Synthesis of natural (-)-hamigeran B

Article abstract of DOI:10.1016/j.tetlet.2003.08.089

Alkylation of lactam 10, first with iodide 15 and then with MeI, gave mainly (18:1) lactam 18. This was converted by treatment with t-BuLi and then with aqueous base into enone 4, which was elaborated into (-)-hamigeran B. A key feature of the last part of the synthesis is the use of t-BuMe ₂Si-groups (as in intermediate 24) both to direct hydrogenation from the appropriate face and to protect the benzylic C-O bond from hydrogenolysis.

Full text of DOI:10.1016/j.tetlet.2003.08.089

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7731–7733
Synthesis of natural (−)-hamigeran B
Derrick L. J. Clive* and Jian Wang
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
Received 8 August 2003; revised 20 August 2003; accepted 21 August 2003
Abstract—Alkylation of lactam 10, first with iodide 15 and then with MeI, gave mainly (18:1) lactam 18. This was converted by
treatment with t-BuLi and then with aqueous base into enone 4, which was elaborated into (−)-hamigeran B. A key feature of
the last part of the synthesis is the use of t-BuMe2Si-groups (as in intermediate 24) both to direct hydrogenation from the
appropriate face and to protect the benzylic CꢀO bond from hydrogenolysis.
© 2003 Elsevier Ltd. All rights reserved.
The hamigerans are a small group of structurally
related and unusual natural products that were
isolated1 from a marine sponge. Several hamigerans
show in vitro antitumor activity (IC50 values of 8–74
mM), but the most notable characteristic would seem to
be the fact that (−)-hamigeran B (1) strongly1,2 inhibits
both herpes and polio viruses, with only slight cytotox-
icity. The absolute stereochemistry shown for 1 was
suggested on the basis of structural analogy to another
hamigeran for which the assignment was made by
X-ray analysis.1 Synthesis of the hamigerans presents
some complex stereochemical problems; these were first
solved3 by the Nicolaou group, who described routes to
several members of the family, including 1.4 We have
recently found5 an efficient route to racemic hamigeran
B; here we describe the application of our method to
the synthesis of the optically pure material (−)-
hamigeran (1), having the indicated absolute
configuration.
B
As reported previously,5 our route to ( )-1 is based on
enone 3, as a key intermediate. This was prepared by
base-induced cyclization of the racemic diketone 2. For
synthesis of (−)-hamigeran B, the enantiomer 4 is
required; the asymmetric quaternary center would be
expected to retain its integrity under the conditions
used to elaborate 3.
Our route to 4 is based on Meyers’ method,6 and
required the specific lactam 10 (Scheme 1) and the
halide 15 (Scheme 2). The former was readily assembled
from aldehyde ester 57 (Scheme 1). Reaction with
Scheme 1. Reagents and conditions: (a) 6, Et2O, −78°C, 12 h; (b) AcOH, H2SO4, Na2Cr2O7, room temperature 10 h, reflux 1 h,
ca. 53% from 5; (c) PhMe, add 9, reflux 15 h (Dean–Stark apparatus), 75%.
Keywords: hamigeran B; Meyers’ lactam; hydrogenolysis; silyl groups.
* Corresponding author. Tel.: 780-492-3251; fax: 780-492-8231; e-mail: derrick.clive@ualberta.ca
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.089

7732
D. L. J. Cli6e, J. Wang / Tetrahedron Letters 44 (2003) 7731–7733
The second component (15) was made as summarized
in Scheme 2. Aldehyde 1113 was homologated (11“12)
by Wittig reaction with Ph3P=CH(OMe) and acid
hydrolysis of the resulting enol ethers (99% over two
steps). Reduction (DIBAL-H, 90%) then afforded alco-
hol 13. The same compound could be obtained in
slightly lower yield by Wittig olefination (11“16, 75%),
followed by hydroboration (9-BBN, then NaOH, H2O2,
87%). Conversion of alcohol 13 into its mesylate (MsCl,
Et3N) and displacement of the leaving group by iodide
(NaI, acetone) gave the required iodide 15 (92% from
13).
Alkylation of 10 with 15 (Scheme 3), which required a
prolonged reaction time (36 h at room temperature)
gave 17 (as a mixture of stereoisomers), and then endo6
methylation (12 h at room temperature) generated the
quaternary center, affording 18 and 19 in an 18:1 ratio.
The diastereoisomers were separated chromatographi-
cally, 18 being obtained pure in 90% yield; the other
isomer was not obtained free of starting material (17).
NOE measurements17 established that the major
product of the alkylation has the stereochemistry
shown in 18. Treatment of 18 with t-BuLi, under
standard conditions,6 and in situ hydrolysis, served not
only to form the desired tetralone (cf. 2) but also to
Scheme 2. Reagents and conditions: (a) Ph3P=CH(OMe),
PhMe, 0°C, 2 h, then 10% hydrochloric acid, acetone, reflux,
3.5 h, 99%; (b) DIBAL, CH2Cl2, 0°C, 30 min, 90%; (c) MsCl,
Et3N, CH2Cl2, 0°C, 30 min; (d) NaI, acetone, reflux, 12 h,
92% from 13; (e) Ph3P=CH2, PhMe, 0°C, 2 h, 75%; (f)
9-BBN, THF, 0°C, 30 min, room temperature 12 h, then
NaOH, H2O2, 0°C, 2 h, 87%.
i-BuMgCl (6) gave lactone 78 (which was not obtained
pure), and oxidation9 of the lactone with Na2Cr2O7 in
aqueous AcOH–H2SO4 then afforded keto acid 810 in
54% yield from 5. Finally, condensation with (S)-
valinol11 (9) produced12 the required lactam 10.
Scheme 3. Reagents and conditions: (a) 2 equiv. LDA, THF, HMPA, −78°C, then add 15, 36 h at room temperature, 79%
corrected for recovered 10 (30%), some iodide also recovered; (b) 2 equiv. LDA, THF, HMPA, −78°C, then add MeI, 12 h at
room temperature, 95%, 90% yield of 18; (c) t-BuLi, THF, −78°C, 1.75 h, then aqueous Bu4NH2PO4 (1 M), reflux 24 h, then
NaOH, EtOH, reflux, 24 h, 90%.
Scheme 4. Reagents and conditions: Si*=SiMe2Bu-t. (a) DDQ, dioxane, reflux, 8.5 h, 74%; (b) OsO4, NMO, 5:1:4:6 CCl4–water–t-
BuOH–acetone, 13 h, 81%; (c) t-BuMe2SiOSO2CF3, CH2Cl2, 2,6-lutidine, 6 h, 73%; (d) DIBAL-H, CH2Cl2, 0°C to room
temperature, 10 h; (e) MsCl, Et3N, ClCH2CH2Cl, room temperature for 30 min, then reflux for 8 h, 84% over two steps; (f) Pd–C,
H2, 39 psi, 1:1 MeOH–hexane, 36 h, 78%; (g) Bu4NF, THF, reflux, 24 h, 85%; (h) Swern oxidation, 94%; (i) LiCl, DMF, reflux,
20 h, 87%; (j) NBS, i-Pr2NH, CH2Cl2, 3 h, 88%.

D. L. J. Cli6e, J. Wang / Tetrahedron Letters 44 (2003) 7731–7733
7733
effect cyclization (cf. 2“3), so that 4 was obtained directly
(90%). From this point, the procedures developed for the
racemic series were applied without change (Scheme 4).
Dehydrogenation of 4 with DDQ gave olefin 20 (74%),
and this was subjected to vicinal dihydroxylation (OsO4,
NMO, 81%), which occurred anti to the angular methyl
group (20“21). The diol was protected as its bis-t-
butyldimethylsilyl ether (BuMe2SiOSO2CF3, 73%) (21“
22), this choice of protecting groups being essential, as
explained previously,5 in order to control facial selectivity
in a later hydrogenation step while preserving the integrity
of the benzylic CꢀO bond, which would otherwise
undergo hydrogenolysis. The carbonyl group was then
reduced (22“23, DIBAL-H), and dehydration, achieved
by mesylation (MsCl, Et3N) in ClCH2CH2Cl at 0°C to
reflux temperature, gave diene 24 (84% over two steps).
At this point, hydrogenation (Pd–C, H2, 39 psi, 1:1
MeOH–hexane) delivered 25 (in 78% yield). Desilylation
gave the expected diol (25“26, Bu4NF, 85%). The
compound was examined by HPLC, using a chiral18
column. Although baseline separation of the correspond-
ing racemic material was not possible, the trace for the
optically active sample showed no sign of a shoulder, and
we judge the compound to be optically pure, as expected
from the fact that 18 was a single isomer derived from
optically pure S-valinol. Double Swern oxidation (26“
27, 94%) and demethylation with LiCl in refluxing DMF19
gave phenol 28 (87%) and, finally, bromination (NBS,
i-Pr2NH, 88%)20 produced (−)-hamigeran B (1).21
8. Cf. Barluenga, J.; Ferna´ndez, J. R.; Rubiera, C.; Yus, M.
J. Chem. Soc., Perkin Trans. 1 1988, 3113–3118.
9. Cf. McGhie, J. F.; Ross, W. A.; Evans, D.; Tomlin, J. E.
J. Chem. Soc. 1962, 350–355.
10. Cf. Betancourt de Perez, R. M.; Fuentes, L. M.; Larson,
G. L.; Barnes, C. L.; Heeg, M. J. J. Org. Chem. 1986, 51,
2039–2043.
11. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M.
J. Org. Chem. 1993, 58, 3568–3571.
12. Cf. Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57,
1656–1662.
13. Made from 2,5-dimethylphenol by the method of Ref. 14,
except that the formyl group was best generated by benzylic
bromination (Ref. 15), followed by oxidation with DMSO
(Ref. 16).
14. Gore, M. P.; Gould, S. J.; Weller, D. D. J. Org. Chem. 1992,
57, 2774–2783.
15. Leed, A. R.; Boettger, S. D.; Ganem, B. J. Org. Chem. 1980,
45, 1098–1106.
16. (a) Helms, A.; Heiler, D.; McLendon, G. J. Am. Chem. Soc.
1992, 114, 6227–6238; (b) Epstein, W. W.; Sweat, F. W.
Chem. Rev. 1967, 67, 247–260; (c) Mizutani, T.; Wada, K.;
Kitagawa, S. J. Org. Chem. 2000, 65, 6097–6106.
17. The C(7) H in 18 syn to the adjacent Me group shows an
NOE only to that Me, the other C(7) hydrogen shows NOEs
to the CH2 groups of the ethyl and isobutyl substituents.
The C(7) H in 19 syn to the adjacent Me group shows NOEs
with that Me and with the CH2 group of the isobutyl
substituent, while the other C(7) hydrogen shows NOEs to
the CH2 groups of the ethyl substituent.
18. Chiralcel OD column (0.46×5 cm); eluant 4:1 i-PrOH–hex-
ane; flow rate 1.0 mL/min; detection at 230 nm, temperature
25°C; sample concentration ca. 1 mL/mg in MeOH,
injection volume 20 mL.
19. Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A.
Synthesis 1987, 287–288.
All new compounds, except for 14, 19, and 23, were
characterized spectroscopically, including high resolution
mass measurement.
Acknowledgements
20. (a) Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.;
Nishida, A. Bull. Chem. Soc. Jpn. 1993, 66, 1576–1579; (b)
Krohn, K.; Bernhard, S.; Flo¨rke, U.; Hayat, N. J. Org.
Chem. 2000, 65, 3218–3222.
We thank the Natural Sciences and Engineering Research
Council of Canada for financial support, and Dr. C.
Diaper for the HPLC measurements.
21. Synthetic 1: [h]D −176.4° (c 0.142, CH2Cl2) [Lit.1 [h]D
1
−151.5° (c 0.15, CH2Cl2); H NMR (CDCl3, 400 MHz) l
References
0.44 (d, J=6.5 Hz, 3H), 0.53 (d, J=6.6 Hz, 3H), 1.15–1.23
(m, 1H), 1.28 (s, 3H), 1.49–1.59 (m, 1H), 1.63–1.72 (m, 1H),
1.75–1.85 (m, 1H), 2.25–2.33 (m, 1H), 2.50 (s, 3H), 2.62
(ddd, J=5.5, 7.7, 13.1 Hz, 1H), 3.38 (d, J=9.2 Hz, 1H),
6.82 (s, 1H), 12.61 (s, 1H); 13C NMR (CDCl3, 125.7 MHz)
l 19.7 (q%), 23.3 (q%), 24.3 (q%), 24.4 (q%), 26.7 (t%), 28.1 (d%),
33.8 (t%), 51.3 (d%), 56.2 (q%), 56.9 (s%), 111.5 (s%), 117.2 (s%),
124.2 (d%), 142.7 (s%), 150.2 (s%), 160.8 (s%), 184.4 (s%), 199.0
(s%); exact mass m/z calcd for C18H21O379Br 364.06741,
found 364.06791. Compound 4: FTIR (CHCl3, cast) 2957,
1693, 1610 cm−1; [h]D=−345.1° (c 0.304, CHCl3); 1H NMR
(CDCl3, 400 MHz) l 1.06 (s, 3H), 1.19 (d, J=6.9 Hz, 3H),
1.37 (d, J=7.0 Hz, 3H), 1.66–1.74 (m, 1H), 2.07 (ddd,
J=1.0, 6.9, 13.2 Hz, 1H), 2.20 (d, J=18.5 Hz, 1H), 2.33
(d, J=18.4 Hz, 1H), 2.37 (s, 3H), 2.61–2.71 (m, 1H), 2.86
(dd, J=7.0, 18.8 Hz, 1H), 3.12 (septet, J=7.0 Hz, 1H), 3.83
(s, 3H), 6.70 (s, 1H), 6.86 (s, 1H); 13C NMR (CDCl3, 100.6
MHz) l 19.8 (q%), 20.6 (q%), 20.8 (t%), 21.7 (q%), 23.0 (q%), 25.7
(d%), 36.0 (t%), 38.7 (t%), 51.1 (s%), 55.3 (q%), 111.8 (d%), 120.9
(d%), 123.5 (s%), 131.5 (s%), 136.0 (s%), 140.6 (s%), 157.2 (s%), 170.1
(s%), 208.2 (s%); exact mass m/z calcd for C19H24O2 284.17764,
found 284.17735.
1. Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.;
Bergquist, P. R. J. Nat. Prod. 2000, 63, 79–85.
2. Details of the biological tests have not been published; the
antiviral activity is described as follows: Hamigeran
B...showed 100% virus inhibition against both the Herpes
and Polio viruses, with only slight cytotoxicity throughout
the whole well at a concentration of 132 mg per disk.
3. (a) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem., Int.
Ed. 2001, 40, 3675–3678; (b) Nicolaou, K. C.; Gray, D.;
Tae, J. Angew. Chem., Int. Ed. 2001, 40, 3679–3683.
4. The synthesis confirms the suggested absolute configura-
tion; synthetic 1 had [h]D −168° (CHCl3) (personal commu-
nication from Professor K. C. Nicolaou).
5. Clive, D. L. J.; Wang, J. Angew. Chem., Int. Ed. 2003, 42,
3406–3409.
6. (a) Snyder, L.; Meyers, A. I. J. Org. Chem. 1993, 58,
7507–7515;(b)Sandham, D. A.;Meyers, A. I. J. Chem. Soc.,
Chem. Commun. 1995, 2511–2512.
7. Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.;
Sharpe, J.; Toth, B. J. Org. Chem. 1988, 53, 1064–1071.