute stereochemistries. Particularly noteworthy fea-
tures of the synthesis include the efficient assembly of
the E,E,E-triene and the improved synthesis of advanced
allyl chloride (-)-6. Exploitation of this synthetic strat-
egy, as currently underway, should provide access to
other members of the thiazinotrienomycin family, as well
as a variety of potentially bioactive analogues. Finally,
the efficient construction of (-)-6 constitutes an improved
total synthesis of the closely related (+)-trienomycins A
and F.
67 as a mixture of rotamers (ca. 4:1); removal of the Alloc
group provided an unstable amino acid. Without purifica-
tion, slow addition of this acid via syringe pump to a
mixture of 2-chloro-1-methylpyridinium iodide (Mukaiya-
ma salt)33 and TEA in toluene furnished macrocyclic
lactam (+)-68 in 61% yield for the two steps.
Sid e Ch a in Atta ch m en t: Com p letion of th e Tota l
Syn th esis. All that remained to complete the synthesis
(33) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163-
1166.

Total Synthesis of (+)-Thiazinotrienomycin E
J . Org. Chem., Vol. 65, No. 12, 2000 3745
Exp er im en ta l Section 34
(3 × 30 mL). The combined organic phases were dried over
MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 50:1-20:1) afforded an inseparable (2:
1) mixture of diastereomers as a colorless oil 11 (228 mg, 77%
yield).
To a solution of 11 (85 mg, 0.135 mmol) in anhydrous MeOH
(5 mL) was added K2CO3 (187 mg, 1.35 mmol). The resultant
suspension was stirred at room temperature for 3 h, added to
brine (25 mL), and extracted with ether (3 × 25 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate,
10:1) provided an inseparable (2:1) mixture of diastereomeric
diols as a colorless oil (75 mg, 100% yield).
Ald eh yd e (+)-9. To a solution of (+)-8 (200 mg, 0.82 mmol)
in CH2Cl2 (10 mL) were added 2,6-lutidine (0.382 mL, 3.28
mmol) and trimethylsilyl trifluoromethanesulfonate (TMSOTf,
0.297 mL, 1.64 mmol). After 10 min, the resultant mixture
was added to brine (50 mL) and extracted with ether (3 × 50
mL), and the combined organic phases were dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/
ethyl acetate, 20:1) provided the corresponding TMS ether (246
mg, 95% yield) as a colorless oil: [R]23 -14.8° (c 1.3, CHCl3);
D
IR (CHCl3) 3020 (m), 2960 (s), 2920 (s), 2850 (m), 1550 (w),
1470 (w), 1250 (s), 1217 (s), 1090 (s), 835 (s) cm-1; H NMR
1
(500 MHz, CDCl3) δ 5.82-5.78 (m, 1 H), 5.03-4.94 (m, 2 H),
3.80 (m, 1 H), 3.70-3.60 (m, 2 H), 2.30-2.21 (m, 1 H), 1.68-
1.50 (m, 2 H), 1.00 (d, J ) 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.12 (s,
9 H), 0.04 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ 141.7, 115.2,
73.0, 60.3, 43.9, 37.2, 26.1, 18.4, 15.6, 0.4, -5.3; high-resolution
mass spectrum (CI, NH3) m/z 315.2182 [(M - H)+; calcd for
To a solution of the above diols (75 mg, 0.135 mmol) in
CH2Cl2 (5 mL) was added MnO2 (235 mg, 2.7 mmol). After 12
h, the solution was filtered through a pad of Celite and
concentrated. Flash chromatography (hexanes/ethyl acetate,
20:1) afforded (+)-12 (65 mg, 87% yield) as a colorless oil: [R]23
D
+10.8° (c 0.5, CHCl3); IR (CHCl3) 3490 (m), 3065 (m), 3010
C
16H35O2(Si)2 315.2175].
Ozone was bubbled through a solution of the above TMS
(m), 3000 (s), 2955 (s), 2900 (s), 2847 (s), 1675 (m), 1600 (m),
1
1470 (m), 1420 (m); H NMR (500 MHz, CDCl3) δ 7.68-7.62
ether (100 mg, 0.316 mmol) in CH2Cl2 (20 mL) at -78 °C until
a blue color persisted. Argon was then bubbled through the
solution until it became colorless, and triphenylphosphine (124
mg, 0.474 mmol) was added. The mixture was stirred at
ambient temperature for 12 h and then concentrated in vacuo.
Flash chromatography (hexanes/ethyl acetate, 100:1) afforded
(+)-9 (93 mg, 92% yield) as a colorless oil: [R]23D +11.7° (c 0.6,
CHCl3); IR (plate) 2960 (s), 2920 (s), 2850 (s), 1725 (s), 1470
(m, 4 H), 7.42-7.37 (m, 6 H), 6.03 (t, J ) 5.6 Hz, 1 H), 4.58-
4.47 (m, 2 H), 3.92 (m, 1 H), 3.83 (m, 1 H), 3.76 (m, 1 H), 3.37
(d, J ) 4.1 Hz, 1 H), 2.95 (m, 1 H), 1.98 (s, 3 H), 1.68-1.54 (m,
2 H), 1.05 (s, 9 H), 0.96 (d, J ) 7.1 Hz, 3 H), 0.90 (s, 9 H), 0.08
(s, 6 H); 13C NMR (125 MHz, CDCl3) δ 208.0, 142.9, 135.5,
133.68, 133.65, 133.60, 129.5, 127.64, 127.59, 72.7, 63.0, 61.8,
48.0, 35.8, 26.8, 25.8, 20.6, 19.1, 16.9, 13.0, -5.6; high-
resolution mass spectrum (ES, Na) m/z 577.3143 [(M + Na)+;
calcd for C32H50O4(Si)2Na 577.3145].
1
(m), 1460 (m), 1250 (s), 1100 (s); H NMR (500 MHz, CDCl3)
δ 9.72 (d, J ) 2.2 Hz, 1 H), 4.13 (dt, J ) 4.8, 7.1 Hz, 1 H),
3.72-3.68 (m, 2 H), 2.50-2.43 (m, 1 H), 1.80-1.64 (m, 2 H),
1.09 (d, J ) 7.1 Hz, 3 H), 0.90 (s, 9 H), 0.12 (s, 9 H), 0.05 (s, 6
H); 13C NMR (125 MHz, CDCl3) δ 204.5, 70.4, 59.0, 51.7, 37.8,
25.9, 18.1, 10.4, 0.2, -5.5; high-resolution mass spectrum (ES,
Na) m/z 341.1954 [(M + Na)+; calcd for C15H34O3(Si)2Na
341.1944].
Keton e (+)-12. To a solution of vinyl iodide 10 (746 mg,
1.7 mmol) in ether (20 mL) at -78 °C was added dropwise
t-BuLi (1.7 M in pentane, 2 mL, 3.4 mmol). After 30 min, a
solution of (+)-9 (150 mg, 0.47 mmol) in ether (3 mL) was
introduced via cannula. The solution was then warmed to 0
°C over 2 h. The reaction was quenched with saturated NH4Cl
(10 drops), poured into brine (30 mL), and extracted with ether
Anal. Calcd for C32H50O4(Si)2: C, 69.31; H, 9.03. Found: C,
69.70; H, 9.24.
Diol (+)-13. Tetramethylammonium triacetoxyborohydride
(47.6 mg, 0.181 mmol) was dissolved in CH3CN and HOAc (1
mL each), and the resulting solution was cooled to -20 °C. A
solution of (+)-12 (10 mg, 0.0181 mmol) in CH3CN (0.25 mL)
was then added. The reaction mixture was stirred at -20 °C
for an additional 16 h and quenched with MeOH (0.2 mL). The
mixture was warmed to room temperature, poured into a
saturated NaHCO3 solution (20 mL), and extracted with ether
(3 × 20 mL). The combined organic phases were dried over
MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 10:1) afforded (+)-13 (10 mg, 98% yield)
as a colorless oil: [R]23D +15.2° (c 1.0, CHCl3); IR (CHCl3) 3460
(s), 3005 (s), 2960 (s), 2920 (s), 2850 (s), 1725 (s), 1470 (m),
1420 (s), 1250 (s), 1100 (s); 1H NMR (500 MHz, CDCl3) δ 7.73-
7.70 (m, 4 H), 7.45-7.37 (m, 6 H), 5.50 (m, 1 H), 4.57 (d, J )
3.0 Hz, 1 H), 4.28 (ddd, J ) 13.0, 7.4, 1.2 Hz, 1 H), 4.21 (ddd,
J ) 13.0, 5.6, 1.1 Hz, 1 H), 3.91 (br s, 1 H), 3.85 (m, 1 H), 3.77
(m, 2 H), 3.17 (br s, 1 H), 1.79 (s, 2 H), 1.74 (m, 1 H), 1.52 (m,
1 H), 1.36 (m, 1 H), 1.08 (s, 9 H), 0.93 (d, J ) 7.1 Hz, 3 H),
0.90 (s, 9 H), 0.09 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ 139.0,
135.6, 135.5, 133.8, 133.7, 129.5, 127.6, 127.5, 126.0, 76.3, 71.7,
63.2, 60.2, 42.7, 35.9, 26.8, 25.7, 20.3, 19.1, 18.0, 11.4, -5.61,
-5.63; high-resolution mass spectrum (ES, Na) m/z 579.3304
[(M + Na)+; calcd for C32H52O4(Si)2Na 579.3302].
Aceton id e (+)-14. A solution of (+)-13 (10 mg, 0.018 mmol)
in 2,2-dimethoxypropane (1 mL) at 0 °C was treated with
TsOH (two crystals). After 5 min, the mixture was poured into
a saturated NaHCO3 solution (10 mL) and extracted with ether
(3 × 10 mL). The combined organic phases were dried over
MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 20:1) afforded (+)-14 (10 mg, 93% yield)
as a colorless oil: [R]23D +4.1° (c 0.54, CHCl3); IR (CHCl3) 3020
(m), 2970 (s), 2930 (s), 2860 (m), 1517 (w), 1465 (m), 1420 (s),
1380 (s), 1250 (m), 1220 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.72-7.69 (m, 4 H), 7.48-7.39 (m, 6 H), 5.50 (t, J ) 5.6 Hz,
1 H), 4.51 (d, J ) 6.0 Hz, 1 H), 4.32 (dd, J ) 13.4, 7.1 Hz, 1
H), 4.28 (dd, J ) 13.4, 4.8 Hz, 1 H), 3.68-3.62 (m, 2 H), 3.42
(dt, J ) 9.7, 3.0 Hz, 1 H), 1.71 (s, 3 H), 1.70 (m, 1 H), 1.63-
1.55 (m, 2 H), 1.22 (s, 6 H), 1.08 (s, 9 H), 0.90 (s, 9 H), 0.77 (d,
J ) 7.1 Hz, 3 H), 0.03 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ
135.6, 134.7, 134.04, 133.97, 129.4, 127.5, 126.3, 100.4, 71.0,
70.1, 60.6, 59.4, 40.9, 37.7, 26.8, 25.9, 24.6, 23.9, 20.9, 19.1,
(34) Ma ter ia ls a n d Meth od s. All reactions were carried out in
oven- or flame-dried glassware under an argon atmosphere, unless
otherwise noted. All solvents were reagent grade. Diethyl ether and
tetrahydrofuran (THF) were freshly distilled from sodium/benzophe-
none under argon. Triethylamine (TEA) and diisopropylethylamine
(DIPEA) were distilled from calcium hydride and stored over potassium
hydroxide. Anhydrous pyridine, N,N-dimethylformamide (DMF), tolu-
ene, and dimethyl sulfoxide (DMSO) were purchased from Aldrich and
used without purification. n-Butyllithium (n-BuLi) and tert-butyl-
lithium (t-BuLi) were purchased from Aldrich and standardized by
titration with diphenylacetic acid or N-pivaloyl-o-toluidine. Except as
otherwise indicated, all reactions were magnetically stirred and
monitored by thin-layer chromatography with Whatman 0.25-mm
precoated silica gel plates. Flash column chromatography was per-
formed using silica gel 60 (particle size 0.023-0.040 mm) supplied by
E. Merck. High-performance liquid chromatography (HPLC) was
performed with a Waters component analytical system. Yields refer
to chromatographically and spectroscopically pure compounds, unless
otherwise stated. All melting points were obtained on a Thomas-Hoover
apparatus and are corrected. Infrared spectra were recorded on a
Perkin-Elmer Model 283B spectrometer with polystyrene as external
standard. Proton NMR spectra were recorded on a Bruker AM-500
spectrometer. Carbon-13 NMR spectra were recorded on a Bruker AM-
500 or AM250 spectrometer. Chemical shifts are reported relative to
internal tetramethylsilane (δ 0.00), chloroform (δ 7.26), methanol (δ
4.78), pyridine (δ 7.55), or benzene (δ 7.15) for 1H and chloroform (δ
77.0), methanol (δ 49.0), pyridine (δ 149.9), or benzene (δ 128.0) for
13C. Optical rotations were measured with a Perkin-Elmer model 241
polarimeter. High-resolution mass spectra were obtained at the
University of Pennsylvania Mass Spectrometry Service Center with
either a VG Micromass 70/70H or VG ZAB-E spectrometer. Micro-
analyses were performed by Robertson Laboratories, Madison, NJ , or
at the University of Pennsylvania. Single-crystal X-ray structure
determinations were performed at the University of Pennsylvania with
an Enraf Nonius CAD-4 automated diffractometer.

3746 J . Org. Chem., Vol. 65, No. 12, 2000
Smith and Wan
18.1, 12.1, -5.38, -5.42; high-resolution mass spectrum (ES,
Na) m/z 619.3619 [(M + Na)+; calcd for C35H56O4(Si)2Na
619.3614].
Anal. Calcd for C35H56O4(Si)2: C, 70.47; H, 9.40. Found: C,
70.25; H, 9.21.
Alcoh ol (-)-15. A solution of (+)-14 (10 mg, 0.0168 mmol)
in DMPU (1 mL) was treated with NaOH (16.8 mg, 0.42 mmol)
in water (0.1 mL). The mixture was stirred for 1 h, poured
into a saturated NH4Cl solution (20 mL) and extracted with
ether (3 × 20 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 10:1) afforded (-)-15 (5.5 mg, 91%
yield) as a colorless oil that was spectroscopically and analyti-
cally identical to that prepared in the trienomycin project.
(s, 3 H), 4.04 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 160.7,
156.6, 156.5, 154.4, 138.6, 132.0, 124.9, 120.9, 120.8, 64.0, 53.9.
Anal. Calcd for C9H7FN2O7: C, 39.42; H, 2.55; N, 10.27.
Found: C, 39.80; H, 2.76; N, 9.93.
Su lfid e 19. To a solution of methyl thioglycolate (0.755 mL,
8.0 mmol) in DMF (40 mL) was added LiOH (161.4 mg, 6.7
mmol). The mixture was stirred until all the LiOH was
dissolved (3 h). The resultant yellow solution was then added
to 18 (1.68 g, 6.13 mmol) in DMF (20 mL) at -78 °C via
cannula. The mixture was stirred at room temperature for an
additional 3 h. The resultant dark red solution was diluted
with ethyl acetate (300 mL), washed with brine (3 × 100 mL),
dried over MgSO4, filtered, and concentrated. Flash chroma-
tography (hexanes/ethyl acetate, 4:1) provided 19 (2.2 g, 90%
yield) as a yellow foam: IR (CHCl3) 3025 (w), 2960 (w), 1745
(s), 1590 (s), 1540 (s), 1440 (m), 1400 (w), 1350 (s), 1270 (s),
Bis-Nitr o Ben zoa te 18. To a white suspension of 2-fluoro-
6-methoxybenzonitrile (16, 10 g, 66.2 mmol) in toluene (250
mL) at -78 °C was added DIBAL (1 M in hexanes, 70 mL) via
addition funnel. After the addition, the ice bath was removed,
and the mixture was stirred at ambient temperature for 12 h.
The reaction was then quenched by slow addition of MeOH
(50 mL) at 0 °C and the resultant precipitate dissolved in HCl
(1 N, 300 mL). The organic part was separated, and the
aqueous part was extracted with ether (3 × 300 mL). The
combined organic phases were washed with brine (500 mL),
dried over MgSO4, filtered, and concentrated. Flash chroma-
tography (ethyl acetate/hexanes, 1:3) afforded the correspond-
ing aldehyde (9.7 g, 95% yield) as a light yellow solid: mp 60-
61 °C (hexane/ethyl acetate); IR (CHCl3) 3010 (m), 1695 (s),
1615 (s), 1575 (m), 1477 (s), 1440 (m), 1400 (m), 1290 (m), 1250
1
1160 (m), 1140 (m) cm-1; H NMR (500 MHz, CDCl3) δ 8.45
(s, 1 H), 4.04 (s, 3 H), 4.03 (s, 3 H), 3.74 (s, 2 H), 3.72(s, 3 H);
13C NMR (125 MHz, CDCl3) δ 168.2, 163.8, 152.9, 149.0, 142.5,
140.5, 131.9, 122.6, 64.3, 53.5, 52.8, 38.6; high-resolution mass
spectrum (CI, NH3) m/z 378.0601 [(M + NH4)+; calcd for
C
12H16N3O9S 378.0607].
An ilin e 20. To a yellow suspension of 19 (1.776 g, 4.93
mmol) in MeOH (25 mL) was added SnCl2 (3.74 g, 19.73 mmol)
in HCl (2 M, 25 mL, 50 mmol). The mixture was heated at
reflux for 14 h. The resultant dark green solution was cooled
to room temperature, treated with a solution of NaOH (5 M,
8 mL, 40 mmol), and mixed with a saturated NaHCO3 solution
(25 mL). The resultant precipitate was removed by filtration
and the filtrate extracted with ethyl acetate (4 × 200 mL).
The combined organic phases were dried over MgSO4, filtered,
and concentrated. Gradient flash chromatography (ether/
hexanes, 4:1; ether/ethyl acetate, 1:1; ethyl acetate) provided
20 (462 mg, 35% yield) as a yellow oil: IR (CHCl3) 3400 (w),
3200 (w), 3000 (w), 1730 (m), 1680 (s), 1620 (m), 1480 (m),
1435 (m), 1365 (m), 1260 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 8.64 (s, 1 H), 6.39 (s, 1 H), 3.99 (s, 3 H), 3.82 (s, 3 H), 3.33
(s, 2 H); 13C NMR (125 MHz, CDCl3) δ 166.7, 166.3, 141.7,
139.7, 133.5, 126.7, 107.6, 106.0, 61.3, 52.6, 30.5; high-
resolution mass spectrum (CI, NH3) m/z 286.0868 [(M + NH4)+;
calcd for C11H16N3O4S 286.0862].
(m), 1180 (m), 1090 (s) cm-1 1H NMR (500 MHz, CDCl3) δ
;
10.44 (s, 1 H), 7.47-7.50 (m, 1 H), 6.72-6.80 (m, 2 H), 3.95 (s,
3 H); 13C NMR (125 MHz, CDCl3) δ 187.2, 164.4, 162.4, 162.2,
162.1, 136.0, 135.9, 114.3, 114.2, 108.7, 108.6, 107.3, 107.2,
56.4; high-resolution mass spectrum (CI, NH3) m/z 172.0772
[(M + NH4)+; calcd for C8H11FNO2 172.0774].
A solution of the above aldehyde (35 g, 0.227 mol) in acetone
(100 mL) was added to a mechanically stirred suspension of
KMnO4 (53.9 g, 0.34 mol) in water (400 mL). After addition,
the mixture was heated at reflux for 3 h, cooled to room
temperature, and added to a NaOH solution (3.5 M, 100 mL,
0.35 mol). The resultant black precipitate was removed by
filtration, and the filtrates were extracted with ethyl acetate
(300 mL). The aqueous part was then treated with HCl (5 M,
70 mL) and extracted with ethyl acetate (3 × 400 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated to afford 17 (37.9 g, 98% yield) as a yellow solid.
A solution of 17 (29 g, 0.171 mol) and concentrated H2SO4
(1 mL) in MeOH (150 mL) was heated at reflux for 24 h. The
reaction mixture was then cooled to room temperature and
concentrated to dryness in vacuo. The residue was dissolved
in ethyl acetate (1 L) and washed in turn by NaOH (1 N, 100
mL) and brine (2 × 500 mL). The combined organic phases
were dried over MgSO4, filtered, and concentrated to provide
the corresponding methyl benzoate (30.4 g, 97% yield) as a
brown oil that was used without further purification: IR
(CHCl3) 3020 (m), 2960 (w), 1730 (s), 1620 (s), 1600 (m), 1585
(m), 1475 (s), 1435 (s), 1310 (s), 1290 (s), 1270 (s), 1240 (s)
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35-7.31 (m, 1 H), 6.74-
6.71 (m, 2 H), 3.93 (s, 3 H), 3.86 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 164.4, 161.3, 159.3, 158.2, 158.1, 131.8, 131.7, 112.1,
111.9, 108.4, 108.2, 107.0, 106.9, 56.3, 52.5; high-resolution
mass spectrum (CI, NH3) m/z 185.0608 [(M + H)+; calcd for
C9H10FO3 185.0613].
N-Cbz Am id e 23. A solution of 20 (520 mg, 1.94 mmol) in
acetone (15 mL) was treated with aqueous K2CO3 (5 M, 1.55
mL, 7.76 mmol) and CbzCl (1.166 mL, 7.76 mmol). The mixture
was stirred for 4 h, diluted with ethyl acetate (50 mL), and
washed in turn with saturated NaHCO3 (30 mL) and brine
(30 mL). The combined organic phases were then dried over
MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 4:1 to 1:1) afforded 23 (741 mg, 95%
yield) as a yellow solid: mp 174-176 °C (hexane/ethyl acetate);
IR (CHCl3) 3400 (m), 3020 (w), 1730 (s), 1690 (s), 1600 (m),
1515 (s), 1460 (m), 1370 (m), 1260 (m), 1195 (m) cm-1; 1H NMR
(500 MHz, CDCl3) δ 9.15 (s, 1 H), 8.02 (s, 1 H), 7.42-7.29 (m,
6 H), 5.23 (s, 2 H), 3.99 (s, 3 H), 3.80 (s, 3 H), 3.35 (s, 2 H); 13
C
NMR (125 MHz, CDCl3) δ 166.1, 165.8, 153.2, 142.7, 135.6,
133.7, 130.7, 128.7, 128.6, 128.5, 125.6, 113.8, 109.6, 67.7, 62.6,
52.7, 30.0; high-resolution mass spectrum (CI, NH3) m/z
420.1238 [(M + NH4)+; calcd for C19H22N3SO6 420.1229].
Anal. Calcd for C19H18N2SO6: C, 56.72; H, 4.48; N, 6.97.
Found: C, 56.35; H, 4.49; N, 6.60.
Alcoh ol 21. A solution of 23 (11.2 g, 27.9 mmol) and 15-
crown-5 ether (46 g, 209 mmol) in THF (100 mL) at 0 °C was
treated with super hydride (1 M in THF, 209 mL, 209 mmol).
The resultant mixture was stirred at ambient temperature for
an additional 12 h and then recooled to 0 °C and quenched
with HCl (1 N, 20 mL). The mixture was diluted with ethyl
acetate (1 L) and washed with brine (5 × 500 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated. Flash chromatography (ethyl acetate/hexanes,
1:1 to 3:1) afforded 21 (6.25 g, 60% yield) as a white solid: mp
189-190 °C (hexane/methanol); IR (CHCl3) 3400 (m), 2960 (m),
1730 (m), 1680 (s), 1600 (m), 1520 (s), 1510 (m), 1375 (m), 1240
A solution of the above methyl benzoate (15 g, 81.5 mmol)
and NO2BF4 (25 g, 179 mmol) in sulfolane (240 mL) was heated
to 50 °C for 15 h. The solution was then cooled to room
temperature, diluted with ethyl acetate (1 L), and washed in
turn with saturated NaHCO3 (500 mL) and brine (3 × 500
mL). The combined organic phases were dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/
ethyl acetate, 3:1) afforded 18 (21.2 g, 95% yield) as a yellow
oil: IR (CHCl3) 3100 (w), 3040 (w), 2960 (w), 1700 (s), 1610
(s), 1115(m), 1060 (m), 1000(s) cm-1 1H NMR (500 MHz,
;
(s), 1550 (s), 1350 (s), 1310 (s), 1270 (s), 1155 (s), 1080 (s) cm-1
1H NMR (500 MHz, CDCl3) δ 8.75 (d, J ) 7.7 Hz, 1 H), 4.09
;
CD3OD) δ 7.65-7.30 (m, 6 H), 5.21 (s, 2 H), 4.73 (s, 2 H), 3.74
(s, 3 H), 3.35 (s, 2 H); 13C NMR (125 MHz, CD3OD) δ 167.2,

Total Synthesis of (+)-Thiazinotrienomycin E
J . Org. Chem., Vol. 65, No. 12, 2000 3747
154.3, 145.0, 136.6, 133.6, 131.6, 130.4, 128.2, 127.8, 127.7,
116.8, 109.7, 66.5, 61.7, 56.2, 29.3; high-resolution mass
spectrum (CI, NH3) m/z 392.1292 [(M + NH4)+; calcd for
(100 mL), and washed with ice-cold water (3 × 100 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated to afford (+)-27 (1.07 g, 92% yield) as a colorless
C
18H22N3O5S 392.1281].
oil: [R]23 +50.2° (c 1.30, CHCl3); IR (CHCl3) 3300 (s), 3080
D
Su lfon e 22. To a solution of 21 (1.02 g, 2.73 mmol) in
(w), 3000 (w), 2940 (s), 2820 (w), 1650 (m), 1450 (m), 1360 (s),
1
CH2Cl2 (60 mL) were added triethylamine (5.7 mL, 41 mmol),
4-(dimethylamino)pyridine (333 mg, 2.73 mmol), and p-tolu-
enesulfonyl chloride (2.6 g, 13.64 mmol). The mixture was
stirred for 6.5 h, diluted with CH2Cl2 (300 mL), and washed
with brine (200 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. The resultant dark
residue was dissolved in DMF (50 mL) and treated with NaI
(2.05 g, 13.64 mmol) and PhSO2Na (4.48 g, 27.3 mmol). The
mixture was then stirred at 60 °C for 13 h. The solution was
next cooled to room temperature, diluted with ethyl acetate
(200 mL), and washed in turn with saturated NaHCO3 (100
mL) and brine (100 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated. Flash chroma-
tography (ethyl acetate/hexanes, 1:1 to 2:1) provided 22 (0.90
g, 66% yield) as a light yellow solid: mp 184-186 °C (hexane/
chlorofom); IR (CHCl3) 3500 (m), 3300 (m), 3000 (s), 2900 (m),
1770 (m), 1720 (w), 1670 (m), 1600 (w), 1450 (w), 1340 (m),
1260 (w), 1100 (s), 990 (m), 920 (s) cm-1; H NMR (500 MHz,
CDCl3) δ 5.90 (m, 1 H), 5.15 (m, 2 H), 4.05 (ddd, J ) 6.5, 6.4,
2.0 Hz, 1 H), 3.41 (s, 3 H), 2.52 (m, 2 H), 2.49 (d, J ) 2 Hz);
13C NMR (125 MHz, CDCl3) δ 133.3, 117.8, 82.0, 74.2, 70.6,
56.4, 39.9; high-resolution mass spectrum (CI, NH3) m/z
128.1076 [(M + NH4)+; calcd for C7H14NO 128.1074].
Ald eh yd e (+)-28. Ozone was bubbled through a solution
of (+)-27 (0.5 g, 4.54 mmol) in diethyl ether (40 mL) at -78
°C. The reaction was closely monitored by TLC, and the O3
bubbling was immediately stopped when the starting material
disappeared. The solution was then treated with triphenylphos-
phine (1.43 g, 5.46 mmol) and allowed to warm to room
temperature. After being stirred at ambient temperature for
12 h, the mixture was concentrated in vacuo. Flash chroma-
tography (ether/pentane, 1:1) afforded (+)-28 (346 mg, 68%
yield) as a light yellow oil: [R]23 +57.3° (c 1.50, CHCl3); IR
D
(CHCl3) 2940 (s), 2920 (s), 2840 (s), 1721 (m), 1463 (m), 1432
1240 (m), 1175 (s) cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.84
(w), 1390 (w), 1360 (m), 1255 (s) cm-1 1H NMR (500 MHz,
;
(m, 2 H), 7.73 (br s, 1 H), 7.65 (m, 1 H), 7.53 (m, 2 H), 7.44 (m,
5 H), 7.01 (s, 1 H), 5.25 (s, 2 H), 4.64 (s, 2 H), 3.75 (s, 3 H),
3.19 (s, 2 H); 13C NMR (125 MHz, CDCl3) δ 165.8, 153.0, 144.8,
139.1, 135.5, 134.0, 133.8, 130.9, 129.1, 128.8, 128.67, 128.65,
128.5, 120.9, 117.4, 108.9, 67.7, 61.8, 56.2, 30.5; high-resolution
mass spectrum (ES, Na) m/z 521.0811 [(M + Na)+; calcd for
CDCl3) δ 9.81 (t, J ) 2.0 Hz, 1 H), 4.47 (m, 1 H), 3.47 (s, 3 H),
2.86 (ddd, J ) 2.1, 7.1, 17.2 Hz, 1 H), 2.78 (ddd, J ) 1.8, 5.1,
17.2 Hz, 1 H), 2.55 (d, J ) 2.0 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 199.1, 80.8, 75.2, 65.7, 56.8, 48.7; high-resolution
mass spectrum (CI, NH3) m/z 130.0860 [(M + NH4)+; calcd for
C6H12NO2 130.0868].
C
24H22N2O6S2Na 521.0817].
Acid (+)-4. To a suspension of PDC (1.13 g, 3 mmol) in DMF
(2 mL) was added (+)-28 (110 mg, 1 mmol) in ether (3.5 mL).
The resultant mixture was stirred for 19 h, poured into water
(60 mL), and extracted with ether (4 × 20 mL). The combined
organic phases were washed twice with brine (40 mL, with 5
mL of 1 N HCl), dried over MgSO4, filtered, and concentrated
Anal. Calcd for C24H22N2O6S2: C, 57.82; H, 4.45; N, 5.62.
Found: C, 57.43; H, 4.17; N, 5.37.
TBS An ilin e 7. A suspension of 22 (80 mg, 0.16 mmol) in
CH2Cl2 at 0 °C was treated with BBr3 (1 M in CH2Cl2, 1.6 mL,
1.6 mmol). The mixture was stirred at ambient temperature
for 12 h and then quenched with MeOH (1 mL). The solution
was concentrated to dryness in vacuo. The crude dark residue
was dissolved in ethyl acetate (25 mL), treated with HCl (1
N, 5 mL), and washed with brine (25 mL). After separation,
the aqueous phase was mixed with saturated NaHCO3 (25 mL)
and washed with ethyl acetate (4 × 50 mL). The combined
organic phases were dried over MgSO4, filtered, and concen-
trated to provide the corresponding phenol-aniline (47.8 mg,
85% yield) as a glassy solid that was used without any further
purification: IR (Plate) 3400 (m), 2940 (s), 2920 (s), 2850 (s),
to provide (+)-4 (98 mg, 78% yield) as a colorless oil: [R]23
D
+53.4° (c 1.05, CHCl3); IR (CHCl3) 3300 (m), 3000 (br s), 1715
(s), 1410 (m), 1340 (w), 1290 (s), 1105 (s), 905 (m) cm-1 1H
;
NMR (500 MHz, CDCl3) δ 4.42 (ddd, J ) 8.3, 5.1, 3.2 Hz, 1
H), 3.46 (s, 3 H), 2.84 (dd, J ) 16.1, 8.3 Hz, 1 H), 2.78 (dd, J
) 16.1, 5.1 Hz, 1 H), 2.52 (d, J ) 2.2 Hz, 1 H); 13C NMR (125
MHz, CDCl3) δ 175.6, 80.7, 74.7, 66.9, 56.8, 40.8; high-
resolution mass spectrum (CI, NH3) m/z 146.0825 [(M + NH4)+;
calcd for C6H12NO3 146.0817].
Allyl Br om id e 30. A solution of 29 (3 g, 8.65 mmol) and
triphenylphosphine (4.53 g, 17.3 mmol) in acetonitrile (80 mL)
was treated with carbon tetrabromide (3.44 g, 10.38 mmol)
and 2,6-lutidine (0.201 mL, 1.73 mmol). After 10 min, the
mixture was added to saturated NaHCO3 (100 mL) and
extracted with hexanes (3 × 100 mL). The combined organic
phases were dried over MgSO4, filtered, and concentrated.
Flash chromatography (hexanes/ethyl acetate, 100:1) provided
30 (3.08 g, 87% yield) as a colorless oil: IR (CHCl3) 2980 (s),
2930 (s), 2880 (s), 2860 (s), 1590 (w), 1460 (m), 1380 (m), 1200
1675 (s), 1590 (s), 1463 (s), 1357 (s), 1340 (m), 1250 (s) cm-1
;
1H NMR (500 MHz, CD3OD) δ 7.83-7.81 (m, 2 H), 7.76-7.72
(m, 1 H), 7.62-7.58 (m, 2 H), 7.12 (s, 1 H), 4.95 (s, 2 H), 3.05
(s, 2 H); 13C NMR (125 MHz, CD3OD) δ 166.6, 146.2, 138.3,
134.3, 131.8, 129.2, 128.4, 125.7, 119.1, 116.5, 113.3, 55.5, 29.2;
high-resolution mass spectrum (ES, Na) m/z 373.0295 [(M +
Na)+; calcd for C15H14N2O4S2Na 373.0293].
To a solution of the above phenol-aniline (180 mg, 0.51
mmol) in DMF (10 mL) were added triethylamine (1.075 mL,
7.71 mmol) and tert-butyldimethylsilyl trifluoromethane-
sulfonate (1.24 mL, 5.14 mmol). After 2 h, the reaction was
quenched with brine (40 mL). The resultant mixture was
extracted with ether (3 × 50 mL), and the combined organic
phases were dried over MgSO4, filtered, and concentrated.
Flash chromatography (hexanes/ethyl acetate, 1:1) provided
7 (178 mg, 60% yield) as a light yellow oil: IR (CHCl3) 3400
(m), 2940 (s), 2880 (m), 1680 (s), 1600 (m), 1470 (s), 1350 (m),
(m), 1070 (m), 990 (s), 860 (m) cm-1 1H NMR (500 MHz,
;
CDCl3) δ 6.33 (dd, J ) 18.6, 1.0 Hz, 1 H), 6.17 (dt, J ) 18.6,
6.7 Hz, 1 H), 3.98 (dd, J ) 6.7, 1.0 Hz, 2 H), 1.55 (m, 6 H),
1.35 (m, 6 H); 13C NMR (125 MHz, CDCl3) δ 143.1, 135.1, 35.8,
29.1, 27.2, 13.7, 9.6.
Anal. Calcd for C15H31BrSn: C, 43.94; H, 7.62. Found: C,
43.67; H, 7.59.
P h osp h on a te 31. To a solution of 30 (120 mg, 0.29 mmol)
in DMF (2 mL) were added NaH (60% in mineral oil, 83 mg,
1.45 mmol) and diethyl phosphite (0.185 mL, 1.45 mmol) in
DMF (2 mL). The resultant clear mixture was stirred for 3 h,
added to water (25 mL) and extracted with ether (3 × 25 mL).
The combined organic phases were dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes/ethyl ace-
tate, 1:1) afforded 31 (123 mg, 90% yield) as a colorless oil:
IR (CHCl3) 2995 (m), 2960 (m), 2930 (m), 2580 (w), 2860 (w),
1
1320 (w), 1260 (s), 1140 (m), 1090 (m), 940 (s) cm-1; H NMR
(500 MHz, C6D6) δ 7.64 (m, 2 H), 6.94-6.82 (m, 3 H), 6.76 (s,
1 H), 4.74 (s, 2H), 3.50 (s, 1 H), 2.82 (s, 2 H), 0.98 (s, 9 H),
0.87 (s, 9 H), 0.27 (s, 6 H), -0.03 (s 6 H); 13C NMR (125 MHz,
C6D6) δ 168.0, 139.6, 139.2, 132.7, 132.6, 129.1, 128.2, 128.0,
118.9, 109.5, 105.1, 57.2, 30.7, 26.4, 25.5, 18.4, 18.1, -3.9, -4.6;
high-resolution mass spectrum (ES, Na) m/z 579.2220 [(M +
H)+; calcd for C27H43N2O4S2(Si)2 579.2202].
Meth yl Eth er (+)-27. A solution of (+)-26 (1.013 g, 10.55
mmol) in diethyl ether-DMSO (5:1, 48 mL) at 0 °C was treated
with n-BuLi (2.5 M in hexanes, 4.3 mL, 10.75 mmoL) and
methyl iodide (0.985 mL, 15.82 mmol). The mixture was heated
to reflux for 1 h, cooled to room temperature, diluted with ether
1600 (m), 1460 (m), 1395 (w), 1250 (s), 1060 (s), 960 (s) cm-1
;
1H NMR (500 MHz, CDCl3) δ 6,15 (ddt, J ) 18.8, 4.5, 1.2 Hz,
1 H), 5.91 (m, 1 H), 4.10 (m, 4 H), 2.73 (ddd, J ) 21.6, 6.9, 1.2
Hz, 2 H), 1.49 (m, 6 H), 1.32 (m, 12 H); 13C NMR (125 MHz,
CDCl3) δ 136.5, 136.4, 135.4, 135.3, 61.81, 61.76, 36.3, 35.2,

3748 J . Org. Chem., Vol. 65, No. 12, 2000
Smith and Wan
29.0, 27.2, 16.43, 16.38, 13.7, 9.5; high-resolution mass spec-
trum (ES, Na) m/z 491.1705 [(M + Na)+; calcd for C19H41O3-
PSnNa 491.1713].
2 H), 3.15 (br s, 2 H), 3.03 (s, 2 H), 2.98 (m, 2 H), 2.52 (m, 1
H), 2.36 (m, 1 H), 1.91 (s, 3 H), 1.85 (m, 2 H), 1.71 (m, 1 H),
1.42 (s, 3 H), 1.41 (s, 3 H), 1.00 (s, 9 H), 0.97 (s, 9 H), 0.87 (d,
J ) 7.0 Hz, 3 H), 0.12 (s, 6 H), 0.05 (s, 3 H), 0.04 (s, 3 H); 13C
NMR (125 MHz, C6D6) δ 167.2, 138.1, 137.6, 135.3, 132.3,
131.0, 124.9, 108.2, 103.3, 100.5, 70.9, 69.2, 59.4, 41.6, 38.0,
30.1, 29.3, 27.9, 25.9, 25.8, 24.6, 24.1, 20.9, 18.4, 18.1, 12.3,
-3.62, -3.64, -5.49, -5.54; high-resolution mass spectrum
(ES, Na) m/z 687.3872 [(M + Na)+; calcd for C34H60N2O5S(Si)2-
Na 687.3863].
Vin yl Iod id e 5. To a solution of 31 (40 mg, 0.086 mmol) in
CH2Cl2 (1 mL) was added I2 in CH2Cl2 until a purple color
persisted. The mixture was stirred for an additional 30 min
and then was quenched with saturated Na2SO3 (1 mL). The
mixture was poured into brine (20 mL) and extracted with
ether (3 × 20 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 1:1) provided 5 (26 mg, 100% yield) as
a light yellow oil: IR (CHCl3) 3000 (s), 2930 (w), 1650 (w), 1445
(w), 1250 (s), 1025 (s), 970 (s), 940 (s) cm-1; 1H NMR (500 MHz,
CDCl3) δ 6.55 (m, 1 H), 6.30 (ddt, J ) 14.5, 4.9, 1.2 Hz, 1 H),
4.13 (m, 4 H), 2.63 (ddd, J ) 21.5, 7.6, 1.2 Hz, 2 H), 1.40 (t, J
) 7.1 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ 134.7, 134.6,
79.6, 79.5, 62.3, 62.2, 34.5, 33.4, 16.49, 16.45; high-resolution
mass spectrum (CI, NH3) m/z 305.3102 [(M + H)+; calcd for
C7H15IO3P 305.3118].
Anal. Calcd for C34H60N2O5S(Si)2: C, 61.44; H, 9.04; N, 4.22.
Found: C, 61.54; H, 9.03; N, 3.82.
Am id e (+)-35. A solution of (+)-4 (20 mg, 0.156 mmol) in
chloroform (3 mL) was treated with thionyl chloride (0.04 mL,
0.548 mmol). The resultant mixture was heated to reflux for
8 h and then concentrated to dryness in vacuo to afford the
corresponding acid chloride as a yellow oil. The acid chloride
was used immediately in the following step.
A solution of (-)-3 (15 mg, 0.0226 mmol) and triethylamine
(0.080 mL, 0.574 mmol) in THF (3 mL) was treated with the
above acid chloride in THF (1 mL). The resultant mixture was
stirred for 30 min, added to brine (20 mL), and extracted with
ether (3 × 25 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 2:1) afforded (+)-35 (14 mg, 80% yield)
as a white foam: [R]23D +4.8° (c 0.5, benzene); IR (CHCl3) 3300
(w), 2960 (s), 2920 (s), 2860 (s), 1630 (s), 1600 (s), 1510 (s),
1440 (s), 1380 (m), 1250 (m), 1220 (m), 1100 (s) cm-1; 1H NMR
(500 MHz, C6D6) δ 8.12 (br s, 1 H), 7.70 (br s, 2 H), 5.38 (t, J
) 7.6 Hz, 1 H), 5.01 (d, J ) 5.5 Hz, 1 H), 4.42 (dt, J ) 6.0, 1.9
Hz, 1 H), 3.83 (m, 1 H), 3.68 (m, 2 H), 3.20 (s, 3 H), 2.90-2.80
(m, 2 H), 2.85 (s, 2 H), 2.76 (d, J ) 6.0 Hz, 2 H), 2.44 (m, 1 H),
2.32 (m, 1 H), 2.06 (d, J ) 1.9 Hz, 1 H), 1.90 (s, 3 H), 1.73 (m,
2 H), 1.70 (m, 1 H), 1.43 (s, 3 H), 1.41 (s, 3 H), 0.98 (s, 9 H),
0.94 (s, 9 H), 0.87 (d, J ) 6.9 Hz, 3 H), 0.06 (s, 3 H), 0.05 (s, 3
H), 0.02 (s, 3 H), -0.01 (s, 3 H); 13C NMR (125 MHz, C6D6) δ
167.5, 167.1, 164.3, 138.5, 136.0, 133.2, 131.1, 124.9, 115.5,
108.1, 101.1, 81.7, 75.1, 71.3, 69.7, 68.2, 59.7, 56.8, 44.7, 41.9,
38.2, 30.0, 29.4, 27.9, 25.9, 25.8, 24.8, 24.2, 21.1, 18.4, 18.2,
12.4, -3.9, -4.0, -5.5, -5.6; high-resolution mass spectrum
(ES, Na) m/z 797.4045 [(M + Na)+; calcd for C40H66N2O7S(Si)2-
Na 797.4027].
Su lfon e 33. A solution of (-)-6 (120 mg, 0.32 mmol) in
acetone (4 mL) was treated with 2,6-di-tert -butyl-4-methyl-
pyridine (4 mg, 0.0192 mmol) and sodium iodide (192 mg, 1.28
mmol). The resultant cloudy solution was stirred for 1 h and
then filtered through a short plug of neutral alumina. The
filtrate was concentrated to dryness in vacuo to afford the
corresponding unstable allyl iodide as a yellow oil. The allyl
iodide was used immediately in the following step.
A solution of 7 (185 mg, 0.32 mmol) in THF (2 mL) at -78
°C was treated with sodium bis(trimethylsilyl)amide (1 M in
THF, 1.28 mL, 1.28 mmol). After 5 min, the above allyl iodide
in THF (2 mL) was introduced via cannula. The resultant
yellow solution was stirred at -78 °C for 1.5 h, quenched with
methanol (0.5 mL), added to brine (25 mL), and extracted with
ether (3 × 25 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 4:1 to 1:1) gave recovered 7 (88 mg)
and afforded 33 (147 mg, 50% yield or 95% yield based on
recovered 7) as a yellow foam: IR (CHCl3) 3400 (m), 2960 (s),
2940 (s), 2860 (s), 1682 (s), 1600 (s), 1460 (s), 1362 (s), 1260
(s), 1145 (s), 1088 (s), 830 (s) cm-1; 1H NMR (500 MHz, C6D6)
δ 7.68-7.60 (complex series of m, 2 H), 6.97-6.90 (complex
series of m, 1 H), 6.86-6.79 (complex series of m, 2 H), 6.78,
6.76 (diastereomers, s, s, 1 H), 5.82, 5.63 (diastereomers, t, t,
J ) 6.1 Hz, 1 H), 5.28-5.22 (complex series of m, 1 H), 5.17,
5.03 (diastereomers, d, d, J ) 5.4 Hz, 1 H), 4.24-3.61 (complex
series of m, 5 H), 3.37, 3.28 (diastereomers, s, s, 1 H), 3.08-
2.90 (complex series of m, 2 H), 2.09-1.97 (complex series of
m, 1 H), 1.86, 1.84 (diastereomers, s, s, 3 H), 1.82-1.73
(complex series of m, 2 H), 1.51-1.40 (overlapping s, 6 H),
1.06-0.90 (overlapping s, 30 H), 0.30-0.02 (overlapping s, 18
H); 13C NMR (125 MHz, C6D6) δ169.4, 169.3, 140.2, 139.8,
139.5, 139.4, 139.2, 137.4, 136.8, 134.0, 133.9, 132.8, 129.5,
128.62, 128.61, 128.5, 128.3, 123.5, 123.2, 122.7, 122.2, 109.0,
105.9, 105.7, 100.9, 99.0, 71.4, 71.3, 70.5, 70.3, 69.7, 65.43,
65.38, 59.9, 59.7, 41.5, 41.4, 38.5, 38.3, 31.3, 30.4, 26.9, 26.79,
26.75, 26.18, 26.16, 26.10, 25.6, 25.2, 25.1, 24.5, 24.3, 21.6, 21.4,
19.04, 19.01, 18.9, 18.6, 18.5, 18.4, 12.72, 12.68, -3.2, -3.4,
-3.6, -3.7, -4.1, -4.3, -4.4, -5.1, -5.2; high-resolution mass
spectrum (ES, Na) m/z 941.4641 [(M + Na)+; calcd for
P h en ol (+)-36. A solution of (+)-35 (385 mg, 0.50 mmol)
in methylene chloride (10 mL) at 0 °C was treated with bis-
(triphenylphosphine)palladium(II) chloride (40 mg, 0.05 mmol)
and tributyltin hydride (0.88 mL, 3.27 mmol). After 30 min,
the mixture was filtered through a short plug of silica gel with
ethyl acetate as eluant, and the filtrate was concentrated to
dryness in vacuo. The crude residue was then dissolved in THF
(10 mL), cooled to 0 °C, and treated with tetrabutylammonium
fluoride (1 M in THF, 1 mL, 1 mmol). After 5 min, the resultant
mixture was poured into brine (30 mL) and extracted with
ethyl acetate (3 × 30 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated. Flash chroma-
tography (hexanes/ethyl acetate, 2:1) provided (+)-36 (280 mg,
59% yield for two steps) as a yellow oil: [R]23 +5.0° (c 0.3,
D
CHCl3); IR (CHCl3) 3400 (w), 2950 (s), 2920 (s), 2840 (m), 1670
(s), 1590 (w), 1520 (w), 1450 (s), 1370 (s), 1240 (m), 1080 (s),
830 (s) cm-1; 1H NMR (500 MHz, C6D6) δ 9.78 (s, 1 H), 9.52 (s,
1 H), 8.33 (s, 1 H), 6.48 (s, 1 H), 6.28 (d, J ) 19.1 Hz, 1 H),
5.90 (dd, J ) 19.1, 6.7 Hz, 1 H), 5.41 (t, J ) 7.4 Hz, 1 H), 5.05
(d, J ) 5.6 Hz, 1 H), 3.86-3.79 (m, 2 H), 3.74-3.65 (m, 2 H),
3.17 (s, 3 H), 3.20-3.08 (m, 2 H), 3.03 (s, 2 H), 2.56-2.48 (m,
2 H), 2.42-2.37 (m, 2 H), 1.91 (s, 3 H), 1.90-1.78 (m, 3 H),
1.70-1.50 (m, 6 H), 1.45 (s, 3 H), 1.43 (s, 3 H), 1.45-1.30 (m,
6 H), 0.99-0.93 (m, 27 H), 0.072 (s, 3 H), 0.067 (s, 3 H); 13C
NMR (125 MHz, C6D6) δ 171.3, 166.8, 146.4, 144.5, 135.5,
133.1, 131.4, 130.1, 125.6, 125.5, 119.0, 109.4, 100.8, 82.0, 71.4,
69.7, 59.8, 56.4, 42.9, 42.0, 38.4, 30.1, 29.5, 27.6, 26.1, 25.0,
24.4, 21.3, 18.4, 17.3, 13.9, 12.7, 9.8, -5.15, -5.20; high-
resolution mass spectrum (ES, Na) m/z 975.4375 [(M + Na)+;
calcd for C46H80N2O7S(Si)(Sn)Na 975.4390].
C
46H78N2O7S2(Si)3Na 941.4660].
An ilin e (-)-3. A suspension of 33 (145 mg, 0.158 mmol)
and Na2HPO4 (217 mg, 1.58 mmol) in anhydrous methanol (5
mL) at 0 °C was treated with excess sodium amalgam (5%,
ca. 1.2 g). After 2 h, the mixture was filtered through a plug
of silica gel with ethyl acetate as eluant, and the filtrate was
concentrated to dryness in vacuo. The crude residue was then
dissolved in chloroform (15 mL) and added to silica gel (ca. 2
g). After 20 min, the silica gel was removed by filtration, and
the filtrate was concentrated in vacuo. Flash chromatography
(hexanes/ethyl acetate, 4:1 to 1:1) afforded (-)-3 (79 mg, 75%
yield for two steps) as a yellow foam: [R]23 -2.5° (c 1.5,
D
benzene); IR (CHCl3) 3400 (m), 3000 (s), 2960 (s), 2935 (s), 2860
(s), 1680 (s), 1615 (s), 1470 (s), 1380 (s), 1360 (s), 1240 (s), 1090
(s) cm-1; 1H NMR (500 MHz, C6D6) δ 6.22 (s, 1 H), 5.43 (t, J )
7.1 Hz, 1 H), 5.02 (d, J ) 5.7 Hz, 1 H), 3.81 (m, 1 H), 3.70 (m,
Alcoh ol (+)-37. A solution of (+)-36 (130 mg, 0.137 mmol)
in THF (5 mL) was treated with tetrabutylammonium fluoride
(1 M in THF, 0.5 mL, 0.50 mmol). After 8 h, the resultant

Total Synthesis of (+)-Thiazinotrienomycin E
J . Org. Chem., Vol. 65, No. 12, 2000 3749
mixture was added to brine (25 mL) and extracted with ethyl
acetate (3 × 25 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(ethyl acetate/hexanes, 4:1) afforded (+)-37 (93.8 mg, 82%
(1 M in THF, 1.5 mL, 1.5 mmol). The resultant yellow solution
was stirred for 12 h, poured into brine (20 mL), and extracted
with ether (3 × 20 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated. Flash chroma-
tography (hexanes/ethyl acetate, 1:1) afforded the correspond-
ing alcohol (119 mg, 100% yield) as a colorless oil: [R]23D +11.2°
(c 0.9, CHCl3); IR (CHCl3) 3510 (s), 2990 (s), 2930 (m), 1715
(s), 1480 (m), 1452 (m), 1380 (s), 1281 (s), 1205 (s), 1160 (s),
1120 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.40-5.38 (m, 1
H), 4.72-4.56 (m, 3 H), 3.79-3.70 (m, 2 H), 3.50 (dt, J ) 9.1,
2.9 Hz, 1 H), 2.52 (br s, 1 H), 1.83-1.62 (m, 3 H), 1.70 (s, 3 H),
1.36 (s, 3 H), 1.32 (s, 3 H), 1.17 (s, 9 H), 0.80 (d, J ) 6.7 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 178.5, 138.2, 121.3, 101.0,
75.0, 70.5, 61.6, 61.0, 40.8, 38.7, 36.2, 27.2, 24.6, 24.0, 21.1,
12.2; high-resolution mass spectrum (ES, Na) m/z 351.2146
[(M + Na)+; calcd for C18H32O5Na 351.2147].
yield) as a yellow oil: [R]23 +4.6° (c 0.98, CHCl3); IR (CHCl3)
D
3500-2500 (br s), 3040 (w), 2960 (s), 2920 (s), 2860 (m), 1660
(s), 1580 (w), 1520 (w), 1450 (s), 1370 (s), 1060 (s) cm-1 1H
;
NMR (500 MHz, C6D6) δ 9.52 (br s, 1 H), 9.01 (br s, 1 H), 8.37
(s, 1 H), 6.30 (s, 1 H), 6.28 (d, J ) 19.1 Hz, 1 H), 5.92 (dd, J )
19.1, 6.7 Hz, 1 H), 5.50 (t, J ) 7.6 Hz, 1 H), 5.02 (d, J ) 5.6
Hz, 1 H), 3.84-3.70 (m, 3 H), 3.50 (dt, J ) 8.1, 3.7 Hz, 1 H),
3.17 (s, 3 H), 3.19-3.04 (m, 2 H), 3.02 (s, 2 H), 2.52-2.34 (m,
5 H), 1.90 (s, 3 H), 1.91-1.82 (m, 1 H), 1.64-1.58 (m, 6 H),
1.43-1.21 (m, 8 H), 1.32 (s, 3 H), 1.31 (s, 3 H), 1.02-0.91 (m,
15 H), 0.79 (d, J ) 6.9 Hz, 3 H); 13C NMR (125 MHz, C6D6) δ
171.6, 166.8, 146.7, 144.6, 135.3, 133.0, 132.6, 131.2, 130.0,
125.8, 119.0, 109.8, 100.9, 82.2, 74.5, 69.3, 61.0, 56.5, 43.0, 41.6,
37.1, 30.2, 29.5, 27.6, 24.9, 24.2, 21.1, 17.3, 13.9, 13.7, 12.8,
9.8; high-resolution mass spectrum (ES, Na) m/z 861.3510 [(M
+ Na)+; calcd for C40H66N2O7S(Sn)Na 861.3527].
Ald eh yd e (+)-38. A solution of (+)-37 (27 mg, 0.032 mmol)
in DMSO (1.5 mL) was treated with triethylamine (0.5 mL)
and pyridine‚SO3 complex (103 mg, 0.64 mmol). The solution
was stirred for 1 h, poured into ethyl acetate (20 mL), and
washed with brine (10 mL). After separation, the combined
organic phases were dried over MgSO4, filtered, and concen-
trated to dryness in vacuo to provide the corresponding
aldehyde. The aldehyde was used immediately in the following
step.
A solution of the above alcohol (22 mg, 0.067 mmol) in
dimethyl sulfoxide (1.5 mL) was treated with triethylamine
(0.5 mL) and Py‚SO3 complex (106 mg, 0.67 mmol). After 20
min, the resultant yellow mixture was added to brine (20 mL)
and extracted with ether (3 × 20 mL). The combined organic
phases were dried over MgSO4, filtered, and concentrated.
Flash chromatography (hexanes/ethyl acetate, 3:1) provided
(+)-41 (20 mg, 90% yield) as a yellow oil: [R]23 +12.6° (c 1.2,
D
CHCl3); IR (CHCl3) 2990 (s), 2940 (s), 2880 (m), 1720 (s), 1450
(m), 1380 (s), 1282 (m), 1210 (s), 1160 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 9.72 (m, 1 H), 5.41-5.35 (m, 1 H), 4.80-4.70
(m, 2 H), 4.66-4.57 (m, 1 H), 3.83 (dt, J ) 9.2, 8.7 Hz, 1 H),
2.60 (ddd, J ) 16.3, 9.3, 2.6 Hz, 1 H), 2.50 (ddd, J ) 16.3, 3.7,
1.7 Hz, 1 H), 1.86-1.82 (m, 1 H), 1.71 (s, 3 H), 1.36 (s, 3 H),
1.31 (s, 3 H), 1.17 (s, 9 H), 0.83 (d, J ) 6.7 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ 201.0, 178.5, 138.0, 121.5, 101.2, 70.3,
70.1, 61.0, 47.6, 40.5, 38.7, 27.2, 24.3, 23.9, 21.1, 12.1; high-
resolution mass spectrum (ES, Na) m/z 349.1993 [(M + Na)+;
calcd for C18H30O5Na 349.1991].
A solution of the above aldehyde in DMF (2 mL) was treated
with triethylamine (0.089 mL, 0.64 mmol) and TBSOTf (0.073
mL, 0.32 mmol). After 20 min, the mixture was added to ether
(20 mL) and washed with brine (2 × 10 mL). The organic phase
was dried over MgSO4, filtered, and concentrated. Preparative
TLC (ethyl acetate/hexanes, 1:1) afforded (+)-38 (13 mg, 42%
yield for two steps) as a yellow oil: [R]23 +10.6° (c 1.01,
Alcoh ol (+)-44. A solution of (+)-28 (100 mg, 0.89 mmol)
and tributyltin hydride (1.2 mL, 4.45 mmol) in toluene (10 mL)
was immersed in a preheated oil bath (90 °C) for 5 min before
AIBN (36.5 mg, 0.225 mmol) was added in one portion. The
solution was then heated to 100 °C for 12 h. The mixture was
cooled to room temperature and then concentrated to dryness
in vacuo. Flash chromatography (hexanes/ethyl acetate, 10:1)
D
EtOAc); IR (CHCl3) 2920 (s), 2840 (m), 1680 (s), 1590 (m), 1510
(m), 1430 (m), 1360 (m) cm-1; 1H NMR (500 MHz, C6D6) δ 9.42
(m, 1 H), 9.05 (s, 1 H), 8.51 (s, 1 H), 8.18 (s, 1 H), 6.37 (d, J )
19 Hz, 1 H), 6.10 (dd, J ) 19.0, 6.8 Hz, 1 H), 5.33 (t, J ) 7.4
Hz, 1 H), 4.89 (d, J ) 5.7 Hz, 1 H), 4.10 (m, 1 H), 3.72 (ddd, J
) 8.8, 8.7, 3.0 Hz, 1 H), 3.20 (s, 3 H), 3.00-2.83 (m, 3 H), 2.89
(s, 2 H), 2.74 (dd, J ) 14.5, 8.5 Hz, 1 H), 2.32-2.17 (m, 4 H),
1.99-1.95 (m, 1 H), 1.80 (s, 3 H), 1.62-1.47 (m, 6 H), 1.41-
1.18 (m, 12 H), 1.03-0.82 (m, 24 H), 0.63 (d, J ) 6.9 Hz, 3 H),
0.06 (s, 3 H), -0.06 (s, 3 H); 13C NMR (125 MHz, C6D6) δ 199.3,
169.3, 164.6, 146.8, 138.3, 135.0, 133.0, 131.7, 130.5, 129.9,
124.8, 115.0, 108.1, 100.8, 82.0, 70.0, 68.9, 56.2, 47.3, 44.7, 40.9,
29.8, 29.7, 29.2, 27.4, 27.3, 25.8, 24.1, 23.7, 20.7, 18.3, 13.6,
12.1, 9.5, -3.5, -4.3; high-resolution mass spectrum (ES, Na)
m/z 973.4211 [(M + Na)+; calcd for C46H78N2O7S(Si)(Sn)Na
973.4200].
afforded (+)-44 (242 mg, 67% yield) as a colorless oil: [R]23
D
+17.7° (c 1.20, CHCl3); IR (CHCl3) 3500 (br s), 2960 (s), 2930
(s), 2880 (m), 2860 (m), 1600 (w), 1450 (m), 1100 (m), 1070 (s)
cm-1; 1H NMR (500 MHz, CDCl3) δ 6.12 (d J ) 19.1 Hz, 1 H),
5.80 (dd, J ) 19.1, 7.2 Hz, 1 H), 3.72 (m, 3 H), 3.21 (s, 3 H),
2.53 (dd, J ) 6.3, 4.5 Hz, 1 H), 1.75 (m, 2 H), 1.48 (m, 6 H),
1.24 (m, 6 H), 0.95 (m, 15 H); 13C NMR (125 MHz, CDCl3) δ
147.8, 131.9, 85.5, 60.9, 56.17, 37.7, 29.1, 27.2, 13.7, 9.5; high-
resolution mass spectrum (CI, NH3) m/z 349.1192 [(M -
C4H9)+; calcd for C14H29O2Sn 349.1189].
P iva loa te (+)-43. To a solution of (-)-15 (150 mg, 0.42
mmol) in THF (5 mL) were added triethylamine (0.584 mL,
4.2 mmol), DMAP (5.1 mg, 0.042 mmol), and trimethylacetyl
chloride (0.18 mL, 2.1 mmol). The resulting white suspension
was stirred for an additional 30 min, added to brine-saturated
NaHCO3 (1:1, 40 mL), and extracted with ether (3 × 40 mL).
The combined organic phases were dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes/ethyl ace-
tate, 8:1) afforded (+)-43 (186 mg, 100% yield) as a colorless
Anal. Calcd for C18H38O2Sn: C, 53.33; H, 9.38. Found: C,
53.44; H, 9.45.
Vin yl Iod id e (+)-45. To a solution of (+)-44 (110 mg, 0.272
mmol) in CH2Cl2 (2 mL) was added I2 in CH2Cl2 until purple
color persisted. The solution was stirred for an additional 30
min, then quenched with a saturated Na2SO3 solution (1 mL).
The mixture was added to brine (20 mL) and extracted with
methylene chloride (3 × 20 mL). The combined organic phases
were dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 2:1) provided (+)-45
(66 mg, 100% yield) as a light yellow oil: [R]23D +46.8° (c 0.90,
CHCl3); IR (CHCl3) 3500 (br m), 3040 (m), 2990 (s), 2930 (s),
2820 (m), 1610 (s), 1440 (s), 1350 (m), 1260 (s), 1170 (m), 1100
oil: [R]23 +0.9° (c 0.8, CHCl3); IR (CHCl3) 2960 (s), 2930 (s),
D
2880 (m), 1809 (s), 1713 (s), 1460 (m), 1380 (m), 1280 (m), 1210
(s), 1160 (s), 1130 (m), 1095 (s) cm-1 1H NMR (500 MHz,
;
CDCl3) δ 5.37-5.31 (m, 1 H), 4.72-4.68 (m, 1 H), 4.63-4.59
(m, 2 H), 3.66-3.62 (m, 2 H), 3.49-3.47 (td, J ) 9.3, 2.8 Hz,
1 H), 1.80-1.60 (m, 3 H), 1.69 (s, 3 H), 1.31 (s, 3 H), 1.30 (s, 3
H), 1.17 (s, 9 H), 0.87 (s, 9H), 0.80 (d, J ) 6.9, 3 H), 0.02 (s, 6
H); 13C NMR (125 MHz, CDCl3) δ 178.5, 138.6, 121.0, 100.7,
71.1, 70.6, 61.2, 59.4, 41.0, 38.7, 37.8, 27.2, 25.9, 24.7, 24.0,
21.2, 18.2, 12.0, -5.33, -5.37; high-resolution mass spectrum
(ES, Na) m/z 465.3000 [(M + Na)+; calcd for C24H46O5SiNa
465.3012].
1
(s), 950 (s) cm-1; H NMR (500 MHz, CDCl3) δ 6.44 (dd, J )
14.6, 7.4 Hz, 1 H), 6.36 (d, J ) 14.6 Hz, 1 H), 3.75 (m, 3 H),
3.30 (s, 3 H), 2.57 (dd, J ) 6.1, 4.5 Hz, 1 H), 1.80 (m, 2 H); 13
C
NMR (125 MHz, CDCl3) δ 145.9, 82.8, 78.7, 59.8, 56.7, 37.2;
high-resolution mass spectrum (CI, NH3) m/z 260.0156 [(M +
NH4)+; calcd for C6H15INO2 260.0148].
Alcoh ol (+)-46. To a solution of (+)-45 (108.4 mg, 0.448
mmol) in DMF (3 mL) was added bis(acetonitrile)palladium(II)
chloride (11.6 mg, 0.0448 mmol). After 2 min, 31 (230 mg, 0.49
mmol) in DMF (1 mL) was added via a syringe. The resultant
Ald eh yd e (+)-41. To a solution of (+)-43 (160 mg, 0.36
mmol) in THF (5 mL) was added tetrabutylammonium fluoride

3750 J . Org. Chem., Vol. 65, No. 12, 2000
Smith and Wan
dark red solution was stirred at room temperature for 21 h,
poured into brine (20 mL), and extracted with ether (3 × 30
mL). The combined organic phases were dried over MgSO4,
filtered, and concentrated. Flash chromatography (methanol/
ethyl acetate, 1:10) provided (+)-46 (91.6 mg, 70% yield) as a
After 2 min, a solution of (+)-55 (26.8 mg, 0.077 mmol) in THF
(0.5 mL) was added. The resultant dark green solution was
stirred at room temperature for an additional 12 h. The
mixture was then added to brine (20 mL) and extracted with
ether (3 × 30 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 4:1) provided the corresponding alcohol
yellow oil: [R]23 +10.7° (c 1.3, CHCl3); IR (CHCl3) 3400 (br
D
s), 3000 (s), 2920 (m), 2820 (w), 1720 (w), 1400 (m), 1230 (s),
1
1160 9m), 1100 (m), 920 (s), 890 (m), 860 (s) cm-1; H NMR
(19.3 mg, 96% yield) as a yellow oil: [R]23 +4.0° (c 1.05,
D
(500 MHz, CDCl3) δ 6.18-6.11 (m, 2 H), 5.63-5.54 (m, 1 H),
5.49-5.42 (m, 1 H), 4.07-4.02 (m, 4 H), 3.81-3.75 (m, 1 H),
3.72-3.64 (m, 2 H), 3.24 (s, 3 H), 2.73-2.61 (br s, 1 H), 2.60-
2.55 (dd, J ) 22.3, 7.4 Hz, 2 H), 1.81-1.66 (m, 2 H), 1.27 (t, J
) 7.1 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ 134.1, 134.0,
132.64, 132.60, 131.99, 131.96, 122.9, 122.8, 81.4, 62.02, 61.97,
60.4, 56.3, 37.9, 31.2, 30.1, 16.44, 16.39; high-resolution mass
spectrum (ES, Na) m/z 315.1340 [(M + Na)+; calcd for
CHCl3); IR (CHCl3) 3604 (m), 3050 (s), 2960 (s), 2930 (s), 2860
(s), 1460 (m), 1250 (s), 1205 (s), 1090 (s), 990 (s) cm-1; 1H NMR
(500 MHz, CDCl3) δ 6.30-6.21 (m, 2 H), 5.85-5.79 (m, 1 H),
5.56-5.52 (dd, J ) 14.9, 7.9 Hz, 1 H), 4.15 (d, J ) 6.0 Hz, 2
H), 3.82-3.69 (m, 2 H), 3.64-3.58 (m, 1 H), 3.21 (s, 3 H), 1.70-
1.62 (m, 2 H), 0.87 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 134.3, 132.2, 131.6, 130.6, 78.7, 63.1,
59.3, 56.2, 38.7, 25.9, 18.3, -5.34, -5.36; high-resolution mass
spectrum (CI, NH3) m/z 269.1935 [(M - OH)+; calcd for
C15H29O2Si 269.1937].
C
13H25O5PNa 315.1337].
TBS Eth er (+)-42. To a solution of (+)-46 (25 mg, 0.086
mmol) in DMF (2 mL) were added imidazole (11.7 mg, 0.17
mmol) and tert-butyldimethylsilyl chloride (19.3 mg, 0.13
mmol). The solution was stirred for 10 min, added to brine
(20 mL), and extracted with ethyl acetate (3 × 20 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated. Flash chromatography (ethyl acetate/hexanes,
Anal. Calcd for C15H30O3Si: C, 62.89; H, 10.55. Found: C,
63.13; H, 10.70.
To a solution of oxalyl chloride (2 M in CH2Cl2, 0.148 mL,
0.296 mmol) in CH2Cl2 (1 mL) at -78 °C was added dimethyl
sulfoxide (0.042 mL, 0.592 mmol). After 5 min, to the mixture
was added the above alcohol (18 mg, 0.063 mmol) in CH2Cl2
(0.4 mL) and triethylamine (0.206 mL, 1.48 mmol). The
resultant light yellow solution was stirred for an additional 5
min, poured into brine-saturated NaHCO3 (10 mL each), and
extracted with ether (3 × 20 mL). The combined organic phases
were dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 4:1) afforded (-)-54
5:1) afforded (+)-42 (34 mg, 98% yield) as a colorless oil: [R]23
D
+2.1° (c 1.0, CHCl3); IR (CHCl3) 3000 (s), 2960 (s), 2940 (s),
1460 (m), 1390 (m), 1250 (s), 1210 (s), 1100 (s), 1060 (s), 1030
(s) cm-1 1H NMR (500 MHz, CDCl3) δ 6.17-6.14 (m, 2 H),
;
5.64-5.60 (m, 1 H), 5.48-5.44 (m, 1 H), 4.11-4.05 (m, 4 H),
3.74-3.66 (m, 2 H), 3.61-3.57 (m, 1 H), 3.22 (s, 3 H), 2.60
(dd, J ) 22.3, 7.1 Hz, 2 H), 1.75-1.60 (m, 2 H), 1.29 (t, J )
6.7 Hz, 6 H), 0.87 (s, 9 H), 0.020 (s, 3 H), 0.013 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 134.4, 134.3, 133.6, 133.5, 131.69,
131.65, 122.4, 122.3, 78.6, 62.02, 61,97, 59.3, 56.3, 38.8, 31.3,
30.2, 25.9, 18.3, 16.5, 16.4, -5.34, -5.36; high-resolution mass
spectrum (ES, Na) m/z 429.2210 [(M + Na)+; calcd for
(16.1 mg, 90% yield) as a yellow oil: [R]23 -11.0° (c 1.0,
D
CHCl3); IR (CHCl3) 3002 (s), 2950 (s), 2930 (s), 2860 (s), 2820
(m), 1675 (s), 1640 (s), 1460 (m), 1250 (s), 1205 (s), 1160 (m),
1
1100 (s) cm-1; H NMR (500 MHz, CDCl3) δ 9.52 (d, J ) 8.2
Hz, 1 H), 7.04 (dd, J ) 15.3, 11.0 Hz, 1 H), 6.44 (dd, J ) 15.3,
11.0 Hz, 1 H), 6.10 (m, 2 H), 3.96 (m, 1 H), 3.73-3.68 (m, 1
H), 3.64-3.59 (m, 1 H), 3.27 (s, 3 H), 1.82-1.71 (m, 2 H), 0.91
(s, 9 H), 0.025 (s 3 H), 0.018 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 193.6, 151.1, 145.5, 131.8, 129.1, 78.1, 58.9, 57.0, 38.3,
25.9, 18.3; high-resolution mass spectrum (CI, NH3) m/z
285.2250 [(M + H)+; calcd for C15H29O3Si 285.2245].
C
19H39O5PSiNa 429.2202].
Vin yl Iod id e (+)-55. A solution of (+)-44 (210 mg, 0.568
mmol) in CH2Cl2 (6 mL) was treated with triethylamine (0.3
mL, 2.1 mmol) and TBSOTf (0.2 mL, 0.86 mmol). After 5 min,
the solution was added to brine-saturated NaHCO3 (1:1, 20
mL) and extracted with ether (3 × 20 mL). The combined
organic phases were dried over MgSO4, filtered, and concen-
trated. Flash chromatography (hexanes/ethyl acetate, 15:1)
afforded the corresponding TBS ether (295 mg, 100% yield)
as a colorless oil: [R]23D +7.7° (c 0.75, CHCl3); IR (CHCl3) 3001
(m), 2960 (s), 2930 (s), 2860 (s), 1460 (m), 1250 (m), 1200 (s),
1080 (s), 990 (m), 920 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ
6.10 (dd, J ) 19.0, 0.8 Hz, 1 H), 5.75 (dd, J ) 19.0, 7.6 Hz, 1
H), 3.72-3.60 (m, 3 H), 3.22 (s, 3 H), 1.82-1.78 (m, 1 H), 1.68-
1.61 (m, 1 H), 1.54-1.47 (m, 6 H), 1.30-1.21 (m, 6 H), 1.89-
1.81 (m, 24 H), 0.03 (s, 3 H), 0.02 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 148.6, 131.2, 82.5, 59.5, 56.1, 38.5, 29.2, 27.3, 25.9,
18.1, 13.7, 9.51, -5.3; high-resolution mass spectrum (CI, NH3)
m/z 538.3100 [(M + NH4)+; calcd for C24H56NO2SnSi 538.3102].
A solution of the above TBS ether (290 mg, 0.559 mmol) in
CH2Cl2 was treated dropwise with a CH2Cl2 solution of I2 until
the purple color persisted. The reaction was then quenched
with saturated Na2SO3 solution (10 mL), poured into brine (20
mL), and extracted with CH2Cl2 (3 × 30 mL). The combined
organic phases were dried over MgSO4, filtered, and concen-
trated. Flash chromatography (hexanes/ethyl acetate, 10:1)
Su lfon e (+)-53. A solution of (+)-56 (190 mg, 0.58 mmol)
in THF (10 mL) was treated with triphenylphosphine (304.3
mg, 1.16 mmol), 2-mecaptobenzothiazole (262 mg, 1.57 mmol),
and diethyl azodicarboxylate (0.22 mL, 1.39 mmol). After 5
min, the resultant mixture was added to saturated NaHCO3
(25 mL) and extracted with ether (3 × 25 mL). The combined
organic phases were dried over MgSO4, filtered, and concen-
trated. Flash chromatography (hexanes/ethyl acetate, 4:1)
afforded the corresponding sulfide (310 mg, contaminated with
a small amount of triphenylphosphine).
A solution of the above sulfide in ethanol (10 mL) at 0 °C
was treated with (NH4)6Mo7O24‚4H2O (143 mg, 0.116 mmol)
in hydrogen peroxide (30%, 1.3 mL, 1.16 mmol). The resultant
suspension was stirred at ambient temperature for 12 h, added
to brine (25 mL), and extracted with ether (3 × 25 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate,
4:1) afforded (+)-53 (251 mg, 85% yield for two steps) as a
colorless oil: [R]23D +2.3° (c 1.20, CHCl3); IR (CHCl3) 3009 (s),
2980 (s), 2930 (m), 1720 (s), 1465 (m), 1380 (m), 1330 (s), 1280
(m), 1200 (s), 1150 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 8.21
(d, J ) 8.6 Hz, 1 H), 8.04 (d, J ) 8.2 Hz, 1 H), 7.66-7.58 (m,
2 H), 5.34 (t, J ) 5.6 Hz, 1 H), 4.71-4.65 (m, 1 H), 4.63-4.55
(m, 2 H), 3.79-3.71 (m, 1 H), 3.53-3.47 (m, 1 H), 3.42-3.37
(m, 1 H), 2.23-2.18 (m, 1 H), 2.04-1.97 (m, 1 H), 1.75-1.70
(m, 1 H), 1.64 (s, 3 H), 1.28 (s, 3 H), 1.27 (s, 3 H), 1.16 (s, 9 H),
0.79 (d, J ) 7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 178.4,
165.8, 152.8, 137.8, 136.8, 128.1, 127.7, 125.5, 122.4, 121.5,
101.1, 72.8, 70.4, 61.0, 52.0, 40.8, 27.2, 27.1, 24.4, 23.9, 21.1,
12.2; high-resolution mass spectrum (ES, Na) m/z 532.1806
[(M + Na)+; calcd for C25H35NO6S2Na 532.1803].
provided (+)-55 (191 mg, 96% yield) as a colorless oil: [R]23
D
+10.4° (c 0.95, CHCl3); IR (CHCl3) 3005 (s), 2960 (s), 2930 (s),
2860 (s), 1601 (s), 1470 (m), 1250 (s), 1210 (s), 1100 (s) cm-1
;
1H NMR (500 MHz, CDCl3) δ 6.42 (dd, J ) 14.5, 7.8 Hz, 1 H),
6.24 (d, J ) 14.5, 1 H), 3.73-3.68 (m, 2 H), 3.64-3.59 (m, 1
H), 3.23 (s, 3 H), 1.78-1.72 (m, 1 H), 1.68-1.62 (m, 1 H), 0.87
(s, 9 H), 0.03 (s 3 H), 0.02 (s, 3 H); 13C NMR (125 MHz, CDCl3)
δ 146.7, 80.7, 77.9, 58.8, 56.7, 37.9, 25.9, 18.3, -5.36, -5.40;
high-resolution mass spectrum (CI, NH3) m/z 357.0746 [(M +
H)+; calcd for C12H26IO2Si 357.0746].
Ald eh yd e (-)-54. A solution of 29 (25 mg, 0.07 mmol) in
DMF-THF (2:1, 0.6 mL) was treated with bis(acetonitrile)-
palladium(II) chloride (1.82 mg, 0.007 mmol) in DMF (0.3 mL).
Su lfon e (+)-60. A solution of (+)-56 (1.83 g, 5.58 mmol) in
THF (50 mL) was treated with triphenylphosphine (2.2 g, 8.39
mmol), 1-phenyl-1H-tetrazole-5-thiol (1.99 g, 11.18 mmol), and

Total Synthesis of (+)-Thiazinotrienomycin E
J . Org. Chem., Vol. 65, No. 12, 2000 3751
diethyl azodicarboxylate (1.584 mL, 10.06 mmol). After 5 min,
the mixture was added to saturated NaHCO3 (100 mL) and
extracted with ether (3 × 100 mL). The combined organic
phases were dried over MgSO4, filtered, and concentrated.
Flash chromatography (hexanes/ethyl acetate, 4:1) afforded the
corresponding sulfide (3 g, contaminated with a small amount
of triphenylphosphine).
59.3, 58.8, 56.2, 39.6, 38.9, 37.8, 25.9, 24.9, 23.9, 21.7, 18.3,
12.6, -5.33, -5.35; high-resolution mass spectrum (CI, NH3)
m/z 512.3770 [(M + NH4)+; calcd for C28H54NO5Si 512.3771].
Allyl Ch lor id e (+)-40. A solution of (-)-61 (185 mg, 0.374
mmol) in DMF (4 mL) was treated with 2,6-lutidine (0.175 mL,
1.5 mmol), lithium chloride (63.6 mg, 1.5 mmol), and mesyl
chloride (0.058 mL, 0.75 mmol). The mixture was stirred at
room temperature for 1 h and then added to brine and
saturated NaHCO3 (25 mL each). The resultant mixture was
extracted with ether (3 × 50 mL), and the combined organic
phases were dried over MgSO4, filtered, and concentrated.
Flash chromatography (hexanes/ethyl acetate, 20:1) afforded
A solution of the above sulfide in ethanol (40 mL) was cooled
to 0 °C and treated with (NH4)6Mo7O24‚4H2O (0.69 g, 0.558
mmol) in hydrogen peroxide (30%, 10 mL, 88 mmol). The
resultant suspension was stirred at ambient temperature for
12 h, added to brine (100 mL), and extracted with ether (3 ×
100 mL). The combined organic phases were dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/
ethyl acetate, 4:1) afforded (+)-60 (2.06 g, 71% yield for two
steps) as a colorless oil: [R]23D +5.4° (c 1.15, CHCl3); IR (CHCl3)
3005 (s), 2980 (s), 1720 (s), 1450 (m), 1380 (m), 1340 (s), 1150
(+)-40 (150 mg, 78% yield) as a colorless oil: [R]23 +2.9° (c
D
0.75, CHCl3); IR (CHCl3) 3001 (s), 2940 (s), 2880 (m), 1470 (m),
1380 (s), 1210 (s), 1100 (s), 1000 (s) cm-1; 1H NMR (500 MHz,
CDCl3) δ 6.22-6.08 (m, 4 H), 5.82-5.76 (m, 1 H), 5.52-5.37
(m, 2 H), 4.65 (d, J ) 5.6 Hz, 1 H), 4.22-4.17 (m, 2 H), 3.81-
3.70 (m, 2 H), 3.67-3.55 (m, 1 H), 3.38-3.31 (m, 1 H), 3.22 (s,
3 H), 2.35-2.27 (m, 2 H), 1.90-1.81 (m, 2 H), 1.70-1.59 (m, 1
H), 1.68 (s, 3 H), 1.31 (s, 6 H), 0.87 (s, 9 H), 0.80 (d, J ) 6.7
Hz, 3 H), 0.020 (s, 3 H), 0.014 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 139.0, 133.5, 133.0, 132.6, 132.3, 131.2, 130.4, 122.8,
100.9, 78.8, 74.5, 70.9, 59.3, 56.2, 41.1, 40.2, 38.9, 37.6, 26.0,
24.7, 23.9, 21.4, 17.6, 12.6, -5.33, -5.35; high-resolution mass
1
(s) cm-1; H NMR (500 MHz, CDCl3) δ 7.71 (m, 2 H), 7.62-
7.51 (m, 3 H), 5.34 (t, J ) 6.7 Hz, 1 H), 4.74-4.70 (m, 1 H),
4.63 (d, J ) 5.6 Hz, 1 H), 4.59-4.56 (m, 1 H), 4.01-3.90 (m, 1
H), 3.80-3.72 (m, 1 H), 3.46-3.41 (m, 1 H), 2.30-2.21 (m, 1
H), 2.12-2.03 (m, 1 H), 1.82-1.76 (m, 1 H), 1.68 (s, 3 H), 1.31
(s, 6 H), 1.16 (s, 9 H), 0.83 (d, J ) 6.7 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 178.4, 153.5, 137.8, 133.1, 131.5, 129.7, 125.1,
121.6, 101.2, 72.6, 70.4, 61.0, 53.2, 40.8, 38.7, 27.2, 26.9, 24.4,
24.0, 21.1, 12.2; high-resolution mass spectrum (ES, Na) m/z
543.2265 [(M + Na)+; calcd for C25H36N4O6SNa 543.2253].
Tr ien e (+)-48. A solution of (+)-60 (1.9 g, 3.65 mmol) in
THF (20 mL) at -78 °C was treated with potassium bis-
(trimethylsilyl)amide (0.5 M in toluene, 9.5 mL, 4.75 mmol).
The resultant yellow solution was stirred for 20 min before
(-)-54 (1.1 g, 3.84 mmol) in THF (10 mL) was introduced via
cannula. The mixture was stirred for 1 h at -78 °C, warmed
to room temperature, and stirred for an additional 1 h. The
mixture was poured into brine (100 mL) and extracted with
ether (3 × 100 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 20:1) provided (+)-48 (1.8 g, 85% yield)
as a colorless oil: [R]23D +9.0° (c 1.04, CHCl3); IR (CHCl3) 3010
(s), 2970 (s), 2940 (s), 1720 (s), 1470 (m), 1380 (s), 1200 (s)
cm-1; 1H NMR (500 MHz, CDCl3) δ 6.23-6.07 (m, 4 H), 5.79-
5.70 (m, 1 H), 5.50 (dd, J ) 14.5, 7.8 Hz, 1 H), 5.32 (t, J ) 6.3
Hz, 1 H), 4.73-4.68 (m, 1 H), 4.66-4.57 (m, 2 H), 3.80-3.68
(m, 2 H), 3.64-3.57 (m, 1 H), 3.38-3.32 (m, 1 H), 3.23 (s, 3
H), 2.32-2.25 (m, 2H), 1.85-1.74 (m, 2 H), 1.67 (s, 3 H), 1.70-
1.60 (m, 1 H), 1.27 (s, 6 H), 1.15 (s, 9 H), 0.87 (s, 9 H), 0.80 (d,
J ) 7.1 Hz, 3 H), 0.014 (s, 3 H), 0.008 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 178.4, 138.4, 133.4, 133.0, 132.6, 132.2, 131.3,
130.3, 121.2, 100.8, 78.8, 74.5, 70.6, 61.1, 59.3, 56.2, 40.3, 38.9,
38.7, 37.8, 27.2, 25.9, 24.7, 23.9, 21.2, 18.3, 12.4, -5.33, -5.36;
high-resolution mass spectrum (ES, Na) m/z 601.3899 [(M +
Na)+; calcd for C33H58O6SiNa 601.3900].
spectrum (CI, NH3) m/z 530.3427 [(M + NH4)+; calcd for C28H53
ClNO4Si 530.3432].
-
Su lfon e 63. A solution of (+)-40 (530 mg, 1.03 mmol) in
acetone (10 mL) was treated with 2,6-di-tert-butyl-4-methyl-
pyridine (12.8 mg, 0.062 mmol) and sodium iodide (186 mg,
1.24 mmol). The resultant cloudy solution was stirred for 1 h
and filtered through a short pack of neutral alumina. The
filtrate was concentrated and dried under high vacuum for 1
h to afford the corresponding unstable allyl iodide as a yellow
oil. The allyl iodide was used immediately in the following step.
A solution of 7 (620 mg, 1.073 mmol) in THF (10 mL) at
-78 °C was treated with sodium bis(trimethylsilyl)amide (1
M in THF, 4.29 mL, 4.29 mmol). To the resultant yellow
solution was added the above allyl iodide in THF (5 mL) via
cannula. The resultant mixture was stirred at -78 °C for an
additional 1.5 h, quenched with methanol (1 mL), added to
brine (50 mL), and extracted with ether (3 × 50 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate,
4:1) afforded recovered 7 (220 mg) and provided 63 (695 mg,
64% yield or 95% yield based on recovered 7) as a yellow foam.
NMR analysis of 63 indicated a 2:1 mixture of diastereomers:
IR (CHCl3) 3390 (m), 2940 (s), 2920 (s), 2860 (s), 1670 (s), 1590
1
(s), 1450 (s), 1360 (m), 1352 (s), 1250 (s) cm-1; H NMR (500
MHz, CDCl3) δ 9.50, 9.40 (diastereomers, s, s, 1 H), 7.51
(complex series of m, 2 H), 7.46 (complex series of m, 1 H),
7.23 (complex series of m, 2 H), 6.42, 6.39 (diastereomers, s,
s, 1 H), 6.25-6.10 (complex series of m, 4 H), 5.79-5.72
(complex series of m, 1 H), 5.60-5.47 (complex series of m, 1
H), 5.35, 5.15 (diastereomers, t, t, J ) 6.0 Hz, 1 H), 5.03-4.96
(complex series of m, 1 H), 4.78, 4.72 (diastereomers, d, d, J )
5.1 Hz, 1 H), 3.80-3.50 (complex series of m, 4 H), 3.42-3.39
(complex series of m, 2 H), 3.28-3.26 (complex series of s, 6
H), 2.45-2.33 (complex series of m, 2 H), 1.95 (m, 1 H), 1.76
(m, 1 H), 1.70 (overlapping s, 4 H), 1.32 (overlapping s, 6 H),
1.02-0.80 (complex series of s, 30 H), 0.21-0.0 (complex series
of s, 18 H); 13C NMR (125 MHz, CDCl3) δ 168.04, 167.99, 140.0,
139.6, 139.3, 138.1, 136.3, 133.3, 133.2, 133.09, 133.05, 132.98,
132.94, 132.88, 132.63, 131.96, 131.91, 131.5, 130.22, 130.18,
128.9, 127.9, 122.4, 122.0, 108.3, 108.2, 105.2, 105.0, 100.6,
78.8, 74.6, 69.9, 69.83, 69.78, 64.89, 64.80, 60.3, 59.3, 56.2, 56.1,
40.4, 40.3, 38.8, 37.9, 31.33, 31.27, 26.46, 26.43, 25.95, 25.87,
24.8, 24.7, 24.03, 24.00, 21.1, 18.6, 18.34, 18.30, 18.2, 12.6,
-3.67, -3.72, -4.4, -4.51, -4.58, -5.40, -5.43; high-resolu-
tion mass spectrum (ES, Na) m/z 1077.5370[(M + Na)+; calcd
for C55H90N2O8S2(Si)3Na 1077.5344].
Anal. Calcd for C33H58O6(Si): C, 68.47; H, 10.10. Found: C,
68.25; H, 10.03.
Alcoh ol (-)-61. A solution of (+)-48 (1.74 g, 3.01 mmol) in
CH2Cl2 (20 mL) at -78 °C was treated with DIBAL (1 M in
hexane, 6.02 mL, 6.02 mmol). The resultant solution was
stirred for 10 min, quenched with methanol (5 mL), diluted
with ether (150 mL), and then stirred vigorously with a
saturated Rochelle salt solution (200 mL) until two clear layers
appeared. After separation, the aqueous phase was extracted
with ether (3 × 150 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated. Flash chroma-
tography (hexanes/ethyl acetate, 3:1) afforded (-)-61 (1.38 g,
93% yield) as a colorless oil: [R]23 -6.1° (c 0.9, CHCl3); IR
D
(CHCl3) 3500 (br s), 3004 (s), 2960 (s), 2930 (s), 1740 (s), 1380
(s), 1210 (s), 1190 (s), 1100 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 6.21-6.10 (m, 4 H), 5.75-5.70 (m, 1 H), 5.56-5.40 (m, 2 H),
4.50 (d, J ) 5.2 Hz, 1 H), 4.21-4.13 (m, 1 H), 4.09-4.01 (m, 1
H), 3.80-3.68 (m, 2 H), 3.64-3.57 (m, 1 H), 3.40-3.35 (m, 1
H), 3.19 (s, 3 H), 2.31-2.27 (m, 2 H), 2.18-2.12 (m, 1 H), 1.80-
1.73 (m, 2 H), 1.67 (s, 3 H), 1.68-1.60 (m, 1 H), 1.36 (s, 3 H),
1.34(s, 3 H), 0.87 (s, 9 H), 0.79 (d, J ) 7.4 Hz, 3 H), 0.020 (s,
3 H), 0.014 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 136.8, 134.2,
133.5, 132.6, 132.4, 131.1, 130.6, 126.3, 101.0, 78.8, 74.6, 71.9,
An ilin e (+)-64. A suspension of 63 (140 mg, 0.133 mmol)
and Na2HPO4 (183 mg, 1.33 mmol) in anhydrous methanol (5
mL) at 0 °C was treated with excess sodium amalgam (5%,
ca. 0.5 g). The mixture was stirred vigorously at 0 °C for 1.5
h, diluted with ethyl acetate (5 mL), and filtered through a

3752 J . Org. Chem., Vol. 65, No. 12, 2000
Smith and Wan
plug of silica gel with ethyl acetate as eluant. The filtrate was
concentrated in vacuo; the crude residue was dissolved in
chloroform (20 mL), added to silica gel (ca. 2 g), and stirred
vigorously for 20 min. The silica gel was removed by filtration,
and the filtrate was concentrated in vacuo. Flash chromatog-
raphy (hexanes/ethyl acetate, 4:1 to 2:1) afforded (+)-64 (95
mg, 89% yield for two steps) as a colorless oil: [R]23D +12.9° (c
0.45, CHCl3); IR (CHCl3) 3400 (m), 3010 (s), 2960 (m), 2940
1.29 (s, 3 H), 0.87 (s, 9 H), 0.74 (d, J ) 7.0 Hz, 3 H), 0.029 (s,
3 H), 0.023 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 165.6, 153.2,
142.1, 135.3, 133.8, 133.7, 133.4, 133.1, 132.6, 132.4, 132.3,
132.0, 131.6, 131.0, 124.7, 118.0, 114.2, 106.4, 101.0, 100.6,
78.8, 74.5, 69.3, 65.9, 59.4, 57.6, 56.2, 40.8, 38.8, 37.8, 30.1,
29.2, 27.8, 26.0, 24.7, 24.0, 20.8, 18.3, 12.7, -5.32, -5.34; high-
resolution mass spectrum (ES, Na) m/z 837.4184 [(M + Na)+;
calcd for C43H66N2O9SSiNa 837.4156].
1
(m), 1675 (s), 1615 (m), 1460 (s), 1380 (m), 1200 (s) cm-1; H
Alcoh ol (+)-66. A solution of (+)-65 (115 mg, 0.141 mmol)
in THF (3 mL) was treated with tetrabutylammonium fluoride
(1 M in THF, 0.5 mL, 0.50 mmol). The resultant brown solution
was stirred for 2.5 h, added to brine (40 mL), and extracted
with ethyl acetate (3 × 40 mL). The combined organic phases
were dried over MgSO4, filtered, and concentrated. Flash
chromatography (ethyl acetate/hexanes, 4:1) afforded (+)-66
NMR (500 MHz, CDCl3) δ 8.75 (s, 1 H), 6.22-6.05 (m, 5 H),
5.79-5.70 (m, 1 H), 5.56-5.49 (m, 1 H), 5.22 (t, J ) 7.4 Hz, 1
H), 4.82 (d, J ) 4.5 Hz, 1 H), 3.79-3.60 (m, 5 H), 3.38-3.30
(m, 1 H), 3.32 (s, 2 H), 3.22 (s, 3 H), 2.70 (m, 2 H), 2.32-2.06
(m, 4 H), 1.82-1.66 (m, 3 H), 1.98 (s, 3 H), 1.96 (s, 3 H), 1.78
(s, 3 H), 1.02 (s, 9 H), 0.88 (s, 9 H), 0.74 (d, J ) 7.1 Hz, 3 H),
0.20 (s, 6 H), 0.027 (s, 3 H), 0.021 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 166.8, 137.8, 136.3, 134.9, 133.5, 133.2, 133.0, 132.7,
132.6, 131.9, 131.8, 130.9, 124.9, 108.6, 102.9, 100.6, 78.8, 74.5,
72.7, 59.4, 56.2, 40.8, 38.9, 37.8, 30.6, 29.1, 27.6, 26.1, 26.0,
24.7, 24.4, 20.8, 18.7, 18.3, 12.6, -3.2, -3.3, -5.31, -5.34; high-
resolution mass spectrum (ES, Na) m/z 823.4542 [(M + Na)+;
calcd for C43H72N2O6S(Si)2Na 823.4547].
(87 mg, 88% yield) as a light yellow oil: [R]23 +17.6° (c 0.50,
D
CHCl3); IR (CHCl3) 3700 (w), 3620 (w), 3405 (m), 3020 (s), 1730
1
(s), 1680 (s), 1600 (s), 1520 (s), 1450 (m), 1375 (m) cm-1; H
NMR (500 MHz, CDCl3) δ 8.68 (s, 1 H), 8.00 (s, 1 H), 7.74 (s,
1 H), 6.28-6.10 (m, 4 H), 6.05-5.97 (m, 1 H), 5.61-5.52 (m, 1
H), 5.43 (dd, J ) 17.5, 1.5 Hz, 1 H), 5.34-5.28 (m, 2 H), 5.03
(s, 2 H), 4.72 (d, J ) 5.6 Hz, 1 H), 4.70 (d, J ) 5.6 Hz, 1 H),
3.91-3.88 (m, 1 H), 3.82-3.72 (m, 2 H), 3.69 (s, 3 H), 3.41 (m,
1 H), 3.40 (s, 2 H), 3.32 (s, 3 H), 2.80-2.70 (m, 2 H), 2.66 (br
s, 1 H), 2.40-2.15 (m, 4 H), 1.92-1.82 (m, 1 H), 1.80-1.67
(m, 2 H), 1.72 (s, 3 H), 1.38 (s, 3 H), 1.37 (s, 3 H), 0.78 (d, J )
7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 166.2, 153.5, 142.3,
135.6, 134.2, 134.0, 133.40, 133.37, 132.8, 132.6, 132.3, 132.2,
131.1, 130.2, 125.1, 118.3, 114.5, 107.0, 101.3, 101.0, 82.1, 74.8,
69.5, 66.3, 60.9, 57.9, 56.6, 41.2, 38.3, 37.9, 30.4, 29.6, 28.2,
25.0, 24.4, 21.2, 13.1; high-resolution mass spectrum (ES, Na)
m/z 723.3277 [(M + Na)+; calcd for C37H52N2O9SNa 723.3291].
Anal. Calcd for C37H52N2O9S: C, 63.43; H, 7.43; N, 4.00.
Found: C, 63.64; H, 7.57; N, 4.16.
Acid (+)-67. To a solution of (+)-66 (20 mg, 0.0286 mmol)
in CH2Cl2 (4 mL) were added triethylamine (0.3 mL, 2.15
mmol), dimethyl sulfoxide (0.1 mL, 1.43 mmol), and SO3‚Py
complex (180 mg, 1.13 mmol). After 30 min, the solution was
added to brine-saturated NaHCO3 (1:1, 20 mL) and extracted
with ethyl acetate (3 × 20 mL). The combined organic phases
were dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 1:1) afforded the
corresponding unstable aldehyde (20 mg) as a colorless oil. The
aldehyde was used immediately in the following step.
Anal. Calcd for C43H72N2O6S(Si)2: C, 64.45; H, 9.06; N, 3.50.
Found: C, 64.70; H, 9.27; N, 3.83.
MOM Eth er (+)-65. A solution of (+)-64 (200 mg, 0.25
mmol) in acetone (5 mL) was treated with aqueous K2CO3 (5
M, 1.5 mL, 7.5 mmol) and allyl chloroformate (0.261 mL, 2.5
mmol). The resultant mixture was stirred for 1 h, poured into
brine (50 mL), and extracted with ether (3 × 50 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate,
4:1) afforded the corresponding amide (186 mg, 84% yield) as
a colorless oil: [R]23 +11.7° (c 0.70, CHCl3); IR (CHCl3) 3010
D
(s), 2940 (s), 2960 (s), 1725 (s), 1680 (s), 1590 (m), 1514 (s),
1440 (m), 1380 (m), 1240 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.85 (s, 1 H), 7.52 (s, 1 H), 6.81 (s, 1 H), 6.22-6.06 (m, 4 H),
5.98-5.92 (m, 1 H), 5.80-5.70 (m, 1 H), 5.58-5.50 (m, 1 H),
5.37 (dd, J ) 17.1, 1.1 Hz, 1 H), 5.26 (dd, J ) 10.8, 1.1 Hz, 1
H), 5.18 (t, J ) 6.7 Hz, 1 H), 4.76 (d, J ) 5.2 Hz, 3 H), 3.81-
3.68 (m, 2 H), 3.66-3.52 (m, 1 H), 3.36-3.30 (m, 1 H), 3.32 (s,
2 H), 3.21 (s, 3 H), 2.72 (t, J ) 7.4 Hz, 2 H), 2.33-2.04 (m, 4
H), 1.82-1.76 (m, 1 H), 1.72-1.59 (m, 2 H), 1.64 (s, 3 H), 1.28
(s, 3 H), 1.26 (s, 3 H), 1.03 (s, 9 H), 0.88 (s, 9 H), 0.71 (d, J )
7.1 Hz, 3 H), 0.026 (s, 6 H), 0.021 (s, 6 H); 13C NMR (125 MHz,
CDCl3) δ 166.6, 152.8, 138.6, 135.2, 133.3, 133.2, 133.1, 132.7,
132.29, 132.16, 131.29, 131.17, 130.2, 129.1, 124.5, 118.0,
114.7, 106.4, 100.6, 78.8, 74.5, 69.2, 66.0, 59.3, 56.2, 40.9, 38.9,
37.7, 30.2, 29.2, 27.5, 25.95, 25.92, 24.9, 24.2, 20.8, 18.6, 18.3,
12.7, -3.55, -3.63, -5.32, -5.35; high-resolution mass spec-
trum (ES, Na) m/z 907.4750 [(M + Na)+; calcd for C47H76N2O8-
S(Si)2Na 907.4758].
To a solution of the above aldehyde in tert-butyl alcohol and
2-methyl-2-butene (1 mL each) were added sodium chlorite (26
mg, 0.277 mmol) and NaH2PO4‚2H2O (33 mg, 0.212 mmol) in
water (1 mL). After 20 min, the phases were separated, and
the aqueous phase was mixed with brine (10 mL) and extracted
with ethyl acetate (3 × 10 mL). The combined organic phases
were dried over MgSO4, filtered, and concentrated. Flash
chromatography (ethyl acetate/hexanes, 3:1; CH2Cl2/MeOH,
20:1 to 10:1) provided (+)-67 (8.8 mg, 43% yield for two steps)
To a solution of the above amide (167 mg, 0.19 mmol) in
THF (5 mL) at 0 °C were added tetrabutylammonium fluoride
(1 M in THF, 0.56 mL, 0.56 mmol) and acetic acid (0.032 mL,
0.56 mmol). After 5 min, the mixture was poured into brine
(25 mL) and extracted with ether (3 × 25 mL). The combined
organic phases were dried over MgSO4, filtered, and concen-
trated. The resultant residue was dissolved in CH2Cl2 and
treated with N,N-diisopropylethylamine (0.33 mL, 1.9 mmol)
and chloromethyl methyl ether (0.072 mL, 0.95 mmol). The
resultant yellow solution was stirred for 30 min, added to
brine-saturated NaHCO3 (1:1, 40 mL), and extracted with
ether (3 × 40 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 1:1) afforded (+)-65 (115 mg, 75% yield
as a colorless oil: [R]23 +26.5° (c 0.40, CHCl3); IR (CHCl3)
D
3500 (br s), 2920 (s), 2840 (s), 1760 (m), 1740 (s), 1605 (s), 1505
(s), 1460 (m), 1370 (m), 1245 (s) cm-1 1H NMR (500 MHz,
;
CDCl3) δ 8.92 (s, 1 H), 8.05 (overlapping s, 1H), 7.82 (s, 1 H),
6.42 (dd, J ) 14.9, 10.1 Hz, 1 H), 6.23 (dd, J ) 15.6, 11.2 Hz,
1 H), 6.15-5.38 (complex series of m, 6 H), 5.30 (m, 2 H), 5.06-
4.81 (complex series of m, 2 H), 4.72 (m, 3 H), 4.17 (m, 1 H),
3.67 (overlapping s, 3 H), 3.51-3.32 (m, 3 H), 3.22-3.18 (m, 3
H), 2.88-2.77 (m, 2 H), 2.60-2.50 (m, 2 H), 2.38-2.10 (m, 3
H), 1.92-1.81 (m, 1 H), 1.73 (overlapping s, 3 H), 1.80-1.70
(m, 1 H), 1.40 (overlapping s, 6 H), 0.80 (overlapping d, J )
7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 173.6, 166.1, 153.7,
141.8, 136.3, 135.6, 134.4, 133.9, 133.6, 132.5, 132.4, 132.1,
131.6, 131.0, 130.7, 129.5, 123.7, 118.6, 118.1, 114.8, 107.3,
106.9, 101.0, 100.5, 78.8, 73.3, 69.2, 66.2, 66.0, 57.6, 57.5, 56.1,
40.5, 38.6, 36.3, 30.6, 29.3, 29.1, 28.6, 24.9, 24.1, 24.0, 20.74,
20.67, 12.7, 12.5; high-resolution mass spectrum (ES, Na) m/z
737.3082 [(M + Na)+; calcd for C37H50N2O10SNa 737.3084].
Ma cr ola cta m (+)-68. A solution of (+)-67 (8 mg, 0.0112
mmol) in THF (2 mL) was treated with dimedone (16 mg, 0.112
mmol) and tetrakis(triphenylphosphine)palladium(0) (13 mg,
0.0112 mmol). The resultant yellow solution was stirred for 1
for two steps) as a white foam: [R]23 +12.6° (c 0.50, CHCl3);
D
IR (CHCl3) 3680 (m), 3400 (m), 3010 (s), 2960 (s), 2940 (s),
1730 (s), 1680 (s), 1600 (s), 1515 (s), 1440 (m), 1380 (m), 1220
(s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 2 H), 7.61 (s, 1
H), 6.23-6.07 (m, 4 H), 5.98-5.92 (m, 1 H), 5.80-5.70 (m, 1
H), 5.57-5.49 (m, 1 H), 5.33 (d, J ) 17.8 Hz, 1 H), 5.24 (m, 2
H), 4.93 (s, 2 H), 4.68 (m, 3 H), 3.80-3.68 (m, 2 H), 3.65-3.57
(m, 1 H), 3.60 (s, 3 H), 3.38-3.30 (m, 1 H), 3.34 (s, 2 H), 3.21
(s, 3 H), 2.72 (t, J ) 7.1 Hz, 2 H), 2.34-2.10 (m, 4 H), 1.81-
1.77 (m, 1 H), 1.74-1.62 (m, 2 H), 1.68 (s, 3 H), 1.30 (s, 3 H),

Total Synthesis of (+)-Thiazinotrienomycin E
J . Org. Chem., Vol. 65, No. 12, 2000 3753
h at room temperature and then concentrated in vacuo. Flash
chromatography (ethyl acetate/hexanes, 1:1; CH2Cl2/MeOH,
20:1 to 1:1) afforded the corresponding unstable amino acid
as a yellow solid. The acid was used immediately in the
following step.
A solution of the above acylation products in THF (2 mL)
was treated with diethylamine (1 mL). After being stirred at
room temperature for 1 h, the mixture was concentrated in
vacuo to afford the corresponding primary amines.
A solution of the above amines in THF (1.5 mL) was treated
with triethylamine (0.1 mL, 0.717 mmol), benzotriazol-1-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate (15 crys-
tals, excess), and cyclohexanecarboxylic acid (2 drops, excess).
After 1 h, the solution was added to NaHCO3-brine (1:1, 4
mL), and extracted with ethyl acetate (6 × 4 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated to provide the corresponding thiazinotrienomycin
MOM ethers as a yellow powder; high-resolution mass spec-
trum (ES, Na) m/z 776.3563 [(M + Na)+; calcd for C40H55N3O9-
SNa 776.3557].
A solution of the above amino acid in THF-toluene (2:3, 5
mL) was treated with triethylamine (0.02 mL, 0.143 mmol).
The resultant yellow solution was then added over a 2 h period
via a syringe pump to a suspension of 2-chloro-1-methylpyri-
dinium iodide (30 mg, 0.117 mmol) and triethylamine (0.03
mL, 0.215 mmol) in toluene (5 mL). After addition, the mixture
was stirred for an additional 1 h. The resultant solid was then
removed by filtration and the yellow filtrate concentrated in
vacuo. Flash chromatography (ethyl acetate/hexanes, 3:1)
provided (+)-68 (4.2 mg, 61% yield for two steps) as a light
yellow foam: [R]23 +43.2° (c 0.25, CHCl3); IR (CHCl3) 3400
D
(m), 2980 (s), 2920 (s), 2900 (s), 2850 (s), 1660 (s), 1611 (m),
1473 (s), 1380 (s), 1360 (m) cm-1; 1H NMR (500 MHz, CDCl3)
δ 8.27 (s, 1 H), 7.88 (s, 1 H), 7.51 (s, 1 H), 6.20-5.95 (m, 4 H),
5.81 (m, 1 H), 5.53 (dd, J ) 15.0, 8.5 Hz, 1 H), 5.17 (t, J ) 5.6
Hz, 1 H), 4.84 (d, J ) 5.8 Hz, 1 H), 4.71 (d, J ) 5.8 Hz, 1 H),
4.45 (d, J ) 5.8 Hz, 1 H), 4.07 (m, 1 H), 3.62 (s, 3 H), 3.51 (m,
1 H), 3.34 (s, 2 H), 3.32 (s, 3 H), 2.90 (m, 2 H), 2.60 (dd, J )
12.9, 3.9 Hz, 1 H), 2.50 (m, 1 H), 2.31 (t, J ) 11.1 Hz, 1 H),
2.20-2.02 (m, 3 H), 1.87-1.80 (m, 1 H), 1.72 (s, 3 H), 1.40 (s,
3 H), 1.28 (s, 3 H), 0.91 (d, J ) 7.1 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 168.2, 165.4, 143.6, 143.0, 136.1, 133.8, 133.53,
133.50, 133.1, 132.6, 132.4, 131.2, 130.1, 129.9, 124.2, 108.1,
100.7, 100.5, 79.9, 73.1, 70.6, 68.8, 57.5, 56.4, 45.9, 36.0, 29.9,
29.1, 27.4, 24.5, 23.9, 20.0, 12.5; high-resolution mass spectrum
(ES, Na) m/z 635.2785 [(M + Na)+; calcd for C33H44N2O7SNa
635.2767].
A solution of the above ethers in THF (0.5 mL) was treated
with HCl (3 N, 0.5 mL). The resultant mixture was stirred at
room temperature for 5.5 h, added to saturated NaHCO3 (4
mL), and extracted with ethyl acetate (6 × 4 mL). The
combined organic phases were dried over MgSO4, filtered, and
concentrated. HPLC (3.9 × 300 mm analytical column, Waters
Co. Ltd.; mobile phase, 95% ethyl acetate and 5% hexanes;
flow rate, 1 mL/min.; detection, 254 nm; temperature, room
temperature; retention time, 15.5-19 min) provided (+)-
th ia zin otr ien om ycin E (1.4 mg, 28% yield for four steps) as
a white powder: [R]23D +195° (c 0.035, CH3OH); 1H NMR (500
MHz, pyridine-d5) δ 11.82 (s, 1 H), 10.83 (s, 1 H), 9.74 (br s, 1
H), 9.10 (d, J ) 6.1 Hz, 1 H), 7.63 (s, 1 H), 6.56 (dd, J ) 15.6,
10.1 Hz, 1 H), 6.37 (dd, J ) 15.0, 10.0 Hz, 1 H), 6.32 (dd, J )
15.0, 10.0 Hz, 1 H), 6.20 (dd, J ) 15.3, 10.1 Hz, 1 H), 5.95 (m,
1 H), 5.75 (dd, J ) 15.6, 8.9 Hz, 1 H), 5.56 (t, J ) 4.6, 1 H),
5.41 (m, 1 H), 5.34 (m, 1 H), 5.23 (br s, 1 H), 4.78 (m, 1 H),
4.45 (m, 1 H), 3.60 (d, J ) 14.6 Hz, 1 H), 3.54 (d, J ) 14.6 Hz,
1 H), 3.27 (s, 3 H), 3.16 (dd, J ) 12.2, 4.3 Hz, 1 H), 3.18-3.06
(m, 2 H), 2.95 (m, 1 H), 2.84-2.27 (m, 6 H), 2.03 (s, 3 H), 2.05-
1.70 (m, 4 H), 1.58 (d, J ) 7.3 Hz, 3 H), 1.55-1.17 (m, 6 H),
0.94 (d, J ) 6.7 Hz, 3 H); 13C NMR (125 MHz, pyridine-d5) δ
176.9, 173.1, 170.4, 165.9, 143.9, 140.6, 135.2, 134.8, 133.7,
131.6, 131.5, 130.8, 129.9, 129.6, 126.9, 124.2, 117.8, 109.4,
80.8, 75.4, 68.3, 56.2, 49.6, 44.4, 43.7, 39.0, 33.5, 30.7, 30.1,
29.8, 29.2, 27.3, 26.2, 26.1, 26.0, 21.2, 17.3, 10.3; high-
resolution mass spectrum (ES, Na) m/z 732.3293 [(M + Na)+;
calcd for C38H51N3O8SNa 732.3295].
Diol (+)-69. A solution of (+)-68 (4.2 mg, 0.00686 mmol) in
methanol (2 mL) was treated with camphorsulfonic acid (three
crystals). The mixture was stirred for 15 min and then
quenched with triethylamine (three drops). After concentration
to dryness, the residue was dissolved in ethyl acetate (5 mL),
added to silica gel (ca. 0.2 g), and concentrated again. Flash
chromatography (ethyl acetate) provided (+)-69 (4 mg, 90%
yield) as a white foam: [R]23 +16.1° (c 0.13, CHCl3); IR
D
(CHCl3) 3390 (w), 2980 (m), 2940 (m), 2920 (s), 2850 (m), 1670
(s), 1610 (m), 1517 (s), 1372 (m), 1350 (m) cm-1; 1H NMR (500
MHz, CDCl3) δ 8.41 (s, 1 H), 7.90 (s, 1 H), 7.52 (s, 1 H), 6.17-
5.90 (m, 4 H), 5.73 (m, 1 H), 5.58 (dd, J ) 15.2, 7.3 Hz, 1 H),
5.24 (t, J ) 5.6 Hz, 1 H), 4.97 (d, J ) 5.8 Hz, 1 H), 4.82 (m, 1
H), 4.81 (d, J ) 5.8 Hz, 1 H), 4.14 (m, 1 H), 3.78 (m, 1 H), 3.62
(s, 3 H), 3.31 (overlapping s, 5 H), 2.86 (m, 2 H), 2.60 (dt, J )
12.4, 4.4 Hz, 1 H), 2.55 (m, 1 H), 2.36 (m, 2 H), 2.11-1.90 (m,
4 H), 1.82 (s, 3 H), 1.84-1.72 (m, 1 H), 0.95 (d, J ) 7.1 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 152.0, 150.4, 141.9, 139.6,
138.4, 132.1, 133.7, 133.2, 132.7, 132.6, 131.4, 130.5, 130.3,
129.2, 124.6, 107.3, 100.7, 96.1, 73.4, 70.1, 57.6, 56.6, 39.3, 29.9,
29.7, 29.5, 29.3, 20.3, 14.1, 11.0; high-resolution mass spectrum
(ES, Na) m/z 595.2442 [(M + Na)+; calcd for C30H40N2O7SNa
595.2454].
Ack n ow led gm en t. Financial support was provided
by the National Institutes of Health (National Institute
of General Medical Sciences) through grant GM 29028.
Z.W. gratefully acknowledges a SAS dissertation fellow-
ship from the University of Pennsylvania. In addition,
we thank Drs. George T. Furst and Patrick J . Carroll
and Mr. J ohn Dykins of the University of Pennsylvania
Spectroscopic Service Center for assistance in securing
and interpreting high-field NMR spectra, X-ray crystal
structures, and mass spectra, respectively. In addition,
we thank Debora Wendte and Mike Corbett (Depart-
ment of Chemistry, University of Pennsylvania) for the
cover design.
(+)-Th ia zin otr ien om ycin E (1). A solution of (+)-69 (4
mg, 0.007 mmol) and DMAP (1 mg, 0.008 mmol) in THF (1
mL) at -78 °C was treated dropwise with a freshly prepared
Fmoc-D-alanine anhydride (0.025 mM, 0.040 mmol) in CH2Cl2
(1.6 mL). The reaction solution was stirred for 2 at -78 °C
and then quenched with pH 7 buffer solution (3 mL). The
mixture was warmed to room temperature and extracted with
ethyl acetate (6 × 5 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated. Flash chroma-
tography (ethyl acetate) afforded the two inseparable mono-
acylation products as a white powder: high-resolution mass
spectrum (ES, Na) m/z 888.3539 [(M + Na)+; calcd for
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for selected synthetic intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
C
48H55N3O10SNa 888.3506].
J O991958J