An approach towards the C1-C16 fragment of antineoplastic macrolide bryostatins by kinetic resolution of a racemic terminal epoxide using Jacobsen's catalyst

Article abstract of DOI:10.1016/S0040-4039(01)00841-3

A stereo- and enantioselective approach towards the C₁-C₁₆ fragment of bryostatins is reported using Jacobsen's catalyst for kinetic resolution of a terminal epoxide, a Horner-Wadsworth-Emmons coupling reaction and a 1,4-Michael type cyclization as key steps.

Full text of DOI:10.1016/S0040-4039(01)00841-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4907–4911
An approach towards the C1–C16 fragment of antineoplastic
macrolide bryostatins by kinetic resolution of a racemic terminal
epoxide using Jacobsen’s catalyst†
J. S. Yadav,* A. Bandyopadhyay and A. C. Kunwar‡
Organic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 21 March 2001; revised 2 May 2001; accepted 16 May 2001
Abstract—A stereo- and enantioselective approach towards the C1–C16 fragment of bryostatins is reported using Jacobsen’s
catalyst for kinetic resolution of a terminal epoxide, a Horner–Wadsworth–Emmons coupling reaction and a 1,4-Michael type
cyclization as key steps. © 2001 Elsevier Science Ltd. All rights reserved.
Bryostatins1 and related biologically active marine
macrolides, which exhibit exceptional antineoplastic
activity against lymphocytic leukemia, ovarian car-
cinoma,2 inhibition of the tumour promotion of phor-
bols related to protein kinase C1b and presently
undergoing phase II clinical trials,1g were isolated from
marine bryozoan Bugula neritina Linnaeus and Amathia
convoluta. Even though these highly oxygenated
Scheme 1.
Keywords: bryostatins; antitumour compounds; coupling reactions; Michael reactions.
* Corresponding author. Tel./fax: 091 40 7170512; e-mail: yadav@iict.ap.nic.in
† IICT Communication No: 4704.
‡ Centre for Nuclear Magnetic Resonance Spectroscopy.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00841-3

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J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 4907–4911
asymmetric epoxidation (SAE)10 on 6 afforded epoxy
alcohol 7. Compound 7 was converted to the epoxy
iodide 8 by TPP–I2–imidazole,11 which under reflux
with Zn and NaI in MeOH12 afforded the secondary
allyl alcohol 9. After protection of the hydroxyl group
as a TIPS ether, hydroboration followed by Swern
oxidation13 gave aldehyde 12. An aldol condensation
between 12 and methyl isobutyrate gave 13 and 14 in a
2:3 ratio.
macrolides have attracted interest from organic
chemists worldwide, only three bryostatins have been
synthesized so far.3–5 This may be attributed to the
complex skeleton of the bryostatins. However, many
approaches towards their synthesis have been reported
(Scheme 1).6
Our own interest in the total synthesis of macrolide
natural products, especially those with antibiotic and
anti-cancer activity, prompted us to take up the total
synthesis of bryostatins. Herein, we report our latest
results which describe a synthesis directed towards the
C1–C16 fragment.
The TIPS ether of 14 was deprotected with TBAF–
HOAc in THF followed by acetonide formation to give
16. The stereochemistry of the C7 hydroxyl group was
assigned by the 13C NMR spectra14 of product 16,15 in
which the gem-dimethyl group of the dioxane ring
appears at l 24.33 and 24.78. The phosphonate 17 was
then obtained by condensation of the dimethyl
methylphosphonate anion with the methyl ester 16
(Scheme 4).
Synthesis of the C1–C9 fragment: The synthesis of the
C1–C9 fragment began with the kinetic resolution of the
racemic epoxide 1 with Jacobsen’s catalyst7 to afford
the chiral epoxide 28 {[h]D20 −17.242 (c 2.5, CHCl3)
Scheme 2}.
Synthesis of the C10–C16 fragment: The synthesis of the
C10–C16 fragment began with dimethyl 1,3-acetone
dicarboxylate 18. After protection of the keto group16
as a cyclic ketal, the ester groups were reduced with
LiAlH4 to afford diol 20. Monobenzyl ether formation
followed by one-pot oxidation and Wittig olefination17
gave the a,b-unsaturated ester 22. DIBAL-H reduction
followed by SAE10 gave the epoxy alcohol 24. Com-
pound 24 was converted to 26, as described in Scheme
3. Protection of the hydroxyl group as a TBDMS ether
followed by dihydroxylation and NaIO4 treatment gave
aldehyde 29, which on reduction with NaBH4 gave
alcohol 30. After protection of the hydroxyl group as a
MOM ether, the benzyl group was hydrogenated fol-
lowed by a Swern oxidation13 to give the aldehyde 33 in
good yield (Scheme 5).
Epoxide 2 was opened by the Yamaguchi method9 to
produce the THP protected propargyl alcohol 3. After
protection of the hydroxyl group as a benzyl ether, the
THP group was deprotected using PTSA–MeOH to
give the propargyl alcohol 5. Compound 5 was con-
verted into the allyl alcohol 6 using LiAlH4. Sharpless
Scheme 2. Reaction conditions: (a) Co-salen (Jacobsen’s cata-
lyst) 0.05 mol%, neat, 0.55 equiv. H2O, 0°C to rt, 12 h (43%
yield, 97% ee).
Scheme 3. Reaction conditions: (a) 2-(2-propynyloxy)tetrahydro-2H-pyran, n-BuLi, BF3·Et2O, THF, −78°C (90%); (b) NaH,
BnBr, THF, rt (92%); (c) PTSA, MeOH, rt (82%); (d) LiAlH4, THF, reflux (91%); (e) D(−)DIPT, Ti(OiPr)4, TBHP, DCM, −20°C,
7 h (90%); (f) TPP, I2, imidazole, ether–CH3CN (3:1), rt (90%); (g) Zn, NaI, MeOH, reflux (84%); (h) TIPS-OTf, 2,6-lutidine,
DCM, 0°C (97%); (i) BH3·THF, THF, 0°C then H2O2–NaOH (75%); (j) (COCl)2, DMSO, DCM, −78°C then Et3N (70%); (k)
methyl isobutyrate, LDA, THF, −78 to 0°C (96%).

J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 4907–4911
4909
Scheme 4. Reaction conditions: (a) TBAF–HOAc, THF, rt (82%); (b) 2,2-DMP, PTSA, DCM, rt (90%); (c) (MeO)2P(O)Me,
n-BuLi, THF, −78°C to rt (74%).
Scheme 5. Reaction conditions: (a) ethylene glycol, TMSCl, DCM, reflux (90%); (b) LiAlH4, THF, reflux (80%); (c) NaH, BnBr,
THF, 0°C (75%); (d) (COCl)2, DMSO, DCM, −78°C then Et3N, 0°C then Ph3PCHCO2Et (70%); (e) DIBAL-H, DCM, −78°C
(85%); (f) D(−)DIPT, Ti(OiPr)4, TBHP, DCM, −20°C, 9 h (82%); (g) TPP, I2, imidazole, ether–CH3CN (3:1), rt (90%); (h) Zn,
NaI, MeOH, reflux (95%); (i) TBDMSCl, imidazole, DMF, rt (97%); (j) OsO4, NMO, acetone–H2O, rt (90%); (k) NaIO4,
i
THF–H2O, rt (87%); (l) NaBH4, MeOH, 0°C (80%); (m) MOMCl, Pr2NEt, DCM, rt (95%); (n) 10% Pd–C, EtOAc, H2, rt (96%);
(o) (COCl)2, DMSO, DCM, −78°C then Et3N (85%).
Construction of the C1–C16 framework: The Horner–
Wadsworth–Emmons coupling between the phospho-
nate 17 and the aldehyde 33 gave the desired
a,b-unsaturated ketone 34.15 Deprotection of the TBS
group with TBAF resulted in tetrahydropyran ring
formation18 to give required isomer 3515 in 67% yield.
The stereochemistry of 35 was determined with the help
of extensive 1H NMR studies including two dimen-
sional correlation experiments. The two protons at C10
resonate at l 2.61 and 2.94 ppm. They are coupled to
the C11 proton at l 4.08 ppm. The C11 proton shows
nuclear Overhauser enhancement (NOE) with the pro-
ton at l 3.81 ppm (proton at C15). This confirms the
diaxial disposition of the protons at C11 and C15 and
fixes the stereochemistry at C11.
Deacetonization in PPTS–MeOH led to the second
pyran cyclization3c,5e in 65% yield in favour of the
required isomer 36.15 NMR experiments confirmed the
assigned stereochemistry at C9. Only one of the two

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J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 4907–4911
Scheme 6. Reaction conditions: (a) LDA, −78°C, 17, 1 h then 33, −78°C to rt (60%); (b) TBAF, THF, rt (67%); (c) PPTS, MeOH,
rt (65%).
methyls at C8 show an NOE cross peak with the
methoxy at C9. This implies that the methoxy is axial
and shows an NOE with the equatorial methyl at C8 (l
1.02) only. The methoxy also shows NOE cross peaks
with the proton at C11 and with the equatorial proton
at C12. The assignment of the axial methyl at C8 (l
0.94) was further confirmed by the diaxial NOE
between it and the axial proton at C6 (l 1.37) (Scheme
6).
3. (a) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts,
J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J.
Am. Chem. Soc. 1990, 112, 7407; (b) Masamune, S. Pure
Appl. Chem. 1988, 60, 1587; (c) Blanchette, M. A.; Mala-
mas, M. S.; Nantz, M. H.; Roberts, J. C.; Somfai, P.;
Whritenour, D. C.; Masamune, S.; Kageyama, M.;
Tamura, T. J. Org. Chem. 1989, 54, 2817; (d) Duplantier,
A. J.; Nantz, M. H.; Roberts, J. C.; Short, R. P.; Somfai,
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In conclusion, we have demonstrated an approach
towards the C1–C16 fragment of bryostatins. Further
investigation towards the total synthesis of the target
natural product is in progress.
Acknowledgements
Author (A.B.) is thankful to UGC New Delhi for
financial support.
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24.37, 24.80, 29.66, 33.34, 34.62, 37.54, 40.55, 41.66,
45.18, 50.49, 55.15, 63.62, 64.28, 64.36, 66.66, 70.20,
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the structures assigned, and only selected data are cited:
14: [h]2D0 −16.654 (c 0.5, CHCl3); IR (neat) 3400 (-OH),
1
1728 cm−1; H NMR (200 MHz, CDCl3) 1.07 (brs, 24H),
1.10 (s, 3H), 1.47 (m, 2H), 1.77 (m, 4H), 3.57 (m, 2H),
3.59 (s, 3H), 3.61 (m, 1H), 3.67 (m, 1H), 4.09 (m, 1H),
4.46 (m, 4H), 7.21 (m, 10H); 13C NMR (50 MHz, CDCl3)
12.46, 12.84, 18.10, 20.75, 34.42, 36.15, 40.87, 47.11,
51.69, 66.66, 69.94, 70.83, 72.85, 73.10, 73.71, 127.54,
127.66, 127.84, 127.97, 128.32, 138.40, 138.56, 177.47; MS
(m/z) 601 [M++1]. 16: IR (neat) 1735 cm−1 1H NMR
;
(200 MHz, CDCl3) 1.12 (s, 3H), 1.19 (s, 3H), 1.29 (s, 3H),
1.31 (s, 3H), 1.67 (m, 4H), 1.91 (m, 2H), 3.59 (m, 2H),
3.69 (s, 3H), 3.79 (m, 1H), 4.03 (m, 2H), 4.51 (m, 4H),
7.31 (m, 10H); 13C NMR (50 MHz, CDCl3) 20.46, 24.33,
24.78, 33.60, 34.81, 41.91, 45.74, 51.48, 63.77, 66.64,
70.51, 71.60, 72.93, 73.45, 96.20, 100.40, 127.40, 127.54,
127.61, 128.26, 138.61, 138.88, 176.38; MS (m/z) 485
[M+1+1]. 32: [h]D20 +9.656 (c 0.5, CHCl3); IR (neat) 3400
1
138.69, 212.49. 36: H NMR (500 MHz, CDCl3) 0.94 (s,
3H), 1.02 (s, 3H), 1.37 (m, 1H), 1.50 (dd, J=12.9, 11.8
Hz, 1H), 1.55 (dd, J=13.0, 11.4 Hz, 1H), 1.64 (m, 1H),
1.67 (m, 1H), 1.68 (m, 2H), 1.76 (dd, J=16.0, 5.4 Hz,
1H), 1.90 (m, 2H), 1.94 (m, 1H), 2.07 (dd, J=16.0, 4.8
Hz, 1H), 3.08 (s, 3H), 3.35 (s, 3H), 3.54 (m, 2H), 3.58 (m,
2H), 3.70 (m, 1H), 3.76 (m, 1H), 3.82 (m, 1H), 3.84 (m,
1H), 3.93 (m, 4H), 3.96 (dd, J=11.9, 4.8 Hz, 1H), 4.42
(d, J=11.0 Hz, 1H), 4.49 (s, 2H), 4.53 (d, J=11.0 Hz,
1H), 4.63 (A of AB d, J=6.4 Hz, 1H), 4.65 (B of AB d,
J=6.4 Hz, 1H), 7.24–7.36 (m, 10H).
1
(-OH); H NMR (400 MHz, CDCl3) 0.07 (s, 6H), 0.94 (s,
9H), 1.84 (m, 1H), 1.97 (m, 3H), 2.67 (brs, 1H), 3.39 (s,
3H), 3.44 (m, 1H), 3.47 (m, 1H), 3.76 (m, 1H), 3.97 (m,
1H), 3.99 (m, 4H), 4.61 (s, 2H); 13C NMR (50 MHz,
CDCl3) −4.65, −4.36, 18.06, 25.87, 38.96, 41.39, 55.19,
58.78, 64.44, 64.57, 68.37, 72.28, 96.75, 111.16; MS (m/z)
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351 [M++1]. 34: IR (neat) 1654 cm−1 1H NMR (200
;
MHz, CDCl3) 0.09 (s, 6H), 0.89 (s, 9H), 1.06 (s, 3H), 1.12
(s, 3H), 1.27 (s, 3H), 1.29 (s, 3H), 1.64 (m, 4H), 1.89 (m,
4H), 2.56 (d, J=6.0 Hz, 2H), 3.36 (s, 3H), 3.41 (m, 1H),
3.52 (m, 3H), 3.77 (m, 1H), 3.91 (m, 7H), 4.47 (m, 4H),
4.59 (s, 2H), 6.55 (d, J=16.0 Hz, 1H), 6.79 (dd, J=16.0
Hz, 6.0 Hz, 1H), 7.29 (m, 10H); 13C NMR (50 MHz,
.