1. Planteamiento y justificación del problema
1.1 Objetivos
Since a key intermediate in our intended route to halichomycin was the bromide 199
(Scheme 6 8), an early aim of our synthetic programme was to create the intermediate 204.
OH MeO
V
Me 207 TBDPSCI (1 eq) Imidazole (2 eg) DMF(1.4M) 0°C to r.t., 24 hrs 89% MeOV
Me 208OTBDPS DIBAL (2.2 eq) CH2CI2 (0.5M)
-7 8 °C /3 h rs 98%
OH OTBDPS SOg.Py (4eq) EtaN(IOeq), DMSO Me 209 CH2CI2, 0 ° C /3 h r s 88% O OTBDPS Me 210 211 CCfelPr( 2 eq) •B-0‘^'"CCfelPr OH Toluene, -78°C / 24 hrs Me Me 212
Scheme 69: Synthesis of the anti-anti alcohol 212
OH
OTBDPS Me Me
213
For this we needed first to create the anti-anti alcohol 212 (Scheme 69). The commercially available Roche methyl ester 207 was protected as a TBDPS (terf-butyldiphenylsilyl) ether in
8 8% yield. The NMR spectrum of 208 contained a 9 proton singlet at 8 1.01, and a 10 proton
Chapter 3: Discussion
ester in 208 with DIBAL (dllsobutyialuminium hydride) a t-7 8 °C in dichloromethane furnished the primary alcohol 209 in 98% yield, whose IR spectrum now displayed a broad peak at 3385 cm \ indicative of the newly installed OH group. Oxidation of this alcohol with sulfur trioxide pyridine complex, DMSO (dimethylsulfoxide) and triethylamine in dichloromethane was next effected to obtain the aldehyde 210 in 8 8% yield. A doublet at ô 9.75 in the 500 MHz ^H NMR spectrum in
CDCI3, along with an intense aldehyde carbonyl absorption at 1735cm’^ (and the disappearance
of the broad OH peak) in the IR spectrum confirmed the formation of aldehyde 210. Other methods evaluated included the Swern oxidation in DMSO and (0 0 0 1 ) 2 (oxalyl chloride), (yields
of between 61-82%), and the TRAP o x i d a t i o n . T h e TRAP and Swern oxidation were found to give many more impurities (as judged by tic), and were therefore deemed less satisfactory.
The 0(17), 0(16) and 0(25) stereocentres in 212 were set via a Roush asymmetric crotylboration^°® reaction between aldehyde 210 and the (R,R)-diisopropyl tartrate (E)- crotylboronate^*^ 211. The latter reagent is prepared by metalation of trans-2-butene with n- butyllithium and KO^Bu (potassium fert-butoxide) in tetrahydrofuran, and treatment of the resulting (£)-crotylpotassium with (/-RrO)3B (triisopropylborate); after aqueous hydrolysis, and
trans estérification with DIRT (diisopropyl tartrate) 211 is obtained in good yield. 500 MHz ^H NMR analysis of alcohol 212 in ODOI3 confirmed the presence of the terminal alkene as there
was a doublet of doublet of doublets at 6 5.98 and a multiplet at 5 5.05, and the aldehyde singlet
was now missing. The broad absorption at 3498 cm'^ in the IR spectrum confirmed the presence of a free hydroxyl group, and the (M+H)+ peak at miz 383.2406 in the high resolution mass spectrum confirmed that 2 1 2 had an empirical formula of C2 4H3 4 0 2Si.
According to Roush^°^, the asymmetric crotylboration reaction between aldehyde 210
and (£)-crotylboronate 211 should be carried out in toluene at -78°C, for the desired anti-anti alcohol 212 to be produced as the major reaction product with a 9:1 level of diastereoselectivity. In our hands, however, this reaction has so far consistently yielded a 2:1 ratio, which has been confirmed by three independent workers!!
OTBDPS .Me 0 ^ 8 r x /P0 2C"'< ^ /P1O2C via chair OTBDPS transition state Me OH Me Me 212 OTBDPS
[Favoured Transition State A |
Me
Me B '
iPrO
Disfavoured Transition State B iPrO
Me
OTBDPS
Scheme 70: Synthesis of anti-anti alcohol via favoured chair transition state A
It has been suggested^°^ that crotylboronate 211 preferentially reacts with aldehyde 210 by way of transition state A (Scheme 70), in which:-
i) the aldehyde and the two tartrate ester units occupy axial positions with respect to the dioxaborolane unit, and
ii) the tartrate esters are syn-coplanar to the adjacent dioxaborolane C -0 bonds.
According to Roush, the stereochemically favoured transition state A is stabilised by a favourable dipole-dipole interaction between the aldehyde carbonyl (8+) and the proximate ester
carbonyl oxygen (8-), while the alternative transition state B is destabilised by unfavourable
interactions between the non-bonding electrons on the ester carbonyl and the boron-complexed aldehyde.
Chapter 3: Discussion
An alternative method for the formation of 212 has also been investigated, involving the use of indium and crotylbromide^°® in tetrahydrofuran and water. However, this reaction proved to be unfavourable since the undesired diastereomer 213 was now the major product in a 2:1 ratio as revealed by NMR analysis on the crude material.
After removal of the minor undesired diastereomer of our 2:1 mixture, by flash column chromatography, the desired alcohol 2 1 2 was 0-benzylated^°® (Scheme 71) under mildly acidic
conditions using catalytic amounts of TfOH (trifluoromethanesulfonic acid) and benzyl-2,2,2- trichloroacetimidate as the benzylating agent; the benzyl ether 214 was isolated in 80% yield. 500 MHz ^H NMR analysis in CDCI3 now revealed a total of 15 protons between 5 7.71 (4H) and
Ô 7.46 (1 1H) which indicated an extra phenyl group was present in 214. Moreover, the lack of
an OH absorption in the IR spectrum further corroborated that the alcohol had been protected as its benzyl ether. Numerous attempts were made to benzylate the alcohol. Other less successful efforts at obtaining 214, involved the use of PPTS (pyridinium para-toluene sulfonate) at room temperature, and alkylation under basic conditions using n-butyllithium and benzyl bromide. The former proceeded very slowly to give 214, while the latter reaction did not lead to any of 214
being produced.
OH
1
o '^ c c ig BHa-THFOM. 1.1 eq)
__________ (1.5 eq) 2 " THF (0.2M) Caf. TfOH (0.765 eq) OTBDPS o°C to r.t., 3 hrs then,
CH2CI2 (0.3IVI), r.t., 2 hrs, 80% Me Me 212 Me Me 214 H2O2 / MeOH, 6 8% OBn Me Me 215 OTBDPS n-BuaBOTf (1.1 eq) CH2CI2 (0.3M) 0 - ^ 0
EtaN, 0°C, then cool ^ I to -78°C, then add
RUCI3 (0 .1 eq), Nal0 4 (2 .1 eq) CCI4/CH3CN/H2O (2:2:3) (0.3M) r.t., 24 hrs, 61% OTBDPS OBn . . Me Me Me OPMB 204 CHD 218 OPMB
EtaN (1 eq), PvCI (1 eq) T H F /0 °C , n-BuLi (1 eq)
men add, OBn
OTBDPS o
Me Me O Me Me
219 (1 eq) 216
Hydroboration^°^ of the terminal alkene in 214 using a 1M solution of borane in tetrahydrofuran at 0°C, followed by oxidation, procured the primary alcohol 215 in 6 8% yield.
The appearance of a broad absorption band at 3389 cm"' on the IR spectrum, and the absence of the olefinic proton signals in the 500 MHz NMR spectrum confirmed that 215 had been formed. This reaction was initially attempted using 9-BBN (9-borabicyclo[3.3.1 jnonane) in THF at 0°C, and later with catecholborane.'°® The former reaction was unsuccessful, with starting material remaining unchanged as judged by tic analysis. The latter process was found to produce variable yields of 215, and was therefore deemed unreliable. We believe that this is probably due to inconsistent quality catecholborane being sold commercially.
Further oxidation of alcohol 215 to acid 216 was accomplished with RuO^ generated in situ from NalO^ (sodium periodate) and RuClg in carbon tetrachloride, acetonitrile and water at room temperature.''® The appearance of an intense absorption at 1707 cm"* was consistent with the newly formed carbonyl group in 216 PDC in DM F at room temperature was also evaluated for this oxidation, but the reaction took longer and not much of the product was formed according to tic analysis. Acylation of acid 216 with the lithiated oxazolidinone 217 was then carried out to obtain 219 in 58% yield. The 500 MHz ^H NMR spectrum in CDCI3 now displayed multiplets at 5
7.61 (4H) and 5 7.38 (16H) which indicated an extra phenyl group was present. The lack of a broad OH stretch, and the presence of two strong absorptions at 1787 cm"' and 1695 c m '\ further corroborated the production of 219. Also, the presence of an (M+H)+ peak at m/z 664.3450 in the high resolution mass spectrum indicated that 219 had an empirical formula of C4iH4 9 0 5NSi. An Evans asymmetric aldol r e a c t i o n w a s now attempted between the (Z)-di-n-
butylboron enolate (obtained from 219), and aldehyde 218 This reaction failed to deliver any of the syn-aldol adduct 204. The starting material appeared to have degraded, as shown by tic. The problem was thought to lie in the benzylated oxygen behaving as a nucleophile towards the Lewis-acid activated carbonyl group, thus forming a lactone ring. It was reasoned that use of a para-bromobenzyl group instead of the benzyl group (Scheme 72) would cause this oxygen to be less nucleophilic, but again, the aldol reaction was unsuccessful.
Chapter 3: Discussion OH NH A . / — Br BH3 THF (1M, 1.1 eq) B r ^ (1 2eq) ? THF (0.2M)
Cat. TfOH (0.765 eqT 0°C to rt. 3 h then,
CH2CI2 (0.3M), r.t.. ■ 2 hrs, 60% Br OTBDPS Me Me 212 Me Me 220 H2O2 / MeOH. 60% Me Me 221
RuClg (0.1 eq). NalO^ (2.1 eq) CCI4/CH3CN/H2O (2:2:3) (0.3M)
r.t., 24 hrs. 61%
0 ^ 0
O EtaN, 0°C. then cool ( r ^ QBnBr to-780C, then add,
'OTBDPS Ph'"^ n-Bu2B0Tf (1.1 eq) CH2CI2 (0.3M) .0 ^ 0 N^^O OBnBr Me Me CHO
Et3N (leq), PvCI (1 eq) THF/0°C, n-BuLI (1 eq) . then add. Br ' OTBDPS M.-S Me Me 223 ORVIB OPMB 224
Scheme 72: Attempted Evans Asymmetric Aldol Reaction using the para-bromobenzyl molecule
OTBDPS o
217 O Me Me
( (1 eq) 222
Ph
Concerns about the PMB group on aldehyde 218 being somehow cleaved further encouraged us to investigate different protecting groups, such as the benzyl group for this aldol. Again, these new aldol processes still failed to proceed satisfactorily. In view of this, we decided to investigate an alternative approach for creating 204.
o A r ' o \ ^ Evans Syn-Aldol Me Me ° 225 Me Me Diol Protection, then
Protection
T T
Nitnie Reductloi ^Me Me OTBDPS DIBAL Reduction. Sharpless Epoxidation, then Regioseiective opening of epoxide OBn Me Me 214 , Diol Generation / OHC and Cleavage OBn Et0 2C OTBDPS Me Me
WIttIg Reaction OBn
OTBDPS
229
Me Me
228 Scheme 73: Retrosynthetic analysis of a new route to the syn-aldol adduct 225
We envisaged creating 225 from aldehyde 226 via an Evans asymmetric aldol reaction. We thought that 226 could be derived from nitrile 227 by protection of the diol as its acetonide ring, followed by DIBAL reduction on the nitrile group. A Wittig reaction using Ph3P=CHC0 2Et
would give the (£)-olefin 228 from aldehyde 229, which could be derived from the benzyl ether 214 by OSO4 induced diol generation, followed by diol cleavage.
?" . . . .
nMO (1.5eq) OTBDPS 0°C. 20 min. OTBDPS
Me Me r.t., 5.5 hrs Me Me 93% Me Me
76%
214 230 229
Ph3P=CHC0 2E t(2eq) EtOsC. DIBAL (2.2 eq) HO' OBn
CH2CI2 (0.3M) E CH2CI2 (0.5M)
r.t., 48 h, 76% I I OTBDPS -7 8 ° C /2 h , 92% | | OTBDPS
Me Me Me Me
228 231
Scheme 74: Synthesis of the allylic alcohol 231
The terminal alkene in 214 was reacted with a catalytic amount of OsO^ (osmium tetroxide) and NMO (4-methylmorpholine-N-oxide), in acetone, f-BuGH, and water at room temperature to access the diol 230 in 76% yield. The very broad absorption at 3411 cm'^ in the IR spectrum of 230, and the absence of the olefinic protons in the NMR spectrum confirmed 230 had been made. This diol was now cleaved using Pb(OAc) 4 in tetrahydrofuran at 0°C, the
aldehyde 229 being isolated in 93% yield. Initially, a one-step conversion of alkene 214 to aldehyde 229 was attempted using OSO4 and Nal0 4, and although a clean reaction, this route
only gave 229 in 45-50% yield. The overall yield of aldehyde 229 via the two-step route was calculated to be 72%. Hence this route was favoured, since it led to a yield improvement of greater than 20%. Aldehyde 229 was next reacted with carbethoxymethylene- triphenylphosphorane in CHgClg at room temperature; the desired (E)-olefin 228 was isolated in 76% yield. Its 500 MHz ^H NMR spectrum was now devoid of any aldehyde signal, and the presence of an (M +Na^ peak at m/z 567.2907 in the high resolution mass spectrum indicated that 228 had an empirical formula of C3 4H4 4 0 4SiNa. DIBAL reduction of the ester in 228
furnished the allylic alcohol 231 in 92% yield. The olefinic peaks at 5 5.77 (1H) and 5 5.63 (1H)
Chapter 3: Discussion
broad OH band at 3389 cm \ but now lacked the Intense carbonyl absorption at 1718 cm‘\ The catalytic Sharpless epoxidation of allylic alcohol 231 using (+)-DET (diethyl tartrate), Ti(0 -'Pr) 4
(titanium (IV) isopropoxide) and TBHP (tert-butylhydroperoxide) in dichloromethane at -35°C provided the epoxy alcohol 232 (Scheme 75) in 87% yield. The loss of the NMR olefinic signals and the presence of an (M+Na)+ peak at m/z 541.2750 in the high resolution mass spectrum indicated that 232 had an empirical formula of CagH^gO^SINa.
HO OBn
Me Me
231
(+)-DET (1 eq), Ti(0iPr)4 (1 eq) 4A molecular sieves OTBCPS TBHP (10 eq), CH2CI2
-4 5 °C /2 4 h , 87% Me Me
OTBDPS
Et2AICN (5 eq). Toluene (0.3M) 0°C to rt / 2.5 h, 48% Me Me NC Y Y OTBDPS Me Me 227 Me2C(OMe)2 / Acetone PPTS (0.25 eq) 4 0 °C / 6h, 78% NO T T OTBDPS Me Me 234 A. ° ^ ^ 2 3 5 , n-BugBOTf (1.1 eq), \ CH2CI2 (0.5M) X --- ' -78°C /1 h, 60% O H C ' Y ^ OTBDPS ^ \
Me Me EtsN (1.2 eq), 0°C, then cool to DIBAL (1 eq), CH2CI2 (0.26M)
226
-78°C and add 226 (1.1 eq, 0.16M)
Ph
OTBDPS Me Me
225
Scheme 75: Sharpless epoxidation and another attempted Evans asymmetric aidoi reaction
Regioseiective opening of the epoxide 232 using a 1M solution of EtgAICN (diethylaluminum
cyanide) in toluene rendered the 1,2-dlol 227 as the major product in 48% yield. The minor regioisomer 233 was also formed in 28% yield. In an attempt to try and increase the yield of the major product, the solvent was changed from toluene to dichloromethane, although this made no real difference to the ratio according to tic. Other efforts to improve the situation included the use of a 1M solution of (CHajgAICI (dimethylaluminium chloride) in hexane with KCN (potassium cyanide), and also Ti(0 -'Pr) 4 with lithium acetylide in THF, but both these systems failed to open
and catalytic PPTS in acetone at 40°C, successfully afforded 234 in 78% yield. The two new singlets in the 500 MHz NMR spectrum at S 1.38 (3H) and ô 1.26 (3H) unveiled the presence of the two new methyl groups in 234, and a very distinctive characteristic peak at 109.5 in the NMR gave further confirmation of 234. DIBAL reduction of the nitrile in 234 at -78°C in dichloromethane then gave the aldehyde 226, which was used in an Evans asymmetric aldol r e a c t i o n w i t h the acylated oxazolidinone 235. However, this failed to generate any of the syn- aldol adduct 225 even though this reaction was repeated by another member of the group.
In view of these unforeseen events, we elected to abandon this route and try a different approach to forming the A-ring of halichomycin.
OBn HO.
Hz / Pd(OH)2 (20%, 0.2 eq), ^
MeOH (0.09M), 2d, r.t., 8 8% Y " ^ 'OTBDPS then add (1.2 eq)
O Me Me Me Me p N
Br
216 236
LDA (1.3 eq), THF-HMPA (10:1, 0.2M).
' OTBCPS (100:1, 0.2M). reflux, 3 hrs, 79% LIBH4(1 0eq), T H F /M eO H Me Me 237 Me, HO- Me OTBCPS Me 238 In THF at -78°C dropwise and stir at -78°C for 2 h, 82% Scheme 76
We decided to create a lactone ring from our previously formed carboxylic acid 216 by hydrogenolysis of the 0 -benzyl group, using 2 0% Pd(OH) 2 (palladium hydroxide) on carbon
catalyst in methanol; this effected a clean, but rather slow, deprotection to permit in situ butyrolactonisation. The benzyl signals in the ^H NMR spectrum of 236 were now absent, and replacement of the broad OH absorption with a strong carbonyl stretch at 1778 cm'^ (characteristic in 5-ring lactones in the IR), confirmed that 236 had been formed. A stereoselective C-alkylation of butyrolactone 236 was achieved by low-temperature énolisation with LDA and addition of the allylic bromide (Scheme 76).^°® Total stereocontrol was observed In this reaction, and was attributable to the stereodirecting influence of the C(25)-Me group (which hinders syn-approach of the bulky electrophile to the enolate). Preservation of the reaction
Chapter 3: Discussion
temperature at -78°C throughout also contributed to the high selectivity attained. In this regard, premature warming markedly lowered the selectivity levels that were observed. The configuration of the newly induced stereocenter in 237 was verified by NOE analysis.
Having fulfilled its role in stereoselective attachment of the C(8)-methallyl unit, the
butyrolactone ring of 237 was reductively ring-opened with lithium borohydride to give the diol
238. Initial attempts to open the lactone 237, with DIBAL at -78°C in dichloromethane were unsuccessful, the hemi-acetal being the only product recovered. Identical results were obtained when LiEtgBH (super-hydride) also at -78°C in THF was used. UAIH4 (lithium aluminium
hydride) in diethyl ether at 0°C was also p r o b l e m a t i c a l W i t h diol 238 in hand, we now proposed a new route to the A-ring of halichomycin (Scheme 77), which would feature an intramolecular Stille process as the key ring-forming step. We believed that by protecting the
Me' OTBCPS ^ OTBCPS
Me. Me OTBCPS Me BugSn^ SnBua TBSO Me OTBCPS
Scheme 77: Proposed route to the A-ring
primary alcohol in 238, using TESCI (triethylsilylchloride) and EtgN, in dichloromethane at 0°C, the secondary alcohol would be left open for attack.
Unfortunately, reaction of the secondary alcohol in 238 with KgCOg and t- butylbromoacetate in dioxane at reflux, did not lead to any of the desired product. The alcohol remained un reacted (Scheme 78).
Imidazole (2.2 eq), DMF (0.1 M) 0°C. add TESCI (1.2 eq) t e s q- over 5 mins. then stir OTBDPS at 0°C for 1.5 h,
70%
lE S O
OTBDPS OTBDPS
Scheme 78: Attempted attack of secondary alcohol
An OTBS for OTES protecting group interchange was now effected, and a similar reaction was then attempted using n-BuLi, HMPA (hexamethylphosphoramide), and f-butylbromoacetate in THF at -78°C. But this reaction was also unsuccessful.
Our attentions then focused on trying to attach a different group onto the secondary alcohol.
TBSO TBSO
Me OTBDPS IVIe OTBDPS
240
Me' OTBDPS
TBSO
KH (1.2eq). THF (0.3M),
Me t— \ Bu4NI (4 eq). 0°C to rt Me OTBDPS then stir for 40 mins.
240 Me, Me, TBSO- TBSO- -H Me Me Me 241 Me 242 Scheme 79: Other attempted attacks on the secondary alcohol
Reaction of the secondary alcohol in 240 was attempted using KH (potassium hydride), n-Bu^NI (tetrabutylammonium iodide) and 4-bromo-1-butene in THF at 0°C, but to our disappointment, this was unsuccessful, as was the reaction using allyltrichloroacetimidate. The former gave no reaction at all, whereas the latter produced a suspected desilylated product. However, reaction of 240 with KH, n-Bu^NI and allyl bromide in THF was found to desilylate the OTBDPS group, replacing it with the allyl group, forming the allyl ether 241. But the secondary alcohol in 240
was also found to react slightly, producing a small (20%) amount of 242 (Scheme 79).
Although these approaches were largely unsuccessful, this new evidence nevertheless proved that it was indeed possible to attack the secondary alcohol. This led us to consider the
Chapter 3: Discussion
possibility of changing the terminal OTBDPS protecting group to a smaller OPMB (para- methoxybenzyl) group. We thought that such a tactic might potentially side-step the steric over crowding problems, associated with the attacking of the secondary alcohol, which we reasoned was the more likely origin of this lack of reactivity.
An OPMB for OTBDPS protecting group interchange was now effected much earlier in the sequence, which successfully delivered the PMB-ether 244 (Scheme 80).
40% aq. HF/THF/MeCN (1 :2 :1 ) OTBDPS (0 Me Me 24 237 .09M), r.t., I \ h, 85% Me Me 243 NH