Stereospecific total synthesis of the antiviral agent hamigeran B - Use of large silyl groups to enforce facial selectivity and to suppress hydrogenolysis

Article abstract of DOI:10.1002/anie.200351519

Stereoselective hydrogenation of the tetrasubstituted double bond in enone 1 is possible, provided the keto group at C7 is first removed and the α face is blocked by tert-butyldimethylsiloxy groups at positions 10 and 11. The resulting product 2 is easily

Full text of DOI:10.1002/anie.200351519

Communications
Natural Product Synthesis
Stereospecific Total Synthesis of the Antiviral
Agent Hamigeran B—Use of Large Silyl Groups
to Enforce Facial Selectivity and to Suppress
Hydrogenolysis**
Derrick L. J. Clive* and Jian Wang
We report the stereospecific synthesis of hamigeran B (1,
Scheme 1), which is an important member of a group of
related compounds isolated[1] from a marine sponge. Hami-
geran B has been found to have strong in vitro activity against
Scheme 1. Hamigeran B (1) and the radical cyclization of 2.
polio and herpes viruses but little cytotoxicity.[1] The com-
pound presents a number of constructional problems, and the
significant biological properties enhance the potential value
of work on its synthesis. One route to hamigeran B and
several congeners has been reported.[2] We aimed to deal only
with the synthesis of hamigeran B itself and to do so in a
stereospecific manner.
The most obvious synthetic difficulty resides in the
stereochemistry at C6 (see 1), as the bulky isopropyl group
extends into the more hindered concave face of the structure.
This orientation probably disqualifies methods that rely on
stereochemical equilibration at C6. Likewise, radical cycliza-
tion (see 2), which is a powerful method for making [4.3.0]
bicyclic structures with cis ring fusion, does not[3] generate the
correct stereochemistry at C6 because the required transition
state is destabilized by steric interactions engendered by the
isopropylidene group. Further synthetic analysis, as well as
experimental work, suggested that double-bond reduction
(Scheme 2, 3!4), possibly directed by a suitably placed
substituent, would merit detailed investigation. We recog-
nized, however, that the double bond in 3, being tetrasub-
stituted, might be resistant to hydrogenation.[4] Also, exami-
nation of Dreiding models exposed another potential diffi-
culty: it was not obvious from the shape of 3 whether
[*] Prof. Dr. D. L. J. Clive, J. Wang
Chemistry Department
University of Alberta
Edmonton, Alberta, T6G 2G2 (Canada)
Fax: (+1)780-492-8231
E-mail: derrick.clive@ualberta.ca
[**] We thank NSERC for financial support, Dr. R. McDonald (X-Ray
Crystallography Laboratory) for crystal-structure determinations,
and Professor S. Bergens and S. Fletcher for valuable advice.
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DOI: 10.1002/anie.200351519
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Chemie
Scheme 2. Key transformation in the synthesis of hamigeran B (1).
Scheme 4. Some transformations of enone 13. DIBAL-H=diisobutyl-
aluminum hydride.
hydrogenation would occur preferentially from the a or b
face. Nonetheless, we decided to examine the approach shown
in Scheme 2, and we were eventually able, through the
temporary introduction of additional steric factors, to develop
it into a powerful approach for solving the stereochemical
problems inherent in the convex shape and substitution
pattern of hamigeran B.
The phenolic carboxylic acid 5 (Scheme 3), easily pre-
pared from m-cresol by Friedel–Crafts acylation with succinic
anhydride[5] followed by Clemmensen reduction,[6] was
assumption that the desired a stereochemistry was generated
initially but that the product underwent carbonyl-mediated
epimerization, we attempted to reduce ketone 13 to the
corresponding allylic alcohol in order to remove that possi-
bility. Treatment of 13 with NaBH4 and CeCl3·7H20, was
unsuccessful, as the compound reacted much too slowly, but
reaction with DIBAL-H (08C to room temperature) was
rapid. However, the resulting allylic alcohol is very sensitive,
and exposure to silica gel during flash chromatography caused
dehydration, so that the material isolated (98%) was the
diene 15 (Scheme 4). Hydrogenation of this diene (Pd/C, H2,
345 kPa, MeOH) did saturate the two double bonds, but an
inseparable mixture (ca. 1:1 in some experiments) of stereo-
isomers was formed. We attributed this result to a lack of
facial selectivity, and so we decided to introduce a bulky
group to block the a face of ketone 13. To this end, the ketone
was dehydrogenated with DDQ (Scheme 5, 13!16). Dihy-
droxylation (16!17) with OsO4 and NMO occurred anti to
the adjacent methyl substituent, as desired, and the stage was
now set to mask the hydroxy groups with a bulky substituent,
so as to direct subsequent hydrogenation exclusively to the
opposite face.
Scheme 3. Preparation of the key intermediate 13. Reagents and condi-
tions: a) Me2SO4, aqueous NaOH, reflux, 12 h, 67% from m-cresol;
b) LDA, THF, HMPA, ꢀ788C, MeI, 96%; c) POCl3, Cl2CHCHCl2, reflux,
5 h, 83%; d) LDA, THF, ꢀ788C, allyl bromide, 91%; e) OsO4, NaIO4,
dioxane/water 3:1, 3.5 h, 76%; f) iBuMgCl, Et2O, ꢀ788C, 89%;
g) PCC, CH2Cl2, 3.5 h, 87%; h) aqueous EtOH, NaOH, reflux, 36 h,
98%. HMPA=hexamethylphosphoric triamide, LDA=lithium diisopro-
pylamide, PCC=pyridinium chlorochromate.
treated with Me2SO4 under alkaline conditions (5!6),[5] and
then methylated[7] at the position a to the carboxy group.
Cyclization, by treatment with POCl3 (7!8[7]), and allylation
gave the substituted tetralone 9. Double-bond cleavage (9!
10) and exposure to iBuMgCl at low temperature then led to
keto alcohols 11, and oxidation afforded the corresponding
diketone 12. This was cyclized under basic conditions in good
yield to produce our first key intermediate, 13.
Hydrogenation of 13 over Pd/C in MeOH (H2, 345 kPa)
gave the crystalline ketone 14 (Scheme 4) as the major
product[8] (52% yield), which has the undesired b stereo-
chemistry at C6, as determined by X-ray analysis. On the
Scheme 5. Reagents and conditions: a) DDQ, dioxane, reflux, 8.5 h,
78%; b) OsO4, NMO, CCl4/water/tBuOH/acetone 5:1:4:6, 13 h, 98%;
c) Me2C(OMe)2, TsOH·pyridine, acetone, 4 h, 88%; d) DIBAL-H,
CH2Cl2, 08C, 8 h, 54% of 19, 23% of 20; e) Pd/C, H2, 345 kPa, MeOH.
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, NMO=5-methyl-
morpholine N-oxide, Ts=toluene-4-sulfonyl.
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Communications
Conversion of diol 17 into ketal 18 was achieved by
standard procedures, and the carbonyl group was then
reduced with DIBAL-H to give a 2.3:1 mixture of allylic
alcohol 19 (tentative stereochemistry shown at C7[9]) and
diene 20. Hydrogenation of 19 gave 21 and a mixture of
substances lacking a benzylic oxygen at C11 (absence of
1H NMR signals at d ꢁ 5 ppm for the benzylic CH–O). With
short reaction times (1 h) 21 was the major product (ca. 80%
yield). Only the C7–C8 double bond of diene 20 was reduced
when we used Rh/Al2O3 (H2, 4826 kPa, 508C, MeOH),
Wilkinson's catalyst (H2, 2758 kPa, MeOH, 508C), or Raney
2800 Ni (Aldrich; 7929 kPa, 608C, MeOH). Hydrogenation of
20 gave 22 (92% yield, stereochemistry at C5 and C6 not
established, Scheme 5). Olefin 21 did not react in refluxing
THF with BH3 or 9-borabicyclo[3.3.1]nonane (9-BBN). Our
failure to effect hydroboration and the finding that hydro-
genolysis occurred at C11 in experiments with Pd/C caused us
to modify the route in a small but effective way.
Scheme 7. Reagents and conditions: a) MsCl, Et3N, ClCH2CH2Cl, room
temperature for 30 min, then reflux for 8 h, 80%; b) Pd/C, H2, 269 kPa,
1:1 MeOH/hexane, 36 h, 85%; c) Bu4NF, THF, reflux, 24 h, 95%;
d) (COCl)2, DMSO, Et3N, ꢀ788C, 1 h, room temperature, 2 h, 92%;
e) LiCl, DMF, reflux, 20 h, 78%; f) NBS, iPr2NH, CH2Cl2, 3 h, 94%.
Si*=SitBuMe2. DMSO=dimethyl sulfoxide, Ms=methanesulfonyl,
NBS=N-bromosuccinimide.
refluxing DMF (29!30);[13] other standard reagents (BBr3,
AlCl3, Me3SiI) destroyed the starting methyl ether. Finally,
bromination of 30 with NBS in the presence of iPr2NH, a
reagent system known to favor ortho bromination of phe-
nols,[14] gave hamigeran B (1) in 94% yield. The 1H and
13C NMR, FTIR, and MS characteristics of our synthetic
material match those reported[1] for the natural product.
The special features of this synthesis are the use of very
simple reactions—a fact which should make the route
amenable to scale-up, the application of steric factors to
ensure facial selectivity, and the protection against hydro-
genolysis[15] that is afforded by the bulky tBuMe2Si groups.
With the aim of avoiding hydrogenolysis of the C11
oxygen, we decided to protect the hydroxy groups of diol 17
with substituents having sufficient bulk to hinder coordina-
tion[10,11] of the benzylic oxygen to the catalyst surface, and so
we silylated the hydroxy group with tBuMe2SiOSO2CF3
(Scheme 6, 17!23). DIBAL-H reduction gave an allylic
Received: March 31, 2003 [Z51519]
Keywords: hamigeran B · hydrogenolysis · natural products ·
.
silyl groups · total synthesis
Scheme 6. Reagents and conditions: a) tBuMe2SiOSO2CF3, CH2Cl2,
2,6-lutidine, 6 h, 84%; b) DIBAL-H, CH2Cl2, 08C to room temperature,
10 h, 94%; c) Pd/C, H2, 345 kPa, MeOH, 18%; d) Pd/C, H2, 345 kPa,
MeOH, 35%; e) Pd/C, H2, 345 kPa, MeOH, 93%. Si*=SitBuMe2.
[1] K. D. Wellington, R. C. Cambie, P. S. Rutledge, P. R. Bergquist,
J. Nat. Prod. 2000, 63, 79–85.
[2] a) K. C. Nicolaou, D. Gray, J. Tae, Angew. Chem. 2001, 113,
3787–3790; Angew. Chem. Int. Ed. 2001, 40, 3675–3678; b) K. C.
Nicolaou, D. Gray, J. Tae, Angew. Chem. 2001, 113, 3791–3795;
Angew. Chem. Int. Ed. 2001, 40, 3679–3683.
alcohol (23!24, stereochemistry at C7 not determined).
Hydrogenation of 24 provided the desired product 26 but in
low yield (18%). When the reaction time was only 6.5 h, one
of the products was monoene 25 (35%), and this compound
could be hydrogenated in high yield to give the desired 26.
These observations showed that the hydroxy group of 24 had
a deleterious effect on the outcome of our hydrogenation
experiments. Accordingly, we dehydrated allylic alcohol 24 to
give the corresponding diene 27 (Scheme 7). Elimination of
the intermediate mesylate is slow and required higher
temperatures, but the diene, once formed, was very well-
behaved and could be reduced to 26 with the required relative
stereochemistry at the three contiguous asymmetric centers,
C5, C6, and C9. Compound 26 is crystalline, but the crystals
were unsuitable for X-ray analysis. However, desilylation
(Scheme 7, 26!28), which required unusually harsh condi-
tions but worked efficiently, gave a nicely crystalline diol,
whose structure was determined by X-ray analysis. Diol
oxidation (28!29) was easily performed under Swern con-
ditions, and the next task was to remove the O-methyl group
of 29. This was done in 78% yield by treatment with LiCl in
[3] J. Wang, unpublished observations.
[4] a) M. Freifelder, Catalytic Hydrogenation in Organic Synthesis.
Procedures and Commentary, Wiley, New York, 1978, p. 15;
b) P. N. Rylander, Catalytic Hydrogenation over Platinum
Metals, Academic Press, New York, 1967, p. 91; c) Examples of
hydrogenation of tetrasubstituted double bonds conjugated with
benzene rings are known (Beilstein database); see, especially:
A. C. G. Gray, H. Hart, J. Am. Chem. Soc. 1968, 90, 2569–2578.
[5] R. G. Cooke, H. Dowd, Aust. J. Chem. 1953, 6, 53–57.
[6] G. L. Martin, J. Am. Chem. Soc. 1936, 58, 1438–1442.
[7] Cf.L. Ruzicka, H. Hösli, K. Hofmann, Helv. Chim. Acta 1936, 19,
370–377.
[8] Another stereoisomer was formed for which no NOE was
observed between H5 and the methyl group at C9.
[9] Based on observation of NOE effects.
[10] Cf. M. J. Gaunt, J. Yu, J. B. Spencer, J. Org. Chem. 1998, 63,
4172–4173.
[11] It is believed that hydrogenolysis is facilitated by development of
a partial positive charge on the benzylic carbon (see ref. [10]);
siloxy groups are not as effective at stabilizing an adjacent
positive charge as alkoxy groups (see ref. [12]).
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[12] E. Colvin, Silicon in Organic Synthesis, Butterworths, London,
1981, p. 12.
[13] A. M. Bernard, M. R. Ghiani, P. P. Piras, A. Rivoldini, Synthesis
1987, 287–288.
[14] a) S. Fujisaki, H. Eguchi, A. Omura, A. Okamoto, A. Nishida,
Bull. Chem. Soc. Jpn. 1993, 66, 1576–1579; b) K. Krohn, S.
Bernhard, U. Flörke, N. Hayat, J. Org. Chem. 2000, 65, 3218–
3222.
[15] Examples of the following have been reported (without com-
ment): A benzylic tert-butyldimethylsilyl ether survives hydro-
genation of disubstituted (e.g. ref. [16]) and trisubstituted
(ref. [2a]) double bonds. A tertiary benzylic trimethylsilyl ether
survives hydrogenation of
(ref. [17]).
a tetrasubstituted double bond
[16] a) T. J. Connoly, T. Durst, Tetrahedron 1997, 53, 15969–15982;
b) C. R. Mateus, W. P. Almeida, F. Coelho, Tetrahedron Lett.
2000, 41, 2533–2536.
[17] B. M. Trost, P. D. Greenspan, B. V. Yang, M. G. Saulnier, J. Am.
Chem. Soc. 1990, 112, 9022–9024.
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