Total synthesis of (+)-damavaricin D

Full text of DOI:10.1021/ja971828x

J. Am. Chem. Soc. 1997, 119, 11331-11332
11331
The successful completion of this synthesis was critically
dependent on three issues: (i) use of acetate protecting groups
for the C(11,13)-diol;11 (ii) use of an allyl ester to protect the
C(10)-carboxyl of 3, thereby facilitating removal of the two
acetates at the end of the synthesis; and (iii) use of acid labile
methoxymethyl (MOM) ethers (see 2) to protect the 1,4-
dihydronaphthoquinone precursors to 1.10 Use of phenolic
MOM ethers was required by our finding that attempted
oxidative demethylation of 4 (and related intermediates) pro-
vided 5 which could not be elaborated to DmD.10 This
necessitated that the 1,4-dihydronaphthoquinone deprotection
and oxidation steps be decoupled.
Total Synthesis of (+)-Damavaricin D
William R. Roush,*,1 D. Scott Coffey, and David J. Madar
Department of Chemistry, Indiana UniVersity
Bloomington, Indiana 47405
ReceiVed June 4, 1997
Damavaricin D (DmD, 1) is both a biosynthetic precursor of
the streptovaricin antibiotic family as well as a degradation
product of streptovaricin D (SvD).2,3 The damavaricins, like
the streptovaricins, are inhibitors of RNA-directed DNA poly-
merase (i.e., reverse transcriptase),4 and certain derivatives have
other interesting biological properties.5 The stereochemistry of
1 has been assigned on the basis of its biosynthetic conversion
into streptovaricin C (SvC),3 the structure and absolute config-
uration of which have been determined by X-ray analysis of a
heavy atom derivative.6 The only stereocenter of DmD/SvD
Acid hydrolysis of 610,12 and reprotection of the phenol as a
tert-butyldiphenylsilyl (TBDPS) ether provided 7 (87% yield)
(Scheme 1). This protecting group switch was required because
bromination of 9 was possible only when the C(19) phenol was
unprotected. Dithionite reduction of 713 followed by in situ
protection of the air-sensitive hydroquinone with MOM-Cl and
50% aqueous NaOH under phase transfer conditions provided
8 in 82% yield. Carboxylation of the aryllithium intermediate
generated from 8 followed by Mitsunobu esterification14 of the
naphthoic acid with â-(trimethylsilyl)ethanol provided 9 in 75%
overall yield. Finally, removal of the TBDPS ether, bromination
of C(18) with N-bromosuccinamide (NBS), and reprotection of
the phenol as a MOM ether provided 2.
Metallation of 2 (1.8 equiv) with n-BuLi (1.5 equiv) in THF
at -100 °C followed by addition of enal 3 (1.0 equiv) provided
a mixture of allylic alcohols (83%) that was oxidized with the
Dess-Martin periodinane to give enone 10 in 94% yield as a
1:1 mixture of atropisomers (Scheme 2).15 After deprotection
of the TBDPS ether (Et3N-HF, CH3CN, 89%),16 the primary
alcohol was oxidized via the Swern protocol17 and the aldehyde
chain extended via Still’s (Z)-selective olefination procedure,18
thereby providing 11 in 72% yield along with 5% of the (E)-
olefin isomer. The carbamate functionality of 12 was then
introduced in 66% yield via a Curtius reaction19 of the carboxylic
acid generated by tetrabutylammonium fluoride mediated depro-
tection of 11.20
Selective reduction of the (Z)-enoate unit of 12 required
careful control of the reaction conditions to prevent competitive
reduction of the C(11) and C(13) acetates. Treatment of 12
with 5 equiv of diisobutylaluminum hydride (DIBAL-H) in THF
at -100 to -78 °C for 1.5 h provided the (Z)-enal 14 (14%),
(Z)-allylic alcohol 13 (33%), and recovered 12 (49%). After
not known with certainty prior to our work is C(14). However,
the stereochemistry proposed for the C(6)-C(14) segment of
DmD/SvD is identical to that found in awamycin.7 We report
herein a total synthesis of damavaricin D, the first synthesis of
any member of this family,8 by a route that utilizes the highly
functionalized bromonaphthalene 2 and the ansa chain aldehyde
39,10 as key intermediates.
(1) Present address: Department of Chemistry, University of Michigan,
Ann Arbor, MI 48109.
(2) Rinehart, K. L.; Shield, L. S. Prog. Chem. Org. Nat. Prod. 1976,
33, 231.
(3) Rinehart, K. L., Jr.; Antosz, F. J.; Deshmukh, P. V.; Kakinuma, K.;
Martin, P. K.; Milavetz, B. I.; Sasaki, K.; Witty, T. R.; Li, L. H.; Ruesser,
F. J. Antibiot. 1976, 29, 201.
(4) Rinehart, K. L.; Clark, T. D.; Moran, D. M.; Gray, L. G.; Cowie, C.
H.; Li, L. H. J. Nat. Cancer Inst. 1977, 58, 239.
(5) n-Pentyldamavaricin Fc (deriving from damavaricin C) is potentially
useful as an antiviral agent and for treatment of adult T-cell leukemia:
Onodera, K.; Ito, S.; Sasaki, K. In Subcellular Biochemistry; Plenum
Press: New York, 1989; Vol. 15, p 69. Ito, S.; Gilljams, G.; Wahern, B.;
Wigzell, H.; Yamamoto, N.; Sasaki, K.; Onodera, K. J. Antibiot. 1990, 43,
1045.
(6) Wang, A. H.-J.; Paul, I. C. J. Am. Chem. Soc. 1976, 98, 4612.
(7) Herlt, A. J.; Rickards, R. W.; Robertson, G. B. Aust. J. Chem. 1992,
45, 309.
(8) For previous synthetic studies on the streptovaricins, see: McCarthy,
P. A. Tetrahedron Lett. 1982, 23, 4199. Trost, B. M.; Pearson, W. H.
Tetrahedron Lett. 1983, 24, 269. Fraser-Reid, B.; Magdzinski, L.; Molino,
B. F.; Mootoo, D. R. J. Org. Chem. 1987, 52, 4495. Fraser-Reid, B.; Molino,
B. F.; Magdzinski, L.; Mootoo, D. R. J. Org. Chem. 1987, 52, 4505. Mootoo,
D. R.; Fraser-Reid, B. J. Org. Chem. 1987, 52, 4511. Schreiber, S. L.; Wang,
Z.; Schulte, G. Tetrahedron Lett. 1988, 29, 4085. Wang, Z.; Schreiber, S.
L. Tetrahedron Lett. 1990, 31, 31. Mottoo, D. R.; Fraser-Reid, B.
Tetrahedron 1990, 46, 185.
(11) The crotylchromium addition used to establish the C(11,12) bond
in our inital approach (ref 9) could not be scaled up. Ultimately, the C(11,-
12) bond was constructed with excellent stereoselectivity via a crotylboration
sequence after first reducing the C(10)-acyl unit to a -CH2OH group.
Subsequent reoxidation of this substituent proceeded with acceptable
efficiency only when C(11)-OH was protected as an acetate (ref 10). Full
details of the synthesis of 3 are provided in the Supporting Information.
(12) Roush, W. R.; Madar, D. J. Tetrahedron Lett. 1993, 34, 1553.
(13) Seitz, U.; Daub, J. Synthesis 1986, 686.
(14) Hughes, D. L. Org. React. 1992, 42, 335.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(16) Hunig, S.; Wehner, G. Synthesis 1975, 180.
(17) Tidwell, T. T. Synthesis 1990, 857.
(9) Roush, W. R.; Palkowitz, A. D. J. Org. Chem. 1989, 54, 3009.
(10) Roush, W. R.; Coffey, D. S.; Madar, D. J.; Palkowitz, A. D. J.
Brazil. Chem. Soc. 1996, 7, 327.
(18) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(19) Ninomiya, K.; Shiori, T.; Yamada, S. Tetrahedron 1974, 30, 2151.
(20) Sieber, P. HelV. Chim. Acta 1977, 60, 2711.
S0002-7863(97)01828-3 CCC: $14.00 © 1997 American Chemical Society

11332 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Communications to the Editor
Scheme 1
methylsilicate (TAS-F) in DMF.23 The crude seco acid
underwent smooth macrolactamization by using the Mukaiyama
salt protocol,24,25 giving macrolactam 16 in 76% yield from 15.
Although all intermediates from the stage of 10 through 15 were
ca. 1:1 mixtures of atropisomers, macrocycle 16 was a single
1
atropisomer by H NMR analysis.26
With 16 in hand, we anticipated that the DmD synthesis
would be completed in a straightforward manner since the
remaining deprotection steps had been developed using 4 and
9 as substrates.10 However, 4 proved to be a uniquely poor
model for 16, since the two macrocycles exist in opposite
atropisomeric series27 and the reactivity of 16 was substantially
different than that of 4.28 Both 4 and 16 exist in thermodynamic
wells (as determined by variable temperature 1H NMR studies);
why this pair of structurally similar compounds exhibit such
strikingly different conformational properties and reactivity
remains a mystery. Ultimately, a successful deprotection
sequence was developed as follows. Hydrolysis of 16 in a two-
phase mixture of 1 N HCl and THF (7:9) at 23 °C for 14 h
provided a mixture of diol phenol 17, phenol acetonide 18, diol
19, and recovered 16. Resubjection of 16, 18, and 19 to these
conditions (three recycles) provided 17 in 54% yield. The
phenolic allyl ether and the C(10) allyl ester of 17 were removed
by using catalytic (Ph3P)4Pd and n-Bu3SnH in toluene containing
HOAc.29 Treatment of the resulting C(10)-carboxylic acid with
excess LiOH in 2:2:1 THF-MeOH-H2O, followed by esteri-
fication with Me3SiCHN2,30 effected clean removal of both
acetate protecting groups and provided 20 in 50% overall yield.
Finally, hydrolysis of 20 with 9:1 TFA-H2O in CH2Cl2 and
air oxidation of the resulting hydroquinone provided totally
synthetic (+)-damavaricin D in 70% yield. The identity of the
synthetic material was determined by comparison with an
authentic sample of the natural product kindly provided by Prof.
Rinehart.
Scheme 2
Acknowledgment. Financial support provided by grants from the
National Institutes of Health (GM 38436 and RR 10537 to W.R.R.)
and the Abbott Fellowship to D.S.C. is gratefully acknowledged.
Supporting Information Available: Experimental procedures
(including procedures for the synthesis of the ansa chain aldehyde 3)
and characterization data for all new compounds (54 pages). See any
current masthead page for ordering and Internet access instructions.
JA971828X
(23) Noyori, R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem.
Soc. 1980, 102, 1223.
(24) Meng, Q.; Hesse, M. Top. Curr. Chem. 1991, 161, 107.
(25) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163.
(26) Rinehart, K. L., Jr.; Kno¨ll, W. M. J.; Kakinuma, K.; Antosz, F. J.;
Paul, I. C.; Wang, A. H.-J.; Reusser, F.; Li, L. H.; Krueger, W. C. J. Am.
Chem. Soc. 1975, 97, 196.
(27) Rinehart has argued that the major contribution to the optical
rotations of the streptovaricins and damavaricins is the helicity of these
molecules, since all natural Sv’s and Dm’s have positive rotations, whereas
all of the known atropisomers have negative rotations (see refs 3 and 26).
recycle of 12 (5 equiv of DIBAL-H, -100 to -78 °C, 1 h;
then -60 °C for 30 s), 13 and 14 were obtained in 62 and 16%
aggregate yields, respectively. Allylic alcohol 13 was oxidized
by using the Swern protocol, giving 14 (82%), which was further
elaborated to the (E,Z)-dienoate 15 by a Horner-Wadsworth-
Emmons reaction (86%).21,22 The carbamate and dienoate
protecting groups were removed in a single operation by
treatment of 15 with tris(dimethylamino)sulfonium difluorotri-
On this basis, macrocycles 16 ([R]25 +85.7°) and 4 ([R]25 -10.0°) are
D
believed to be in the natural and unnatDural atropisomeric series, respectively.
(28) Attempted deprotection of the acetonide and MOM ethers of 16
with p-TsOH in MeOH gave a complex mixture of products, whereas the
analogous treatment of 4 provided the corresponding dihydroxy phenol in
93% yield. Similarly, attempts to remove the allyl and acetate protecting
groups of 16 by using (Ph3P)4Pd and dimedone followed by LiOH resulted
in total decomposition, whereas the analogous deprotection sequence was
successfully performed on 4.
(21) Mori, K.; Matsushima, Y. Synthesis 1993, 406.
(22) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; T. Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(29) Four, P.; Guibe, F. Tetrahedron Lett. 1982, 23, 1825.
(30) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. Jpn.
1981, 29, 1475.