Convergent enantioselective syntheses of two potential C25-C40 subunits of (-)-caylobolide A

Article abstract of DOI:10.1016/j.tetlet.2011.07.105

The convergent syntheses of two possible diastereomers of the C25-C40 subunit resident in (-)-caylobolide A have been accomplished. The key reaction featured a chemoselective Ru-catalyzed cross-metathesis between a fully elaborated type I and two function

Full text of DOI:10.1016/j.tetlet.2011.07.105

Tetrahedron Letters 52 (2011) 5124–5127
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convergent enantioselective syntheses of two potential C25–C40 subunits
of (ꢀ)-caylobolide A
Dripta De Joarder, Michael P. Jennings
⇑
Department of Chemistry, 250 Hackberry Lane, The University of Alabama, Tuscaloosa, AL 35487-0336, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The convergent syntheses of two possible diastereomers of the C25–C40 subunit resident in (ꢀ)-caylobo-
Received 28 June 2011
Revised 21 July 2011
Accepted 22 July 2011
Available online 29 July 2011
lide A have been accomplished. The key reaction featured a chemoselective Ru-catalyzed cross-metath-
esis between a fully elaborated type I and two functionalized type II a,b-unsaturated ketones.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Allylation
Reduction
Natural products
Cross-metathesis
Caylobolide
Marine sources continually provide the synthetic community a
variety of structurally challenging natural products.1 One aspect
that makes the total synthesis of natural products so challenging
is the uncertain configuration of multiple stereogenic centers with-
in a target compound. It is well known that diastereomeric possi-
bilities increase exponentially by a factor of 2n, where n is equal
to the number of chiral centers. Thus, the greater number of unde-
fined stereogenic centers can rapidly complicate a synthetic ap-
proach. One such natural product, termed caylobolide A (1), was
isolated via bioassay-guided purification in 2002 from the marine
cyanobacteria Lyngbya majuscule collected at Cay Lobos, Bahamas
by Molinski and MacMillan.2 As shown in Scheme 1, caylobolide
A contains eight undefined stereocenters, thus 256 diastereomeric
structural possibilities. Another interesting feature of 1 is the
repeating 1,5-diol motif present along the 36-membered lactone
core. In addition to its intriguing macrocyclic structure, caylobolide
A has shown cytotoxic properties against the human colon tumor
constructing the C25–C40 segment of 1 due to the defined stereo-
centers (relative configuration via the Kishi universal NMR data-
base and absolute configuration by Mosher analysis) at C25, C27,
C29, and C33.3,4
With this idea in mind, the two potential C25–C40 segments 2
and 3 would be synthesized via a cross-metathesis of homoallylic
alcohol 4 and the two
a,b-unsaturated ketones 5 and 6. We arbi-
trarily chose the S-configuration at C36 for compounds 5 and 6
to simply illustrate the synthetic approach to 2 and 3.
With the initial synthetic plan in hand, our focus was turned to
completing the homoallylic diol 4. As shown in Scheme 2, treat-
ment of the known TBS protected aldehyde 75 with (+)-Ipc2Ballyl
under the standard reaction conditions as pioneered by Brown fur-
nished the requisite homoallylic alcohol.6 An ensuing protection of
the free hydroxyl group with BnBr, NaH, and Bu4NI afforded benzyl
ether 8 in 69% yield over two steps from 7. Oxidative cleavage with
O3 and PPh3 mediated reductive quench of the olefin moiety resi-
dent in 8 was readily accomplished and provided the aldehyde 9
in 60% yield. With the required aldehyde in hand, we envisioned
a chelation-controlled allylation with an appropriate stannane uti-
lizing the benzyl directing group and TiCl4.7 Much to our delight,
treatment of 9 with TiCl4 and Bu3Snallyl at ꢀ78 °C furnished the
desired anti-homoallylic alcohol with excellent diastereoselectivity
(ꢁ12:1 dr) as deduced by 1H NMR.
cell line HCT 116 (IC50 = 9.9 lM). Based on the limited biological
data and very unique and challenging structural features of cayl-
obolide A, we sought to undertake the synthesis of 1. Herein, we
disclose our synthetic approach to the C25–C40 subunit of 1.
The retrosynthetic strategy of caylobolide centered on a highly
convergent approach is highlighted in Scheme 1. Thus, we envis-
aged esterification at C35 (either standard or macrocyclic) and ole-
fin metathesis (either cross or ring-closing) process at C23–C24 to
forge the 36-membered ring of 1. We initially decided to focus on
An ensuing protection of the free hydroxyl moiety as a TBS
ether was readily accomplished under standard reaction condi-
tions (TBSCl and imidazole) to afford the protected diol 4 in 75%
yield over two steps from 9.8
⇑
Corresponding author. Tel.: +1 205 348 0351; fax: +1 205 348 9104.
E-mail address: jenningm@bama.ua.edu (M.P. Jennings).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.105

D. De Joarder, M. P. Jennings / Tetrahedron Letters 52 (2011) 5124–5127
5125
Our outline to the C25–C40 segment of 1 required the synthesis
of chiral aldehyde 13 as delineated in Scheme 3. Hence, an asym-
metric alkylation of the known chiral oxazolidinone 10 with NaH-
MDS and MeI provided 11 in 81% yield with excellent
diastereoselectivity (>15:1 dr).9 Subsequent reduction of the oxa-
zolidinone moiety with LiBH4 readily afforded the chiral primary
alcohol 12 in 93% yield. Final oxidation of the hydroxyl group of
12 with TEMPO and PhI(OAc)2 furnished the desired aldehyde 13
in 82% yield and set the stage for building the subunits 5 and 6.10
With the chiral aldehyde 13 readily in hand and in multi-gram
quantities, we next focused our effort on the completion of the
cross-metathesis precursor ketones 5 and 6 as delineated in
Schemes 4 and 5. Thus, treatment of the chiral aldehyde 13 with
(+)-Ipc2Ballyl provided the corresponding homoallylic alcohol with
a respectable 66% yield and dr of ꢁ10:1. Ensuing protection of the
free hydroxyl group with TESCl, DMAP, and imidazole furnished
the triethylsilyl ether 14 in 73% yield. Ozonolysis of the terminal
olefin followed by the addition of PPh3 resulted in the formation
of the requisite aldehyde 15 in 63% yield. In order to complete
the cross-metathesis coupling type II olefin 5, a vinyl addition
OH
OH
OH
O
Esterification
1
O
1
caylobolide A ( )
40
HO
OH OH OH
OH
HO
25
olefin metathesis
TBSO
OBn OTBS
OBn OTBS
O
O
2
+
TBSO
O
O
3
and subsequent oxidation to furnish the
a,b-unsaturated ketone
O
O
OTES
OTES
5 were required. Thus, the addition of vinyl Grignard reagent to
15 provided the allylic alcohol as an extraneous mixture of diaste-
reomers and ensuing oxidation of the hydroxyl moiety with Dess–
Martin periodinane (DMP) afforded ketone 5 in 38% yield over two
steps from 15.11 Access to ketone 6 followed a very similar syn-
thetic pathway, but differed only in utilizing the (ꢀ)-Ipc2Ballyl re-
agent as shown in Scheme 5. All of the other steps (b–e) were
TBSO
OBn OTBS
5
6
+
4
Scheme 1. Retrosynthetic analysis of caylobolide (1).
O
OTES
a) (+)-Ipc2Ballyl
O
OBn
H
b) TESCl, imid.
DMAP
a) (+)-Ipc2allyl
13
14
RO
H
RO
b) BnBr, NaH
Bu4NI
7
8
c) O3,
PPh3
c) O3,
PPh3
R = TBS
O
OTES
O
OTES
d)
MgBr
SnBu3
d)
H
OBn OTBS
e) DMP
OBn O
TiCl4
5
15
RO
RO
H
e) TBSCl, Imid.,
DMAP
9
4
Scheme 4. Synthesis of intermediate 5. Reagents and conditions: (a) (+)-Ipc2BOMe
(1.6 equiv), allylMgBr (1.5 equiv), Et2O, ꢀ78 °C to rt, 3 h 66%; (b) TESCI (1.5 equiv),
imidazole (3.0 equiv), DMAP (0.1 equiv), CH2Cl2, rt, 12 h, 73%; (c) CH2Cl2 ꢀ78 °C,
1 h, then PPh3 (4.0 equiv), rt, 6 h, 63%; (d) vinylMgBr, (2.0 equiv), Et2O, ꢀ78 °C, 4 h,
60%; (e) DMP (2.0 equiv), pyridine (5.0 equiv), CH2Cl2, rt, 15 h, 63%.
Scheme 2. Synthesis of intermediate 4. Reagents and conditions: (a) (+)-Ipc2BOMe
(1.6 equiv), allylMgBr (1.5 equiv) Et2O, 0 °C to ꢀ78 °C to rt, 6 h, 83%; (b) BnBr
(1.1 equiv), NaH (2.0 equiv), Bu4NI (0.1 equiv), DMF, rt, 24 h, 83%; (c) CH2Cl2,
ꢀ78 °C, then PPH3 (4.0 equiv), rt, 6 h, 60%; (d) allylSnBu3 (2.0 equiv), TiCl4
(1.0 equiv), CH2Cl2, ꢀ78 °C, 8 h, 81%; (e) TBSCl (2.0 equiv), imidazole (4.0 equiv),
DMAP (0.2 equiv), DMF, rt, 24 h, 92%.
O
OTES
a) (-)-Ipc2Ballyl
H
O
O
O
O
b) TESCl, imid.
DMAP
13
16
a) NaHMDS
MeI
O
N
O
N
c) O3,
PPh3
11
10
Bn
b) LiBH4
Bn
O
OTES
O
OTES
d)
MgBr
O
H
e) DMP
c) TEMPO
PhI(OAc)2
6
HO
H
17
13
12
Scheme 5. Synthesis of intermediate 6. Reagents and conditions: (a) (ꢀ)-Ipc2BOMe
(1.6 equiv), allylMgBr (1.5 equiv), Et2O, ꢀ78 °C to rt, 3 h 86%; (b) TESCI (1.5 equiv),
imidazole (3.0 equiv), DMAP (0.1 equiv), CH2Cl2, rt, 12 h, 75%; (c) CH2Cl2, ꢀ78 °C,
1 h, then PPh3 (4.0 equiv), rt, 6 h, 60%; (d) vinylMgBr, (2.0 equiv), Et2O, ꢀ78 °C, 4 h,
75%; (e) DMP (2.0 equiv), pyridine (5.0 equiv), CH2Cl2, rt, 15 h, 70%.
Scheme 3. Synthesis of intermediate 13. Reagents and conditions: (a) NaHMDS
(1.2 equiv), Mel (2.5 equiv), THF, ꢀ78 to ꢀ20 °C, 2 h, 81%; (b) LiBH4 (3.0 equiv),
MeOH (3.0 equiv), Et2O, rt, 6 h, 93%; (c) TEMPO (0.15 equiv), PhI(OAc)2 (1.1 equiv),
CH2Cl2, rt, 20 h, 82%.

5126
D. De Joarder, M. P. Jennings / Tetrahedron Letters 52 (2011) 5124–5127
OBn OTBS
O
OTES
OBn OTBS
O
OTES
a) 18
a) 18
+
+
6
4
5
4
TBSO
TBSO
23
19
N
N
b) [(Ph3P)CuH]6
PhSiH3
b) [(Ph3P)CuH]6
PhSiH3
Cl
Cl
Ru
Ph
18
PCy3
OBn OTBS
O
O
OTES
OBn OTBS
O
O
OTES
TBSO
TBSO
20
24
c) PPTS
c) PPTS
OBn OTBS
OH
OBn OTBS
25
OH
TBSO
TBSO
TBSO
TBSO
21
d) Et2BOMe,
NaBH4
d) Me4NBH(OAc)3
OBn OTBS
OH OH
OBn OTBS
OH OH
22
26
e) 2,2-DMP
CSA
e) 2,2 -DMP
CSA
OBn OTBS
O
O
OBn OTBS
O
O
TBSO
TBSO
2
3
Scheme 6. Synthesis of intermediate 2. Reagents and conditions: (a) 5 (2.0 equiv),
18 (0.10 equiv), CH2Cl2, 40 °C, 24 h, 75%; (b) [(PhP3)CuH]6 (0.10 equiv) PhSiH3
(1.5 equiv), toluene, rt, 24 h, 70%; (c) PPTS (0.2 equiv), MeOH, CH2Cl2 rt, 0.5 h, 80%;
(d) Et2BOMe (1.1 equiv), NaBH4 (1.1 equiv), THF, MeOH, ꢀ78 °C, 3 h, 90%; (e) 2,2-
DMP (2.0 equiv), CSA (0.10 equiv), CH2Cl2, rt, 5 h, 90%.
Scheme 7. Synthesis of intermediate 3. Reagents and conditions: (a) 6 (2.0 equiv),
18 (0.10 equiv), CH2Cl2, 40 °C, 24 h, 77%; (b) [(PhP3)CuH]6 (0.10 equiv), PhSiH3
(1.5 equiv), toluene, rt, 24 h, 69%; (c) PPTS (0.20 equiv), MeOH, CH2Cl2, rt, 0.5 h, 80%;
(d) Me4NBH(OAc)3 (6.0 equiv), MeCN, AcOH, ꢀ20 °C, 48 h, 70%; (e) 2,2-DMP
(2.0 equiv), CSA (0.10 equiv), CH2Cl2, rt, 5 h, 90%.
carried out in an analogous fashion and the isolated yields were
quite comparable.
Similar to that of ketone 6 in Scheme 5, access to the other C25–
C40 diastereomer 3 followed a very similar synthetic pathway to
that of 2.17 It did, however, differ by utilizing the diastereomeric cou-
pling partner 6 (instead of 5) and a subsequent Me4B(OAc)3H direc-
ted anti-reduction of the b-hydroxy ketone 25 as shown in Scheme 7.
The remaining steps were carried out in a similar manner and the
isolated yields were quite comparable.
In conclusion, we have completed the convergent syntheses of
two possible diastereomers of the C25–C40 subunit resident in
(ꢀ)-caylobolide A. One of the key reactions utilized a b-hydroxy di-
rected anti-stannane allylation of aldehyde 9 to provide the neces-
sary stereochemistry for the type I olefin coupling partner 4. In
addition, a chemoselective cross-metathesis of 4 with the two dia-
With all the three precursors in hand (type I (4) and type II (5
and 6) olefins) , we proceeded to converge the aliphatic subunits
via a Ru-catalyzed cross-metathesis reaction and complete the
C25–C40 segment of 1 as delineated in Schemes 6 and 7.
Inspired by Grubbs’ report on selective cross-metathesis, we
were hopeful that the treatment of 4 (type I) with an excess of 5
(type II) in the presence of Grubbs’ second generation catalyst
(18) would chemoselectively couple the two subunits.12,13 In this
specific example, the stereochemistry of the corresponding olefin
product would be inconsequential, as it would be reduced at a later
stage. Hence, the cross-metathesis of 4 with 2.0 equiv of 5 and
10 mol % of 18 readily proceeded to provide 19 in 75% yield with
high levels of selectivity for the E-isomer. Subsequent conjugate
stereomeric
a,b-unsaturated ketones 5 and 6 in the presence of
catalyst 18 allowed for the completion of the two C25–C40 sub-
units 2 and 3. While the remaining stereochemistry of 1 is cur-
rently unknown, other natural products suggest that the
stereochemistry of the 1,5-diol subunit might be syn based on bio-
synthetic polyketide assembly.18 However, it is worth noting that
the 1,5-diol subunit has been shown to be anti in some natural
products, that is, marinisporolide A.18 Studies toward the total syn-
thesis of 1 are ongoing and will be reported in due course.
reduction of the a,b-unsaturated carbonyl by means of Stryker’s re-
agent and PhSiH3 afforded the fully saturated compound 20 in 70%
yield.14 A chemoselective desilylation of the TES ether resident in
20 by utilizing PPTS in MeOH furnished b-hydroxy ketone 21 and
set the stage for the introduction of the final chiral center in the
C25–C40 fragment of 1.
Thus, a directed syn-reduction was readily accomplished upon
treatment of ketone 21 with the obligatory reagents (Et2BOMe and
NaBH4) as described by Prasad and afforded diol 22 in 90% with high
levels of diastereoselectivity (>20:1 by 1H NMR).15 Final protection
of the diol moiety resident in 22 utilizing 2,2-dimethoxy propane
and a catalytic amount of CSA (10 mol %) furnished acetonide 2 in
90% yield and completed one of the C25–C40 diastereomers of 1.16
Acknowledgments
Support for this project was provided by the University of Ala-
bama and in part the National Science Foundation CAREER pro-
gram under CHE-0845011.

D. De Joarder, M. P. Jennings / Tetrahedron Letters 52 (2011) 5124–5127
5127
12. For a very recent review, see: (a) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev.
2010, 110, 1746; (b) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
13. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
14. (a) Brestensky, D. M.; Huseland, D. E.; McGettigan, C.; Stryker, J. M. Tetrahedron
Lett. 1988, 29, 3749; (b) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291; (c) Brestensky, D. M.; Stryker, J. M. Tetrahedron Lett.
1989, 30, 5677; (d) Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M.
Tetrahedron Lett. 1990, 31, 3237.
References and notes
1. Bugni, T. S.; Ireland, C. M. Nat. Prod. Rep. 2004, 21, 143.
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3. (a) Lee, J.; Kobayashi, Y.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2181; (b)
Kobayashi, Y.; Tan, C.-H.; Kishi, Y. Helv. Chim. Acta 2000, 83, 2562.
4. (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092; Seco, J. M.; Quiñoa, E.; Riguera, R. Tetrahedron: Asymmetry 2000, 2781,
11; (c) Seco, J. M.; Martino, M.; Quiñoa, E.; Riguera, R. Org. Lett. 2000, 2, 3261.
5. Miles, W. H.; Connell, K. B.; Ulas, G.; Tuson, H. H.; Dethoff, E. A.; Mehta, V.;
Thrall, A. J. J. Org. Chem. 2010, 75, 6820.
15. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron
Lett. 1987, 28, 155.
16. Data for 2: 1H NMR (360 MHz, CDCl3) d 7.5 (m, 1H), 7.3 (m, 4H), 4.6 (d,
J = 11.4 Hz, 1H), 4.5 (d, J = 11.4 Hz, 1H), 3.9 (m, 1H), 3.7 (m, 4H), 3.5 (m, 1H), 1.7
(m, 3H), 1.5 (s, 6H), 1.4 (m, 5H), 1.3 (m, 7H), 1.2 (m, 5H), 1.0 (m, 2H), 0.89 (m,
18H), 0.83 (d, J = 6.6 Hz, 3H), 0.05 (m, 12H). 13C NMR (125 MHz, CDCl3) d 139.1,
129.6, 128.3, 127.5, 98.2, 73.7, 72.7, 70.8, 69.5, 69.0, 59.6, 42.7, 37.8, 37.7, 36.9,
33.1, 32.0, 30.2, 29.1, 25.9, 25.8, 23.0, 20.2, 19.8, 18.2, 18.1, 18.0, 14.3, 14.1,
6. (a) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401; (b) Jadhav, P. K.;
Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432.
7. (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556; (b) Reetz, M. T. Acc.
Chem. Res. 1993, 26, 462.
8. Data for 4: 1H NMR (360 MHz, CDCl3) d 7.4 (m, 4H), 7.3 (m, 1H), 5.8 (m, 1H), 5.1
(m, 2H), 4.6 (d, J = 11.4 Hz, 1H), 4.5 (d, J = 11.4 Hz, 1H), 4.0 (m, 1H), 3.7 (m, 3H),
2.3 (m, 2H), 1.8 (m, 3H), 1.6 (m, 1H), 0.9 (m, 18H), 0.08 (m, 12H). 13C NMR
(125 MHz, CDCl3) d 139.1, 134.7, 128.2, 127.4, 127.2, 116.8, 73.5, 70.6, 68.9,
59.5, 53.3, 42.5, 42.4, 37.7, 34.1, 25.9, 22.3, 18.2, 18.0, 13.9, ꢀ4.1, ꢀ4.5, ꢀ5.4. IR
(CH2Cl2): 3072, 3031, 2949, 2927, 2857, 1468, 1431, 1383, 1353, 1253, 1209,
ꢀ4.0, ꢀ4.3, ꢀ5.3. IR (CH2Cl2): 3051, 2984, 2852, 2252, 910, 729, 649 cmꢀ1
.
Rf = 0.84 in 10% EtOAc in hexanes. ½a D24
ꢀ0.10 (c 0.084 g/mL, CH2Cl2). HRMS (EI)
ꢂ
calculated for C35H65O5Si2 (M-C4H9): 621.4375 found: 621.4371
17. Data for 3: 1H NMR (360 MHz, CDCl3) d 7.5 (m, 1H), 7.3 (m, 4H), 4.6 (d,
J = 11.4 Hz, 1H), 4.5 (d, J = 11.4 Hz, 1H), 3.7 (m, 4H), 3.5 (m, 2H), 1.7 (m, 3H), 1.4
(m, 8H), 1.3 (s, 6H), 1.2 (m, 5H), 1.1 (m, 3H), 0.97 (m, 2H), 0.88 (m, 21H), 0.04
(m, 12H). 13C NMR (125 MHz, CDCl3) d 139.0, 129.5, 128.3, 127.5, 100.8, 73.7,
70.8, 70.4, 69.5, 66.8, 59.6, 42.7, 37.7, 37.8, 37.9, 36.7, 36.3, 31.5, 30.8, 29.18,
25.9, 24.7, 24.4, 22.9, 20.8, 18.1, 15.2, 14.0, ꢀ4.0, ꢀ4.3, ꢀ5.3. IR (CH2Cl2): 3054,
2986, 2956, 2934, 2857, 2305, 1418, 1267, 893, 733 cmꢀ1. Rf = 0.77 in 10%
1093, 1004, 934, 912, 837, 804, 774 cmꢀ1. Rf = 0.2, 3% EtOAc in hexane. ½a 2D4
ꢂ
+3.8° (c 0.034 g/mL, CH2Cl2). HRMS (EI) calculated for C23H41O3Si2 (M-C4H9):
421.2610 found: 421.2594.
9. (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737; (b)
Decicco, C. P.; Grover, P. J. Org. Chem. 1996, 61, 3534.
10. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974.
EtOAc in hexanes. ½a D24
ꢀ3.80 (c 0.012 g/mL, CH2Cl2) HRMS (EI) calculated for
ꢂ
C
38H71O5Si2 (M-CH3): 663.4832 found: 663.4840.
11. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
18. Friestad, G. K.; Sreenilayam, G. Pure Appl. Chem. 2011, 83, 461.