Stereoselective synthesis of C19-C27 fragment of bryostatin 11

Article abstract of DOI:10.1016/j.tetlet.2014.05.116

A convergent synthesis of C19-C27 fragment (2) of bryostatin-11 is described. The key steps involved in this approach are kinetic resolution, Grignard reaction, and Sharpless dihydroxylation. AIBN catalyzed radical cyclization strategy has been used for the first time to construct the six-membered pyran system.

Full text of DOI:10.1016/j.tetlet.2014.05.116

Accepted Manuscript
Stereoselective synthesis of C19-C27 fragment of bryostatin 11
J.S. Yadav, T. Swamy, B.V. Subba Reddy, V. Ravinder
PII:
S0040-4039(14)00949-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.116
TETL 44707
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
19 February 2014
28 May 2014
29 May 2014
Please cite this article as: Yadav, J.S., Swamy, T., Subba Reddy, B.V., Ravinder, V., Stereoselective synthesis of
C19-C27 fragment of bryostatin 11, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.116
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Graphical Abstract
Stereoselective synthesis of C19-C27 fragment
of bryostatin 11
Leave this area blank for abstract info.
J. S. Yadav,* T. Swamy, B. V. Subba Reddy, V. Ravinder

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Stereoselective synthesis of C19-C27 fragment of bryostatin 11
J. S. Yadav,*a T. Swamy,a,b B. V. Subba Reddy,a V. Ravinderb
aNatural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
bDepartment of Chemistry, Kakatiya University, Warangal-506 009, India
Fax: 91-40-27160512; E-mail:yadavpub@iict.res.in
ARTICLE INFO
ABSTRACT
A convergent synthesis of C19-C27 fragment (2) of bryostatin-11 is described. The key steps
involved in this approach are kinetic resolution, Grignard reaction and Sharpless
dihydroxylation. AIBN catalyzed radical cyclization strategy has been used for the first time to
construct the six-membered pyran system.
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Kinetic resolution, Grignard reaction, Sharpless
dihydroxylation, AIBN, radical cyclization
Bryostatins are a family of 20 structurally different
complex marine natural products that display a wide
range of biological activities, most notably anticancer
activity.1 Bryostatins were originally isolated from the
marine Bryozoan bugula neritina Linnaeus by Pettit and
co-workers in 1968 and was fully characterized in
1982.2 These bryostatins are biologically active marine
macrolides, which are found to exhibit an exceptional
antineoplastic activity against lymphocytic leukaemia,
β-cell lymphoma, reticulum cell sarcoma, ovarian
carcinoma, and melanoma and are presently undergoing
phase II clinical trials. This effect is attributed to their
ability to modulate the functions of protein kinase C
isozymes within the cells. As a result, bryostatins are
evaluated as chemotherapeutic candidates for the
treatment of different types of cancer3 owing to their
low toxicity and prominent antineoplastic activity.
Furthermore, bryostatins are very promising in
enhancing memory in animal models. They were able to
increase the duration of memory retention of the marine
slug Hermissenda crassicornis by over 500%.4 These
features make them as possible drug candidates for the
treatment of Alzheimer's disease.5
Interestingly, some of them are found to exhibit greater
potency, which may provide a practical supply for
clinical use (Figure 1).
Figure 1. Naturally occurring bryostatins (1a-e)
As a part of our ongoing research program on the
total synthesis of biologically active marine anticancer
natural products,7 we attempted the total synthesis of
these rare and biologically inspiring bryostatins.8 We
herein report a concise and efficient synthesis of C19-
C27 fragment (2) of bryostatin 11, starting from easily
accessible starting materials. Our strategy utilizes a
readily available and inexpensive (±)-epichlorohydrin 6
as the starting material. The target fragment 2 could be
synthesized from a key intermediate 5, which in turn
could be prepared from the kinetic resolution of racemic
oxirane 7. Retrosynthetic analysis of the target fragment
2 is outlined in Scheme 1.
Low abundance of bryostatins in nature makes the
extraction unsuitable for large-scale production. Due to
their structural complexity and difficulty in total
synthesis, only a few approaches have been reported so
far.6 A number of structurally simple synthetic analogs
have been reported to evaluate their efficiency.

2
Tetrahedron Letters
9
(9:1) gave the alcohol 12. Oxidation of the alcohol
under Swern oxidation9 conditions afforded the
aldehyde 13 in 85% yield. The aldehyde 13 was further
treated with allylmagnesium bromide after chelating
with MgBr2.OEt2 to afford the compound 14 in 85%
yield.10 The exclusive formation of erythro-isomer was
observed due to Re-face attack of the allyl nucleophile.
However, in the absence of a chelating agent, the
diastereomers were formed in 1:1 ratio, which was
1
confirmed by H NMR spectrum of the crude reaction
mixture. Protection of 14 with BnBr in the presence of
NaH afforded the benzyl ether 15. Sharpless asymmetric
dihydroxylation11 of 15 with AD-mix-β gave the diol 16
in 85% yield as a major diastereomer (dr 88:12), which
1
was confirmed by H NMR spectrum of the crude
reaction mixture. Treatment of 16 with p-TsCl in the
presence of TEA in CH2Cl2 for 16h afforded the mono-
tosylate 17 in 71% yield, which was then converted into
epoxide 18 in 75% yield using K2CO3 in MeOH.
Metallation of the methyl propiolate (n-BuLi, THF, at -
78 C) followed by addition to epoxide 18 in the
presence of BF3.OEt2 afforded the desired alcohol 5 in
80% yield (Scheme 3).
Scheme 1. Retrosynthesis of C19-C27 fragment 2 of
bryostatin 11(1d)
o
Accordingly, (±)-epichlorohydrin 6 was converted
into p-methoxybenzyl glycidol ether (±)-7 in 81% yield
using p-methoxybenzyl alcohol. Kinetic resolution of
the racemic epoxide (±)-7 in the presence of 0.2 mol%
(salen)-Co(III)(OAc) complex [(S,S)-N,N-bis-(3,5-di-
tert-butylsalicylidene)-1,2-cyclohexanediamino-Co(III)-
acetate] under solvent-free conditions afforded the
enantioenriched epoxide 8 in 45% yield (Scheme 2).
The optical purity of the epoxide 8 was also confirmed
by comparing the optical rotation with the reported
value.9
Scheme 3. Reagents and conditions: (a) LAH, THF, 0-
25 oC, 1h, 83%; (b) NaH, BnBr, THF, 0 oC-reflux, 93%;
o
(c) CAN, MeCN:H2O (9:1), 0 C-rt, 1h, 90%; (d)
o
(COCl)2, DMSO, CH2Cl2, -78 C, 2h, 85%; (e) Allyl
o
bromide, MgBr2.Et2O, Mg, -78 C, 1h, 85%; (f) NaH,
o
BnBr, THF, 0 C-reflux, 16h, 85%; (g) AD-mix β, t-
o
BuOH-H2O, 0 C, 18h, 85%; (h) p-TsCl, TEA, CH2Cl2,
Scheme 2. Reagents and conditions: (a) NaH, THF, 0
C-rt, 16h, 81%; (b) C, H2O, 25 C, 36h, 45%.
o
rt, 16h, 71%; (i) K2CO3, MeOH, 0 C, 1h, 75%; (j)
o
Methyl propionate, nBuLi, BF3.Et2O, CH2Cl2, -78 C,
1h, 80%.
The enantioenriched epoxide 8 was converted into
the corresponding alcohol 10 using LiAlH4 in THF.
Protection of the alcohol 10 with BnBr in the presence
of NaH afforded the benzyl ether 11 in 93% yield.
Deprotection of the p-methoxybenzyl group of 11 using
ceric ammonium nitrate (CAN) in acetonitrile:water
Further treatment of 5 with NBS and ethyl vinyl
ether afforded the bromoacetal12 19, which was then
subjected to radical cyclization using a freshly distilled
nBu3SnH in the presence of a catalytic amount of

3
azobisisobutyronitrile (AIBN) to afford the cyclic ether
20 in 92% yield.13 Deprotection of the ethyl group from
20 using 80% aqueous acetic acid at 55-60 ºC afforded
the free lactol 21 in 82% yield, which was further
oxidized under Dess-Martin periodinane conditions to
afford the required fragment 2 in 85% yield (Scheme 4).
of allylmagnesium bromide to aldehyde 13 in the
presence of MgBr2.OEt2 afforded the erythro-isomer
exclusively due to Re-face attack of the allyl-
nucleophile, which is also an interesting aspect of this
approach.
Acknowledgement
T. S. thanks CSIR, New Delhi for the financial
support in the form of fellowship.
References
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Scheme 4. Reagents and conditions: (a) Ethyl vinyl
ether, NBS, CH2Cl2, 0 C, 16h, 88%; (b) nBu3SnH,
AIBN, toluene, reflux, 2h, 92%; (c) 80% aq. AcOH, 55
oC, 1h, 82%; (d) Dess-Martin periodinane, CH2Cl2, 0
oC-rt, 2h, 85%.
o
5. Sun, M. K.; Alkon, D. L. Eur. J. Pharmacol. 512,
1, 43.
In 2D NOESY spectrum of the C19-C27 fragment 2,
the olefinic proton shows a strong nOe correlation with
CH2 protons adjacent to the carbonyl group of the
lactone (Figure 2).13 In the absence of nOe cross-peak
between the olefinic proton and the CH2 protons
adjacent to alkyl side chain clearly indicates the
geometry of the double bond as an E-configuration.
6. 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)
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Reddy, B. V. S. Tetrahedron Lett. 2010, 51, 5529; c)
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Narasimhulu, G.; Reddy, N. M.; Reddy, B. V. S.
Tetrahedron Lett. 2010, 51, 1574.
Figure 2. Characteristic nOe cross peaks of 2
In conclusion, we have developed an efficient stereo-
and enantioselective approach for the synthesis of C19-
C27 fragment 2 of bryostatin-11 (1d). The geometry of
the olefin at C21 position and the chirality at C23, C25,
and C26 were successfully established through the
highly stereo- and enantioselective pathways. The pyran
ring system has been constructed through AIBN
catalyzed radical cyclization, which is an interesting
feature of this approach. The chelate-controlled addition
8. a) Yadav, J. S.; Aravind, S.; Kumar, G. M.;
Reddy, B. V. S. Tetrahedron Lett. 2012, 53, 6163; b)
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S. Synthesis 2012, 3077; c) Yadav, J. S.;
Bandyopadhyay, A.; Kunwar, A. C. Tetrahedron Lett.
2001, 42, 4907.

4
Tetrahedron Letters
9. Yadav, J. S.; Swamy, T.; Reddy, B. V. S. Synlett
(neat): max 3442, 3015, 2915, 1636, 1151, 776 cm-1; 1H
2008, 18, 2773.
NMR (200 MHz, CDCl3):  7.25-7.32 (m, 10H), 5.85 (s,
1H), 4.45-4.65 (m, 4H), 3.95-3.99 (m, 1H), 3.72 (s, 3H),
3.62-3.70 (m, 2H), 3.22 (s, 2H), 2.32-2.40 (m, 2H),
1.95-2.02 (m, 1H), 1.65-1.74 (m, 1H), 1.16 (d, J = 6.0
Hz, 3H); ESI-MS: m/z: 456 (M+18).
10. a) Keck, G. E.; Boden, E. P. Tetrahedron Lett.
1984, 25, 265; b) Williams, D. R.; Klingler, F. D.
Tetrahedron Lett. 1987, 28, 869; c) Annunziata, R.;
Cinquini, M. P. G. J. Org. Chem. 1992, 57, 456.
11. Sharpless, K. B.; Bennani, W. A.; Crispino, G.
A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa,
K.; Wang, Z. M.; Xu, D.; Zhang, X. L. J. Org. Chem.
1992, 57, 2768.
12. Ueno, Y.; Chino, K. J. Chem. Soc. Perkin Trans.
I, 1986, 1351.
13. a) Rama Rao, A. V.; Sharma, G. V. M.; Bhanu,
M. N. Tetrahedron Lett. 1984, 33, 3907; b) Yadav, J. S.;
Reddy, A. S.; Reddy, Ch. S.; Reddy, B. V. S.;
Venkateshwarlu, S.; Anthony, A. Eur. J. Org. Chem.
2011, 696.
14. Spectral data for selected compounds. 2-(4-
20
Methoxybenzyloxymethyl)-(R)-oxirane (8): [α]D
+3.2 (c = 3.5, CHCl3); IR (neat): υmax 2922, 1610, 1245
1
cm-1; H NMR (200 MHz, CDCl3): δ 7.25 (d, J = 8.2
Hz, 2H), 6.81 (d, J = 8.2 Hz, 2H), 4.45 (brs, 2H), 3.81
(s, 3H), 3.69-3.63 (m, 1H), 3.45-3.34 (m, 1H), 3.23-3.18
(m, 1H), 2.76-2.69 (m, 1H), 2.57-2.54 (m, 1H); 13C
NMR (50 MHz, CDCl3): δ 132.2, 130.0, 129.5, 113.5,
74.2, 70.5, 55.3, 50.7, 44.1. ESI-MS: m/z: 194 (M+).
20
(2R,3R)-2-(Benzyloxy)hex-5-en-3-ol (14): [α]D
-
17.58 (c = 3, CHCl3); IR (neat): max 3420, 2927, 1638,
1
1453, 1377, 1091, 748, 698 cm-1; H NMR (200 MHz,
CDCl3): δ 7.31-7.20 (m, 5H), 5.85-5.73 (m, 1H), 5.12-
5.02 (m, 2H), 4.54 (d, J = 6.7 Hz, 2H), 3.74-3.68 (m,
1H), 3.51-3.45 (m, 1H), 2.22 (t, J = 6.5 Hz, 2H), 2.04
(brs, 1H), 1.15 (d, J = 6.0 Hz, 3H); 13C NMR (50 MHz,
CDCl3): δ 138.5, 135.2, 128.5, 128.0, 117.1, 77.4, 74.5,
71.2, 37.8, 15.5; ESI-MS: m/z: 229 (M+Na).
(R)-2-((2R,3R)-2,3-Bis(benzyloxy)butyl)oxirane
(18): [α]D20 +18.4 (c = 3.5, CHCl3); IR (neat): max 3031,
2864, 1733, 1617, 1496, 1453, 1352, 1093, 737, 698 cm-
1
1; H NMR (200 MHz, CDCl3): δ 7.32-7.25 (m, 10H),
4.62-4.52 (m, 4H), 3.74-3.65 (m, 2H), 3.05-2.95 (m,
1H), 2.80-2-65 (m, 1H), 2.52-2.45 (m, 1H), 1.65-1.31
(m, 2H), 1.15 (d, J = 6.0 Hz, 3H); ESI-MS: m/z: 313
(M+1).
(5S,7R,8R)-Methyl
hydroxynon-2-ynoate (5): [α]D +14.28 (c = 2,
7,8-bis(benzyloxy)-5-
20
CHCl3); IR (neat): max 3555, 3031, 2953, 2238, 1714,
1
1435, 1260, 1075, 1027, 947, 771, 753, 700 cm-1; H
NMR (200 MHz, CDCl3): δ 7.35-7.22 (m, 10H), 4.65-
4.50 (m, 4H), 3.95-3.91 (m, 1H), 3.72 (s, 3H), 3.71-3.65
(m, 2H), 2.45 (t, J = 6.0 Hz, 2H), 1.75 (t, J = 6.0 Hz,
2H), 1.16 (d, J = 6.0 Hz, 3H); 13C NMR (50 MHz,
CDCl3): δ 154.5, 138.5, 129.0, 128.1, 86.5, 78.5, 78.0,
77.2, 75.1, 72.5, 71.3, 67.5, 53.1, 36.5, 27.4, 14.7; ESI-
MS: m/z): 397 (M+1).
(E)-Methyl
2-((S)-2-((2R,3R)-2,3-
bis(benzyloxy)butyl)tetrahydro-6-oxopyran-4-
20
ylidene)acetate (2): [α]D +30.0 (c = 0.3, CHCl3); IR